45 results on '"Prashant Kumar Modi"'
Search Results
2. Tyrosine Phosphorylation Profiling Revealed the Signaling Network Characteristics of CAMKK2 in Gastric Adenocarcinoma
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Mohd. Altaf Najar, Mohammad Arefian, David Sidransky, Harsha Gowda, T. S. Keshava Prasad, Prashant Kumar Modi, and Aditi Chatterjee
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CAMKK2 ,mass spectrometry ,gastric cancer ,PTK2 ,STAT3 ,Genetics ,QH426-470 - Abstract
Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is a serine/threonine protein kinase which functions via the calcium-triggered signaling cascade with CAMK1, CAMK4, and AMPKα as the immediate downstream substrates. CAMKK2 is reported to be overexpressed in gastric cancer; however, its signaling mechanism is poorly understood. We carried out label-free quantitative tyrosine phosphoproteomics to investigate tyrosine-mediated molecular signaling associated with CAMKK2 in gastric cancer cells. Using a high-resolution Orbitrap Fusion Tribrid Fourier-transform mass spectrometer, we identified 350 phosphotyrosine sites mapping to 157 proteins. We observed significant alterations in 81 phosphopeptides corresponding to 63 proteins upon inhibition of CAMKK2, among which 16 peptides were hyperphosphorylated corresponding to 13 proteins and 65 peptides were hypophosphorylated corresponding to 51 proteins. We report here that the inhibition of CAMKK2 leads to changes in the phosphorylation of several tyrosine kinases such as PKP2, PTK2, EPHA1, EPHA2, PRKCD, MAPK12, among others. Pathway analyses revealed that proteins are differentially phosphorylated in response to CAMKK2 inhibition involved in focal adhesions, actin cytoskeleton, axon guidance, and signaling by VEGF. The western blot analysis upon inhibition and/or silencing of CAMKK2 revealed a decrease in phosphorylation of PTK2 at Y925, c-JUN at S73, and STAT3 at Y705, which was in concordance with the mass spectrometry data. The study indicates that inhibition of CAMKK2 has an anti-oncogenic effect in gastric cells regulating phosphorylation of STAT3 through PTK2/c-JUN in gastric cancer.
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- 2022
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3. Identification of Molecular Network Associated with Neuroprotective Effects of Yashtimadhu (Glycyrrhiza glabra L.) by Quantitative Proteomics of Rotenone-Induced Parkinson’s Disease Model
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Gayathree Karthikkeyan, Mohd. Altaf Najar, Ravishankar Pervaje, Sameera Krishna Pervaje, Prashant Kumar Modi, and Thottethodi Subrahmanya Keshava Prasad
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Chemistry ,QD1-999 - Published
- 2020
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4. Deep Metabolomic Profiling Reveals Alterations in Fatty Acid Synthesis and Ketone Body Degradations in Spermatozoa and Seminal Plasma of Astheno-Oligozoospermic Bulls
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Mohua Dasgupta, Arumugam Kumaresan, Kaustubh Kishor Saraf, Pradeep Nag, Manish Kumar Sinha, Muhammad Aslam M. K., Gayathree Karthikkeyan, T. S. Keshava Prasad, Prashant Kumar Modi, Tirtha Kumar Datta, Kerekoppa Ramesha, Ayyasamy Manimaran, and Sakthivel Jeyakumar
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metabolomics ,spermatozoa ,seminal plasma ,dairy bulls ,mass spectrometry ,semen quality ,Veterinary medicine ,SF600-1100 - Abstract
Male fertility is extremely important in dairy animals because semen from a single bull is used to inseminate several thousand females. Asthenozoospermia (reduced sperm motility) and oligozoospermia (reduced sperm concentration) are the two important reasons cited for idiopathic infertility in crossbred bulls; however, the etiology remains elusive. In this study, using a non-targeted liquid chromatography with tandem mass spectrometry-based approach, we carried out a deep metabolomic analysis of spermatozoa and seminal plasma derived from normozoospermic and astheno-oligozoospermic bulls. Using bioinformatics tools, alterations in metabolites and metabolic pathways between normozoospermia and astheno-oligozoospermia were elucidated. A total of 299 and 167 metabolites in spermatozoa and 183 and 147 metabolites in seminal plasma were detected in astheno-oligozoospermic and normozoospermic bulls, respectively. Among the mapped metabolites, 75 sperm metabolites were common to both the groups, whereas 166 and 50 sperm metabolites were unique to astheno-oligozoospermic and normozoospermic bulls, respectively. Similarly, 86 metabolites were common to both the groups, whereas 45 and 37 seminal plasma metabolites were unique to astheno-oligozoospermic and normozoospermic bulls, respectively. Among the differentially expressed metabolites, 62 sperm metabolites and 56 seminal plasma metabolites were significantly dysregulated in astheno-oligozoospermic bulls. In spermatozoa, selenocysteine, deoxyuridine triphosphate, and nitroprusside showed significant enrichment in astheno-oligozoospermic bulls. In seminal plasma, malonic acid, 5-diphosphoinositol pentakisphosphate, D-cysteine, and nicotinamide adenine dinucleotide phosphate were significantly upregulated, whereas tetradecanoyl-CoA was significantly downregulated in the astheno-oligozoospermia. Spermatozoa from astheno-oligozoospermic bulls showed alterations in the metabolism of fatty acid and fatty acid elongation in mitochondria pathways, whereas seminal plasma from astheno-oligozoospermic bulls showed alterations in synthesis and degradation of ketone bodies, pyruvate metabolism, and inositol phosphate metabolism pathways. The present study revealed vital information related to semen metabolomic differences between astheno-oligozoospermic and normospermic crossbred breeding bulls. It is inferred that fatty acid synthesis and ketone body degradations are altered in the spermatozoa and seminal plasma of astheno-oligozoospermic crossbred bulls. These results open up new avenues for further research, and current findings can be applied for the modulation of identified pathways to restore sperm motility and concentration in astheno-oligozoospermic bulls.
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- 2022
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5. Data on dose-dependent cytotoxicity of rotenone and neuroprotection conferred by Yashtimadhu (Glycyrrhiza glabra L.) in an in vitro Parkinson's disease model
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Gayathree Karthikkeyan, Ashwini Prabhu, Ravishankar Pervaje, Sameera Krishna Pervaje, Prashant Kumar Modi, and Thottethodi Subrahmanya Keshava Prasad
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Neurodegeneration ,Complementary and alternative medicine ,Ayurveda ,Actionable molecules ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
The data described in this article presents the toxicity of rotenone and the neuroprotective effect of Yashtimadhu choorna (powder) in an in vitro Parkinson's disease model [1]. Yashtimadhu choorna is prepared from the roots of Glycyrrhiza glabra L., commonly known as licorice/ liquorice. The effects of rotenone and Yashtimadhu was assessed using cellular and molecular assays such as cell cytotoxicity assay, live-dead cell staining assay, cell cycle analysis, and western blotting. Protein-protein interaction was studied using ANAT plug-in in Cytoscape. Rotenone displayed time and dose-dependent toxicity, as evidenced by cell cytotoxicity assay and live-dead cell staining assay. Yashtimadhu showed no toxicity and prevented rotenone-induced toxicity. Rotenone and Yashtimadhu displayed differential control on the cell cycle. The Protein-interaction network showed the proteins interacting with ERK-1/2 and the pathways regulated by these interactions. The pathways regulated were primarily involved in cellular oxidative stress and apoptosis response. The data described here will enable the extent of cellular toxicity as a result of rotenone treatment and the neuroprotection conferred by Yashtimadhu choorna. This will enable understanding and exploring the effect of traditional and complementary medicine and aiding the identification of molecular targets to confer neuroprotection in Parkinson's disease.
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- 2021
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6. CusVarDB: A tool for building customized sample-specific variant protein database from next-generation sequencing datasets [version 2; peer review: 2 approved]
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Sandeep Kasaragod, Varshasnata Mohanty, Ankur Tyagi, Santosh Kumar Behera, Arun H. Patil, Sneha M. Pinto, T. S. Keshava Prasad, Prashant Kumar Modi, and Harsha Gowda
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Medicine ,Science - Abstract
Cancer genome sequencing studies have revealed a number of variants in coding regions of several genes. Some of these coding variants play an important role in activating specific pathways that drive proliferation. Coding variants present on cancer cell surfaces by the major histocompatibility complex serve as neo-antigens and result in immune activation. The success of immune therapy in patients is attributed to neo-antigen load on cancer cell surfaces. However, which coding variants are expressed at the protein level can’t be predicted based on genomic data. Complementing genomic data with proteomic data can potentially reveal coding variants that are expressed at the protein level. However, identification of variant peptides using mass spectrometry data is still a challenging task due to the lack of an appropriate tool that integrates genomic and proteomic data analysis pipelines. To overcome this problem, and for the ease of the biologists, we have developed a graphical user interface (GUI)-based tool called CusVarDB. We integrated variant calling pipeline to generate sample-specific variant protein database from next-generation sequencing datasets. We validated the tool with triple negative breast cancer cell line datasets and identified 423, 408, 386 and 361 variant peptides from BT474, MDMAB157, MFM223 and HCC38 datasets, respectively.
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- 2020
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7. Temporal Quantitative Phosphoproteomics Profiling of Interleukin-33 Signaling Network Reveals Unique Modulators of Monocyte Activation
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Devasahayam Arokia Balaya Rex, Yashwanth Subbannayya, Prashant Kumar Modi, Akhina Palollathil, Lathika Gopalakrishnan, Yashodhar P. Bhandary, Thottethodi Subrahmanya Keshava Prasad, and Sneha M. Pinto
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IL-33 ,cytokine signaling ,phosphoproteomics ,mass spectrometry ,DNA damage ,DNA repair ,Cytology ,QH573-671 - Abstract
Interleukin-33 (IL-33), a member of the IL-1 superfamily cytokines, is an endogenous danger signal and a nuclear-associated cytokine. It is one of the essential mediators of both innate and adaptive immune responses. Aberrant IL-33 signaling has been demonstrated to play a defensive role against various infectious and inflammatory diseases. Although the signaling responses mediated by IL-33 have been previously reported, the temporal signaling dynamics are yet to be explored. To this end, we applied quantitative temporal phosphoproteomics analysis to elucidate pathways and proteins induced by IL-33 in THP-1 monocytes. Employing a TMT labeling-based quantitation and titanium dioxide (TiO2)-based phosphopeptide enrichment strategy followed by mass spectrometry analysis, we identified and quantified 9448 unique phosphopeptides corresponding to 3392 proteins that showed differential regulation. Of these, 171 protein kinases, 60 phosphatases and 178 transcription factors were regulated at different phases of IL-33 signaling. In addition to the confirmed activation of canonical signaling modules including MAPK, NFκB, PI3K/AKT modules, pathway analysis of the time-dependent phosphorylation dynamics revealed enrichment of several cellular processes, including leukocyte adhesion, response to reactive oxygen species, cell cycle checkpoints, DNA damage and repair pathways. The detailed quantitative phosphoproteomic map of IL-33 signaling will serve as a potentially useful resource to study its function in the context of inflammatory and pathological conditions.
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- 2022
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8. Effect of calcium glucoheptonate on proliferation and osteogenesis of osteoblast-like cells in vitro.
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Prashant Kumar Modi, Ashwini Prabhu, Yashodhar P Bhandary, Sudheer Shenoy P, Aparna Hegde, Sindhu Priya Es, Renjith P Johnson, Shankar Prasad Das, Sahil Vazirally, and Punchappady-Devasya Rekha
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Medicine ,Science - Abstract
Calcium is the key macromineral having a role in skeletal structure and function, muscle contraction, and neurotransmission. Bone remodeling is maintained through a constant balance between calcium resorption and deposition. Calcium deficiency is resolved through calcium supplementation, and among the supplements, water-soluble organic molecules attracted great pharmaceutical interest. Calcium glucoheptonate is a highly water-soluble organic calcium salt having clinical use; however, detailed investigations on its biological effects are limited. We assessed the effects of calcium glucoheptonate on cell viability and proliferation of osteoblast-like MG-63 cells. Calcium uptake and mineralization were evaluated using Alizarin red staining of osteoblast-like MG-63 cells treated with calcium glucoheptonate. Expression of osteogenic markers were monitored by western blotting, immunofluorescence, and qRT-PCR assays. Increased proliferation and calcium uptake were observed in the MG-63 cells treated with calcium glucoheptonate. The treatment also increased the expression of osteopontin and osteogenic genes such as collagen-1, secreted protein acidic and cysteine rich (SPARC), and osteocalcin. Calcium glucoheptonate treatment did not exert any cytotoxicity on colorectal and renal epithelial cells, indicating the safety of the treatment. This is the first report with evidence for its beneficial effect for pharmaceutical use in addressing calcium deficiency conditions.
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- 2019
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9. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitors: a novel approach in small molecule discovery
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Rex Devasahayam Arokia Balaya, Jaikanth Chandrasekaran, Saptami Kanekar, Prashant Kumar Modi, Shobha Dagamajalu, Kirthika Gopinathan, Rajesh Raju, and T. S. Keshava Prasad
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Structural Biology ,General Medicine ,Molecular Biology - Published
- 2023
10. CusVarDB: A tool for building customized sample-specific variant protein database from next-generation sequencing datasets [version 1; peer review: 2 approved with reservations]
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Sandeep Kasaragod, Varshasnata Mohanty, Ankur Tyagi, Santosh Kumar Behera, Arun H. Patil, Sneha M. Pinto, T. S. Keshava Prasad, Prashant Kumar Modi, and Harsha Gowda
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Software Tool Article ,Articles ,Next-generation sequencing ,Variant protein database ,NGS-pipeline - Abstract
Cancer genome sequencing studies have revealed a number of variants in coding regions of several genes. Some of these coding variants play an important role in activating specific pathways that drive proliferation. Coding variants present on cancer cell surfaces by the major histocompatibility complex serve as neo-antigens and result in immune activation. The success of immune therapy in patients is attributed to neo-antigen load on cancer cell surfaces. However, which coding variants are expressed at the protein level can’t be predicted based on genomic data. Complementing genomic data with proteomic data can potentially reveal coding variants that are expressed at the protein level. However, identification of variant peptides using mass spectrometry data is still a challenging task due to the lack of an appropriate tool that integrates genomic and proteomic data analysis pipelines. To overcome this problem, and for the ease of the biologists, we have developed a graphical user interface (GUI)-based tool called CusVarDB. We integrated variant calling pipeline to generate sample-specific variant protein database from next-generation sequencing datasets. We validated the tool with triple negative breast cancer cell line datasets and identified 423, 408, 386 and 361 variant peptides from BT474, MDMAB157, MFM223 and HCC38 datasets, respectively.
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- 2020
- Full Text
- View/download PDF
11. A comparative proteomic analysis for non-invasive early prediction of hypoxic-ischemic injury in asphyxiated neonates
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Sumrati Gurtoo, Gayathree Karthikkeyan, Santosh Kumar Behera, Chinmaya Narayana Kotimoole, Mohd. Altaf Najar, Prashant Kumar Modi, Sahana K.S., Sneha M Pinto, and Arun A.B.
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Aim: Hypoxic Ischemic Encephalopathy (HIE) is one of the principal causes of neonatal mortality and long-term morbidity worldwide. The neonatal signs of mild cerebral injury are subtle, making an early precise diagnosis difficult. Delayed detection, poor prognosis, and lack of specific biomarkers for the disease are increasing mortality rates. In this study, we intended to identify specific biomarkers using comparative proteomic analysis to predict the severity of perinatal asphyxia so that its outcome can also be prevented. Experimental Design: A case-control study was conducted on 38 neonates, and urine samples were collected within 24 and 72 hours of life. A tandem mass spectrometry-based quantitative proteomics approach followed by validation via sandwich ELISA was performed. Results: The LC-MS/MS-based proteomics analysis resulted in the identification of 1,201 proteins in urine with 229, 244 and 426 being differentially expressed in HIE-1, HIE-2 and HIE-3, respectively. Axon guidance, Diseases of programmed cell death, and Detoxification of reactive oxygen species pathways were significantly enriched in mild HIE vs severe HIE. Of the differentially expressed proteins in various stages of HIE, we chose to validate four proteins- APP, AGT, FABP1, and FN1 via sandwich ELISA. Individual and cumulative ROC curves were plotted. AGT and FABP1 together showed high sensitivity, specificity, and accuracy as potential biomarkers for early diagnosis of HIE Conclusion: Establishing putative urinary biomarkers will facilitate clinicians to more accurately screen neonates for brain injury and monitor the disease progression. Prompt treatment of neonates may reduce mortality and neurodevelopmental impairment.
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- 2023
12. A network map of GDNF/RET signaling pathway in physiological and pathological conditions
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Praseeda Mol, Rex Devasahayam Arokia Balaya, Shobha Dagamajalu, Sreeranjini Babu, Pavithra Chandrasekaran, Reshma Raghavan, Sneha Suresh, Namitha Ravishankara, Anu Hemalatha Raju, Bipin Nair, Prashant Kumar Modi, Anita Mahadevan, Thottethodi Subrahmanya Keshava Prasad, and Rajesh Raju
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Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
13. Metabolomics analysis highlights Yashtimadhu ( Glycyrrhiza glabra L.) ‐ mediated neuroprotection in a rotenone‐induced cellular model of Parkinson's disease by restoring the <scp>mTORC1‐AMPK1</scp> axis in autophagic regulation
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Gayathree Karthikkeyan, Santosh Kumar Behera, Shubham Sukerndeo Upadhyay, Ravishankar Pervaje, Thottethodi Subrahmanya Keshava Prasad, and Prashant Kumar Modi
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Pharmacology - Published
- 2022
14. Hyperactivation of MEK/ERK pathway by Ca 2+ /calmodulin‐dependent protein kinase kinase 2 promotes cellular proliferation by activating cyclin‐dependent kinases and minichromosome maintenance protein in gastric cancer cells
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Anjana Aravind, Duane T. Smoot, Shobha Dagamajalu, Hassan Ashktorab, Aditi Chatterjee, David Sidransky, T. S. Keshava Prasad, Prashant Kumar Modi, Harsha Gowda, and Mohd Altaf Najar
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Cancer Research ,Cyclin-dependent kinase 1 ,biology ,Kinase ,Cyclin-dependent kinase ,Cyclin-dependent kinase 2 ,biology.protein ,Phosphoproteomics ,MAPK1 ,Protein kinase A ,Molecular Biology ,Cell biology ,CAMKK2 - Abstract
Although CAMKK2 is overexpressed in several cancers, its role and relevant downstream signaling pathways in gastric cancer (GC) are poorly understood. Treatment of AGS GC cells with a CAMKK2 inhibitor, STO-609, resulted in decreased cell proliferation, cell migration, invasion, colony-forming ability, and G1/S-phase arrest. Quantitative phosphoproteomics in AGS cells with the CAMKK2 inhibitor led to the identification of 9603 unique phosphosites mapping to 3120 proteins. We observed decreased phosphorylation of 1101 phosphopeptides (1.5-fold) corresponding to 752 proteins upon CAMKK2 inhibition. Bioinformatics analysis of hypo-phosphorylated proteins revealed enrichment of MAPK1/MAPK3 signaling. Kinase enrichment analysis of hypo-phosphorylated proteins using the X2K Web tool identified ERK1, cyclin-dependant kinase 1 (CDK1), and CDK2 as downstream substrates of CAMKK2. Moreover, inhibition of CAMKK2 and MEK1 resulted in decreased phosphorylation of ERK1, CDK1, MCM2, and MCM3. Immunofluorescence results were in concordance with our mass spectroscopy data and Western blot analysis results. Taken together, our data reveal the essential role of CAMKK2 in the pathobiology of GC through the activation of the MEK/ERK1 signaling cascade.
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- 2021
15. Novel Post-Translational Modifications and Molecular Substrates in Glioma Identified by Bioinformatics
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Prashant Kumar Modi, D A B Rex, Akhila Balakrishna Rai, Chinmaya Narayana Kotimoole, Sumaithangi Thattai Arun Kumar, and Thottethodi Subrahmanya Keshava Prasad
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Proteomics ,MAPK/ERK pathway ,Drug discovery ,Computational Biology ,Cancer ,Glioma ,Biology ,medicine.disease ,Bioinformatics ,Biochemistry ,Transcriptome ,Phosphatidylinositol 3-Kinases ,Genetics ,medicine ,Humans ,Molecular Medicine ,Protein Processing, Post-Translational ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Biotechnology - Abstract
Glioma is the most common type of brain cancer that originates from the glial cells. It constitutes about one-third of all brain cancers. Recently, transcriptomics, proteomics, and multiomics approaches have been harnessed to discover potential biomarkers and therapeutic targets in glioma. Moreover, post-translational modifications (PTMs) of proteins play a major role in cell biology and function and offer new avenues of research in cancer. Using unbiased multi-PTM bioinformatics analyses of two proteomic datasets of glioma available in the public domain, we identified 866 proteins with common PTMs from both studies. Out of these 866 proteins, 19 proteins were identified with the common PTMs, with the same site modifications pertaining to glioma. Importantly, the identified PTMs belonged to proteins involved in integrin PI3K/Akt/mTOR, JAK/STAT, and Ras/Raf/MAPK pathways. These pathways are essential for cell proliferation in tumor cells and thus involved in glioma progression. Taken together, these findings call for validation in larger datasets in glioma and brain cancers and with an eye to future drug discovery and diagnostic innovation. Bioinformatics-guided discovery of novel PTMs from the publicly available proteomic data can offer new avenues for innovation in cancer research.
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- 2021
16. The unique molecular targets associated antioxidant and antifibrotic activity of curcumin in in vitro model of acute lung injury: A proteomic approach
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Ashwini Prabhu, Yashodhar P. Bhandary, D A B Rex, Santosh Kumar Behera, Prashant Kumar Modi, Jaikanth Chanderasekaran, Mohd Altaf Najar, Sadiya Bi Shaikh, and Thottethodi Subrahmanya Keshava Prasad
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Protein Conformation, alpha-Helical ,Proteomics ,0301 basic medicine ,medicine.medical_treatment ,Clinical Biochemistry ,Kinesins ,Autoantigens ,Biochemistry ,Antioxidants ,Receptor, IGF Type 2 ,Receptor, IGF Type 1 ,chemistry.chemical_compound ,0302 clinical medicine ,Gene Regulatory Networks ,Acetyl-CoA C-Acetyltransferase ,Antibiotics, Antineoplastic ,biology ,Drug discovery ,In vitro toxicology ,General Medicine ,Non-Fibrillar Collagens ,Molecular Docking Simulation ,Cytokine ,030220 oncology & carcinogenesis ,Molecular Medicine ,Protein Binding ,Signal Transduction ,Curcumin ,Acute Lung Injury ,Quantitative proteomics ,Lung injury ,Models, Biological ,Transforming Growth Factor beta1 ,Bleomycin ,03 medical and health sciences ,medicine ,Humans ,Binding Sites ,CENPF ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,A549 Cells ,biology.protein ,Cancer research ,Protein Conformation, beta-Strand ,Acyl-CoA Oxidase ,Calreticulin - Abstract
Bleomycin (BLM) injury is associated with the severity of acute lung injury (ALI) leading to fibrosis, a high-morbidity, and high-mortality respiratory disease of unknown etiology. BLM-induced ALI is marked by the activation of a potent fibrogenic cytokine transcription growth factor beta-1 (TGFβ-1), which is considered a critical cytokine in the progression of alveolar injury. Previously, our work demonstrated that a diet-derived compound curcumin (diferuloylmethane), represents its antioxidative and antifibrotic application in TGF-β1-mediated BLM-induced alveolar basal epithelial cells. However, curcumin-specific protein targets, as well as its mechanism using mass spectrometry-based proteomic approach, remain elusive. To elucidate the underlying mechanism, a quantitative proteomics approach and bioinformatics analysis were employed to identify the protein targets of curcumin in BLM or TGF-β1-treated cells. With subsequent in vitro experiments, curcumin-related pathways and cellular processes were predicted and validated. The current study discusses two separate proteomics experiments using BLM and TGF-β1-treated cells with the proteomics approach, various unique target proteins were identified, and proteomic analysis revealed that curcumin reversed the expressions of unique proteins like DNA topoisomerase 2-alpha (TOP2A), kinesin-like protein (KIF11), centromere protein F (CENPF), and so on BLM or TGF-β1 injury. For the first time, the current study reveals that curcumin restores TGF-β1 induced peroxisomes like PEX-13, PEX-14, PEX-19, and ACOX1. This was verified by subsequent in vitro assays. This study generated molecular evidence to deepen our understanding of the therapeutic role of curcumin at the proteomic level and may be useful to identify molecular targets for future drug discovery.
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- 2021
17. Preliminary comparative deep metabolomic analysis of spermatozoa from zebu and crossbred cattle suggests associations between metabolites, sperm quality and fertility
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Sakthivel Jeyakumar, K. P. Ramesha, Gayathree Karthikkeyan, Kaustubh Kishor Saraf, Prashant Kumar Modi, Mohua DasGupta, T. S. Keshava Prasad, Ayyasamy Manimaran, and Arumugam Kumaresan
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Male ,Infertility ,endocrine system ,Taurine ,animal structures ,animal diseases ,Cattle Diseases ,Hypotaurine ,Glycerophospholipids ,Reproductive technology ,Biology ,Crossbreed ,Andrology ,Semen quality ,chemistry.chemical_compound ,Endocrinology ,Species Specificity ,Genetics ,medicine ,Animals ,Metabolomics ,Molecular Biology ,Crosses, Genetic ,Infertility, Male ,reproductive and urinary physiology ,urogenital system ,medicine.disease ,Zebu ,Spermatozoa ,Sperm ,Semen Analysis ,Fertility ,Reproductive Medicine ,chemistry ,Metabolome ,Cattle ,Animal Science and Zoology ,Metabolic Networks and Pathways ,Developmental Biology ,Biotechnology - Abstract
Poor semen quality and infertility/subfertility are more frequent in crossbred than zebu bulls. Using a high-throughput liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based approach, we established the preliminary metabolomic profile of crossbred and zebu bull spermatozoa (n = 3 bulls each) and identified changes in sperm metabolomics between the two groups. In all, 1732 and 1240 metabolites were detected in zebu and crossbred bull spermatozoa respectively. After excluding exogenous metabolites, 115 and 87 metabolites were found to be unique to zebu and crossbred bull spermatozoa respectively whereas 71 metabolites were common to both. In the normalised data, 49 metabolites were found to be differentially expressed between zebu and crossbred bull spermatozoa. The significantly enriched (P 1.5) was downregulated, whereas that of l-cysteine, acetyl coenzyme A and 2′-deoxyribonucleoside 5′-diphosphate (VIP scores >1.0) was upregulated in crossbred bull spermatozoa. In conclusion, this study established the metabolomic profile of zebu and crossbred bull spermatozoa and suggests that aberrations in taurine, hypotaurine and glycerophospholipid metabolism may be associated with the higher incidence of infertility/subfertility in crossbred bulls.
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- 2021
18. A complete map of the Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) signaling pathway
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Nupur Agarwal, Shobha Dagamajalu, M. Vijayakumar, Aditi Chatterjee, D A B Rex, Prashant Kumar Modi, Gayathree Karthikkeyan, Mohd Altaf Najar, Uma Sankar, and T. S. Keshava Prasad
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0301 basic medicine ,Calmodulin ,biology ,Nuts and Bolts ,Chemistry ,Kinase ,Autophosphorylation ,Cell Biology ,Biochemistry ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,biology.protein ,Glucose homeostasis ,Signal transduction ,Protein kinase A ,Molecular Biology ,Protein kinase B ,CAMKK2 - Abstract
Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is a serine/threonine-protein kinase belonging to the Ca(2+)/calmodulin-dependent protein kinase subfamily. CAMKK2 has an autocatalytic site, which gets exposed when Ca(2+)/calmodulin (CAM) binds to it. This results in autophosphorylation and complete activation of CAMKK2. The three major known downstream targets of CAMKK2 are 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPKα), calcium/calmodulin-dependent protein kinase 1 (CAMK1) and calcium/calmodulin-dependent protein kinase 4 (CAMK4). Activation of these targets by CAMKK2 is important for the maintenance of different cellular and physiological processes within the cell. CAMKK2 is found to be important in neuronal development, bone remodeling, adipogenesis, and systemic glucose homeostasis, osteoclastgensis and postnatal myogensis. CAMKK2 is reported to be involved in pathologies like Duchenne muscular dystrophy, inflammation, osteoporosis and bone remodeling and is also reported to be overexpressed in prostate cancer, hepatic cancer, ovarian and gastric cancer. CAMKK2 is involved in increased cell proliferation and migration through CAMKK2/AMPK pathway in prostate cancer and activation of AKT in ovarian cancer. Although CAMKK2 is a molecule of great importance, a public resource of the CAMKK2 signaling pathway is currently lacking. Therefore, we carried out detailed data mining and documentation of the signaling events associated with CAMKK2 from published literature and developed an integrated reaction map of CAMKK2 signaling. This resulted in the cataloging of 285 reactions belonging to the CAMKK2 signaling pathway, which includes 33 protein–protein interactions, 74 post-translational modifications, 7 protein translocation events, and 22 activation/inhibition events. Besides, 124 gene regulation events and 25 activator/inhibitors involved in CAMKK2 activation were also cataloged. The CAMKK2 signaling pathway map data is made freely accessible through WikiPathway database (https://www.wikipathways.org/index.php/Pathway:WP4874). We expect that data on a signaling map of CAMKK2 will provide the scientific community with an improved platform to facilitate further molecular as well as biomedical investigations on CAMKK2 and its utility in the development of biomarkers and therapeutic targets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12079-020-00592-1) contains supplementary material, which is available to authorized users.
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- 2020
19. Identification of Molecular Network Associated with Neuroprotective Effects of Yashtimadhu (Glycyrrhiza glabra L.) by Quantitative Proteomics of Rotenone-Induced Parkinson’s Disease Model
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Prashant Kumar Modi, Gayathree Karthikkeyan, Thottethodi Subrahmanya Keshava Prasad, Sameera Krishna Pervaje, Ravishankar Pervaje, and Mohd Altaf Najar
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General Chemical Engineering ,Quantitative proteomics ,Autophagy ,Hyperphosphorylation ,General Chemistry ,Rotenone ,Pharmacology ,Biology ,medicine.disease_cause ,Proteomics ,Neuroprotection ,Nootropic ,chemistry.chemical_compound ,Chemistry ,chemistry ,medicine ,QD1-999 ,Oxidative stress - Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder, whose treatment with modern therapeutics leads to a plethora of side effects with prolonged usage. Therefore, the management of PD with complementary and alternative medicine is often pursued. In the Ayurveda system of alternative medicine, Yashtimadhu choorna, a Medhya Rasayana (nootropic), prepared from the dried roots of Glycyrrhiza glabra L. (licorice), is prescribed for the management of PD with a favorable outcome. We pursued to understand the neuroprotective effects of Yashtimadhu choorna against a rotenone-induced cellular model of PD using differentiated IMR-32 cells. Cotreatment with Yashtimadhu choorna extract rescued rotenone-induced apoptosis and hyperphosphorylation of ERK-1/2. Quantitative proteomic analysis of six peptide fractions from independent biological replicates acquired 1,561,169 mass spectra, which when searched resulted in 565,008 peptide-spectrum matches mapping to 30,554 unique peptides that belonged to 4864 human proteins. Proteins commonly identified in biological replicates and >4 PSMs were considered for further analysis, leading to a refined set of 3720 proteins. Rotenone treatment differentially altered 144 proteins (fold ≥1.25 or ≤0.8), involved in mitochondrial, endoplasmic reticulum, and autophagy functions. Cotreatment with Yashtimadhu choorna extract rescued 84 proteins from the effect of rotenone and an additional regulation of 4 proteins. Network analysis highlighted the interaction of proteins and pathways regulated by them, which can be targeted for neuroprotection. Validation of proteomics data highlighted that Yashtimadhu confers neuroprotection by preventing mitochondrial oxidative stress and apoptosis. This discovery will pave the way for understanding the molecular action of Ayurveda drugs and developing novel therapeutics for PD.
- Published
- 2020
20. Metabolomics analysis highlights Yashtimadhu (Glycyrrhiza glabra L.)-mediated neuroprotection in a rotenone-induced cellular model of Parkinson's disease by restoring the mTORC1-AMPK1 axis in autophagic regulation
- Author
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Gayathree, Karthikkeyan, Santosh Kumar, Behera, Shubham Sukerndeo, Upadhyay, Ravishankar, Pervaje, Thottethodi Subrahmanya Keshava, Prasad, and Prashant Kumar, Modi
- Subjects
Neuroprotective Agents ,Rotenone ,Autophagy ,Glycyrrhiza ,Humans ,Metabolomics ,Parkinson Disease ,Mechanistic Target of Rapamycin Complex 1 ,Neuroprotection - Abstract
Parkinson's disease (PD) is an age-associated progressive neurodegenerative movement disorder, and its management strategies are known to cause complications with prolonged usage. We aimed to explore the neuroprotective mechanism of the Indian traditional medicine Yashtimadhu, prepared from the dried roots of Glycyrrhiza glabra L. (licorice) in the rotenone-induced cellular model of PD. Retinoic acid-differentiated IMR-32 cells were treated with rotenone (PD model) and Yashtimadhu extract. Mass spectrometry-based untargeted and targeted metabolomic profiling was carried out to discover altered metabolites. The untargeted metabolomics analysis highlighted the rotenone-induced dysregulation and Yashtimadhu-mediated restoration of metabolites involved in the metabolism of nucleic acids, amino acids, lipids, and citric acid cycle. Targeted validation of citric acid cycle metabolites showed decreased α-ketoglutarate and succinate with rotenone treatment and rescued by Yashtimadhu co-treatment. The dysregulation of the citric acid cycle by rotenone-induced energetic stress via dysregulation of the mTORC1-AMPK1 axis was prevented by Yashtimadhu. Yashtimadhu co-treatment restored rotenone-induced ATG7-dependent autophagy and eventually caspases-mediated cell death. Our analysis links the metabolic alterations modulating energy stress and autophagy, which underlies the Yashtimadhu-mediated neuroprotection in the rotenone-induced cellular model of PD.
- Published
- 2022
21. A network map of endothelin mediated signaling pathway
- Author
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Sumrati Gurtoo, Prashant Kumar Modi, M Mujeeburahiman, Varshasnata Mohanty, Shobha Dagamajalu, Lathika Gopalakrishnan, Vinod Tiwari, D A B Rex, Gayathree Karthikkeyan, Sowmya Soman, Rajesh Raju, and T. S. Keshava Prasad
- Subjects
Text mining ,Nuts and Bolts ,business.industry ,Chemistry ,Network mapping ,Cell Biology ,Computational biology ,Signal transduction ,business ,Endothelin receptor ,Molecular Biology ,Biochemistry - Published
- 2020
22. Molecular Targets from Traditional Medicines for Neuroprotection in Human Neurodegenerative Diseases
- Author
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Thottethodi Subrahmanya Keshava Prasad, Ravishankar Pervaje, Yashwanth Subbannayya, Sayali Chandrashekhar Deolankar, and Prashant Kumar Modi
- Subjects
Proteomics ,0301 basic medicine ,medicine.medical_specialty ,Neurology ,Context (language use) ,Disease ,Neuropsychological Tests ,Biochemistry ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Humans ,Amyotrophic lateral sclerosis ,Molecular Biology ,Biomedicine ,Behavior ,business.industry ,Neurodegeneration ,Neurodegenerative Diseases ,Genomics ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Molecular targets ,Molecular Medicine ,Disease Susceptibility ,Medicine, Traditional ,business ,Neuroscience ,Biomarkers ,Biotechnology - Abstract
Neurodegeneration is one of the greatest threats to global public health. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the major causes of chronic neurological conditions in the elderly populations. Hence, neuroprotection is at the epicenter of the current 21st-century research agenda in biomedicine. Yet, novel molecular targets are limited and solely needed for neuroprotection. Marked person-to-person variations in outcomes require a deeper understanding of drug targets in neurology and clinical neurosciences. In this context, traditional medicines offer untapped potentials for discovery and translation of novel molecular targets to human neurodegenerative disease research and clinical neurology. This expert review offers a synthesis of the prospects and challenges of harnessing new molecular targets from traditional medicines, with a view to applications for neuroprotection in human neurodegenerative diseases.
- Published
- 2020
23. Metabolomic fingerprinting of bull spermatozoa for identification of fertility signature metabolites
- Author
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Sakthivel Jeyakumar, Arumugam Kumaresan, Ayyasamy Manimaran, Gayathree Karthikkeyan, K. P. Ramesha, Thottethodi Subrahmanya Keshava Prasad, Mohua DasGupta, Kaustubh Kishor Saraf, and Prashant Kumar Modi
- Subjects
Male ,0301 basic medicine ,endocrine system ,Metabolite ,Spermine ,Hypotaurine ,Biology ,Peptide Mapping ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Metabolomics ,Tandem Mass Spectrometry ,Genetics ,Animals ,Humans ,Human Metabolome Database ,Databases, Protein ,reproductive and urinary physiology ,030219 obstetrics & reproductive medicine ,Selenocysteine ,urogenital system ,Cell Biology ,Spermatozoa ,Sperm ,Fold change ,Semen Analysis ,Fertility ,030104 developmental biology ,chemistry ,Biochemistry ,Metabolome ,Cattle ,Chromatography, Liquid ,Developmental Biology - Abstract
The objective of the study was to identify the fertility-associated metabolites in bovine spermatozoa using liquid chromatography-mass spectrometry (LC-MS). Six Holstein Friesian crossbred bulls (three high-fertile and three low-fertile bulls) were the experimental animals. Sperm proteins were isolated and protein-normalized samples were processed for metabolite extraction and subjected to LC-MS/MS analysis. Mass spectrometry data were processed using iMETQ software and metabolites were identified using Human Metabolome DataBase while, Metaboanalyst 4.0 tool was used for statistical and pathway analysis. A total of 3,704 metabolites belonging to various chemical classes were identified in bull spermatozoa. After sorting out exogenous metabolites, 56 metabolites were observed common to both the groups while 44 and 35 metabolites were found unique to high- and low-fertile spermatozoa, respectively. Among the common metabolites, concentrations of 19 metabolites were higher in high-fertile compared to low-fertile spermatozoa (fold change > 1.00). Spermatozoa metabolites with variable importance in projections score of more than 1.5 included hypotaurine, d-cysteine, selenocystine. In addition, metabolites such as spermine and l-cysteine were identified exclusively in high-fertile spermatozoa. Collectively, the present study established the metabolic profile of bovine spermatozoa and identified the metabolomic differences between spermatozoa from high- and low-fertile bulls. Among the sperm metabolites, hypotaurine, selenocysteine, l-malic acid, d-cysteine, and chondroitin 4-sulfate hold the potential to be recognized as fertility-associated metabolites.
- Published
- 2020
24. Antioxidant Activity and Role of Culture Condition in the Optimization of Red Pigment Production by Talaromyces purpureogenus KKP Through Response Surface Methodology
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Rajesh P. Shastry, Prashant Kumar Modi, Kishor Kumar Keekan, and Sweta Hallur
- Subjects
0303 health sciences ,Talaromyces purpureogenus ,Limonene ,Antioxidant ,Central composite design ,030306 microbiology ,medicine.medical_treatment ,General Medicine ,Biology ,Industrial microbiology ,Applied Microbiology and Biotechnology ,Microbiology ,03 medical and health sciences ,Pigment ,chemistry.chemical_compound ,chemistry ,visual_art ,visual_art.visual_art_medium ,medicine ,Food science ,Response surface methodology ,Delphinidin ,030304 developmental biology - Abstract
The red pigment production by Talaromyces purpureogenus KKP, a soil isolate, was optimized by response surface methodology (RSM) in the present study. The cultural parameters, such as pH, temperature, dextrose, and peptone concentrations, were optimized for red pigment production using the central composite design (CCD) experimental design. A second-order quadratic model was used to calculate the relationships between the values at different levels of response. The optimum values of the selected variables under coded factors are 6.0, 27 °C, 2.25%, and 1.10% for pH, temperature, dextrose, and peptone, respectively. The selected variables were most effective in the enhancement of red pigment production at optimized culture conditions. In addition to optimization, the antioxidant activity of the pigment isolated in the present study was found to be promising with IC50 value (40 µg/ml). The HRMS data revealed the identification of delphinidin, limonene, 6-hydroxymethyl-7,8-dihydropterin, d-mannose 6-phosphate, and CDP-DG (18:0/18:0). The results of the present investigation will be added to the existing literature of red pigment production and its optimization by T. purpureogenus
- Published
- 2020
25. From LC-MS/MS metabolomics profiling of
- Author
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Santosh Kumar, Behera, Prashant Kumar, Modi, Gayathree, Karthikkeyan, Sameera Krishna, Pervaje, Ravishankar, Pervaje, Rajesh, Raju, Thottethodi Subrahmanya, Keshava Prasad, and Yashwanth, Subbannayya
- Abstract
Kanchanara Guggulu (KG) is an important traditional medicine that is prescribed by the Ayurveda physicians for the treatment of swellings in various organs such as the thyroid, and lymph nodes. High-resolution mass-spectrometry-based metabolomics found metabolites in KG. LC-MS/MS-based metabolomics analysis of KG identified 2,579 compounds including quercetin and kaempferol derivatives. The molecular docking and dynamics analysis of quercetin pentaacetate with aldose reductase is documented for further consideration in drug discovery.
- Published
- 2021
26. Deciphering metabolomic alterations in seminal plasma of crossbred ( Bos taurus X Bos indicus ) bulls through comparative deep metabolomic analysis
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Kaustubh Kishor Saraf, Arumugam Kumaresan, K. P. Ramesha, T. S. Keshava Prasad, Thankappan Sajeevkumar, Nilendu Paul, Sakthivel Jeyakumar, Gayathree Karthikkeyan, Prashant Kumar Modi, Ayyasamy Manimaran, and Mohua DasGupta
- Subjects
Male ,Taurine ,animal structures ,animal diseases ,Urology ,Metabolite ,Bos taurus x Bos indicus ,Biology ,Crossbreed ,Andrology ,Increased lipid ,chemistry.chemical_compound ,Endocrinology ,Metabolomics ,Semen ,Tandem Mass Spectrometry ,Animals ,Inositol ,reproductive and urinary physiology ,urogenital system ,General Medicine ,Zebu ,Spermatozoa ,chemistry ,Cattle ,Chromatography, Liquid - Abstract
The incidence of sub-fertility is higher in crossbred bulls compared to zebu bulls. In the present study, we analysed the metabolomic profile of seminal plasma from crossbred and zebu bulls and uncovered differentially expressed metabolites between these two breeds. Using a high-throughput LC-MS/MS-based approach, we identified 990 and 1,002 metabolites in crossbred and zebu bull seminal plasma respectively. After excluding the exogenous metabolites, we found that 50 and 68 putative metabolites were unique to crossbred and zebu bull seminal plasma, respectively, whilst 87 metabolites were common to both. After data normalisation, 63 metabolites were found to be dysregulated between crossbred and zebu bull seminal plasma. Observed pathways included Linoleic acid metabolism (observed metabolite was phosphatidylcholine) in crossbred bull seminal plasma whereas inositol phosphate metabolism (observed metabolites were phosphatidylinositol-3,4,5-trisphosphate/inositol 1,3,4,5,6-pentakisphosphate/myo-inositol hexakisphosphate) was observed in zebu bull seminal plasma. Abundance of Tetradecanoyl-CoA was significantly higher, whilst abundance of Taurine was significantly lower in crossbred bull seminal plasma. In conclusion, the present study established the seminal plasma metabolomic profile in crossbred and zebu bulls and suggest that increased lipid peroxidation coupled with low concentrations of antioxidants in seminal plasma might be associated with high incidence of sub-fertility in crossbred bulls.
- Published
- 2021
27. Hyperphosphorylation of HDAC2 promotes drug resistance in a novel dual drug resistant mouse melanoma cell line model: an
- Author
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Bhuvanesh Sukhlal, Kalal, Prashant Kumar, Modi, Mohd Altaf, Najar, Santosh Kumar, Behera, Dinesh, Upadhya, Thottethodi Subrahmanya Keshava, Prasad, and Vinitha Ramanath, Pai
- Subjects
Original Article - Abstract
Drug-resistant melanoma is very difficult to treat, and a novel approach is needed to overcome resistance. The present study aims at identifying the alternate pathways utilized in the dual drug-resistant mouse melanoma cells (B16F10R) for their survival and proliferation. The dual drug-resistant mouse melanoma, B16F10R, was established by treating the cells with a combination of U0126 (MEK1/2 inhibitor) and LY294002 (PI3K-AKT kinase inhibitor) in a dose-escalating manner till they attained a resistance fold factor of ≥2. The altered phosphoproteome in the B16F10R, as compared to the parental B16F10C, was analyzed using a high-resolution Orbitrap Fusion Tribrid mass spectrometer. Histone deacetylases 2 (HDAC2) was validated for its role in drug resistance by using its inhibitor, valproic acid (VPA). In the B16F10R cells, 363 altered phosphoproteins were identified, among which 126 were hyperphosphorylated, and 137 were hypophosphorylated (1.5-fold change). Pathway analysis shows the altered phosphoproteins are from RNA metabolism and cell cycle proteins. Inhibition of HDAC2 by VPA induces apoptosis in B16F10C and B16F10R. The present study highlights the role of HDAC2, a cell cycle regulator, in the development of resistance to dual drugs in murine melanoma. Therefore, designing leads for targeting HDAC2 along with key signaling pathways may be explored in treatment strategies.
- Published
- 2021
28. Dissecting
- Author
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Devasahayam Arokia Balaya, Rex, Arun H, Patil, Prashant Kumar, Modi, Mrudula Kinarulla, Kandiyil, Sandeep, Kasaragod, Sneha M, Pinto, Nandita, Tanneru, Puran Singh, Sijwali, and Thottethodi Subrahmanya Keshava, Prasad
- Abstract
Malaria is a vector-borne disease. It is caused by
- Published
- 2021
29. Broadening COVID-19 Interventions to Drug Innovation: Neprilysin Pathway as a Friend, Foe, or Promising Molecular Target?
- Author
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Prashant Kumar Modi, Sumaithangi Thattai Arun Kumar, Thottethodi Subrahmanya Keshava Prasad, and D A B Rex
- Subjects
Drug ,Coronavirus disease 2019 (COVID-19) ,media_common.quotation_subject ,Bradykinin ,Biochemistry ,Renin-Angiotensin System ,chemistry.chemical_compound ,Renin–angiotensin system ,Genetics ,Medicine ,Molecular Biology ,Neprilysin ,media_common ,business.industry ,Drug discovery ,SARS-CoV-2 ,medicine.disease ,Virology ,chemistry ,Molecular targets ,Molecular Medicine ,business ,Cytokine storm ,Biotechnology - Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is anticipated to transition to an endemic state as vaccines are providing relief in some, but not all, countries. Drug discovery for COVID-19 can offer another tool in the fight against the pandemic. Additionally, COVID-19 impacts multiple organs that call for a systems medicine approach to planetary health and therapeutics innovation. In this context, innovation for drugs that prevent and treat COVID-19 is timely and much needed. As the virus variants emerge under different ecological conditions and contexts in the long haul, a broad array of vaccine and drug options will be necessary. This expert review article argues for a need to expand the COVID-19 interventions, including and beyond vaccines, to stimulate discovery and development of novel medicines against SARS-CoV-2 infection. The Renin-Angiotensin-Aldosterone System (RAAS) is known to play a major role in SARS-CoV-2 infection. Neprilysin (NEP) and angiotensin-converting enzyme (ACE) have emerged as the pharmaceutical targets of interest in the search for therapeutic interventions against COVID-19. While the NEP/ACE inhibitors offer promise for repurposing against COVID-19, they may display a multitude of effects in different organ systems, some beneficial, and others adverse, in modulating the inflammation responses in the course of COVID-19. This expert review offers an analysis and discussion to deepen our present understanding of the pathophysiological function of neprilysin in multiple organs, and the possible effects of NEP inhibitor-induced inflammatory responses in COVID-19-infected patients.
- Published
- 2021
30. Molecular Profiling Associated with Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2)-Mediated Carcinogenesis in Gastric Cancer
- Author
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Prashant Kumar Modi, Mohd Altaf Najar, David Sidransky, Aditi Chatterjee, T. S. Keshava Prasad, Poornima Ramesh, and Harsha Gowda
- Subjects
0301 basic medicine ,Proteomics ,030102 biochemistry & molecular biology ,Kinase ,Cell growth ,Carcinogenesis ,Cancer ,Calcium-Calmodulin-Dependent Protein Kinase Kinase ,General Chemistry ,Biology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,Replication factor C ,Stomach Neoplasms ,medicine ,Cancer research ,Origin recognition complex ,Humans ,Calcium ,Protein kinase A ,CAMKK2 - Abstract
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death worldwide. We showed previously that calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), a serine-threonine kinase, is highly expressed in gastric cancer and leads to progression. In the present study, we identified the molecular networks involved in CAMKK2-mediated progression of gastric adenocarcinoma. Treatment of gastric cancer cell lines with a CAMKK2 inhibitor, STO-609, resulted in decreased cell migration, invasion, and colony-forming ability and a G1/S-phase arrest. In addition, tandem mass tag (TMT)-based quantitative proteomic analysis resulted in the identification of 7609 proteins, of which 219 proteins were found to be overexpressed and 718 downregulated (1.5-fold). Our data identified several key downregulated proteins involved in cell division and cell proliferation, which included DNA replication licensing factors, replication factor C, origin recognition complex, replication protein A and GINS, and mesenchymal markers, upon CAMKK2 inhibition. Immunoblotting and immunofluorescence results showed concordance with our mass spectroscopy data. Taken together, our study supports CAMKK2 as a novel therapeutic target in gastric cancer.
- Published
- 2021
31. Dissecting Alzheimer's Disease Molecular Substrates by Proteomics and Discovery of Novel Post-translational Modifications
- Author
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Thottethodi Subrahmanya Keshava Prasad, Prashant Kumar Modi, Sayali Chandrashekhar Deolankar, Yashwanth Subbannayya, Shashanka G. Koyangana, and Arun H. Patil
- Subjects
Proteomics ,0301 basic medicine ,Proteome ,Protein biomarkers ,Quantitative proteomics ,Context (language use) ,Computational biology ,Disease ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Tandem Mass Spectrometry ,Genetics ,Humans ,Diagnostic biomarker ,Databases, Protein ,Molecular Biology ,Drug discovery ,Computational Biology ,Neurodegenerative Diseases ,Gene Ontology ,030104 developmental biology ,030220 oncology & carcinogenesis ,Posttranslational modification ,Molecular Medicine ,Peptides ,Protein Processing, Post-Translational ,Biomarkers ,Signal Transduction ,Biotechnology - Abstract
Alzheimer's disease (AD) is a common complex disease and a major public health burden in both developed and developing countries. Postgenomic technologies such as proteomics and intelligent mining of multi-omics Big Data offer new prospects for diagnostics and therapeutics innovation for AD. In this context, it is noteworthy that mass spectrometry (MS) data are often searched against proteomics databases to unravel the identity of protein biomarkers. In contrast, only a fraction of the MS data can be matched to known proteins, while a large portion of such raw data remains underutilized. Furthermore, the spectral data can be mined for multiple high-confidence post-translational modifications (PTMs) without a priori enrichment. Thus, AD research stands to gain by greater attention to the biological mechanisms regulated by PTMs. Protein modifications may serve as diagnostic biomarkers or as novel molecular targets for drug discovery. We report here novel PTMs discovered in relation to the AD from MS/MS-based proteomic datasets. Publicly available label-free proteomics data were searched for select PTMs using SEQUEST-HT. Only high-confidence PTMs were analyzed using bioinformatics analysis. We identified 4961 unique modified peptides corresponding to 1856 proteins from AD datasets. Of these, 52 proteins were known to be involved in Alzheimer's pathway. Importantly, 3164 PTMs reported in this study are novel in the context of AD. Furthermore, protein quantification revealed expression of 13 high-abundant secretary proteins across multiple studies, which can be potentially harnessed in the future to develop biomarkers. In summary, this study identifies novel PTMs which might help develop new insights on the molecular substrates of AD and thus inform future development of novel diagnostics and treatments for this highly prevalent disease.
- Published
- 2019
32. Data on multiple post-translational modifications in Alzheimer's disease
- Author
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Sayali Chandrashekhar Deolankar, Shashanka G Koyangana, Arun H Patil, Yashwanth Subbannayya, Prashant Kumar Modi, and T S Keshava Prasad
- Subjects
Cellular and Molecular Neuroscience ,Neurology ,Cognitive Neuroscience ,Neuroscience (miscellaneous) - Abstract
This article describes the data obtained for global post-translational modifications (PTMs) profiled for Alzheimer's Disease (AD) from two distinct human brain regions and one cerebrospinal fluid (CSF) sample. The PTM profiling was performed to identify phosphorylation, O-GluNAcetylation, methylation, acetylation and citrullination using three publicly available LC-MS/MS raw data sets (PRIDE ID: PXD004010, PXD002516, PXD004863). A total of 1,857 PTM harbouring proteins with 4,961 unique post-translationally modified peptides were identified. Among the modified peptides, 75 corresponded uniquely to proteins identified from CSF samples. The data is related to the research article "Dissecting Alzheimer's disease molecular substrates by proteomics and discovery of novel post-translational modifications (PTMs)".
- Published
- 2022
33. A computational workflow for predicting cancer neo-antigens
- Author
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Sandeep, Kasaragod, Chinmaya Narayana, Kotimoole, Sumrati, Gurtoo, Thottethodi Subrahmanya, Keshava Prasad, Harsha, Gowda, and Prashant Kumar, Modi
- Abstract
Neo-antigens presented on cell surface play a pivotal role in the success of immunotherapies. Peptides derived from mutant proteins are thought to be the primary source of neo-antigens presented on the surface of cancer cells. Mutation data from cancer genome sequencing is often used to predict cancer neo-antigens. However, this strategy is associated with significant false positives as many coding mutations may not be expressed at the protein level. Hence, we describe a computational workflow to integrate genomic and proteomic data to predictpotential neo-antigens.
- Published
- 2021
34. Inhibition of bone morphogenetic proteins signaling suppresses metastasis melanoma: a proteomics approach
- Author
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Bhuvanesh Sukhlal, Kalal, Prashant Kumar, Modi, Dinesh, Upadhya, Pratip, Saha, Thottethodi Subrahmanya Keshava, Prasad, and Vinitha Ramanath, Pai
- Subjects
Original Article - Abstract
Background: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β superfamily, known to promote the tumor invasion and metastasis. There are continual progresses in understanding the role of BMP signaling pathways in carcinogenesis. However, the biological significance of BMPs in human melanoma has received very little attention. The study aimed to explore the effect of BMP inhibition on melanoma treated with LDN193189 (BMP inhibitor) using a quantitative proteomics approach in a melanoma xenograft model. Materials and methods: Melanoma tumor was induced in C57BL6 mice and treated intraperitoneally with LDN193189 for ten consecutive days. Post-treatment, tumors were collected, and comparative proteomics was performed using a high-resolution Orbitrap Fusion Tribrid mass spectrometer. Results: Treatment of melanoma with LDN193189 at 3 mg/kg body weight twice daily showed a significant decrease in the growth rate of the tumor compared to the other doses tested. Quantitative proteomic profiling identified 3231 proteins. Bioinformatics analysis of the 131 differentially expressed proteins selected by their relative abundance revealed that LDN193189 induces alterations in the cellular and metabolic process and the proteins that are involved in protein binding and catalytic activity in melanoma. Conclusions: Down-regulation of metallothionein (MT) 1 and MT2, emerging proteins for their role in tumor formation, progression, and drug resistance and transcription factor EB that plays a crucial role in the regulation of basic cellular processes, such as lysosomal biogenesis and autophagy, were identified upon inhibition of the BMP pathway in melanoma, suggesting their roles in melanoma growth. Understanding the role of these proteins will provide new directions for treating cancer.
- Published
- 2020
35. Plant Omics: Metabolomics and Network Pharmacology of Liquorice, Indian Ayurvedic Medicine Yashtimadhu
- Author
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Arun H. Patil, Ravishankar Pervaje, Prashant Kumar Modi, Thottethodi Subrahmanya Keshava Prasad, Gayathree Karthikkeyan, and Yashwanth Subbannayya
- Subjects
0301 basic medicine ,Biology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Metabolomics ,Genetics ,Glycyrrhiza ,Glycyrrhizin ,Molecular Biology ,Neuropharmacology ,PI3K/AKT/mTOR pathway ,Plants, Medicinal ,Traditional medicine ,Plant Extracts ,Computational Biology ,Plants ,biology.organism_classification ,Terpenoid ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Metabolome ,Molecular Medicine ,Quercetin ,Glabridin ,Biotechnology - Abstract
Plant omics is an emerging field of systems science and offers the prospects of evidence-based evaluation of traditional herbal medicines in human diseases. To this end, the powdered root of Yashtimadhu (Glycyrrhiza glabra L.), commonly known as liquorice, is frequently used in Indian Ayurvedic medicine with an eye to neuroprotection but its target proteins, mechanisms of action, and metabolites remain to be determined. Using a metabolomics and network pharmacology approach, we identified 98,097 spectra from positive and negative polarities that matched to ∼1600 known metabolites. These metabolites belong to terpenoids, alkaloids, and flavonoids, including both novel and previously reported active metabolites such as glycyrrhizin, glabridin, liquiritin, and other terpenoid saponins. Novel metabolites were also identified such as quercetin glucosides, coumarin derivatives, beta-carotene, and asiatic acid, which were previously not reported in relation to liquorice. Metabolite-protein interaction-based network pharmacology analyses enriched 107 human proteins, which included dopamine, serotonin, and acetylcholine neurotransmitter receptors among other regulatory proteins. Pathway analysis highlighted the regulation of signaling kinases, growth factor receptors, cell cycle, and inflammatory pathways. In vitro validation confirmed the regulation of cell cycle, MAPK1/3, PI3K/AKT pathways by liquorice. The present data-driven, metabolomics and network pharmacology study paves the way for further translational clinical research on neuropharmacology of liquorice and other traditional medicines.
- Published
- 2020
36. CusVarDB: A tool for building customized sample-specific variant protein database from next-generation sequencing datasets
- Author
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Prashant Kumar Modi, Sneha M. Pinto, Arun H. Patil, Santosh Kumar Behera, Sandeep Kasaragod, T. S. Keshava Prasad, Varshasnata Mohanty, Harsha Gowda, and Ankur Tyagi
- Subjects
0301 basic medicine ,Cancer genome sequencing ,Proteomics ,Computer science ,Computational biology ,Major histocompatibility complex ,DNA sequencing ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,NGS-pipeline ,Coding region ,Humans ,030212 general & internal medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Databases, Protein ,Gene ,030304 developmental biology ,0303 health sciences ,biology ,General Immunology and Microbiology ,Software Tool Article ,Computational Biology ,High-Throughput Nucleotide Sequencing ,General Medicine ,Articles ,Variant protein database ,Pipeline (software) ,Identification (information) ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Next-generation sequencing ,Software ,Coding (social sciences) - Abstract
Cancer genome sequencing studies have revealed a number of variants in coding regions of several genes. Some of these coding variants play an important role in activating specific pathways that drive proliferation. Coding variants present on cancer cell surfaces by the major histocompatibility complex serve as neo-antigens and result in immune activation. The success of immune therapy in patients is attributed to neo-antigen load on cancer cell surfaces. However, which coding variants are expressed at the protein level can’t be predicted based on genomic data. Complementing genomic data with proteomic data can potentially reveal coding variants that are expressed at the protein level. However, identification of variant peptides using mass spectrometry data is still a challenging task due to the lack of an appropriate tool that integrates genomic and proteomic data analysis pipelines. To overcome this problem, and for the ease of the biologists, we have developed a graphical user interface (GUI)-based tool called CusVarDB. We integrated variant calling pipeline to generate sample-specific variant protein database from next-generation sequencing datasets. We validated the tool with triple negative breast cancer cell line datasets and identified 423, 408, 386 and 361 variant peptides from BT474, MDMAB157, MFM223 and HCC38 datasets, respectively.
- Published
- 2020
37. Proteomics Analysis Revealed the Importance of Inflammation-Mediated Downstream Pathways and the Protective Role of Curcumin in Bleomycin-Induced Pulmonary Fibrosis in C57BL/6 Mice
- Author
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Sindhu Priya Es, Yashodhar P. Bhandary, Jaikanth Chanderasekaran, D A B Rex, Prashant Kumar Modi, and Mahesh Manjunath Gouda
- Subjects
0301 basic medicine ,Proteomics ,Curcumin ,Pulmonary Fibrosis ,Inflammation ,Bleomycin ,Biochemistry ,Extracellular matrix ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Pulmonary fibrosis ,medicine ,Animals ,Lung ,030102 biochemistry & molecular biology ,General Chemistry ,medicine.disease ,Blot ,Mice, Inbred C57BL ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Apoptosis ,Cancer research ,Immunohistochemistry ,medicine.symptom - Abstract
Bleomycin (BLM)-induced pulmonary fibrosis is characterized by inflammation in the alveoli, subsequent deposition of extracellular matrix (ECM) and myofibroblasts, and an impaired fibrinolytic system. Here, we describe major hematological changes, the IL-17A-mediated p53-fibrinolytic pathway, and the high throughput hits of liquid chromatography-mass spectrometry (LC-MS) analysis during the progression of pulmonary fibrosis and the therapeutic potential of curcumin against disease progression. C57BL/6 mice were exposed to BLM, followed by curcumin intervention after 24 and 48 h. Mice were sacrificed after 7 days to validate the hematological parameters, molecular pathways, and proteomics. Various techniques such as western blotting, immunofluorescence, reverse transcriptase polymerase chain reaction (RT-PCR), hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry were used to validate the proposed theory. LC-MS analysis was performed using a Q-Orbitrap mass spectrometer. The Schrodinger approach was used to perform the in silico molecular docking studies. BLM-exposed mice exhibited gradual weight loss and altered lung morphology; however, these were reversed by curcumin treatment. Significant changes in the hematological parameters confirmed the severity of BLM exposure in the mice, and expression of IL-17A-mediated p53-fibrinolytic system components and alveolar epithelial cell (AEC) apoptosis further confirmed the pathophysiology of pulmonary fibrosis. Differentially expressed proteins were characterized and mapped using the proteomics approach. A strong interaction of curcumin is observed with p53, uPA, and PAI-I proteins. The key role of IL-17A-mediated inflammation in the impairment of the p53-fibrinolytic system and AEC apoptosis was confirmed during BLM-induced pulmonary fibrosis. Therapeutic efficacy of curcumin exhibited a protective role against the progression of pulmonary fibrosis, which promises potent therapeutic modality to target the IL-17A-mediated p53-fibrinolytic system during pulmonary fibrosis.
- Published
- 2020
38. Aberrant activation of neuronal cell cycle caused by dysregulation of ubiquitin ligase Itch results in neurodegeneration
- Author
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Pushkar Sharma, Prashant Kumar Modi, and Monika Chauhan
- Subjects
Genetically modified mouse ,Cancer Research ,Amyloid ,Cell death in the nervous system ,Immunology ,Hyperphosphorylation ,Mice, Transgenic ,Neuroprotection ,Article ,Mice ,Cellular and Molecular Neuroscience ,medicine ,Animals ,Humans ,lcsh:QH573-671 ,Neurons ,biology ,Ubiquitin ,lcsh:Cytology ,Chemistry ,Cell Cycle ,Neurodegeneration ,Cell Biology ,Cell cycle ,medicine.disease ,Ubiquitin ligase ,Cell biology ,Disease Models, Animal ,biology.protein ,Phosphorylation ,Neurological disorders - Abstract
It is critical for the neuronal cell cycle to remain suppressed in terminally differentiated neurons as its activation results in aberrant cell cycle re-entry that causes neuronal apoptosis (CRNA), which has been observed in several neurodegenerative disorders like Alzheimer’s disease (AD). In the present study, we report that E3 ubiquitin ligase Itch is a major regulator of CRNA and elucidated the mechanism via which it is regulated in this process. Neurotoxic amyloid peptide Aβ42-treated neurons or neurons from an AD transgenic mouse model (TgAD) exhibited aberrant activation of the JNK pathway which resulted in the hyperphosphorylation of Itch. The phosphorylation of Itch primes it for autoubiquitination, which is necessary for its activation. These post-translational modifications of Itch facilitate its interaction with TAp73 resulting in its degradation. These series of events are critical for Itch-mediated CRNA and its phosphorylation and autoubiquitination site mutants reversed this process and were neuroprotective. These studies unravel a novel pathway via which neurodegeneration in AD and possibly other related disorders may be regulated by aberrant regulation of the neuronal cell cycle.
- Published
- 2020
39. Prevention of MEK-ERK-1/2 hyper-activation underlines the neuroprotective effect of Glycyrrhiza glabra L. (Yashtimadhu) against rotenone-induced cellular and molecular aberrations
- Author
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Gayathree Karthikkeyan, Prashant Kumar Modi, Sameera Krishna Pervaje, Ravishankar Pervaje, and Thottethodi Subrahmanya Keshava Prasad
- Subjects
MAPK/ERK pathway ,Programmed cell death ,Cell Survival ,MAP Kinase Signaling System ,Apoptosis ,Pharmacology ,medicine.disease_cause ,Neuroprotection ,Models, Biological ,Mitochondrial Proteins ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Rotenone ,Drug Discovery ,medicine ,Glycyrrhiza ,Humans ,030304 developmental biology ,Mitogen-Activated Protein Kinase Kinases ,0303 health sciences ,Cell Death ,Kinase ,Plant Extracts ,Cell Cycle ,Parkinson Disease ,Cell cycle ,Enzyme Activation ,Neuroprotective Agents ,chemistry ,030220 oncology & carcinogenesis ,Caspases ,Reactive Oxygen Species ,Oxidative stress - Abstract
Ethnopharmacological relevance Yashtimadhu choorna (powder) is prepared from the dried root of Glycyrrhiza glabra L., commonly known as licorice. The Indian Ayurvedic system classifies Yashtimadhu as a Medhya Rasayana that can enhance brain function, improves memory, and possess neuroprotective functions, which can be used against neurodegenerative diseases like Parkinson's disease (PD). Aim of the study We aimed to decipher the neuroprotective effects of G. glabra L., i.e., Yashtimadhu, in a rotenone-induced PD model. Materials and methods Retinoic acid-differentiated IMR-32 cells were treated with rotenone (PD model) and Yashtimadhu, and were assessed for cellular toxicity, live-dead staining, cell cycle, oxidative stress, protein abundance, and kinase phosphorylation. Results Yashtimadhu conferred protection against rotenone-induced cytotoxicity, countered cell death, reduced expression of pro-apoptotic proteins (cleaved-caspases-9, and 3, cleaved-PARP, BAX, and BAK) and increased anti-apoptotic protein, BCL-2. Rotenone-induced cell cycle re-entry (G2/M transition), was negated by Yashtimadhu and was confirmed with PCNA levels. Yashtimadhu countered rotenone-mediated activation of mitochondrial proteins involved in oxidative stress, cytochrome-C, PDHA1, and HSP60. Inhibition of rotenone-induced ERK-1/2 hyperphosphorylation prevented activation of apoptosis, which was confirmed with MEK-inhibitor, highlighted the action of Yashtimadhu via ERK-1/2 modulation. Conclusions We provide the evidence for neuroprotection conferred by G. glabra L. (Yashtimadhu) and its mechanism via inhibiting MEK-ERK-1/2 hyper-phosphorylation, prevention of mitochondrial stress, and subsequent prevention of apoptosis. The study highlights Yashtimadhu as a promising candidate with neuroprotective effects, the potential of which can be harnessed for identifying novel therapeutic targets.
- Published
- 2020
40. Data on dose-dependent cytotoxicity of rotenone and neuroprotection conferred by Yashtimadhu (Glycyrrhiza glabra L.) in an in vitro Parkinson's disease model
- Author
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Thottethodi Subrahmanya Keshava Prasad, Ashwini Prabhu, Sameera Krishna Pervaje, Gayathree Karthikkeyan, Ravishankar Pervaje, and Prashant Kumar Modi
- Subjects
Science (General) ,Multidisciplinary ,biology ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Rotenone ,Cell cycle ,Pharmacology ,biology.organism_classification ,medicine.disease_cause ,Neuroprotection ,Q1-390 ,chemistry.chemical_compound ,Complementary and alternative medicine ,chemistry ,Apoptosis ,Toxicity ,medicine ,Glycyrrhiza ,Neurodegeneration ,Cytotoxicity ,Actionable molecules ,Ayurveda ,Oxidative stress - Abstract
The data described in this article presents the toxicity of rotenone and the neuroprotective effect of Yashtimadhu choorna (powder) in an in vitro Parkinson's disease model [1]. Yashtimadhu choorna is prepared from the roots of Glycyrrhiza glabra L., commonly known as licorice/ liquorice. The effects of rotenone and Yashtimadhu was assessed using cellular and molecular assays such as cell cytotoxicity assay, live-dead cell staining assay, cell cycle analysis, and western blotting. Protein-protein interaction was studied using ANAT plug-in in Cytoscape. Rotenone displayed time and dose-dependent toxicity, as evidenced by cell cytotoxicity assay and live-dead cell staining assay. Yashtimadhu showed no toxicity and prevented rotenone-induced toxicity. Rotenone and Yashtimadhu displayed differential control on the cell cycle. The Protein-interaction network showed the proteins interacting with ERK-1/2 and the pathways regulated by these interactions. The pathways regulated were primarily involved in cellular oxidative stress and apoptosis response. The data described here will enable the extent of cellular toxicity as a result of rotenone treatment and the neuroprotection conferred by Yashtimadhu choorna. This will enable understanding and exploring the effect of traditional and complementary medicine and aiding the identification of molecular targets to confer neuroprotection in Parkinson's disease.
- Published
- 2021
41. Antioxidant Activity and Role of Culture Condition in the Optimization of Red Pigment Production by Talaromyces purpureogenus KKP Through Response Surface Methodology
- Author
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Kishor Kumar, Keekan, Sweta, Hallur, Prashant Kumar, Modi, and Rajesh P, Shastry
- Subjects
Industrial Microbiology ,Inhibitory Concentration 50 ,Talaromyces ,Temperature ,Pigments, Biological ,Hydrogen-Ion Concentration ,Antioxidants ,Culture Media - Abstract
The red pigment production by Talaromyces purpureogenus KKP, a soil isolate, was optimized by response surface methodology (RSM) in the present study. The cultural parameters, such as pH, temperature, dextrose, and peptone concentrations, were optimized for red pigment production using the central composite design (CCD) experimental design. A second-order quadratic model was used to calculate the relationships between the values at different levels of response. The optimum values of the selected variables under coded factors are 6.0, 27 °C, 2.25%, and 1.10% for pH, temperature, dextrose, and peptone, respectively. The selected variables were most effective in the enhancement of red pigment production at optimized culture conditions. In addition to optimization, the antioxidant activity of the pigment isolated in the present study was found to be promising with IC
- Published
- 2019
42. Effect of calcium glucoheptonate on proliferation and osteogenesis of osteoblast-like cells in vitro
- Author
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Sindhu Priya Es, Punchappady-Devasya Rekha, Sudheer Shenoy P, Sahil Vazirally, Ashwini Prabhu, Aparna Hegde, Yashodhar P. Bhandary, Prashant Kumar Modi, Renjith P. Johnson, and Shankar P. Das
- Subjects
Physiology ,Peptide Hormones ,Alizarin Staining ,Ossification ,Biochemistry ,Epithelium ,Bone remodeling ,0302 clinical medicine ,Osteogenesis ,Animal Cells ,Calcium glucoheptonate ,Group-Specific Staining ,Medicine and Health Sciences ,Enzyme assays ,Osteonectin ,Osteopontin ,Colorimetric assays ,Bioassays and physiological analysis ,Cells, Cultured ,Staining ,0303 health sciences ,Multidisciplinary ,MTT assay ,biology ,Cell Staining ,Osteoblast ,Enzymes ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Osteocalcin ,293T cells ,Medicine ,Cell lines ,Bone Remodeling ,Cellular Types ,Anatomy ,Biological cultures ,medicine.drug ,Research Article ,medicine.medical_specialty ,Cell Survival ,Science ,chemistry.chemical_element ,Calcium ,Research and Analysis Methods ,Bone resorption ,Collagen Type I ,03 medical and health sciences ,Internal medicine ,Cell Line, Tumor ,medicine ,Humans ,030304 developmental biology ,Cell Proliferation ,Calcium metabolism ,Osteoblasts ,Phosphatases ,Sugar Acids ,Biology and Life Sciences ,Proteins ,Epithelial Cells ,Cell Biology ,Hormones ,Endocrinology ,HEK293 Cells ,Biological Tissue ,chemistry ,Specimen Preparation and Treatment ,Biochemical analysis ,biology.protein ,Enzymology ,Caco-2 Cells ,Physiological Processes - Abstract
Calcium is the key macromineral having a role in skeletal structure and function, muscle contraction, and neurotransmission. Bone remodeling is maintained through a constant balance between calcium resorption and deposition. Calcium deficiency is resolved through calcium supplementation, and among the supplements, water-soluble organic molecules attracted great pharmaceutical interest. Calcium glucoheptonate is a highly water-soluble organic calcium salt having clinical use; however, detailed investigations on its biological effects are limited. We assessed the effects of calcium glucoheptonate on cell viability and proliferation of osteoblast-like MG-63 cells. Calcium uptake and mineralization were evaluated using Alizarin red staining of osteoblast-like MG-63 cells treated with calcium glucoheptonate. Expression of osteogenic markers were monitored by western blotting, immunofluorescence, and qRT-PCR assays. Increased proliferation and calcium uptake were observed in the MG-63 cells treated with calcium glucoheptonate. The treatment also increased the expression of osteopontin and osteogenic genes such as collagen-1, secreted protein acidic and cysteine rich (SPARC), and osteocalcin. Calcium glucoheptonate treatment did not exert any cytotoxicity on colorectal and renal epithelial cells, indicating the safety of the treatment. This is the first report with evidence for its beneficial effect for pharmaceutical use in addressing calcium deficiency conditions.
- Published
- 2019
43. Curcumin Suppresses the Alveolar Inflammation and Modulates the p53-Fibrinolytic System and Epithelial to Mesenchymal Transition During Lung Injury and Fibrosis In Vitro and In Vivo
- Author
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Mohd Altaf Najar, Sadiya Bi Shaikh, P. Subba, Prashant Kumar Modi, M. Manjunath Gouda, Ashwini Prabhu, and Y. Prabhakar Bhandary
- Subjects
business.industry ,Inflammation ,Lung injury ,medicine.disease ,In vitro ,chemistry.chemical_compound ,chemistry ,Fibrosis ,In vivo ,Cancer research ,Curcumin ,Medicine ,Epithelial–mesenchymal transition ,medicine.symptom ,business - Published
- 2019
44. Interplay between MEK-ERK signaling, cyclin D1, and cyclin-dependent kinase 5 regulates cell cycle reentry and apoptosis of neurons
- Author
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Prashant Kumar Modi, Narayana Komaravelli, Neha Singh, and Pushkar Sharma
- Subjects
MAPK/ERK pathway ,Programmed cell death ,MAP Kinase Signaling System ,Blotting, Western ,Cyclin A ,Apoptosis ,Cell Cycle Proteins ,Biology ,PC12 Cells ,Rats, Sprague-Dawley ,Cyclin D1 ,Nitriles ,Butadienes ,Animals ,Humans ,Extracellular Signal-Regulated MAP Kinases ,Cell Cycle Protein ,Molecular Biology ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Neurons ,Amyloid beta-Peptides ,Kinase ,Cyclin-dependent kinase 5 ,Cell Cycle ,Cyclin-Dependent Kinase 5 ,Articles ,Cell Biology ,Cell cycle ,Signaling ,Peptide Fragments ,Rats ,Cell biology ,HEK293 Cells ,Microscopy, Fluorescence ,nervous system ,biology.protein ,RNA Interference ,Mitogen-Activated Protein Kinases - Abstract
A novel mechanism is described by which neurons reenter the cell cycle, which leads to their apoptosis: β-amyloid peptide activates the MEK-ERK pathway aberrantly, resulting in expression of cyclin D1 and cell death. Cyclin D1, in turn, prevents the activation of neuronal CDK5, which is important for neuronal survival., In response to neurotoxic signals, postmitotic neurons make attempts to reenter the cell cycle, which results in their death. Although several cell cycle proteins have been implicated in cell cycle–related neuronal apoptosis (CRNA), the molecular mechanisms that underlie this important event are poorly understood. Here, we demonstrate that neurotoxic agents such as β-amyloid peptide cause aberrant activation of mitogen-activated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) signaling, which promotes the entry of neurons into the cell cycle, resulting in their apoptosis. The MEK-ERK pathway regulates CRNA by elevating the levels of cyclin D1. The increase in cyclin D1 attenuates the activation of cyclin-dependent kinase 5 (cdk5) by its neuronal activator p35. The inhibition of p35-cdk5 activity results in enhanced MEK-ERK signaling, leading to CRNA. These studies highlight how neurotoxic signals reprogram and alter the neuronal signaling machinery to promote their entry into the cell cycle, which eventually leads to neuronal cell death.
- Published
- 2012
45. Age-dependent Expression of S100β in the Brain of Mice
- Author
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M.S. Kanungo and Prashant Kumar Modi
- Subjects
Male ,Aging ,Cerebellum ,medicine.medical_specialty ,Neurite ,Blotting, Western ,S100 Calcium Binding Protein beta Subunit ,Biology ,Mice ,Cellular and Molecular Neuroscience ,Neurotrophic factors ,Calcium-binding protein ,Internal medicine ,medicine ,Animals ,Nerve Growth Factors ,Cerebral Cortex ,Reverse Transcriptase Polymerase Chain Reaction ,S100 Proteins ,Brain ,Gene Expression Regulation, Developmental ,Long-term potentiation ,Cell Biology ,General Medicine ,medicine.anatomical_structure ,Nerve growth factor ,Endocrinology ,Cerebral cortex ,Neuroscience - Abstract
S100beta is a soluble calcium binding protein released by glial cells. It has been reported as a neurotrophic factor that promotes neurite maturation and outgrowth during development. This protein also plays a role in axonal stability and in long term potentiation in the adult brain. The ability of S100beta to modulate neuronal morphology raises the important question whether there is an age-related difference in the expression of S100beta in the cerebral and cerebellar cortices of AKR strain mice and is this change is region specific. Our RT-PCR and Western blotting experiments show that the expression of S100beta gene in the cerebral and cerebellar cortices starts from 0 day, peaks at about 45 days. However, in 70-week old mice its expression is significantly up-regulated as compared to that of 20-week old mice. S100beta follows the same age-related pattern in both cerebral and cerebellar cortices. These results suggest that S100beta is important for brain development and establishment of proper brain functions. Up-regulation of S100beta in old age may have some role in development of age-related pathological systems in the brain.
- Published
- 2010
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