Publications by authors named "K Prabhu"

384 Publications

Clinical Profile and Mutations Associated with Multiple Endocrine Neoplasia-Type1 (MEN1) and Their First-Degree Relatives at Risk of Developing MEN1: A Prospective Study.

Horm Metab Res 2021 Apr 14;53(4):245-256. Epub 2021 Apr 14.

Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India.

Multiple Endocrine Neoplasia type-1 (MEN1) is an autosomal dominant disorder with a combined occurrence of tumours of parathyroid glands, pancreatic islets, and anterior pituitary. About 90% of these patients carry mutations in the MEN1 gene, though the spectrum is not well defined in India. Forty clinically suspected cases of MEN1 were enrolled prospectively over six years; 32 patients (23 index-cases and nine affected relatives) with≥2 classical endocrine tumours of MEN1 were considered definite, and eight were categorised as 'MEN1-like'. Details of their clinical presentation, treatment and mutational analysis including MEN1 gene, 3' and 5' untranslated regions (UTR) of MEN1, CDKN1B, and CaSR genes were collated. Asymptomatic first-degree relatives were also screened. Among the 32 definite MEN1 patients, all had primary hyperparathyroidism, 22 (68.7%) had gastroentero-pancreatic neuroendocrine tumours, and 21 (66%) had pituitary adenoma. Of the 23 definite index-cases, 13 (56.5%) carried mutations in the MEN1 gene. Five of nine affected first-degree relatives (55.5%), and four of 10 asymptomatic relatives (40%) also had MEN1 mutations. Seven of 10 MEN1 mutation-negative definite index-cases harboured p.V109G polymorphism in the CDKN1B gene. All eight MEN1-like cases were negative for mutations and large deletions in MEN1, mutations in 3' and 5' UTR of MEN1, CaSR and CDKN1B genes. The study has helped to clearly document the pattern of mutations among Indian MEN1 patients. However, the absence of MEN1 mutation in ~44% of cases and the presence of p.V109G polymorphism in CDKN1B gene raise the question whether such polymorphisms could independently contribute to pathogenesis.
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http://dx.doi.org/10.1055/a-1402-0183DOI Listing
April 2021

Adventitious root cultures of Decalepis salicifolia for the production of 2-hydroxy-4-methoxybenzaldehyde, a vanillin isomer flavor metabolite.

Appl Microbiol Biotechnol 2021 Apr 7;105(8):3087-3099. Epub 2021 Apr 7.

Plant Biology and Systematics, CSIR-Central Institute of Medicinal and Aromatic Plants, Research Centre, Bengaluru, 560065, India.

Decalepis salicifolia (Bedd. ex. Hook.f.) Venter is a potential natural source of the vanillin isomer, 2-hydroxy-4-methoxybenzaldehyde (2H4MB), an aromatic compound. However, the utilization of the plant is hindered especially due to its critically endangered status and the root-specific accumulation of the compound. The use of in vitro culture techniques offers a sustainable means for the production of valuable metabolites. In this study, an efficient system was established for the production of 2H4MB in the adventitious root cultures of D. salicifolia. Leaf explants of in vitro grown plants produced on an average 4.33 ± 2.07 number of roots with root initiation frequency of 95.69 ± 3.74% in woody plant medium supplemented with 0.5 mg/L α-naphthalene acetic acid (NAA) and 1.0 mg/L kinetin (Kn). The adventitious root biomass accumulation of 10.61 ± 0.89 g fresh weight (FW) was obtained in woody plant liquid media containing 0.5 mg/L NAA and 0.3 mg/L indole-3-butyric acid (IBA) in 60 days of inoculation. Field-grown plants of the same age produced 0.30 ± 0.02 g FW, which was 35-fold lower than the adventitious root culture. The total production of 2H4MB in the same growth period was 4.9-fold higher in adventitious root culture (139.54 μg) as compared to field-grown plants (28.62 μg). Furthermore, sucrose concentration of 2% was favorable for biomass accumulation, whereas 5% was favorable for 2H4MB production. On the other hand, media pH 5.0 was suitable for biomass production and pH 7.0 was best suited for accumulation of 2H4MB. The adventitious roots also showed stable production of biomass and 2H4MB over 2 years. The established adventitious root culture system is suitable for further large-scale production of 2H4MB for flavor and fragrance industrial applications. KEY POINTS: • Biomass accumulation was higher in adventitious root cultures than in field-grown plants. • Manipulation of sucrose concentration and media pH led to increased 2H4MB production. • Adventitious roots showed stable biomass and 2H4MB production over 2 years.
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http://dx.doi.org/10.1007/s00253-021-11262-6DOI Listing
April 2021

Dual Role of the Rhodium(III) Catalyst in C-H Activation: [4 + 3] Annulation of Amide with Allylic Alcohols to 7-Membered Lactams.

J Org Chem 2021 Mar 9;86(6):4625-4637. Epub 2021 Mar 9.

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.

[4 + 3] annulation of primary and secondary benzamide and cinnamamide derivatives using allyl alcohol as a coupling partner catalyzed by Rh(III) is reported, where Rh(III) is playing a dual role of an oxidant and a catalyst for C-H activation. The Rh-catalyst oxidizes allyl alcohol to its carbonyl derivative, and the in situ-generated carbonyl compound reacts with benzamide in the presence of the Rh-catalyst, forming the corresponding alkylated products. Mechanistic studies show that AgSbF is also playing a dual role. Apart from being a halide scavenger, AgSbF catalyzes the cyclization of the alkylated product, forming the desired lactam. The current method has good synthetic application and is useful for synthesizing a few biologically active compounds that can act as the dopamine D receptor ligand, including berberine-like analogues. The deuteration study and control experiments helped us to propose the mechanism.
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http://dx.doi.org/10.1021/acs.joc.1c00048DOI Listing
March 2021

One-month long foundation course for newly joined Indian medical undergraduates: Faculty and students' perspective.

Med J Armed Forces India 2021 Feb 2;77(Suppl 1):S146-S156. Epub 2021 Feb 2.

Professor (Anatomy), Kasturba Medical College Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India.

Background: A one-month long foundation course has been introduced at the entry-level for first-year MBBS (Bachelor of Medicine and Bachelor of Surgery) students in the medical institutions across India from 2019. Therefore, the present study is aimed at describing the experience of implementing a one-month long foundation course conducted for the Competency-based Undergraduate Medical Curriculum (CBUC) of Indian Medical Graduate as per the guidelines from the National Medical Commission (NMC) (erstwhile Medical Council of India, MCI). We have evaluated the student and faculty perceptions towards the effectiveness of the program.

Methods: The foundation course had six modules Orientation, Skills, Field visit to Community Health Centre, Professional Development including Ethics, Sports and Extracurricular activities, Computer Skills, and Language enhancement program. Regular feedback wascollected from students (N = 250) and teachers (N = 26) involved in the Foundation course using a semi-structured questionnaire. The program's overall feedback was also obtained at the end of the course, using a validated questionnaire. The quantitative findings were expressed in frequency and percentage. The qualitative observations (reflections of students and faculty) were subjected to thematic.

Results: The students and faculty appreciated the one-month long foundation course. The course's defined objectives were met as indicated by most students (98.4%) and faculty (75%). The course seemed to be useful for students to embark on a formal MBBS curriculum. It also exposed them to new knowledge and practices, as indicated by the feedback. Thematic analysis of the students' and faculty's reflections was carried out and two themes were identified, i.e., 'strengths' and 'challenges.' The Foundation Course Committee will work out appropriate remedial measures to overcome the challenges in the future sessions for subsequent batches.

Conclusions: The one-month-long foundation course was found to be beneficial for newly joined students to get introduced and adjusted to higher education systems' demands. Also, the challenges faced during the program needs to be addressed with suitable remedial measures while implementing for subsequent batches. This effort will ensure a smooth conduct of the foundation course for the future batches of medical undergraduates and make the program more effective.
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http://dx.doi.org/10.1016/j.mjafi.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873752PMC
February 2021

Selenium-dependent metabolic reprogramming during inflammation and resolution.

J Biol Chem 2021 Feb 10:100410. Epub 2021 Feb 10.

Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address:

Trace element selenium (Se) is incorporated as the 21 amino acid, selenocysteine (Sec), into selenoproteins through tRNA. Selenoproteins act as gatekeepers of redox homeostasis and modulate immune function to effect anti-inflammation and resolution. However, mechanistic underpinnings involving metabolic reprogramming during inflammation and resolution remain poorly understood. Bacterial endotoxin lipopolysaccharide (LPS) activation of murine bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of Se (as selenite) was used to examine temporal changes in the proteome and metabolome by multiplexed tandem mass tag-quantitative proteomics, metabolomics, and machine-learning approaches. Kinetic deltagram and clustering analysis indicated addition of Se led to extensive reprogramming of cellular metabolism upon stimulation with LPS enhancing PPP, TCA cycle, and OXPHOS, to aid in the phenotypic transition towards alternatively activated macrophages, synonymous with resolution of inflammation. Remodeling of metabolic pathways and consequent metabolic adaptation towards pro-resolving phenotypes began with Se treatment at 0 h and became most prominent around 8 h post LPS stimulation that included succinate dehydrogenase complex (Sdh), pyruvate kinase (Pkm), and Sedoheptulokinase (Shpk). Se-dependent modulation of these pathways predisposed BMDMs to preferentially increase OXPHOS to efficiently regulate inflammation and its timely resolution. Use of macrophages lacking selenoproteins, indicated that all three metabolic nodes were sensitive to selenoproteome expression. Furthermore, inhibition of Sdh with dimethylmalonate affected the pro-resolving effects of Se by increasing the resolution interval in a murine peritonitis model. In summary, our studies provide novel insights into the role of cellular Se via metabolic reprograming to facilitate anti-inflammation and pro-resolution.
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http://dx.doi.org/10.1016/j.jbc.2021.100410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966868PMC
February 2021

Interventional cardiologists' perceptions of percutaneous coronary intervention quality measurement and feedback.

Am Heart J 2021 Feb 7;235:97-103. Epub 2021 Feb 7.

University of Washington, Seattle, WA; VA Puget Sound Health Care System, Seattle, WA. Electronic address:

Background: Interventional cardiologists receive feedback on their clinical care from a variety of sources including registry-based quality measures, case conferences, and informal peer interactions. However, the impact of this feedback on clinical care is unclear.

Methods: We interviewed interventional cardiologists regarding the use of feedback to improve their care of percutaneous coronary intervention (PCI) patients. Interviews were assessed with template analysis using deductive and inductive techniques.

Results: Among 20 interventional cardiologists from private, academic, and Department of Veterans Affairs practice, 85% were male, 75% performed at least 100 PCIs annually, and 55% were in practice for 5 years or more. All reported receiving feedback on their practice, including formal quality measures and peer learning activities. Many respondents were critical of quality measure reporting, citing lack of trust in outcomes measures and poor applicability to clinical care. Some respondents reported the use of process measures such as contrast volume and fluoroscopy time for benchmarking their performance. Case conferences and informal peer feedback were perceived as timelier and more impactful on clinical care. Respondents identified facilitators of successful feedback interventions including transparent processes, respectful and reciprocal peer relationships, and integration of feedback into collective goals. Hierarchy and competitive environments inhibited useful feedback.

Conclusions: Despite substantial resources dedicated to performance measurement and feedback for PCI, interventional cardiologists perceive existing quality measures to be of only modest value for improving clinical care. Catherization laboratories should seek to integrate quality measures into a holistic quality program that emphasizes peer learning, collective goals and mutual respect.
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http://dx.doi.org/10.1016/j.ahj.2021.01.019DOI Listing
February 2021

Development of a Unique Mouse Intervertebral Disc Degeneration Model Using a Simple Novel Tool.

Asian Spine J 2020 Dec 28. Epub 2020 Dec 28.

Department of Neurological Sciences, Christian Medical College, Vellore, India.

Study Design: Animal case control study.

Purpose: To create a simple, reproducible disc degeneration model for mouse coccygeal vertebrae.

Overview Of Literature: Back pain due to disc degeneration is probably the most common problem encountered in neurosurgical practice. An easily reproducible animal model for disc degeneration will help in understanding its pathophysiology, and serve as a platform for examining various therapeutic options.

Methods: A total of 18 mice were divided into injured (n=12) and non-injured (n=6) groups. The disc height index (DHI%) at coccygeal 4-5 level was measured by computed tomography (CT) scan for all mice. Coccygeal 4-5 discs of the injury group were injured using a 32G needle fixed to a novel tool and confirmed by CT. The non-injury group underwent no procedure. DHI% was measured by CT at 2-, 4-, and 6-week post-injury, and all mice tails were sectioned for histopathology grading of disc degeneration at the respective time intervals.

Results: The injured group showed significant variation in DHI% at 2, 4, and 6 weeks, whereas there was no change in the noninjured group. Histopathologic evaluation with Safranin O stain showed a worsening of the disc degeneration score at 2, 4, and 6 weeks in the injured group, but in the non-injured group there was no change. Percutaneous needle injury technique with our novel tool provided 100% accuracy and uniform degeneration.

Conclusions: A simple, easily reproducible mouse model for disc degeneration was created using a simple, cost-effective, novel tool and technique, its advantage being high precision and user friendly.
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http://dx.doi.org/10.31616/asj.2020.0366DOI Listing
December 2020

Mapping genomic regions of moisture deficit stress tolerance using backcross inbred lines in wheat (Triticum aestivum L.).

Sci Rep 2020 12 10;10(1):21646. Epub 2020 Dec 10.

PPV & FR Authority NAAS Complex, New Delhi, 110012, India.

Identification of markers associated with major physiological and yield component traits under moisture deficit stress conditions in preferred donor lines paves the way for marker-assisted selection (MAS). In the present study, a set of 183 backcross inbred lines (BILs) derived from the cross HD2733/2*C306 were genotyped using 35K Axiom genotyping array and SSR markers. The multi-trait, multi-location field phenotyping of BILs was done at three locations covering two major wheat growing zones of India, north-western plains zone (NWPZ) and central zone (CZ) under varying moisture regimes. A linkage map was constructed using 705 SNPs and 86 SSR polymorphic markers. A total of 43 genomic regions and QTL × QTL epistatic interactions were identified for 14 physiological and yield component traits, including NDVI, chlorophyll content, CT, CL, PH, GWPS, TGW and GY. Chromosomes 2A, 5D, 5A and 4B harbors greater number of QTLs for these traits. Seven Stable QTLs were identified across environment for DH (QDh.iari_6D), GWPS (QGWPS.iari_5B), PH (QPh.iari_4B-2, QPh.iari_4B-3) and NDVI (QNdvi1.iari_5D, QNdvi3.iari_5A). Nine genomic regions identified carrying major QTLs for CL, NDVI, RWC, FLA, PH, TGW and biomass explaining 10.32-28.35% of the phenotypic variance. The co-segregation of QTLs of physiological traits with yield component traits indicate the pleiotropic effects and their usefulness in the breeding programme. Our findings will be useful in dissecting genetic nature and marker-assisted selection for moisture deficit stress tolerance in wheat.
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http://dx.doi.org/10.1038/s41598-020-78671-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729395PMC
December 2020

Exosomes: Emerging Diagnostic and Therapeutic Targets in Cutaneous Diseases.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Skin is the largest human organ and is continuously exposed to various exogenous and endogenous trigger factors affecting body homeostasis. A number of mechanisms, including genetic, inflammatory and autoimmune ones, have been implicated in the pathogenesis of cutaneous diseases. Recently, there has been considerable interest in the role that extracellular vesicles, particularly exosomes, play in human diseases, through their modulation of multiple signaling pathways. Exosomes are nano-sized vesicles secreted by all cell types. They function as cargo carriers shuttling proteins, nucleic acids, lipids etc., thus impacting the cell-cell communications and transfer of vital information/moieties critical for skin homeostasis and disease pathogenesis. This review summarizes the available knowledge on how exosomes affect pathogenesis of cutaneous diseases, and highlights their potential as future targets for the therapy of various skin diseases.
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http://dx.doi.org/10.3390/ijms21239264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730213PMC
December 2020

Visible light-mediated ipso-annulation of activated alkynes: access to 3-alkylated spiro[4,5]-trienones, thiaspiro[4,5]-trienones and azaspiro[4,5]-trienones.

Chem Commun (Camb) 2020 Nov 5;56(86):13165-13168. Epub 2020 Oct 5.

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.

A novel method for chemoselective difunctionalization of activated alkynes for synthesizing 3-alkylated spiro[4,5]-trienones, thiaspiro[4,5]-trienones and spirolactams has been uncovered using photoredox catalysis under visible light conditions. The rarely used tricarbonyl compounds in photoredox catalysis were used as the alkylating source. A remarkable functional group tolerance was observed, and the application of the method has been showcased by transforming tricarbonylated spirolactams to their corresponding monocarbonylated products, which are difficult to access using traditional methods.
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http://dx.doi.org/10.1039/d0cc01217cDOI Listing
November 2020

Age-Dependent Reduction in Severity and Discrete Topographical Patterns in Rasmussen Encephalitis: A Link to Cortical Maturation?

Pediatr Neurol 2020 11 11;112:25-33. Epub 2020 Aug 11.

Professor of Neuropathology and Head, General Pathology, Department of General Pathology, Christian Medical College, Vellore, India.

Background: Autopsy studies in Rasmussen encephalitis reveal areas of sparing within the affected hemisphere. Clinical progression and inflammation are milder with an older onset. We sought to demonstrate radiological corroboration for these patterns.

Methods: In our retrospective study, 38 cases were dichotomized into severe pan-hemispheric (all lobes involved) and sub-hemispheric groups (others) to identify age demographics and other severity predictors. The extent and patterns of radiological pathology in the cortex and subcortical structures were assessed by structured visual grading. Relevant clinical data were also reported.

Results: Children with pan-hemispheric involvement were younger at onset (P < 0.001) and were more likely to present with status epilepticus (odds ratio 8.5, 95% confidence interval 1.5 to 50.0, P = 0.022). A history of perinatal asphyxia/hospitalization (P < 0.001) and delayed milestones (P = 0.013) were encountered exclusively in this group, and progression to a low-amplitude record background on electroencephalography, suggesting that cortical damage was identified frequently (P = 0.038, odds ratio = 5.7, 95% confidence interval 1.3 to 25.0). Visual grading revealed significant differences among both cortical (P < 0.001) and subcortical (P < 0.001) regions. On multivariate analysis, the odds for pan-hemispheric disease decreased per year of age at onset (P = 0.022, odds ratio 0.51, 95% confidence interval 0.085 to 0.725). Epilepsy surgery (n = 14) was associated with Engel Class 1 seizure control (P < 0.001). Immunosuppressive therapy (n = 20) did not demonstrate a significant seizure remission (P = 0.157, odds ratio 0.39, 95% confidence interval 0.10 to 1.55).

Conclusions: Our case series confirms the presence of specific topographical patterns of macroscopic radiological pathology over the affected hemisphere with a marked age-associated reduction in the odds for severe pan-hemispheric disease.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.07.016DOI Listing
November 2020

Epigenetic and breast cancer therapy: Promising diagnostic and therapeutic applications.

Semin Cancer Biol 2020 Aug 25. Epub 2020 Aug 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar. Electronic address:

The global burden of breast cancer (BC) is increasing significantly. This trend is caused by several factors such as late diagnosis, limited treatment options for certain BC subtypes, drug resistance which all lead to poor clinical outcomes. Recent research has reported the role of epigenetic alterations in the mechanism of BC pathogenesis and its hallmarks include drug resistance and stemness features. The understanding of these modifications and their significance in the management of BC carcinogenesis is challenging and requires further attention. Nevertheless, it promises to provide novel insight needed for utilizing these alterations as potential diagnostic, prognostic markers, predict treatment efficacy, as well as therapeutic agents. This highlights the importance of continuing research development to further advance the existing knowledge on epigenetics and BC carcinogenesis to overcome the current challenges. Hence, this review aims to shed light and discuss the current state of epigenetics research in the diagnosis and management of BC.
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http://dx.doi.org/10.1016/j.semcancer.2020.08.009DOI Listing
August 2020

The Essential Role of Selenoproteins in the Resolution of -Induced Intestinal Inflammation.

Front Nutr 2020 8;7:96. Epub 2020 Jul 8.

Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, State College, PA, United States.

Enteropathogenic (EPEC) leads to adverse colonic inflammation associated with poor resolution of inflammation and loss of epithelial integrity. Micronutrient trace element selenium (Se) is incorporated into selenoproteins as the 21st amino acid, selenocysteine (Sec). Previous studies have shown that such an incorporation of Sec into the selenoproteome is key for the anti-inflammatory functions of Se in macrophages and other immune cells. An intriguing mechanism underlying the anti-inflammatory and pro-resolving effects of Se stems from the ability of selenoproteins to skew arachidonic acid metabolism from pro-inflammatory mediators, prostaglandin E (PGE) toward anti-inflammatory mediators derived from PGD, such as 15-deoxy-Δ- prostaglandin J (15d-PGJ), via eicosanoid class switching of bioactive lipids. The impact of Se and such an eicosanoid-class switching mechanism was tested in an enteric infection model of gut inflammation by , a murine equivalent of EPEC. C57BL/6 mice deficient in Se (Se-D) experienced higher mortality when compared to those on Se adequate (0.08 ppm Se) and Se supplemented (0.4 ppm Se) diets following infection. Decreased survival was associated with decreased group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) cells in colonic lamina propria of Se-D mice along with deceased expression of epithelial barrier protein Zo-1. Inhibition of metabolic inactivation of PGE by 15-prostaglandin dehydrogenase blocked the Se-dependent increase in ILC3 and Th17 cells in addition to reducing epithelial barrier integrity, as seen by increased systemic levels of FITC-dextran following oral administration; while 15d-PGJ administration in Se-D mice alleviated the effects by increasing ILC3 and Th17 cells. Mice lacking selenoproteins in monocyte/macrophages via the conditional deletion of the tRNA showed increased mortality post infection. Our studies indicate a crucial role for dietary Se in the protection against inflammation following enteric infection via immune mechanisms involving epithelial barrier integrity.
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http://dx.doi.org/10.3389/fnut.2020.00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381334PMC
July 2020

Neuroimaging of pediatric infratentorial tumors and the value of diffusion-weighted imaging (DWI) in determining tumor grade.

Acta Radiol 2021 Apr 15;62(4):533-540. Epub 2020 Jun 15.

Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India.

Background: Diffusion-weighted imaging (DWI) provides information about the cellular density of tumors. This feature is useful in grading and identifying different tumor types.

Purpose: To assess the value of diffusion restriction and apparent diffusion coefficient (ADC) values in differentiating pediatric infratentorial tumors.

Material And Methods: This was a retrospective review of the magnetic resonance imaging (MRI) of 82 children (age range 1-16 years) with infratentorial tumors. Histopathological grading after surgical excision/biopsy was categorized as low grade (WHO grades I and II) (n = 31; 29 pilocytic astrocytomas, 2 ependymomas) and high grade (WHO grade III and IV) (n = 51; 40 medulloblastomas, 8 anaplastic ependymomas, 1 anaplastic astrocytoma, 2 atypical rhabdoid teratoid tumors [ATRT]). MRI features and ADC values were compared among tumor types and grades using a two-tailed t test, Mann-Whitney U test for continuous data and Chi-square test for categorical variables.

Results: Diffusion restriction and low ADC value was a feature of high-grade tumors (<0.001). The mean ADC values of the low-grade and high-grade tumors were 1.567 × 10mm/s and 0.661 × 10mm/s, respectively. Using 0.9 × 10mm/s as the cut-off value, the sensitivity, specificity, positive and negative predictive values for differentiating the grades was 87%, 100%, 100%, and 81.8%, respectively. Significant differences were found between the mean ADC values of the individual tumor types (<0.05), except between medulloblastoma and ATRT.

Conclusion: ADC values and visual assessment of diffusion restriction are useful in tumor grading. The individual tumor types can be identified by an algorithmic approach, using DWI in conjunction with other described MRI features.
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http://dx.doi.org/10.1177/0284185120933219DOI Listing
April 2021

Plasma angiogenesis and oxidative stress markers in patients with diabetic retinopathy.

Biomarkers 2020 Jul 12;25(5):397-401. Epub 2020 Jun 12.

Department of Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India.

Neovascularization in the retina and hyperglycaemia-induced oxidative stress are implicated in the pathogenesis of diabetic retinopathy (DR). In this study, we hypothesized that the plasma angiogenic and oxidative stress markers associated with these derangements could aid in the screening of diabetic patients who are at an increased risk of developing retinopathy. This study included normal ( = 148), type2 diabetes without retinopathy (DNR;  = 148), proliferative DR (PDR;  = 74) and non-PDR (NPDR;  = 148) subjects. Plasma concentrations of vascular endothelial growth factor-A (VEGF-A), hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), pigment epithelium-derived factor (PEDF), nitric oxide (NO), soluble receptors for advanced glycation end products (sRAGE), malondialdehyde (MDA) and protein thiols were estimated. A statistically significant increase was observed in the plasma concentrations of pro-angiogenic factors and markers of oxidative stress in both retinopathy groups. By contrast, the concentrations of anti-angiogenic factors and antioxidants were decreased significantly in these groups. Receiver operating characteristic analysis indicated that the plasma thresholds of HIF-1α and PEDF can be suitable markers in case of NPDR. However, in PDR, HIF-1α, NO, MMP-9 and PEDF showed high sensitivity and specificity. The factors associated with hypoxia, matrix degradation and angiogenic inhibition play a crucial role in predicting DR.
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http://dx.doi.org/10.1080/1354750X.2020.1774654DOI Listing
July 2020

Solar energy storage in a CsAgBiBr halide double perovskite photoelectrochemical cell.

Chem Commun (Camb) 2020 Jul 1;56(53):7329-7332. Epub 2020 Jun 1.

Department of Chemical Engineering, Indian Institute of Technology Madras, Adyar, Chennai 600036, Tamil Nadu, India.

Storing solar energy using a stable visible light absorbing CsAgBiBr double perovskite is achieved using a photoelectrochemical (PEC) device with cobalt complexes and methyl viologen redox mediators. Under illumination, a potential gain of nearly 500 mV is achieved for charging. The charge-discharge cycling was carried out, and using in situ emission and FTIR studies, the self-discharge and solvent crossover were investigated.
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http://dx.doi.org/10.1039/d0cc02743jDOI Listing
July 2020

Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation.

Blood 2020 07;136(2):235-246

Graduate Program in Molecular, Cellular, and Integrative Biosciences, Huck Institutes of the Life Sciences.

Anemic stress induces stress erythropoiesis, which rapidly generates new erythrocytes to restore tissue oxygenation. Stress erythropoiesis is best understood in mice where it is extramedullary and occurs primarily in the spleen. However, both human and mouse stress erythropoiesis use signals and progenitor cells that are distinct from steady-state erythropoiesis. Immature stress erythroid progenitors (SEPs) are derived from short-term hematopoietic stem cells. Although the SEPs are capable of self-renewal, they are erythroid restricted. Inflammation and anemic stress induce the rapid proliferation of SEPs, but they do not differentiate until serum erythropoietin (Epo) levels increase. Here we show that rather than directly regulating SEPs, Epo promotes this transition from proliferation to differentiation by acting on macrophages in the splenic niche. During the proliferative stage, macrophages produce canonical Wnt ligands that promote proliferation and inhibit differentiation. Epo/Stat5-dependent signaling induces the production of bioactive lipid mediators in macrophages. Increased production of prostaglandin J2 (PGJ2) activates peroxisome proliferator-activated receptor γ (PPARγ)-dependent repression of Wnt expression, whereas increased production of prostaglandin E2 (PGE2) promotes the differentiation of SEPs.
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http://dx.doi.org/10.1182/blood.2019003480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357191PMC
July 2020

Sulfoxonium-Ylide-Directed C-H Activation and Tandem (4 + 1) Annulation.

Org Lett 2020 04 31;22(8):2878-2882. Epub 2020 Mar 31.

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India.

Rh(III)-catalyzed C-H activation and cyclization of sulfoxonium ylide with acrylates leads to an efficient synthesis of indanone derivatives. The reaction proceeds under mild and external metal-oxidant-free conditions. The sulfoxonium ylide acts as a traceless directing group as well as an internal oxidant. (4 + 1) Annulation after C-H activation leads to the formation of a carbocyclic ring, and the byproduct obtained is DMSO, which can be easily separated.
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http://dx.doi.org/10.1021/acs.orglett.0c00451DOI Listing
April 2020

Weak Coordinating Carbonyl-Directed Rhodium(III)-Catalyzed C-H Activation at the C4-Position of Indole with Allyl Alcohols.

J Org Chem 2020 04 31;85(8):5516-5524. Epub 2020 Mar 31.

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.

A weakly coordinating carbonyl-directed coupling of allyl alcohols at the C-4 position of indole derivatives under the C-H activation conditions catalyzed by Rh(III) is reported. This results in alkylation at the C-4 position of indole derivatives exclusively. The obtained product forms a tricyclic derivative under aldol reaction conditions, which can be a potential precursor for synthesizing a few alkaloid molecules such as ergot, hapalindole alkaloids, and related heterocyclic compounds.
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http://dx.doi.org/10.1021/acs.joc.0c00277DOI Listing
April 2020

Sanguinarine Induces Apoptosis in Papillary Thyroid Cancer Cells via Generation of Reactive Oxygen Species.

Molecules 2020 Mar 9;25(5). Epub 2020 Mar 9.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Sanguinarine (SNG), a natural compound with an array of pharmacological activities, has promising therapeutic potential against a number of pathological conditions, including malignancies. In the present study, we have investigated the antiproliferative potential of SNG against two well-characterized papillary thyroid cancer (PTC) cell lines, BCPAP and TPC-1. SNG significantly inhibited cell proliferation of PTC cells in a dose and time-dependent manner. Western blot analysis revealed that SNG markedly attenuated deregulated expression of p-STAT3, without affecting total STAT3, and inhibited growth of PTC via activation of apoptotic and autophagy signaling cascade, as SNG treatment of PTC cells led to the activation of caspase-3 and caspase-8; cleavage of PARP and activation of autophagy markers. Further, SNG-mediated anticancer effects in PTC cells involved the generation of reactive oxygen species (ROS) as N-acetyl cysteine (NAC), an inhibitor of ROS, prevented SNG-mediated antiproliferative, apoptosis and autophagy inducing action. Interestingly, SNG also sensitized PTC cells to chemotherapeutic drug cisplatin, which was inhibited by NAC. Finally, SNG suppressed the growth of PTC thyrospheres and downregulated stemness markers ALDH2 and SOX2. Altogether, the findings of the current study suggest that SNG has anticancer potential against PTC cells as well its derived cancer stem-like cells, most likely via inactivation of STAT3 and its associated signaling molecules.
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http://dx.doi.org/10.3390/molecules25051229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179475PMC
March 2020

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance.

Mol Cancer 2020 03 12;19(1):57. Epub 2020 Mar 12.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.

Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets.
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http://dx.doi.org/10.1186/s12943-020-01175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069174PMC
March 2020

Non-Coding RNAs as Regulators and Markers for Targeting of Breast Cancer and Cancer Stem Cells.

Cancers (Basel) 2020 Feb 4;12(2). Epub 2020 Feb 4.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a product generated from erroneous transcription. Even though understanding of biological and molecular functions of noncoding RNA remains enigmatic, researchers have established the pivotal role of these RNAs in governing a plethora of biological phenomena that includes cancer-associated cellular processes such as proliferation, invasion, migration, apoptosis, and stemness. In addition to this, the transmission of microRNAs and long non-coding RNAs was identified as a source of communication to breast cancer cells either locally or systemically. The present review provides in-depth information with an aim at discovering the fundamental potential of non-coding RNAs, by providing knowledge of biogenesis and functional roles of micro RNA and long non-coding RNAs in breast cancer and breast cancer stem cells, as either oncogenic drivers or tumor suppressors. Furthermore, non-coding RNAs and their potential role as diagnostic and therapeutic moieties have also been summarized.
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http://dx.doi.org/10.3390/cancers12020351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072613PMC
February 2020

Large-scale stage-specific regulation of gene expression during host-pathogen interactions in CSP44 bread wheat carrying APR gene Lr48.

Funct Plant Biol 2020 02;47(3):203-225

Division of Genetics, ICAR-Indian Agricultural Research Institute, New Delhi 110012, India; and Protection of Plant Varieties and Farmers' Rights Authority, Govt. of India, Ministry of Agriculture & Farmers Welfare, New Delhi 110012 (India).

Genome-wide transcriptome analysis was undertaken in a leaf-rust resistant bread wheat line CSP44 (selected from Australian cv. Condor) carrying the adult plant resistance (APR) gene Lr48. Two pre-adult plant (P-AP) susceptible stages (S48 and S96) and two adult plant (AP) resistant stages (R48 and R96) were used for RNA-seq. At the susceptible P-AP stage (during S48 to S96), expression increased in 2062 genes, and declined in 130 genes; 1775 of 2062 differentially expressed genes (DEGs) also exhibited high expression during early incompatible stage R48. Comparison of S96 with R96 showed that the expression of 80 genes was enhanced and that of 208 genes declined at the AP stage. At the resistant AP stage (during R48 to R96), expression of mere 25 genes increased and that of 126 genes declined. Apparently, the resistance during late adult stage (R96) is caused by regulation of the expression of relatively fewer genes, although at pre-adult stage (S48 to S96), expression of large number of genes increased; expression of majority of these genes kept on increasing during adult stage at R48 also. These and other results of the present study suggest that APR may mimic some kind of systemic acquired resistance (SAR). The host-specific DEGs belonged to 10 different classes including genes involved in defence, transport, epigenetics, photosynthesis, genes encoding some transcription factors etc. The pathogen (Puccinia triticina) specific DEGs (including three genes encoding known biotrophic effectors) seem to help the pathogen in infection/growth through large-scale stage-specific enhanced expression of host's genes. A putative candidate gene for Lr48 containing protein kinase domain (its ortholog in rice encoding OsWAK8) was also identified.
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http://dx.doi.org/10.1071/FP18336DOI Listing
February 2020

Selenium and selenoproteins in prostanoid metabolism and immunity.

Crit Rev Biochem Mol Biol 2019 12 30;54(6):484-516. Epub 2020 Jan 30.

Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, PA, USA.

Selenium (Se) is an essential trace element that functions in the form of the 21st amino acid, selenocysteine (Sec) in a defined set of proteins. Se deficiency is associated with pathological conditions in humans and animals, where incorporation of Sec into selenoproteins is reduced along with their expression and catalytic activity. Supplementation of Se-deficient population with Se has shown health benefits suggesting the importance of Se in physiology. An interesting paradigm to explain, in part, the health benefits of Se stems from the observations that selenoprotein-dependent modulation of inflammation and efficient resolution of inflammation relies on mechanisms involving a group of bioactive lipid mediators, prostanoids, which orchestrate a concerted action toward maintenance and restoration of homeostatic immune responses. Such an effect involves the interaction of various immune cells with these lipid mediators where cellular redox gatekeeper functions of selenoproteins further aid in not only dampening inflammation, but also initiating an effective and active resolution process. Here we have summarized the current literature on the multifaceted roles of Se/selenoproteins in the regulation of these bioactive lipid mediators and their immunomodulatory effects.
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http://dx.doi.org/10.1080/10409238.2020.1717430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122104PMC
December 2019

Rhodium(III)-Catalyzed C-H Activation: A Cascade Approach for the Regioselective Synthesis of Fused Heterocyclic Lactone Scaffolds.

J Org Chem 2020 03 10;85(5):3548-3559. Epub 2020 Feb 10.

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.

A Rh(III)-catalyzed cascade C-H activation; regioselective [4 + 2] oxidative annulation; and lactonization of aromatic acids, anhydrides, and acrylic acid derivatives with 4-hydroxy-2-alkynoates have been disclosed. This strategy leads to fused heterocyclic lactone scaffolds in a single step with moderate functional group tolerance and excellent site selectivity. Besides, in one step, an antipode of the cephalosol intermediate natural product that contains a tricyclic isocoumarin framework has been synthesized.
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http://dx.doi.org/10.1021/acs.joc.9b03266DOI Listing
March 2020

Withaferin-A Protects the Nigral Dopamine Neuron and Recovers Motor Activity in Aged Rats.

Cells Tissues Organs 2019;208(1-2):59-65. Epub 2020 Jan 24.

Velammal Medical College and Hospital, Madurai, India,

Withaferin-A (WA) was evaluated for its neuroprotective efficacy on the dopamine (DA) neurons of the substantia nigra (SN) and striatum (ST) in aged rats. Wistar albino rats were divided into group I, young (3 months old); group II, aged (24 months old); group III, aged rats supplemented with WA (50 mg/kg bodyweight once per day for 30 days), and group IV, young rats supplemented with WA (50 mg/kg bodyweight). At the end of the experiment period, the animals were subjected to various motor behavior analyses, and were sacrificed by transcardial perfusion. The brains were dissected out and subjected to various analyses, including histological, histomorphometrical, and immunolocalization of the tyrosine hydroxylase (TH) enzyme. The data of rotarod analysis (p < 0.001) showed a significant motor impairment in aged rats (number of falls 10.2 ± 0.86) and reduction in retention time (31.23 ± 2.56 s) compared to young controls (2.41 ± 0.35 and 84.05 ± 5.15 s). The stride length was significantly reduced (p < 0.001) in aged rats (4.21 ± 0.57 and 4.38 ± 0.61 cm) when compared to young control rats (6.98 ± 0.25 and 7.13 ± 0.70 cm). The histomorphometric data of the aged animals showed a significant reduction in the neuronal diameter (p < 0.001), density (p < 0.001), and volume (p < 0.001) in the SN of aged rats when compared to young rats. Immunohistology demonstrated a marked reduction in the levels of TH enzyme in both the SN and ST of aged animals when compared to young rats. Both structural and functional impairments were reversed in the aged animals after the supplementation of WA (p < 0.001). The present study clearly indicates that WA attenuates the ageing-mediated motor degenerative changes in the SN and ST of aged rats and ascertains its neuroprotective potential.
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http://dx.doi.org/10.1159/000505183DOI Listing
August 2020

Curcumin-Mediated Apoptotic Cell Death in Papillary Thyroid Cancer and Cancer Stem-Like Cells through Targeting of the JAK/STAT3 Signaling Pathway.

Int J Mol Sci 2020 Jan 9;21(2). Epub 2020 Jan 9.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.

The constitutive activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signal transduction is well elucidated in STAT3-mediated oncogenesis related to thyroid cancer and is considered to be a plausible therapeutic target. Hence, we investigated whether curcumin, a natural compound, can target the JAK/STAT3 signaling pathway to induce cytotoxic effects in papillary thyroid cancer (PTC) cell lines (BCPAP and TPC-1) and derived thyroid cancer stem-like cells (thyrospheres). Curcumin suppressed PTC cell survival in a dose-dependent manner via the induction of caspase-mediated apoptosis and caused the attenuation of constitutively active STAT3 (the dephosphorylation of Tyr705-STAT3) without affecting STAT3. Gene silencing with STAT3-specific siRNA showed the modulation of genes associated with cell growth and proliferation. The cotreatment of PTC cell lines with curcumin and cisplatin synergistically potentiated cytotoxic effects via the suppression of JAK/STAT3 activity along with the inhibition of antiapoptotic genes and the induction of proapoptotic genes, and it also suppressed the migration of PTC cells by downregulating matrix metalloproteinases and the inhibition of colony formation. Finally, thyrospheres treated with curcumin and cisplatin showed suppressed STAT3 phosphorylation, a reduced formation of thyrospheres, and the downregulated expression of stemness markers, in addition to apoptosis. The current study's findings suggest that curcumin synergistically enhances the anticancer activity of cisplatin in PTC cells as well as in cancer stem-like cells by targeting STAT3, which suggests that curcumin combined with chemotherapeutic agents may provide better therapeutic outcomes.
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http://dx.doi.org/10.3390/ijms21020438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014270PMC
January 2020

Molecular modelling and docking analysis of pleurocidin (an antimicrobial peptide) like peptides with enterotoxin H from Klebsilla pneumonia.

Bioinformation 2019 17;15(11):838-844. Epub 2019 Dec 17.

Department of Human genetics and molecular biology, Bharathiyar University, Coimbatore, Tamilnadu, India.

Enterotoxin H is a key molecular target for replication and establishment of Klebsilla pneumonia in the host. Therefore, it is of interest to study the interaction of enterotoxin H with pleurocidin like peptides using molecular modelling (template PDB ID: 1YCE), Lig-Plot (ligand construction) and docking tools for therapeutic consideration. The hydrophobic pocket and the active site residues (Val 13, Met 16, Gly 25, Ala 25, and Ile 28) were identified using Cast P, Molegro and Sitehound tools. Docking results show that the pleurocidin like peptides interacts with the active sites of enterotoxin H with 300.96 docking score with optimal binding features.
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http://dx.doi.org/10.6026/97320630015838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936665PMC
December 2019

Phosphoproteomic analysis reveals Akt isoform-specific regulation of cytoskeleton proteins in human temporal lobe epilepsy with hippocampal sclerosis.

Neurochem Int 2020 03 27;134:104654. Epub 2019 Dec 27.

Neurophysiology Laboratory, Department of Neurological Sciences, Christian Medical College, Vellore, 632004, Tamilnadu, India.

Akt is one of the most important downstream effectors of phosphatidylinositol 3-kinase/mTOR pathway. Hyperactivation and expression of this pathway are seen in a variety of neurological disorders including human temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Nevertheless, the expression and activation profiles of the Akt isoforms, Akt1, Akt2, and Akt3 and their functional roles in human TLE-HS have not been studied. We examined the protein expression and activation (phosphorylation) patterns of Akt and its isoforms in human hippocampal tissue from TLE and non-TLE patients. A phosphoproteomic approach followed by interactome analysis of each Akt isoform was used to understand protein-protein interactions and their role in TLE-HS pathology. Our results demonstrated activation of the Akt/mTOR pathway as well as activation of Akt downstream substrates like GSK3β, mTOR, and S6 in TLE-HS samples. Akt1 isoform levels were significantly increased in the TLE-HS samples as compared to the non-TLE samples. Most importantly, different isoforms were activated in different TLE-HS samples, Akt2 was activated in three samples, Akt2 and Akt1 were simultaneously activated in one sample and Akt3 was activated in two samples. Our phosphoproteomic screen across six TLE-HS samples identified 183 proteins phosphorylated by Akt isoforms, 29 of these proteins belong to cytoskeletal modification. Also, we were able to identify proteins of several other classes involved in glycolysis, neuronal development, protein folding and excitatory amino acid transport functions as Akt substrates. Taken together, our data offer clues to understand the role of Akt and its isoforms in underlying the pathology of TLE-HS and further, modulation of Akt/mTOR pathway using Akt isoforms specific inhibitors may offer a new therapeutic window for treatment of human TLE-HS.
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http://dx.doi.org/10.1016/j.neuint.2019.104654DOI Listing
March 2020