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Large-scale computational screening of Indian medicinal plants reveals Cassia angustifolia to be a potentially anti-diabetic.
Devaraji, V, Sivaraman, J, Prabhu, S
Journal of biomolecular structure & dynamics. 2024;(1):194-210
Abstract
Researchers are investigating the medicinal properties of herbal plants throughout the world, which often leads to the discovery of novel plants and their chemicals for prophylactic needs of humans. Natural phytochemicals continue to be sought as alternative treatments for various diseases because of their non-toxic and therapeutic properties. In recent years, computational phytochemistry has enabled large-scale screening of phytochemicals, enabling researchers to pursue a wide range of therapeutic research alternatives to traditional ethnopharmacology. We propose to identify an anti-diabetic plant by computational screening on Indian herbal plants in conjunction with experimental characterization and biological validation. The methodology involves the creation of an in-house Indian herbal plant database. Molecular docking is used to screen against alpha amylase for anti-diabetic prophylaxis. Cassia angustifolia was chosen because its phytochemicals are able to bind to alpha amylase. Plants were experimentally extracted, botanically studied and their biological activity was evaluated. Further, the use of molecular dynamics was then applied to pinpoint the phytochemicals responsible for the affinity of alpha amylase. Results in the phytochemical analysis of the extracts revealed strong presence of alkaloids, flavonoids and cardiac glycosides. Moreover, alpha amylase biological activity with C. angustifolia extracts of chloroform, hexane and ethyl acetate demonstrated activity of 3.26, 8.01 and 30.33 µg/ml validating computational predictions. In conclusion, this study developed, validated computational predictions of identifying potential anti-diabetic plants 'Cassia angustifolia' from house herbal databases. Hope this study shall inspire explore plant therapeutic repurposing using computational methods of drug discovery.Communicated by Ramaswamy H. Sarma.
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2.
Dental Perspective on Mucormycosis in COVID-19: a Literature Review.
Prabhu, S, In, A, Balakrishnan, D
Current oral health reports. 2022;(4):211-214
Abstract
PURPOSE OF REVIEW The purpose of this paper is to gain an understanding of existing knowledge and attain familiarity on mucormycosis for early diagnosis and treatment. It highlights the systematic factors, signs and symptoms, diagnostic tests and treatment procedure for mucormycosis from dentistry point of view. PubMed/ Medline, Scopus, Web of Science were the search engine used. Study selection encompassed systematic reviews, critical reviews and case reports related to mucormycosis in COVID-19 patients and only mucormycosis. 19 articles were selected between Years 2001 to 2021. Analysis was done based on patient's comorbidity, site of mucormycosis infection, use of steroids and its effect on people with COVID -19 infection. RECENT FINDINGS Rhino-orbito-cerebral mucormycosis is the most common of all systemic manifestations of mucormycosis. Diabetes mellitus and long-term corticosteroid therapy are the leading risk factors with pre-existing diabetes mellitus accounting for almost 80% cases. Elements that facilitate the growth of mucor in COVID-19 patients are the presence of low oxygen levels, high blood glucose levels, acidic media, high levels of iron, immunosuppression, and episodes of prolonged hospitalization. Mucormycosis is heterogenic in nature. Its management requires an individualized plan that considers the immunity status of the host, stage of the infection, systemic disease, early diagnosis and susceptibility to anti-fungal agents. Supervised use of corticosteroids and betadine gargle prevent the occurance of mucormycosis. SUMMARY The paper sheds some light on the warning signs and diagnostic tests that can help in early identification of infection by a dentist. This enables the timely implementation of therapy resulting in good prognosis of the treatment.
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3.
Coexistent Dedifferentiated Endometrioid Carcinoma of the Uterus and Adenocarcinoma of the Bladder in Lynch Syndrome: Case Report and Review of the Literature.
Groth, JV, Prabhu, S, Periakaruppan, R, Ohlander, S, Emmadi, R, Kothari, R
Applied immunohistochemistry & molecular morphology : AIMM. 2020;(3):e26-e30
Abstract
Lynch syndrome is an autosomal dominant disorder, caused by an abnormality in DNA mismatch repair genes and characterized by the development of a variety of cancers. Upper urinary tract urothelial carcinoma is well characterized in Lynch syndrome; however, support for the inclusion of bladder urothelial carcinoma is limited, except for MSH2 mutation carriers. Urologic adenocarcinoma has not been documented in Lynch syndrome. Here we report, to the best of our knowledge, the first case of bladder adenocarcinoma, synchronous with uterine endometrioid dedifferentiated endometrioid adenocarcinoma in a patient with Lynch syndrome. We present a 47-year-old woman with an MLH1 gene mutation (G133X 397G>T) who presented with menorrhagia. Eleven family members have this mutation, 6 with carcinoma: 5 colorectal and 1 with a gynecologic primary of unknown type. Colonoscopy and endoscopy were unremarkable. Positron emission and computed tomography revealed a 3 cm anterior dome bladder mass without additional extrauterine disease or uterine connection. She underwent partial cystectomy, laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. The uterus demonstrated a dedifferentiated endometrioid adenocarcinoma, immunohistochemically positive for vimentin, ER, CK7, MSH2, MSH6, and p53 (focally) and negative for CEA, CDX2, CK20, β-catenin, MLH1, and PMS2. The bladder demonstrated a well-differentiated, enteric-type adenocarcinoma without muscularis propria invasion, positive for CEA, CDX2, CK20, p53, MSH2, and MSH6 and negative for vimentin, ER, CK7, MLH1, and PMS2. Eleven nodes were negative for carcinoma. The morphologic, immunohistochemical, and clinical findings support synchronous bladder adenocarcinoma, enteric type, and uterine dedifferentiated endometrioid adenocarcinoma, in a patient with Lynch syndrome.
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4.
Effect of Dietary Factors on Cardiac Rhythm.
Voskoboinik, A, Prabhu, S, Sugumar, H, Kistler, PM
The American journal of cardiology. 2018;(7):1265-1271
Abstract
The interaction between arrhythmias and certain lifestyle factors such as obesity and alcohol consumption is well-established. There is significant public and professional interest in the role of various diets, vitamins, and minerals in cardiovascular health. However, many widely held beliefs are not supported by the literature. There is limited evidence for routine magnesium and omega-3 poly-unsaturated fatty acids supplementation, while coffee, tea, nuts, antioxidant vitamins, and even chocolate may have some antiarrhythmic properties. Saturated fat, added salt, and excessive energy drink consumption appear to be harmful for patients with rhythm disorders. However most recommendations are based on observation studies, and this remains a fertile area for further research.
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5.
Potential therapeutic targets and the role of technology in developing novel cannabinoid drugs from cyanobacteria.
Vijayakumar, S, Manogar, P, Prabhu, S
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2016;:362-371
Abstract
Cyanobacteria find several applications in pharmacology as potential candidates for drug design. The need for new compounds that can be used as drugs has always been on the rise in therapeutics. Cyanobacteria have been identified as promising targets of research in the quest for new pharmaceutical compounds as they can produce secondary metabolites with novel chemical structures. Cyanobacteria is now recognized as a vital source of bioactive molecules like Curacin A, Largazole and Apratoxin which have succeeded in reaching Phase II and Phase III into clinical trials. The discovery of several new clinical cannabinoid drugs in the past decade from diverse marine life should translate into a number of new drugs for cannabinoid in the years to come. Conventional cannabinoid drugs have high toxicity and as a result, they affect the efficacy of chemotherapy and patients' life very much. The present review focuses on how potential, safe and affordable drugs used for cannabinoid treatment could be developed from cyanobacteria.
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6.
Aged Garlic Extract Reduces Low Attenuation Plaque in Coronary Arteries of Patients with Metabolic Syndrome in a Prospective Randomized Double-Blind Study.
Matsumoto, S, Nakanishi, R, Li, D, Alani, A, Rezaeian, P, Prabhu, S, Abraham, J, Fahmy, MA, Dailing, C, Flores, F, et al
The Journal of nutrition. 2016;(2):427S-432S
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Abstract
BACKGROUND Although several previous studies have demonstrated that aged garlic extract (AGE) inhibits the progression of coronary artery calcification, its effect on noncalcified plaque (NCP) has been unclear. OBJECTIVE This study investigated whether AGE reduces coronary plaque volume measured by cardiac computed tomography angiography (CCTA) in patients with metabolic syndrome (MetS). METHODS Fifty-five patients with MetS (mean ± SD age: 58.7 ± 6.7 y; 71% men) were prospectively assigned to consume 2400 mg AGE/d (27 patients) or placebo (28 patients) orally. Both groups underwent CCTA at baseline and follow-up 354 ± 41 d apart. Coronary plaque volume, including total plaque volume (TPV), dense calcium (DC), NCP, and low-attenuation plaque (LAP), were measured based upon predefined intensity cutoff values. Multivariable linear regression analysis, adjusted for age, gender, number of risk factors, hyperlipidemia medications, history of coronary artery disease, scan interval time, and baseline %TPV, was performed to examine whether AGE affected each plaque change. RESULTS The %LAP change was significantly reduced in the AGE group compared with the placebo group (-1.5% ± 2.3% compared with 0.2% ± 2.0%, P = 0.0049). In contrast, no difference was observed in %TPV change (0.3% ± 3.3% compared with 1.6% ± 3.0%, P = 0.13), %NCP change (0.2% ± 3.3% compared with 1.4% ± 2.9%, P = 0.14), and %DC change (0.2% ± 1.4%, compared with 0.2% ± 1.7%, P = 0.99). Multivariable linear regression analysis found a beneficial effect of AGE on %LAP regression (β: -1.61; 95% CI: -2.79, -0.43; P = 0.008). CONCLUSIONS This study indicates that the %LAP change was significantly greater in the AGE group than in the placebo group. Further studies are needed to evaluate whether AGE has the ability to stabilize vulnerable plaque and decrease adverse cardiovascular events. This trial was registered at clinicaltrials.gov as NCT01534910.
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Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action.
Harris, F, Prabhu, S, Dennison, SR, Snape, TJ, Lea, R, Mura, M, Phoenix, DA
Protein and peptide letters. 2016;(8):676-87
Abstract
It is becoming increasingly clear that plants ranging across the plant kingdom produce anionic host defence peptides (AHDPs) with potent activity against a wide variety of human cancers cells. In general, this activity involves membrane partitioning by AHDPs, which leads to membranolysis and / or internalization to attack intracellular targets such as DNA. Several models have been proposed to describe these events including: the toroidal pore and Shai-Matsuzaki-Huang mechanisms but, in general, the mechanisms underpinning the membrane interactions and anticancer activity of these peptides are poorly understood. Plant AHDPs with anticancer activity can be conveniently discussed with reference to two groups: cyclotides, which possess cyclic molecules stabilized by cysteine knot motifs, and other ADHPs that adopt extended and α-helical conformations. Here, we review research into the anticancer action of these two groups of peptides along with current understanding of the mechanisms underpinning this action.
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Cardiovascular aspect of Beta-thalassaemia.
Taksande, A, Prabhu, S, Venkatesh, S
Cardiovascular & hematological agents in medicinal chemistry. 2012;(1):25-30
Abstract
Beta-thalassaemia major is a genetic blood disorder caused by the reduced synthesis of beta globin chain. The consequences of the resulting chronic anaemia are also common and include growth retardation, bone marrow expansion, extramedular hematopoiesis, splenomegaly, increased intestinal iron absorption, susceptibility to infections, and hypercoagulability. Transfusional iron overload can affect heart function by directly damaging tissue through iron deposition or via iron-mediated effects at other sites. Cardiac dysfunction is common in patients with thalassaemia and is the leading cause of mortality. The main cardiac abnormalities reported in patients with thalassaemia major (TM) and iron overload are left ventricular systolic and diastolic dysfunction, pulmonary hypertension, valvulopathies, arrhythmias and pericarditis. These cardiac abnormalities are a consequence of the general co-morbid conditions in thalassaemia but are closely related to concomitant endocrine deficiencies, hypercoagulability state and inflammatory milieu. Iron's toxicity within cells arises from its capacity to catalyse the production of reactive oxygen species that cause lipid peroxidation and organelle damage, which lead ultimately to cell death and fibrosis. With the introduction of new technologies such as cardiac magnetic resonance T2* , the early detection of cardiac iron overload and associated cardiac dysfunction is now possible, allowing time for reversal through iron chelation therapy.
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Ultrafast genome-wide scan for SNP-SNP interactions in common complex disease.
Prabhu, S, Pe'er, I
Genome research. 2012;(11):2230-40
Abstract
Long-range gene-gene interactions are biologically compelling models for disease genetics and can provide insights on relevant mechanisms and pathways. Despite considerable effort, rigorous interaction mapping in humans has remained prohibitively difficult due to computational and statistical limitations. We introduce a novel algorithmic approach to find long-range interactions in common diseases using a standard two-locus test that contrasts the linkage disequilibrium between SNPs in cases and controls. Our ultrafast method overcomes the computational burden of a genome × genome scan by using a novel randomization technique that requires 10× to 100× fewer tests than a brute-force approach. By sampling small groups of cases and highlighting combinations of alleles carried by all individuals in the group, this algorithm drastically trims the universe of combinations while simultaneously guaranteeing that all statistically significant pairs are reported. Our implementation can comprehensively scan large data sets (2K cases, 3K controls, 500K SNPs) to find all candidate pairwise interactions (LD-contrast ) in a few hours-a task that typically took days or weeks to complete by methods running on equivalent desktop computers. We applied our method to the Wellcome Trust bipolar disorder data and found a significant interaction between SNPs located within genes encoding two calcium channel subunits: RYR2 on chr1q43 and CACNA2D4 on chr12p13 (LD-contrast test, ). We replicated this pattern of interchromosomal LD between the genes in a separate bipolar data set from the GAIN project, demonstrating an example of gene-gene interaction that plays a role in the largely uncharted genetic landscape of bipolar disorder.
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Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity.
Khojasteh, SC, Prabhu, S, Kenny, JR, Halladay, JS, Lu, AY
European journal of drug metabolism and pharmacokinetics. 2011;(1):1-16
Abstract
The majority of marketed small-molecule drugs undergo metabolism by hepatic Cytochrome P450 (CYP) enzymes (Rendic 2002). Since these enzymes metabolize a structurally diverse number of drugs, metabolism-based drug-drug interactions (DDIs) can potentially occur when multiple drugs are coadministered to patients. Thus, a careful in vitro assessment of the contribution of various CYP isoforms to the total metabolism is important for predicting whether such DDIs might take place. One method of CYP phenotyping involves the use of potent and selective chemical inhibitors in human liver microsomal incubations in the presence of a test compound. The selectivity of such inhibitors plays a critical role in deciphering the involvement of specific CYP isoforms. Here, we review published data on the potency and selectivity of chemical inhibitors of the major human hepatic CYP isoforms. The most selective inhibitors available are furafylline (in co-incubation and pre-incubation conditions) for CYP1A2, 2-phenyl-2-(1-piperidinyl)propane (PPP) for CYP2B6, montelukast for CYP2C8, sulfaphenazole for CYP2C9, (-)-N-3-benzyl-phenobarbital for CYP2C19 and quinidine for CYP2D6. As for CYP2A6, tranylcypromine is the most widely used inhibitor, but on the basis of initial studies, either 3-(pyridin-3-yl)-1H-pyrazol-5-yl)methanamine (PPM) and 3-(2-methyl-1H-imidazol-1-yl)pyridine (MIP) can replace tranylcypromine as the most selective CYP2A6 inhibitor. For CYP3A4, ketoconazole is widely used in phenotyping studies, although azamulin is a far more selective CYP3A inhibitor. Most of the phenotyping studies do not include CYP2E1, mostly because of the limited number of new drug candidates that are metabolized by this enzyme. Among the inhibitors for this enzyme, 4-methylpyrazole appears to be selective.