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Individualized Homeopathic Medicines as Adjunctive Treatment of Pediatric Epilepsy: A Double-Blind, Randomized, Placebo-Controlled Trial.
Gupta, B, Misra, P, Karuppusamy, A, Balamurugan, D, Parewa, M, Tomar, M, Rai, S, Vashishth, H, Sadhukhan, S, Singh, NK, et al
Homeopathy : the journal of the Faculty of Homeopathy. 2023;(3):170-183
Abstract
INTRODUCTION Epilepsy, one of the most common neurological diseases, contributes to 0.5% of the total disease burden. The burden is highest in sub-Saharan Africa, central Asia, central and Andean Latin America, and south-east Asia. Asian countries report an overall prevalence of 6/1,000 and that in India of 5.59/1,000. We examined whether individualized homeopathic medicines (IHMs) can produce a significantly different effect from placebos in treatment of pediatric epilepsy in the context of ongoing standard care (SC) using anti-epileptic drugs (AEDs). METHODS The study was a 6-month, double-blind, randomized, placebo-controlled trial (n = 60) conducted at the pediatric outpatient department of a homeopathic hospital in West Bengal, India. Patients were randomized to receive either IHMs plus SC (n = 30) or identical-looking placebos plus SC (n = 30). The primary outcome measure was the Hague Seizure Severity Scale (HASS); secondary outcomes were the Quality of Life in Childhood Epilepsy (QOLCE-16) and the Pediatric Quality of Life inventory (PedsQL) questionnaires; all were measured at baseline and after the 3rd and 6th month of intervention. The intention-to-treat sample was analyzed to detect group differences and effect sizes. RESULTS Recruitment and retention rates were 65.2% and 91.7% respectively. Although improvements were greater in the IHMs group than with placebos, with small to medium effect sizes, the inter-group differences were statistically non-significant - for HASS (F 1, 58 = 0.000, p = 1.000, two-way repeated measures analysis of variance), QOLCE-16 (F 1, 58 = 1.428, p = 0.237), PedsQL (2-4 years) (F 1, 8 = 0.685, p = 0.432) and PedsQL (5-18 years) (F 1, 47 = 0.000, p = 0.995). Calcarea carbonica, Ignatia amara, Natrum muriaticum and Phosphorus were the most frequently prescribed medicines. No serious adverse events were reported from either of the two groups. CONCLUSION Improvements in the outcome measures were statistically non-significantly greater in the IHMs group than in the placebos group, with small effect sizes. A different trial design and prescribing approach might work better in future trials. TRIAL REGISTRATION CTRI/2018/10/016027.
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Molecular components associated with the regulation of flavonoid biosynthesis.
Naik, J, Misra, P, Trivedi, PK, Pandey, A
Plant science : an international journal of experimental plant biology. 2022;:111196
Abstract
Flavonoids exhibit amazing structural diversity and play different roles in plants. Besides, these compounds have been associated with several health benefits in humans. Several exogenous and endogenous cues, for example, light, temperature, nutrient status, and phytohormones have been reported as modulators of biosynthesis and accumulation of flavonoids. Thus, multiple hormones and stress-related signaling pathways are involved in the regulation of gene expression associated with this pathway. The transcriptional regulators belonging to the MYB and bHLH family transcription factors are well documented as the direct regulators of the structural genes associated with flavonoid biosynthesis. Recent studies also suggest that some of these factors are regulated by molecular components involved in stress and hormone signaling pathways. Adapter proteins for transcriptional activation or repression via recruitment of co-activators and co-repressors, respectively, E2 ubiquitin ligases, miRNA processing complex, and DNA methylation/demethylation factors have been recently discovered in various plants to play key roles in fine-tuning flavonoids synthesis. In the present review, we aim to provide comprehensive information about the role of different factors in the regulation of flavonoid biosynthesis. Besides, we describe the potential upstream regulators involved in the regulation of flavonoid biosynthesis within the context of available information. To sum up, the present review furnishes an updated account of signal transduction pathways modulating the biosynthesis of flavonoids.
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Individualized Homeopathic Medicines in Chronic Rhinosinusitis: Randomized, Double-Blind, Placebo-Controlled Trial.
Misra, P, Nayak, C, Chattopadhyay, A, Palit, TK, Gupta, B, Sadhukhan, S, Bhar, K, Rai, S, Parewa, M, Ali, SS, et al
Homeopathy : the journal of the Faculty of Homeopathy. 2021;(1):13-26
Abstract
BACKGROUND Chronic rhinosinusitis (CRS) is a common disorder, with up to an estimated 134 million Indian sufferers, and having significant impact on quality of life (QOL) and health costs. Despite the evidence favoring homeopathy in CRS being inadequate, it is highly popular. This trial attempts to study the efficacy of individualized homeopathy (IH) medicines in comparison with placebo in patients with CRS. METHODS A double-blind, randomized (1:1), placebo-controlled, preliminary trial (n = 62) was conducted at the National Institute of Homoeopathy, West Bengal, India. Primary outcome measure was the sino-nasal outcome test-20 (SNOT-20) questionnaire; secondary outcomes were the EQ-5D-5L questionnaire and EQ-5D-5L visual analog scale scores, and five numeric rating scales (0-10) assessing intensity of sneezing, rhinorrhea, post-nasal drip, facial pain/pressure, and disturbance in sense of smell, all measured at baseline and after the 2nd and 4th months of intervention. Group differences and effect sizes (Cohen's d) were calculated on the intention-to-treat sample. RESULTS Groups were comparable at baseline. Attrition rate was 6.5% (IH: 1, Placebo: 3). Although improvements in both primary and secondary outcome measures were higher in the IH group than placebo, with small to medium effect sizes, the group differences were statistically non-significant (all p > 0.05, unpaired t-tests). Calcarea carbonica, Lycopodium clavatum, Sulphur, Natrum muriaticum and Pulsatilla nigricans were the most frequently prescribed medicines. No harmful or unintended effects, homeopathic aggravations or any serious adverse events were reported from either group. CONCLUSION There was a small but non-significant direction of effect favoring homeopathy, which ultimately renders the trial as inconclusive. Rigorous trials and independent replications are recommended to arrive at a confirmatory conclusion. [Trial registration: CTRI/2018/03/012557; UTN: U1111-1210-7201].
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Nutrition, atherosclerosis, arterial imaging, cardiovascular risk stratification, and manifestations in COVID-19 framework: a narrative review.
Munjral, S, Ahluwalia, P, Jamthikar, AD, Puvvula, A, Saba, L, Faa, G, Singh, IM, Chadha, PS, Turk, M, Johri, AM, et al
Frontiers in bioscience (Landmark edition). 2021;(11):1312-1339
Abstract
Background: Atherosclerosis is the primary cause of the cardiovascular disease (CVD). Several risk factors lead to atherosclerosis, and altered nutrition is one among those. Nutrition has been ignored quite often in the process of CVD risk assessment. Altered nutrition along with carotid ultrasound imaging-driven atherosclerotic plaque features can help in understanding and banishing the problems associated with the late diagnosis of CVD. Artificial intelligence (AI) is another promisingly adopted technology for CVD risk assessment and management. Therefore, we hypothesize that the risk of atherosclerotic CVD can be accurately monitored using carotid ultrasound imaging, predicted using AI-based algorithms, and reduced with the help of proper nutrition. Layout: The review presents a pathophysiological link between nutrition and atherosclerosis by gaining a deep insight into the processes involved at each stage of plaque development. After targeting the causes and finding out results by low-cost, user-friendly, ultrasound-based arterial imaging, it is important to (i) stratify the risks and (ii) monitor them by measuring plaque burden and computing risk score as part of the preventive framework. Artificial intelligence (AI)-based strategies are used to provide efficient CVD risk assessments. Finally, the review presents the role of AI for CVD risk assessment during COVID-19. Conclusions: By studying the mechanism of low-density lipoprotein formation, saturated and trans fat, and other dietary components that lead to plaque formation, we demonstrate the use of CVD risk assessment due to nutrition and atherosclerosis disease formation during normal and COVID times. Further, nutrition if included, as a part of the associated risk factors can benefit from atherosclerotic disease progression and its management using AI-based CVD risk assessment.
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A Community Based Randomized Controlled Trial to See the Effect of Vitamin D Supplementation on Development of Diabetes Among Women with Prediabetes Residing in A Rural Community of Northern India.
Misra, P, Kant, S, Misra, A, Jha, S, Kardam, P, Thakur, N, Bhatt, SP
Journal of family medicine and primary care. 2021;(8):3122-3129
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Abstract
BACKGROUND The primary objective of this study was to intervene with vitamin D supplementation in rural-based women with pre-diabetes (impaired fasting glucose or impaired glucose tolerance) to prevent development of type 2 diabetes (T2DM). METHODS This was an open-label randomized placebo-controlled trial conducted in rural women with pre-diabetes and vitamin D deficiency (Clinicaltrials.gov NCT02513888). Women aged 20-60 years with pre-diabetes were selected from rural Haryana (north India) and followed up for two years. A semi-structured questionnaire was used to collect information on socio-demographic and behavioral details, like sun exposure, dietary habits, etc., The intervention group received vitamin D supplementation while control group received lactose granules as placebo. Equal doses of calcium carbonate were given to both the groups. RESULTS A total of 132 participants were recruited in the study (58 each in the intervention and control groups). It was observed that there was no statistical significance in the incidence of diabetes in the control group as compared to the intervention group at the end of 2 years (P = 0.701). CONCLUSION Though during the first year there was some delay in development of DM in the intervention group but at the end of two years there was no significant effect of vitamin D supplementation in delaying the incidence of diabetes in these women after two years. TRIAL REGISTRATION (Clinicaltrials.gov NCT02513888).
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Membrane transporters: the key drivers of transport of secondary metabolites in plants.
Gani, U, Vishwakarma, RA, Misra, P
Plant cell reports. 2021;(1):1-18
Abstract
This review summarizes the recent updates in the area of transporters of plant secondary metabolites, including their applied aspects in metabolic engineering of economically important secondary metabolites. Plants have evolved biosynthetic pathways to produce structurally diverse secondary metabolites, which serve distinct functions, including defense against pathogens and herbivory, thereby playing a pivotal role in plant ecological interactions. These compounds often display interesting bioactivities and, therefore, have been used as repositories of natural drugs and phytoceuticals for humans. At an elevated level, plant secondary metabolites could be cytotoxic to the plant cell itself; therefore, plants have developed sophisticated mechanisms to sequester these compounds to prevent cytotoxicity. Many of these valuable natural compounds and their precursors are biosynthesized and accumulated at diverse subcellular locations, and few are even transported to sink organs via long-distance transport, implying the involvement of compartmentalization via intra- and intercellular transport mechanisms. The transporter proteins belonging to different families of transporters, especially ATP binding cassette (ABC) and multidrug and toxic compound extrusion (MATE) have been implicated in membrane-mediated transport of certain plant secondary metabolites. Despite increasing reports on the characterization of transporter proteins and their genes, our knowledge about the transporters of several medicinally and economically important plant secondary metabolites is still enigmatic. A comprehensive understanding of the molecular mechanisms underlying the whole route of secondary metabolite transportome, in addition to the biosynthetic pathways, will aid in systematic and targeted metabolic engineering of high-value secondary metabolites. The present review embodies a comprehensive update on the progress made in the elucidation of transporters of secondary metabolites in view of basic and applied aspects of their transport mechanism.
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Metabolic and transcriptional analyses in response to potent inhibitors establish MEP pathway as major route for camptothecin biosynthesis in Nothapodytes nimmoniana (Graham) Mabb.
Rather, GA, Sharma, A, Jeelani, SM, Misra, P, Kaul, V, Lattoo, SK
BMC plant biology. 2019;(1):301
Abstract
BACKGROUND Nothapodytes nimmoniana, a plant of pivotal medicinal significance is a source of potent anticancer monoterpene indole alkaloid (MIA) camptothecin (CPT). This compound owes its potency due to topoisomerase-I inhibitory activity. However, biosynthetic and regulatory aspects of CPT biosynthesis so far remain elusive. Production of CPT is also constrained due to unavailability of suitable in vitro experimental system. Contextually, there are two routes for the biosynthesis of MIAs: the mevalonate (MVA) pathway operating in cytosol and the methylerythritol phosphate (MEP) pathway in the plastids. Determination of relative precursor flux through either of these pathways may provide a new vista for manipulating the enhanced CPT production. RESULTS In present study, specific enzyme inhibitors of MVA (lovastatin) and MEP pathways (fosmidomycin) were used to perturb the metabolic flux in N. nimmoniana. Interaction of both these pathways was investigated at transcriptional level by using qRT-PCR and at metabolite level by evaluating secologanin, tryptamine and CPT contents. In fosmidomycin treated plants, highly significant reduction was observed in both secologanin and CPT accumulation in the range 40-57% and 64-71.5% respectively, while 4.61-7.69% increase was observed in tryptamine content as compared to control. Lovastatin treatment showed reduction in CPT (7-11%) and secologanin (7.5%) accumulation while tryptamine registered slight increase (3.84%) in comparison to control. These inhibitor mediated changes were reflected at transcriptional level via altering expression levels of deoxy-xylulose-5-phosphate reductoisomerase (DXR) and hydroxymethylglutaryl-CoA reductase (HMG). Further, mRNA expression of four more genes downstream to DXR and HMG of MEP and MVA pathways respectively were also investigated. Expression analysis also included secologanin synthase (SLS) and strictosidine synthase (STR) of seco-iridoid pathway. Present investigation also entailed development of an efficient in vitro multiplication system as a precursor to pathway flux studies. Further, a robust Agrobacterium-mediated transformed hairy root protocol was also developed for its amenability for up-scaling as a future prospect. CONCLUSIONS Metabolic and transcriptional changes reveal differential efficacy of cytosolic and plastidial inhibitors in context to pathway flux perturbations on seco-iridoid end-product camptothecin. MEP pathway plausibly is the major precursor contributor towards CPT production. These empirical findings allude towards developing suitable biotechnological interventions for enhanced CPT production.
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Exploring the functional significance of sterol glycosyltransferase enzymes.
Singh, G, Dhar, YV, Asif, MH, Misra, P
Progress in lipid research. 2018;:1-10
Abstract
Steroidal alkaloids (SAs) are widely synthesized and distributed in plants manifesting as natural produce endowed with potential for medicinal, pesticidal and other high-value usages. Glycosylation of these SAs raises complex and diverse glycosides in plant cells that indeed govern numerous functional aspects. During the glycosylation process of these valuable metabolites, the addition of carbohydrate molecule(s) is catalyzed by enzymes known as sterol glycosyltransferases (SGTs), commonly referred to as UGTs, leading to the production of steryl glycosides (SGs). The ratio of SGs and nonglyco-conjugated SAs are different in different plant species, however, their biosynthesis in the cell is controlled by different environmental factors. The aim of this review is to evaluate the current SGT enzyme research and the functional consequences of glycomodification of SAs on the physiology and plant development, which together are associated with the plant's primary processes. Pharmaceutical, industrial, and other potential uses of saponins have also been discussed and their use in therapeutics has been unveiled by in silico analysis. The field of biotransformation or conversion of nonglycosylated to glycosylated phytosterols by the activity of SGTs, making them soluble, available and more useful for humankind is the new field of interest towards drug therapy.
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Immunoglobulin light chain amyloid aggregation.
Blancas-Mejia, LM, Misra, P, Dick, CJ, Cooper, SA, Redhage, KR, Bergman, MR, Jordan, TL, Maar, K, Ramirez-Alvarado, M
Chemical communications (Cambridge, England). 2018;(76):10664-10674
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Abstract
Light chain (AL) amyloidosis is a devastating, complex, and incurable protein misfolding disease. It is characterized by an abnormal proliferation of plasma cells (fully differentiated B cells) producing an excess of monoclonal immunoglobulin light chains that are secreted into circulation, where the light chains misfold, aggregate as amyloid fibrils in target organs, and cause organ dysfunction, organ failure, and death. In this article, we will review the factors that contribute to AL amyloidosis complexity, the findings by our laboratory from the last 16 years and the work from other laboratories on understanding the structural, kinetics, and thermodynamic contributions that drive immunoglobulin light chain-associated amyloidosis. We will discuss the role of cofactors and the mechanism of cellular damage. Last, we will review our recent findings on the high resolution structure of AL amyloid fibrils. AL amyloidosis is the best example of protein sequence diversity in misfolding diseases, as each patient has a unique combination of germline donor sequences and multiple amino acid mutations in the protein that forms the amyloid fibril.
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Mycobacterium tuberculosis chorismate mutase: A potential target for TB.
Khanapur, M, Alvala, M, Prabhakar, M, Shiva Kumar, K, Edwin, RK, Sri Saranya, PS, Patel, RK, Bulusu, G, Misra, P, Pal, M
Bioorganic & medicinal chemistry. 2017;(6):1725-1736
Abstract
Mycobacterium tuberculosis chorismate mutase (MtbCM) catalyzes the rearrangement of chorismate to prephenate in the shikimate biosynthetic pathway to form the essential amino acids, phenylalanine and tyrosine. Two genes encoding chorismate mutase have been identified in Mtb. The secretory form,∗MtbCM (encoded by Rv1885c) is assumed to play a key role in pathogenesis of tuberculosis. Also, the inhibition of MtbCM may hinder the supply of nutrients to the organism. Indeed, the existence of chorismate mutase (CM) in bacteria, fungi and higher plants but not in human and low sequence homology among known CM makes it an interesting target for the discovery of anti-tubercular agents. The present article mainly focuses on the recent developments in the structure, function and inhibition of MtbCM. The understanding of various aspects of MtbCM as presented in the current article may facilitate the design and subsequent chemical synthesis of new inhibitors against ∗MtbCM, that could lead to the discovery and development of novel and potent anti-tubercular agents in future.