Showing papers by "Manipal University published in 2015"
TL;DR: It is shown that transbilayer interactions are necessary for the generation of cholesterol-dependent nanoclusters of GPI-anchored proteins mediated by membrane-adjacent dynamic actin filaments, and it is found that long saturated acyl-chains are required for forming G PI-anchor Nanoclusters.
308 citations
TL;DR: Asian Indians have one of the highest incidence rates of diabetes, with rapid conversion from normoglycemia to dysglycemia, and public health interventions should target modifiable risk factors to slow down the diabetes epidemic in this population.
Abstract: OBJECTIVE There is little data on the incidence rates of diabetes and prediabetes (dysglycemia) in Asian Indians. This article presents the incidence of diabetes and prediabetes and the predictors of progression in a population-based Asian Indian cohort. STUDY DESIGN AND METHODS Data on progression to diabetes and prediabetes from 1,376 individuals, a subset of 2,207 of the Chennai Urban Rural Epidemiology Study (CURES) cohort with normal glucose tolerance (NGT) or prediabetes at baseline, who were followed for a median of 9.1 years (11,629 person-years), are presented. During follow-up, 534 died and 1,077 with NGT and 299 with prediabetes at baseline were reinvestigated in a 10-year follow-up study. Diabetes and prediabetes were diagnosed based on the American Diabetes Association criteria. Incidence rates were calculated and predictors of progression to prediabetes and/or diabetes were estimated using the Cox proportional hazards model. RESULTS The incidence of diabetes, prediabetes, and “any dysglycemia” were 22.2, 29.5, and 51.7 per 1,000 person-years, respectively. Among those with NGT, 19.4% converted to diabetes and 25.7% to prediabetes, giving an overall conversion rate to dysglycemia of 45.1%. Among those with prediabetes, 58.9% converted to diabetes. Predictors of progression to dysglycemia were advancing age, family history of diabetes, 2-h plasma glucose, glycated hemoglobin (HbA 1c ), low HDL cholesterol, and physical inactivity. CONCLUSIONS Asian Indians have one of the highest incidence rates of diabetes, with rapid conversion from normoglycemia to dysglycemia. Public health interventions should target modifiable risk factors to slow down the diabetes epidemic in this population.
193 citations
03 Sep 2015
TL;DR: Herbal sources provide researchers enormous scope to explore and bring out viable alternatives against viral diseases, considering non-availability of suitable drug candidates and increasing resistance to existing drug molecules for many emerging and re-emerging viral diseases.
Abstract: Herbal plants, plant preparations and phytoconstituents have proved useful in attenuating infectious conditions and were the only remedies available, till the advent of antibiotics (many being of plant origin themselves). Among infectious diseases, viral diseases in particular, remain the leading cause of death in humans globally. A variety of phytoconstituents derived from medicinal herbs have been extensively studied for antiviral activity. Based on this rationale, an online search was performed, which helped to identify a large number of plant species harboring antiviral molecules. These herbal sources have been reported individually or in combinations across a large number of citations studied. Activities against rabies virus, Human immunodeficiency virus, Chandipura virus, Japanese Encephalitis Virus, Enterovirus, Influenza A/H1N1 and other influenza viruses were discovered during the literature search. This review includes all such plant species exhibiting antiviral properties. The review also encompasses composition and methodologies of preparing various antiviral formulations around the globe. An elaborate section on the formulations filed for patent registration, along with non-patented formulations, has also been included in this article. To conclude, herbal sources provide researchers enormous scope to explore and bring out viable alternatives against viral diseases, considering non-availability of suitable drug candidates and increasing resistance to existing drug molecules for many emerging and re-emerging viral diseases.
148 citations
TL;DR: The evidence supporting JNK as a potent therapeutic target, and small molecules from various chemical classes as JNK inhibitors are summarized.
Abstract: JNK pathway regulates various physiological processes including inflammatory responses, cell differentiation, cell proliferation, cell death, cell survival and expression of proteins. Deregulation of JNK is linked with various diseases including neurodegenerative disease, autoimmune disease, diabetes, cancer, cardiac hypertrophy and asthma. Three distinct genes JNK1, JNK2 and JNK3 have been identified as regulator of JNK pathway. JNK1 and JNK2 have broad tissue distribution and play a potential role in insulin resistance, inflammation and cell signaling. JNK3 is predominantly found in the CNS neurons, making it an attractive target for neurodegenerative disorders. In this review, we summarize the evidence supporting JNK as a potent therapeutic target, and small molecules from various chemical classes as JNK inhibitors.
138 citations
TL;DR: The data indicate that despite lower absorption and bioavailability of rutin, maximum efficacy was achieved in the case of GLE, which also comprises of other phytochemical groups including acetogenins that make up its natural complex environment.
Abstract: Phytochemical complexity of plant extracts may offer health-promoting benefits including chemotherapeutic and chemopreventive effects. Isolation of 'most-active fraction' or single constituents from whole extracts may not only compromise the therapeutic efficacy but also render toxicity, thus emphasizing the importance of preserving the natural composition of whole extracts. The leaves of Annona muricata, commonly known as Graviola, are known to be rich in flavonoids, isoquinoline alkaloids and annonaceous acetogenins. Here, we demonstrate phytochemical synergy among the constituents of Graviola leaf extract (GLE) compared to its flavonoid-enriched (FEF) and acetogenin-enriched (AEF) fractions. Comparative quantitation of flavonoids revealed enrichment of rutin (~7-fold) and quercetin-3-glucoside (Q-3-G, ~3-fold) in FEF compared to GLE. In vivo pharmacokinetics and in vitro absorption kinetics of flavonoids revealed enhanced bioavailability of rutin in FEF compared to GLE. However, GLE was more effective in inhibiting in vitro prostate cancer proliferation, viability and clonogenic capacity compared to FEF. Oral administration of 100mg/kg bw GLE showed ~1.2-fold higher tumor growth-inhibitory efficacy than FEF in human prostate tumor xenografts although the concentration of rutin and Q-3-G was more in FEF. Contrarily, AEF, despite its superior in vitro and in vivo efficacy, resulted in death of the mice due to toxicity. Our data indicate that despite lower absorption and bioavailability of rutin, maximum efficacy was achieved in the case of GLE, which also comprises of other phytochemical groups including acetogenins that make up its natural complex environment. Hence, our study emphasizes on evaluating the nature of interactions among Graviola leaf phytochemcials for developing favorable dose regimen for prostate cancer management to achieve optimal therapeutic benefits.
130 citations
TL;DR: Time-dependent exposure to EGCG resulted in reactivation of known tumor-suppressor genes in HeLa cells due to marked changes in the methylation of the promoter regions of these genes.
Abstract: There has been increasing evidence that numerous bioactive dietary agents can hamper the process of carcinogenesis by targeting epigenetic alterations including DNA methylation. This therapeutic approach is considered as a significant goal for cancer therapy due to the reversible nature of epigenetic-mediated gene silencing and warrants further attention. One such dietary agent, green tea catechin, (-)-epigallocatechin-3-gallate (EGCG) has been shown to modulate many cancer-related pathways. Thus, the present study was designed to investigate the role of EGCG as an epigenetic modifier in HeLa cells. DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibition assays were conducted, and the transcription levels of DNMT3B and HDAC1 were assessed by enzymatic activity assay and RT-PCR, respectively. Furthermore, we studied the binding interaction of EGCG with DNMT3B and HDAC1 by molecular modeling as well as promoter DNA methylation and expression of retinoic acid receptor-β (RARβ), cadherin 1 (CDH1) and death-associated protein kinase-1 (DAPK1) in EGCG-treated HeLa cells by RT-PCR and MS-PCR. In the present study, time-dependent EGCG-treated HeLa cells were found to have a significant reduction in the enzymatic activity of DNMT and HDAC. However, the expression of DNMT3B was significantly decreased in a time-dependent manner whereas there was no significant change in HDAC1 expression. Molecular modeling data also supported the EGCG-mediated DNMT3B and HDAC1 activity inhibition. Furthermore, time-dependent exposure to EGCG resulted in reactivation of known tumor-suppressor genes (TSGs) in HeLa cells due to marked changes in the methylation of the promoter regions of these genes. Overall, the present study suggests that EGCG may have a significant impact on the development of novel epigenetic-based therapy.
129 citations
TL;DR: It is shown that Rv1988, a secreted mycobacterial protein, is a functional methyltransferase that localizes to the host nucleus and interacts with chromatin that methylates histone H3 at H3R42 and represses the genes involved in the first line of defence againstMycobacteria.
Abstract: Mycobacteria are successful pathogens that modulate the host immune response through unclear mechanisms. Here we show that Rv1988, a secreted mycobacterial protein, is a functional methyltransferase that localizes to the host nucleus and interacts with chromatin. Rv1988 methylates histone H3 at H3R42 and represses the genes involved in the first line of defence against mycobacteria. H3R42me2, a non-tail histone modification, is present at the entry and exit point of DNA in the nucleosome and not within the regulatory sites in the N-terminal tail. Rv1988 deletion in Mycobacterium tuberculosis reduces bacterial survival in the host, and experimental expression of M. tuberculosis Rv1988 in non-pathogenic Mycobacterium smegmatis negatively affects the health of infected mice. Thus, Rv1988 is an important mycobacterial virulence factor, which uses a non-canonical epigenetic mechanism to control host cell transcription.
118 citations
TL;DR: An overview of dental evidence, its use in forensic identification and its limitations is given.
Abstract: Forensic odontology is primarily concerned with the use of teeth and oral structures for identification in a legal context. Various forensic odontology techniques help in the identification of the human remains in incidents such as terrorists' attacks, airplane, train and road accidents, fires, mass murders, and natural disasters such as tsunamis, earth quakes and floods, etc. (Disaster Victim Identification-DVI). Dental structures are the hardest and well protected structures in the body. These structures resist decomposition and high temperatures and are among the last ones to disintegrate after death. The principal basis of the dental identification lies in the fact that no two oral cavities are alike and the teeth are unique to an individual. The dental evidence of the deceased recovered from the scene of crime/occurrence is compared with the ante-mortem records for identification. Dental features such as tooth morphology, variations in shape and size, restorations, pathologies, missing tooth, wear patterns, crowding of the teeth, colour and position of the tooth, rotations and other peculiar dental anomalies give every individual a unique identity. In absence of ante-mortem dental records for comparison, the teeth can help in the determination of age, sex, race/ethnicity, habits, occupations, etc. which can give further clues regarding the identity of the individuals. This piece of writing gives an overview of dental evidence, its use in forensic identification and its limitations.
110 citations
TL;DR: Proteins indispensable for follicular growth were found to be differentially expressed in follicular fluid of women with PCOS, which may in part explain the aberrant folliculogenesis observed in these women.
Abstract: Context: Polycystic ovary syndrome (PCOS), a major cause of anovulatory infertility, is characterized by arrested follicular growth. Altered protein levels in the follicular fluid surrounding the ovum may reflect the molecular defects of folliculogenesis in these women. Objective: To identify differentially regulated proteins in PCOS by comparing the follicular fluid protein repertoire of PCOS with healthy women. Methods: The follicular fluid samples were collected from PCOS and normo-ovulatory women undergoing in vitro fertilization. Follicular fluid proteins were subjected to digestion using trypsin, and resultant peptides were labeled with isobaric tags for relative and absolute quantification reagents and analyzed by liquid chromatography tandem mass spectrometry. Differential abundance of selected proteins was confirmed by ELISA. Results: A total of 770 proteins were identified, of which 186 showed differential abundance between controls and women with PCOS. Proteins involved in various processes of ...
97 citations
TL;DR: In this article, the velocity filter SHIP of GSI was used as separator for the transfer products while the isotope identification was performed via the α decay chains of the nuclei, revealing that multinucleon transfer reactions together with here applied fast and sensitive separation and detection techniques are promising for the synthesis of new isotopes in the region of heaviest nuclei.
91 citations
TL;DR: Results suggest that the folate tagged doxorubicin loaded GNPs are an attractive platform for targeted delivery of doxorbicin and are agents suitable for photothermal cancer therapy.
Abstract: The current research focuses on the application of folate conjugated and doxorubicin loaded polymeric gold nanoparticles (GNPs) for the targeted treatment of folate receptor overexpressing breast cancers, augmented by adjunctive laser photothermal therapy. Herein, GNPs surface modified with folate, drug doxorubicin and polyethylene glycol were engineered and were used as vehicles for folate receptor targeted delivery of doxorubicin into cancer cells. Subsequently, the GNPs were photo-excited using laser light for mediating hyperthermia in the cancer cells. In vitro studies were performed to validate the efficacy of the combined modality of folate conjugated and doxorubicin loaded polymeric GNP mediated chemotherapy followed by photothermal therapy in comparison to treatment with free drug; and the combination modality showed better therapeutic efficacy than that of plain doxorubicin treatment in MDA-MB-231 breast cancer cells that express increased levels of surface folate receptors when compared to MCF-7 breast cancer cells that express low levels of folate receptor. The mechanism of cell death was investigated using fluorescent microscopy. Immunoassays showed the up-regulation of the pro-apoptotic protein p53 and down-regulation of the anti-apoptotic protein Bcl-2. Collectively, these results suggest that the folate tagged doxorubicin loaded GNPs are an attractive platform for targeted delivery of doxorubicin and are agents suitable for photothermal cancer therapy.
TL;DR: The role of histone modifications that can occur on tumor suppressor genes as well as oncogenes, which regulate tumorigenesis and can thus form the basis of novel strategies for cancer therapy are described.
Abstract: // Muthu K. Shanmugam 1 , Frank Arfuso 2 , Surendar Arumugam 10 , Arunachalam Chinnathambi 3 , Bian Jinsong 1 , Sudha Warrier 4 , Ling Zhi Wang 1,5 , Alan Prem Kumar 1,5,6,7,8 , Kwang Seok Ahn 9 , Gautam Sethi 1 and Manikandan Lakshmanan 10,11 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 2 Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia 3 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia 4 Division of Cancer Stem Cells and Cardiovascular Regeneration, School of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, India 5 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore 6 Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA, Australia 7 National University Cancer Institute, National University Health System, Singapore, Singapore 8 Department of Biological Sciences, University of North Texas, Denton, Texas, USA 9 College of Korean Medicine, Kyung Hee University, Dongdaemun-gu, Seoul, Korea 10 Institute of Molecular and Cell Biology, A*STAR, Biopolis Drive, Proteos, Singapore, Singapore 11 Department of Pathology, National University Hospital Singapore, Singapore, Singapore Correspondence to: Manikandan Lakshmanan, email: // Gautam Sethi, email: // Kwang Seok Ahn, email: // Keywords : cancer; histones; oncogenes; tumor suppressor genes; ubiquitination Received : October 11, 2017 Accepted : December 01, 2017 Published : December 17, 2017 Abstract Oncogenesis is a multistep process mediated by a variety of factors including epigenetic modifications. Global epigenetic post-translational modifications have been detected in almost all cancers types. Epigenetic changes appear briefly and do not involve permanent changes to the primary DNA sequence. These epigenetic modifications occur in key oncogenes, tumor suppressor genes, and transcription factors, leading to cancer initiation and progression. The most commonly observed epigenetic changes include DNA methylation, histone lysine methylation and demethylation, histone lysine acetylation and deacetylation. However, there are several other novel post-translational modifications that have been observed in recent times such as neddylation, sumoylation, glycosylation, phosphorylation, poly-ADP ribosylation, ubiquitination as well as transcriptional regulation and these have been briefly discussed in this article. We have also highlighted the diverse epigenetic changes that occur during the process of tumorigenesis and described the role of histone modifications that can occur on tumor suppressor genes as well as oncogenes, which regulate tumorigenesis and can thus form the basis of novel strategies for cancer therapy.
TL;DR: It was found that the cost for the management of DRP was directly proportional to severity, and polypharmacy and older age were the major risk factors for developing drug related problems.
Abstract: Background
Drug related admissions have significantly increased over the past few decades. According to various studies on drug related hospital admissions, it was estimated that around 5–10% of hospital admissions were due to drug related problems (DRP), in which 50% of them are avoidable.
TL;DR: In vitro and in vivo skin permeation studies of sunscreen creams containing morin NPs indicated excellent deposition of morin within the skin, which confirmed outstanding UV radiation protection as well as antioxidant properties.
Abstract: The objective of present work was to develop novel sunscreen creams containing polymeric nanoparticles (NPs) of morin. Polymeric NPs containing morin were prepared and optimized. The creams containing morin NPs were also prepared and evaluated. Optimized NPs exhibited particle size of 90.6 nm and zeta potential of −31 mV. The entrapment efficiency of morin, within the polymeric NPs, was found to be low (12.27%). Fourier transformed infrared spectroscopy and differential scanning calorimetry studies revealed no interaction between morin and excipients. Transmission electron microscopy and atomic force microscopy revealed that the NPs were spherical in shape with approximately 100 nm diameter. Optimized NPs showed excellent in vitro free radical scavenging activity. Skin permeation and deposition of morin from its NPs was higher than its plain form. Different sunscreen creams (SC1–SC8) were formulated by incorporating morin NPs along with nano zinc oxide and nano titanium dioxide. SC5 and SC8 creams showed excellent sun protection factor values (≈40). In vitro and in vivo skin permeation studies of sunscreen creams containing morin NPs indicated excellent deposition of morin within the skin. Morin NPs and optimized cream formulations (SC5 and SC8) did not exhibit cytotoxicity in Vero and HaCaT cells. Optimized sunscreen creams showed excellent dermal safety. SC5 and SC8 creams demonstrated exceptional in vivo antioxidant effect (estimation of catalase, superoxide dismutase, and glutathione) in UV radiation-exposed rats. The optimized sunscreen creams confirmed outstanding UV radiation protection as well as antioxidant properties.
TL;DR: The present study suggests that simvastatin per se protects the neurons in hippocampus and frontal cortex from AlCl3, an environmental toxin.
Abstract: Objectives. Aluminium, a neurotoxic agent in humans, has been implicated in the pathogenesis of neurodegenerative disorders. In this study, we examined the behavioral and biochemical effects of aluminium in rats with special emphasis on memory centres, namely, hippocampus and frontal cortex. Further, the effect of simvastatin treatment on aluminium intoxication was evaluated. Methods. Rats were exposed to aluminium chloride (AlCl3) for 60 days. Simvastatin (10 mg/kg/p.o.) and rivastigmine (1 mg/kg/p.o.) were administered daily prior to AlCl3. Behavioral parameters were assessed using Morris water maze test and actophotometer followed by biochemical investigations, namely, acetylcholinesterase (AChE) activity, TNF-α level, antioxidant enzymes (GSH, catalase), lipid peroxidation, and nitrite level in hippocampus and frontal cortex. Triglycerides, total cholesterol, LDL, and HDL levels in serum were also determined. Key Findings. Simvastatin treatment improved cognitive function and locomotor activity in rats. Simvastatin reversed hyperlipidemia and significantly rectified the deleterious effect of AlCl3 on AChE activity. Further, in hippocampus and frontal cortex, aluminium-induced elevation in nitrite and TNF-α and reduction in antioxidant enzymes were inhibited by simvastatin. Conclusion. To conclude, the present study suggests that simvastatin per se protects the neurons in hippocampus and frontal cortex from AlCl3, an environmental toxin.
TL;DR: The availability of the whole genome of O.tenuiflorum and the sequence analysis suggests that small amino acid changes at the functional sites of genes involved in metabolite synthesis pathways confer special medicinal properties to this herb.
Abstract: Krishna Tulsi, a member of Lamiaceae family, is a herb well known for its spiritual, religious and medicinal importance in India. The common name of this plant is ‘Tulsi’ (or ‘Tulasi’ or ‘Thulasi’) and is considered sacred by Hindus. We present the draft genome of Ocimum tenuiflurum L (subtype Krishna Tulsi) in this report. The paired-end and mate-pair sequence libraries were generated for the whole genome sequenced with the Illumina Hiseq 1000, resulting in an assembled genome of 374 Mb, with a genome coverage of 61 % (612 Mb estimated genome size). We have also studied transcriptomes (RNA-Seq) of two subtypes of O. tenuiflorum, Krishna and Rama Tulsi and report the relative expression of genes in both the varieties. The pathways leading to the production of medicinally-important specialized metabolites have been studied in detail, in relation to similar pathways in Arabidopsis thaliana and other plants. Expression levels of anthocyanin biosynthesis-related genes in leaf samples of Krishna Tulsi were observed to be relatively high, explaining the purple colouration of Krishna Tulsi leaves. The expression of six important genes identified from genome data were validated by performing q-RT-PCR in different tissues of five different species, which shows the high extent of urosolic acid-producing genes in young leaves of the Rama subtype. In addition, the presence of eugenol and ursolic acid, implied as potential drugs in the cure of many diseases including cancer was confirmed using mass spectrometry. The availability of the whole genome of O.tenuiflorum and our sequence analysis suggests that small amino acid changes at the functional sites of genes involved in metabolite synthesis pathways confer special medicinal properties to this herb.
TL;DR: It is found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India’s traditional medicine has a genetic basis.
Abstract: The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as ``Prakriti''. To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p <= 1 x 10(-5)) were significantly different between Prakritis, without any confounding effect of stratification, after 10(6) permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India's traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine.
TL;DR: Analysis of markers specific to Ct and PC may be valuable in the evaluation of TBI pathobiology and therapeutics, and altered regulation of neurogenesis and cytoskeletal architecture in PC is suggested.
Abstract: Traumatic brain injury (TBI) contributes to fatalities and neurological disabilities worldwide. While primary injury causes immediate damage, secondary events contribute to long-term neurological defects. Contusions (Ct) are primary injuries correlated with poor clinical prognosis, and can expand leading to delayed neurological deterioration. Pericontusion (PC) (penumbra), the region surrounding Ct, can also expand with edema, increased intracranial pressure, ischemia, and poor clinical outcome. Analysis of Ct and PC can therefore assist in understanding the pathobiology of TBI and its management. This study on human TBI brains noted extensive neuronal, astroglial and inflammatory changes, alterations in mitochondrial, synaptic and oxidative markers, and associated proteomic profile, with distinct differences in Ct and PC. While Ct displayed petechial hemorrhages, thrombosis, inflammation, neuronal pyknosis, and astrogliosis, PC revealed edema, vacuolation of neuropil, axonal loss, and dystrophic changes. Proteomic analysis demonstrated altered immune response, synaptic, and mitochondrial dysfunction, among others, in Ct, while PC displayed altered regulation of neurogenesis and cytoskeletal architecture, among others. TBI brains displayed oxidative damage, glutathione depletion, mitochondrial dysfunction, and loss of synaptic proteins, with these changes being more profound in Ct. We suggest that analysis of markers specific to Ct and PC may be valuable in the evaluation of TBI pathobiology and therapeutics. We have characterized the primary injury in human traumatic brain injury (TBI). Contusions (Ct) - the injury core displayed hemorrhages, inflammation, and astrogliosis, while the surrounding pericontusion (PC) revealed edema, vacuolation, microglial activation, axonal loss, and dystrophy. Proteomic analysis demonstrated altered immune response, synaptic and mitochondrial dysfunction in Ct, and altered regulation of neurogenesis and cytoskeletal architecture in PC. Ct displayed more oxidative damage, mitochondrial, and synaptic dysfunction compared to PC.
TL;DR: In this study the 20 mM ammonium formate and acetonitrile in the 57:43 ratio were used as mobile phase for the analysis of valsartan and the responses were peak area, tailing factor and number of theoretical plates.
Abstract: High performance liquid chromatographic method was optimized, developed and validated as per the ICH guidelines. In this study the 20 mM ammonium formate and acetonitrile in the 57:43 ratio were used as mobile phase for the analysis of valsartan. Full factorial design was used to optimize the effect of variable factors. The responses were peak area, tailing factor and number of theoretical plates. The quadratic effect of flow rate and wavelength individually as well as in interaction were most significant (p < 0.0001 and p < 0.0086, respectively) on peak area; the quadratic effect of pH of buffer was also most significant effect (p < 0.0001) on tailing factor (5%) whereas the quadratic effect of flow rate and wavelength individually was significant (p = 0.0006 and p = 0.0265, respectively) on the number of theoretical plates. The high-performance liquid chromatographic separation was performed at the flow rate 1.0 min/mL, UV detector wavelength 250 nm and pH of the buffer 3.0 as optimized parameters using design of experiments. The retention time values of valsartan were found to be 10.177 min. Percent recovery in terms of accuracy for the prepared valsartan nanoparticles was found in the range of 98.57-100.27%.
TL;DR: Altered epigenetic signatures in insulin-2 gene promoter region of Undernourished rats are not reversed by nutrient recuperation, and may contribute to the persistent detrimental metabolic profiles in similar multigenerational undernourishing human populations.
TL;DR: In this paper, the synthesis and characterization of new heterocyclic pyrazole chalcones (4a-e) and diamide derivatives are described, and their biological activity is assessed in vitro using MCF-7 (human breast adenocarcinoma) and HeLa (human cervical tumor cells) cell lines.
TL;DR: The results suggest that NJM/fractions possess significant antiproliferative potential which is mediated through cell cycle perturbation and pro-apoptotic effects in MDA-MB-231 cells, and highlights the antioxidant potential of NJM-fractions which can be attributed to the presence of phenols.
Abstract: Nardostachys jatamansi DC is a Himalayan medicinal herb that has been described in various traditional systems of medicine for its use in cancer. In view of its traditional claims, and chemical constituents, antioxidant and anticancer activities were evaluated in breast carcinoma. Petroleum ether (NJPE), methanol extract (NJM) and subsequent diethyl ether (NJDE), ethyl acetate (NJEA) and aqueous (NJAQ) fractions of roots and rhizomes of N. jatamansi were prepared. Total phenolic, flavonoid content, and antioxidant activities were determined using suitable methods. Antiproliferative activity was assessed in estrogen receptor (ER)-positive (MCF-7) and ER-negative breast carcinoma (MDA-MB-231) cells by MTT and SRB assay. Cell cycle analysis, Hoechst staining, and clonogenic assay were employed to determine the mode of antiproliferative and pro-apoptotic activity in MDA-MB-231 cells. NJM/fractions exhibited prominent antioxidant activity with significant correlation between phenolic content and ABTS (IC50) scavenging (R = −0.9680, P 0.05). In MTT assay, NJM exhibited the highest antiproliferative activity (IC50: 58.01 ± 6.13 and 23.83 ± 0.69 μg/mL in MCF-7 and MDA-MB-231 respectively). Among the fractions, NJPE and NJDE were found to be most potent in MCF-7 (IC50: 60.59 ± 4.78 μg/mL) and MDA-MB-231 (IC50: 25.04 ± 0.90 μg/mL) cells respectively. Statistical analyses revealed NJM and NJDE exhibited significantly higher (P < 0.05) cytotoxicity in MDA-MB-231 cells. Cell cycle analysis demonstrated that NJM, NJPE and NJEA caused G2/M arrest while NJDE caused G0/G1 phase arrest in MDA-MB-231 cells. Further, NJM/fractions induced significant (P < 0.001) cell death by apoptosis characterized by apoptotic morphological changes in Hoechst staining and inhibited long-term proliferation (P < 0.001) of MDA-MB-231 cells in clonogenic assay. Lupeol and β-sitosterol were identified as anticancer principles in NJM/fractions by HPTLC. Our results suggest that NJM/fractions possess significant antiproliferative potential which is mediated through cell cycle perturbation and pro-apoptotic effects in MDA-MB-231 cells. Moreover, this study highlights the antioxidant potential of NJM/fractions which can be attributed to the presence of phenols. NJDE emerged as the most potent fraction and further mechanistic and phytochemical investigations are under way to identify the active principles.
TL;DR: In this article, nano porous activated carbon having specific surface area of 400m 2 ǫg −1 from sugarcane waste (bagasse) has been synthesized and characterized as an electrode material for supercapacitor applications using ionic liquid based polymer gel electrolytes.
Abstract: Low cost with high specific capacitance and energy density is the critical and main requirement for practical supercapacitors. In the present work, nano porous activated carbon having specific surface area of 400 m 2 g −1 from sugarcane waste (bagasse) has been synthesized and characterized as an electrode material for supercapacitor applications using ionic liquid based polymer gel electrolytes. The fabricated cell shows the overall specific capacitance of 372 mF cm −2 which is equivalent to single electrode specific capacitance of 248 F g −1 . The corresponding energy and power density of 16.3 Wh kg −1 and 1.66 kW kg −1 were achieved for EDLCs.
TL;DR: RDGB regulates PtdIns and PTDIns(4,5)P2 homeostasis during G-protein-activated phospholipase C signalling in Drosophila and couples the turnover of both Ptd Ins and PtdOH, key lipid intermediates during G -protein-coupled Ptd inservice 4,5-bisphosphate turnover.
Abstract: Many membrane receptors activate phospholipase C (PLC) during signalling, triggering changes in the levels of several plasma membrane lipids including phosphatidylinositol (PtdIns), phosphatidic acid (PtdOH) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. It is widely believed that exchange of lipids between the plasma membrane and endoplasmic reticulum (ER) is required to restore lipid homeostasis during PLC signalling, yet the mechanism remains unresolved. RDGBα (hereafter RDGB) is a multi-domain protein with a PtdIns transfer protein (PITP) domain (RDGB-PITPd). We find that, in vitro, the RDGB-PITPd binds and transfers both PtdOH and PtdIns. In Drosophila photoreceptors, which experience high rates of PLC activity, RDGB function is essential for phototransduction. We show that binding of PtdIns to RDGB-PITPd is essential for normal phototransduction; however, this property is insufficient to explain the in vivo function because another Drosophila PITP (encoded by vib) that also binds PtdIns cannot rescue the phenotypes of RDGB deletion. In RDGB mutants, PtdIns(4,5)P2 resynthesis at the plasma membrane following PLC activation is delayed and PtdOH levels elevate. Thus RDGB couples the turnover of both PtdIns and PtdOH, key lipid intermediates during G-protein-coupled PtdIns(4,5)P2 turnover.
TL;DR: SFRP4 treatment would help to improve response to commonly used chemotherapeutics in gliomas by modulating EMT via the Wnt/ß-catenin pathway, which could be exploited for designing better targeted strategies to improve chemo-response and eventually eliminate glioblastoma CSCs.
Abstract: The Wnt pathway is integrally involved in regulating self-renewal, proliferation, and maintenance of cancer stem cells (CSCs) We explored the effect of the Wnt antagonist, secreted frizzled-related protein 4 (sFRP4), in modulating epithelial to mesenchymal transition (EMT) in CSCs from human glioblastoma cells lines, U87 and U373 sFRP4 chemo-sensitized CSC-enriched cells to the most commonly used anti-glioblastoma drug, temozolomide (TMZ), by the reversal of EMT Cell movement, colony formation, and invasion in vitro were suppressed by sFRP4+TMZ treatment, which correlated with the switch of expression of markers from mesenchymal (Twist, Snail, N-cadherin) to epithelial (E-cadherin) sFRP4 treatment elicited activation of the Wnt-Ca2+ pathway, which antagonizes the Wnt/s-catenin pathway Significantly, the chemo-sensitization effect of sFRP4 was correlated with the reduction in the expression of drug resistance markers ABCG2, ABCC2, and ABCC4 The efficacy of sFRP4+TMZ treatment was demonstrated in vivo using nude mice, which showed minimum tumor engraftment using CSCs pretreated with sFRP4+TMZ These studies indicate that sFRP4 treatment would help to improve response to commonly used chemotherapeutics in gliomas by modulating EMT via the Wnt/s-catenin pathway These findings could be exploited for designing better targeted strategies to improve chemo-response and eventually eliminate glioblastoma CSCs
TL;DR: The result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treatDDX3 associated oral cancer.
Abstract: DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer. In this work, we employed a High Throughput Virtual screening approach to identify bioactive compounds against DDX3 from ZINC natural database. Ketorolac salt was selected based on its binding free energy less than or equals to −5 Kcal/mol with reference to existing synthetic DDX3 inhibitors and strong hydrogen bond interactions as similar to crystallized DDX3 protein (2I4I). The anti-cancer activity of Ketorolac salt against DDX3 was tested using oral squamous cell carcinoma (OSCC) cell lines. This compound significantly down regulated the expression of DDX3 in human OSCC line (H357) and the half maximal growth inhibitory concentration (IC50) of Ketorolac salt in H357 cell line is 2.6 µM. Ketorolac salt also inhibited the ATP hydrolysis by directly interacting with DDX3. More importantly, we observed decreased number of neoplastic tongue lesions and reduced lesion severity in Ketorolac salt treated groups in a carcinogen induced tongue tumor mouse model. Taken together, our result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treat DDX3 associated oral cancer.
TL;DR: The aim of this review is to provide first time researchers in this area with an introduction to inositol pyrophosphates and a comprehensive overview on their cellular functions.
Abstract: Inositol pyrophosphates are water soluble derivatives of inositol that contain pyrophosphate or diphosphate moieties in addition to monophosphates. The best characterised inositol pyrophosphates, are IP7 (diphosphoinositol pentakisphosphate or PP-IP5), and IP8 (bisdiphosphoinositol tetrakisphosphate or (PP)2-IP4). These energy-rich small molecules are present in all eukaryotic cells, from yeast to mammals, and are involved in a wide range of cellular functions including apoptosis, vesicle trafficking, DNA repair, osmoregulation, phosphate homeostasis, insulin sensitivity, immune signalling, cell cycle regulation, and ribosome synthesis. Identified more than 20 years ago, there is still only a rudimentary understanding of the mechanisms by which inositol pyrophosphates participate in these myriad pathways governing cell physiology and homeostasis. The unique stereochemical and bioenergetic properties these molecules possess as a consequence of the presence of one or two pyrophosphate moieties in the vicinity of densely packed monophosphates are likely to form the molecular basis for their participation in multiple signalling and metabolic pathways. The aim of this review is to provide first time researchers in this area with an introduction to inositol pyrophosphates and a comprehensive overview on their cellular functions.
TL;DR: The present review highlighted the influence of physicochemical factors and structural features of the hydrophobic drug on its solubility in lipid excipients and an attempt was made to explore the role of each component of self-microemulsifying drug delivery systems in the formation of stable microemulsion upon dilution.
Abstract: Pharmaceutical research is focused in designing novel drug delivery systems to improve the bioavailability of poorly water soluble drugs. Self-microemulsifying drug delivery systems, one among the lipid-based dosage forms were proven to be promising in improving the oral bioavailability of such drugs by enhancing solubility, permeability and avoiding first-pass metabolism via enhanced lymphatic transport. Further, they have been successful in avoiding both inter and intra individual variations as well as the dose disproportionality. Aqueous insoluble drugs, in general, show greater solubility in lipid based excipients, and hence they are formulated as lipid based drug delivery systems. The extent of solubility of a hydrophobic drug in lipid excipients i.e. oil, surfactant and co-surfactant (components of self-microemulsifying drug delivery systems) greatly affects the drug loading and in producing stable self-microemulsifying drug delivery systems. The present review highlighted the influence of physicochemical factors and structural features of the hydrophobic drug on its solubility in lipid excipients and an attempt was made to explore the role of each component of self-microemulsifying drug delivery systems in the formation of stable microemulsion upon dilution.
TL;DR: It is suggested that a small subnetwork of highly active and stable neurons supports group stability, and that this endows neuronal networks with the flexibility to continuously remodel without compromising stability and function.
Abstract: Various plasticity mechanisms, including experience-dependent, spontaneous, as well as homeostatic ones, continuously remodel neural circuits. Yet, despite fluctuations in the properties of single neurons and synapses, the behavior and function of neuronal assemblies are generally found to be very stable over time. This raises the important question of how plasticity is coordinated across the network. To address this, we investigated the stability of network activity in cultured rat hippocampal neurons recorded with high-density multielectrode arrays over several days. We used parametric models to characterize multineuron activity patterns and analyzed their sensitivity to changes. We found that the models exhibited sloppiness, a property where the model behavior is insensitive to changes in many parameter combinations, but very sensitive to a few. The activity of neurons with sloppy parameters showed faster and larger fluctuations than the activity of a small subset of neurons associated with sensitive parameters. Furthermore, parameter sensitivity was highly correlated with firing rates. Finally, we tested our observations from cell cultures on an in vivo recording from monkey visual cortex and we confirm that spontaneous cortical activity also shows hallmarks of sloppy behavior and firing rate dependence. Our findings suggest that a small subnetwork of highly active and stable neurons supports group stability, and that this endows neuronal networks with the flexibility to continuously remodel without compromising stability and function.
TL;DR: Hospital wastewaters should be carefully treated to prevent the contamination of Indian environment with antimicrobial-resistant bacteria, according to logistic regression analysis.