Showing papers by "Central Drug Research Institute published in 2018"
TL;DR: The pivotal role of these receptors in the modulation of neurogenesis is highlighted, a possible therapeutic target that might help to slow down the process of neurodegeneration.
Abstract: Dopamine controls various physiological functions in the brain and periphery by acting on its receptors D1, D2, D3, D4, and D5. Dopamine receptors are G protein-coupled receptors involved in the regulation of motor activity and several neurological disorders such as schizophrenia, bipolar disorder, Parkinson's disease (PD), Alzheimer's disease, and attention-deficit/hyperactivity disorder. Reduction in dopamine content in the nigrostriatal pathway is associated with the development of PD, along with the degeneration of dopaminergic neurons in the substantia nigra region. Dopamine receptors directly regulate neurotransmission of other neurotransmitters, release of cyclic adenosine monophosphate, cell proliferation, and differentiation. Here, we provide an update on recent knowledge about the signalling mechanism, mode of action, and the evidence for the physiological and functional basis of dopamine receptors. We also highlight the pivotal role of these receptors in the modulation of neurogenesis, a possible therapeutic target that might help to slow down the process of neurodegeneration.
147 citations
TL;DR: Current understanding on Tf-conjugated nanocarriers as efficient drug delivery system is presented and approach towards successful delivery of antitumor agents to the gliomas has been making possible through targeting these overexpressed TfRs within the CNS and glioma cells.
Abstract: Treatment of glioblastoma multiforme (GBM) is a predominant challenge in chemotherapy due to the existence of blood-brain barrier (BBB) which restricts delivery of chemotherapeutic agents to the brain together with the problem of drug penetration through hard parenchyma of the GBM. With the structural and mechanistic elucidation of the BBB under both physiological and pathological conditions, it is now viable to target central nervous system (CNS) disorders utilizing the presence of transferrin (Tf) receptors (TfRs). However, overexpression of these TfRs on the GBM cell surface can also help to avoid restrictions of GBM cells to deliver chemotherapeutic agents within the tumor. Therefore, targeting of TfR-mediated delivery could counteract drug delivery issues in GBM and create a delivery system that could cross the BBB effectively to utilize ligand-conjugated drug complexes through receptor-mediated transcytosis. Hence, approach towards successful delivery of antitumor agents to the gliomas has been making possible through targeting these overexpressed TfRs within the CNS and glioma cells. This review article presents a thorough analysis of current understanding on Tf-conjugated nanocarriers as efficient drug delivery system.
109 citations
TL;DR: This review presents an overview and critical analysis of pharmaceutical implications and therapeutic feasibility of CNT based scaffolds in improving the cardiac tissue regeneration and functionality and signifies their feasibility in cardiac tissue regenerative medicines and stem cell therapy.
106 citations
TL;DR: An overview of the roles of immune and inflammatory responses and their consequences in PD disease pathogenesis is provided and possible therapeutic strategies for PD are discussed based on these findings.
Abstract: Studies in the last decade have suggested the association of both neuroinflammatory processes and immune responses in Parkinson disease (PD) pathology. PD pathology is related to depleted dopamine levels, α-synuclein aggregation, and death of nigrostriatal dopaminergic neurons. Reports have suggested central and peripheral inflammation in the prodromal stage of the disease, which is sustained during disease progression. Alongside the activation of peripheral immune system exacerbates the dissonant central inflammatory responses and could contribute in synergistic neurodegeneration. Activated glial cells contribute significantly in the neuroinflammatory process during the occurrence of the disease and are also acknowledged as a hallmark of disease progression. However, the contribution of glial cells is not well defined in the context of neurodegeneration and neuroprotection. This review provides an overview of the roles of immune and inflammatory responses and their consequences in PD disease pathogenesis and also discusses possible therapeutic strategies for PD based on these findings.
80 citations
TL;DR: From nanocarrier-based recent researches of PTX with special stress towards TPGS-nanoparticle-mediated delivery in the improvement of cancer treatment, dynamic fabrications of the nanoparticulate therapy stimulate cellular interaction with frontier area for future research in tumor targeting potential.
79 citations
TL;DR: In this paper, luminous carbon quantum dots (CQDs) prepared from aqueous beetroot extract were developed as unique fluorescent nanomaterials for in vivo live animal imaging applications.
Abstract: Luminescent carbon quantum dots (CQDs) prepared from aqueous beetroot extract were developed as unique fluorescent nanomaterials for in vivo live animal imaging applications. Blue (B) and green (G) emitting environmentally benign CQDs (particle size of 5 nm and 8 nm, respectively) exhibited bright fluorescence in aqueous medium and were found to be biocompatible, photostable and non-toxic in animal models. The in vivo imaging and toxicity evaluation of both CQDs were performed for the first time in the Caenorhabditis elegans (C. elegans) model, which revealed consistent fluorescence in the gut tissues of the worms without exerting any sign of toxic effects on the nematodes. The in vivo bio-distribution of G-CQDs given by tail vein injection in live BALB/c mice showed optical signals in the lower abdominal regions, mainly in the intestine, and cleared from the body through faeces. The tremendous potential shown by these eco-friendly CQDs in the C. elegans and mice models advocates new hopes for greener CQD nanomaterials as diagnostic tools in the biomedical field.
71 citations
TL;DR: Employing transgenic C. elegans model of PD, RNase R-mediated cleavage of linear RNA followed by divergent primer-based amplifications are used towards identifying circzip-2, a novel circRNA molecule, which is synthesized from functionally important gene zip-2.
Abstract: Circular RNAs (circRNAs) are peculiar non-coding RNA molecules which are known to be present across taxa. Considering the body of evidence that establishes critical functions of non-coding RNA molecules, we endeavored to study circRNAs in the context of Parkinson’s disease (PD). Employing transgenic C. elegans model of PD, we used RNase R-mediated cleavage of linear RNA followed by divergent primer-based amplifications towards identifying circzip-2, a novel circRNA molecule. We went on to sequence circzip-2 which is synthesized from functionally important gene zip-2. Studying RNAi-induced knockdown conditions of zip-2, we observed a reduced aggregation of α-synuclein protein along with an enhanced lifespan of the worms. We further carried out transcriptome analysis of zip-2 silenced worms, which suggested that zip-2 might be functioning via Daf-16 pathway. Further interaction studies revealed that circzip-2 possibly sponges microRNA molecule miR-60 towards asserting an important role in various processes associated with PD.
69 citations
TL;DR: This review has been written to discuss on the influence of Histone Deacetylases in cancer malignancies and to embrace majority of the developments made till date in the field of HDAC and its inhibitors.
62 citations
60 citations
TL;DR: Enhanced neuroinflammation (increased Glial fibrillary acidic protein (GFAP) & nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF&kgr;B) and diminished insulin signaling was observed in this study in both neurogenic areas, however the extent to which they may have negative impact on neurogenes is yet to be explored.
59 citations
TL;DR: It is demonstrated that MaRAP2‐4 is a positive regulator of waterlogging tolerance, and as energy‐consuming processes such as carbohydrate biosynthesis are reduced under water logging‐induced hypoxia, sugar transport through SWEETs may be the primary option to make sugar available to the required tissue.
Abstract: As waterlogging and successive events severely influence growth and development of economically important plants, we attempted to characterize the role of a waterlogging-responsive group I (A-6) ethylene response factor (MaRAP2-4) from Mentha arvensis. Waterlogging, ethylene and methyl jasmonate rapidly induced the expression of MaRAP2-4. MaRAP2-4 interacted with multiple cis-elements like dehydration response elements (DRE1/2), anoxia/jasmonic acid response element (JARE) and GCC box showing its involvement in multiple responses. MaRAP2-4 localizes in the nucleus and acts as a transcriptional activator. Truncation and internal deletion identified a 20 amino acids potential transactivation domain (PLPSSVDAKLEAICQSLAIN) in MaRAP2-4. MaRAP2-4 transgenic Arabidopsis showed enhanced waterlogging and subsequent oxidative stress tolerance. Microarray analysis revealed that within up-regulated genes 483, 212 and 132 promoters carry either single or multiple copies of DRE, JARE and GCC cis-element/s, respectively. Within these promoters, a large section belongs to carbohydrate metabolism/transport, including many SWEET transporters. Further analysis showed MaRAP2-4 specifically targets two positions in AtSWEEET10 promoter carrying DRE and/or GCC box that might regulate carbohydrate availability and waterlogging tolerance. These results demonstrate that MaRAP2-4 is a positive regulator of waterlogging tolerance, and as energy-consuming processes such as carbohydrate biosynthesis are reduced under waterlogging-induced hypoxia, sugar transport through SWEETs may be the primary option to make sugar available to the required tissue.
TL;DR: Prepared GC-ANLC could be used as a promising drug carrier for delivery of asenapine via intranasal route with better pharmacokinetic and safety profile.
TL;DR: This study highlighted the abundance of actinobacteria from freshwater sediments of two rivers and one lake and the isolates were studied for their ability to produce antimicrobial bioactive compounds.
Abstract: Actinobacteria from freshwater habitats have been explored less than from other habitats in the search for compounds of pharmaceutical value. This study highlighted the abundance of actinobacteria from freshwater sediments of two rivers and one lake, and the isolates were studied for their ability to produce antimicrobial bioactive compounds. 16S rRNA gene sequencing led to the identification of 84 actinobacterial isolates separated into a common genus (Streptomyces) and eight rare genera (Nocardiopsis, Saccharopolyspora, Rhodococcus, Prauserella, Amycolatopsis, Promicromonospora, Kocuria and Micrococcus). All strains that showed significant inhibition potentials were found against Gram-positive, Gram-negative and yeast pathogens. Further, three biosynthetic genes, polyketide synthases type II (PKS II), nonribosomal peptide synthetases (NRPS) and aminodeoxyisochorismate synthase (phzE), were detected in 38, 71 and 29% of the strains, respectively. Six isolates based on their antimicrobial potentials were selected for the detection and quantification of standard antibiotics using ultra performance liquid chromatography (UPLC–ESI–MS/MS) and volatile organic compounds (VOCs) using gas chromatography mass spectrometry (GC/MS). Four antibiotics (fluconazole, trimethoprim, ketoconazole and rifampicin) and 35 VOCs were quantified and determined from the methanolic crude extract of six selected Streptomyces strains. Infectious diseases still remain one of the leading causes of death globally and bacterial infections caused millions of deaths annually. Culturable actinobacteria associated with freshwater lake and river sediments has the prospects for the production of bioactive secondary metabolites.
TL;DR: It was found that exaggerated inflammatory response and oxidative stress were associated with RAS over-activation, suggesting that functionally active AT2R is required for beneficial effects of AT1R blockade, and candesartan shows neuroprotection by inhibiting TLR4/Ang II-induced NF-κB inflammatory signaling.
Abstract: Clinical studies demonstrated a positive correlation between hypertension and cognitive decline. Beneficial effects of angiotensin II receptor blockers on cognitive functions have also been reported earlier; however, its role in chronic neuroinflammation-induced memory impairment in the hypertensive state is not well understood. Therefore, in the present study, we investigated the effect of angiotensin II receptor blockers on memory impairment induced by lipopolysaccharide (LPS) in spontaneously hypertensive rats (SHRs). Our data provides the strong evidence that intracerebroventricular (ICV) administration of LPS (25 μg) on the 1st, 4th, 7th, and 10th days leads to sustained neuroinflammation (as indicated by increased TNF-α, GFAP, COX-2, and NF-κB) and oxidative stress (increased reactive oxygen species (ROS) and nitrite levels) resulting in amyloid beta (Aβ1–42) deposition, apoptosis (increased Bax and decreased Bcl-2 expression as well as increased caspase-3 activity and TUNEL-positive cells), and memory impairment. Further, we found that exaggerated inflammatory response and oxidative stress were associated with RAS over-activation (as evident from the increased ACE expression, angiotensin II (Ang II) level, and angiotensin type 1 receptor (AT1R) expression) and decreased BDNF and p-CREB expression. Oral administration of candesartan (an AT1R blocker) at a non-anti-hypertensive dose (0.1 mg/kg) for 15 days attenuated LPS-induced (ICV) apoptosis, amyloidogenesis, and memory impairment. Candesartan shows neuroprotection by inhibiting TLR4/Ang II-induced NF-κB inflammatory signaling and by enhancing associated BDNF/CREB expression in SHRs. Our study also demonstrated that when both AT1R and angiotensin type 2 receptor (AT2R) were blocked by candesartan and PD123319 concomitantly, the protective effects of candesartan were blunted suggesting that functionally active AT2R is required for beneficial effects of AT1R blockade.
TL;DR: An anti-carbonickelative cyclization via reversible alkenylnickel E/Z isomerization of 2-azido phenyl propargyl alcohols with aryl boronic acids is achieved using Ni(acac)2 as the catalyst to access 2,3-diaryl quinolines.
TL;DR: It is suggested that HA coated LPT-NCs formulation enhances the activity of LPT against triple negative breast cancer, exhibiting magnificent therapeutic outcome at low dose thus presenting a strategy to reduce dose administrations and minimize dose related toxicity.
TL;DR: This review represents a discussion around the molecular targets with their implications in disease progression, available therapeutic options, the emerging targets, and the importance of designing an effective anti‐osteoporotic agent.
Abstract: With an increase in the ageing population worldwide, the prevalence of osteoporosis increases at an alarming rate in both male and female irrespective of their ethnicity. At present, the currently available therapeutic options are mostly limited to either bone resorptive or bone forming efficacies and both approaches are associated with serious side effects. Despite these options, there is still need for newer therapeutics to treat osteoporosis, which can offer beneficial effects for maintaining balanced dynamics between bone formation and bone resorption, devoid of any side effect. The proper understanding of pathophysiology of the disease is essential for designing or investigating an effective and safe anti-osteoporotic agent. This review represents a discussion around the molecular targets with their implications in disease progression, available therapeutic options, the emerging targets, and the importance of designing an effective anti-osteoporotic agent.
TL;DR: In this paper, the authors developed hydrogel dressings with interpolymeric complexation using chitosan to enhance wound healing activity in excision wound model and evaluated the efficacy of the dressings based on the time taken for complete healing of the wounds.
TL;DR: The data revealed that hypertension induces robust microglial and astrocyte activation, neuroinflammation, and cripples hippocampal neurogenesis, and provided the evidence that AT1R blockade by activating Wnt/β-catenin signaling, promotes neuroGenesis during hypertensive state.
Abstract: Hypertension is one of the major risk factors for central nervous system (CNS) disorders like stroke and Alzheimer’s disease (AD). On the other hand, CNS diseases like AD have been associated with gliosis and impaired neurogenesis. Further, renin angiotensin system (RAS) is intricately associated with hypertension; however, the accumulating evidences suggest that over-activity of RAS may perpetuate the brain inflammation related with AD. Therefore, in the present study, we examined the effect of hypertension and RAS on glial (astrocytes and microglia) activation and hippocampal neurogenesis in a rat model of chronic hypertension. We used Candesartan [angiotensin type 1 receptor (AT1R) blocker (ARB)] both at a low dose (0.1 mg/kg) and anti-hypertensive dose (2 mg/kg) to explore whether their effect on astrocyte and microglial activation, neuroinflammation, and neurogenesis is blood pressure (BP) dependent or independent. Our data revealed that hypertension induces robust microglial and astrocyte activation, neuroinflammation, and cripples hippocampal neurogenesis. Importantly, AT1R blockade by Candesartan, even at low dose (0.1 mg/kg), prevented astrocyte and microglial activation and neuroinflammation in the brain of hypertensive rats. Mechanistically, AT1R blockade prevented the activation of NADPH oxidase, reactive oxygen species (ROS) generation, suppression of MAP kinase and NFкB signaling. Importantly, we, for the first time to our knowledge, provided the evidence that AT1R blockade by activating Wnt/β-catenin signaling, promotes neurogenesis during hypertensive state. We conclude that AT1R blockade prevents astrocyte and microglial activation and improves hippocampal neurogenesis in hypertensive state, independent of BP lowering action.
TL;DR: It is reported for the first time that oral administration of Bacillus clausii in postmenopausal osteoporotic mice model enhances bone health, and this effect was found due to skewing of Treg-Th17 cell balance (enhanced Treg and decreased Th17 cells) in vivo.
TL;DR: A new series of 1,2,3-triazole linked 4(3H)-quinazolinones have emerged as promising candidates for treating multidrug resistant Staphylococcus aureus infections and are able to escape current drug-resistance mechanisms.
TL;DR: DMCs can serve as markers for inclusion in infertility screening panels, particularly those in the genes showing differential methylation consistent with previous studies, and the genes validated by deep sequencing are strong candidates for investigations of their roles in spermatogenesis.
Abstract: Study question Do methylation changes in sperm DNA correlate with infertility? Study answer Loss of spermatogenesis and fertility was correlated with 1680 differentially-methylated CpGs (DMCs) across 1052 genes. What is known already Methylation changes in a number of genes have been correlated with reduced sperm count and motility. Study design, size, duration This case-control study used spermatozoal DNA from 38 oligo-/oligoastheno-zoospermic infertile patients and 26 normozoospermic fertile men. Participants/materials, settings, methods Genome-wide methylation analysis was undertaken using 450 K BeadChip on spermatozoal DNA from six infertile and six fertile men to identify DMCs. This was followed by deep sequencing of spermatozoal DNA from 32 infertile patients and 20 fertile controls. Main results and the role of chance A total of 1680 DMCs were identified, out of which 1436 were hypermethylated and 244 were hypomethylated. Classification of DMCs according to the genes identified BCAN, CTNNA3, DLGAP2, GATA3, MAGI2 and TP73 among imprinted genes, SPATA5, SPATA7, SPATA16 and SPATA22 among spermatogenesis-associated genes, KDM4C and JMJD1C, EZH2 and HDAC4 among genes which regulate methylation and gene expression, HLA-C, HLA-DRB6 and HLA-DQA1 among complementation and immune response genes, and CRISPLD1, LPHN3 and CPEB2 among other genes. Genes showing significant differential methylation in deep sequencing, i.e. HOXB1, GATA3, EBF3, BCAN and TCERG1L, are strong candidates for further investigations. The role of chance was ruled out by deep sequencing of select genes. Large-scale data N/A. Limitations, reason for caution Genome-wide analyses are fairly accurate, but may not be exactly validated in replication studies across all DMCs. We used the 't' test in the genome-wide methylation analysis, whereas other tests could provide a more robust and powerful analysis. Wider implications of the findings DMCs can serve as markers for inclusion in infertility screening panels, particularly those in the genes showing differential methylation consistent with previous studies. The genes validated by deep sequencing are strong candidates for investigations of their roles in spermatogenesis. Study funding/competing interest(s) The study was funded by the Council of Scientific and Industrial Research (CSIR), Govt. of India with grant number BSC0101 awarded to Rajender Singh. None of the authors has any competing interest to declare.
TL;DR: The present study shows that the novel curcumin mimic 6a is a safe and efficacious anticancer compound, however, it needs to be optimized for better efficacy.
TL;DR: Nanoemulsion is a multifunctional nanocarrier capable of enhancing drug delivery potential of cytotoxic agents, thereby, can improve the outcomes of cancer treatment by increasing the life-span of the patient and quality of life, however, further clinical research and characterization of interactive reactions should need to be explored.
Abstract: Background Targeting chemotherapeutic agents to the tumor tissues and achieving accumulation with ideal release behavior for desired therapy requires an ideal treatment strategy to inhibit division of rapid growing cancerous cells and as an outcome improve patient's quality of life. However, majority of the available anticancer therapies are well known for their systemic toxicities and multidrug resistance. Methods Application of nanotechnology in medicine have perceived a great evolution during past few decades. Nanoemulsion, submicron sized thermodynamically stable distribution of two immiscible liquids, has gained extensive importance as a nanocarrier to improve chemotherapies seeking to overcome the limitations of drug solubilization, improving systemic delivery of the chemotherapeutics to the site of action to achieve a promising inhibitory in tumor growth profile with reduced systemic toxicity. Results and conclusion This review has focused on potential application of nanoemulsion in the translational research and its role in chemotherapy using oral, parenteral and transdermal route to enhance systemic availability of poorly soluble drug. In summary, nanoemulsion is a multifunctional nanocarrier capable of enhancing drug delivery potential of cytotoxic agents, thereby, can improve the outcomes of cancer treatment by increasing the life-span of the patient and quality of life, however, further clinical research and characterization of interactive reactions should need to be explored.
TL;DR: It is suggested that kaempferol reduced GC-induced bone loss and enhanced bone regeneration at fractured site, thus emphasizing the positive role of flavonoids on bone health.
TL;DR: Results revealed that prototype 2-methyl-4-phenylquinoline-3-carboxylate derivatives synthesized via click chemistry inspired molecular hybridization approach represents a new structural lead for antileishmanial chemotherapy.
TL;DR: The data suggest that pharmacological/genetic manipulation of Wnt signaling that enhances the endogenous regenerative capacity of DAergic neurons may have implication for regenerative approaches in Parkinson's disease.
TL;DR: Semen parameters in Indian men have declined with time and the deterioration is quantitatively higher in the infertile group than in the fertile group, according to systematic review and quantitative analysis.
Abstract: Since the first report of a decline in semen quality in 1974, there have been several reports of similar declines across populations. Despite some scattered reports of declining semen quality in the Indian sub-continent, comprehensive studies analyzing semen quality over the last few decades have not been undertaken. We undertook the present study to investigate the temporal trend in semen parameters in Indian populations over a period of 37 years (1979–2016). Publications providing semen analysis details for fertile and infertile men from the Indian sub-continent were collected by a thorough literature search. Semen quality data for 6466 normal fertile or presumptive normal men (from 119 studies/data sets) and 7020 infertile men (from 63 studies/data sets) published between 1979 and 2016 were retrieved. We undertook systematic review and quantitative analysis of mean sperm count, motility, normal morphology and other available parameters. Data were analyzed to estimate semen parameters reference values for Indian men and to assess temporal trends in infertile, fertile and all subjects. Seminal quality shows a decreasing temporal trend and the decrease is higher in infertile than fertile males. In pooled analysis for all individuals, significant (p < 0.05 or < 0.001) declines in sperm concentration and normal morphology are observed; however, isolated analysis for each group shows declines without statistical significance. The mean (± SD) semen volume, sperm concentration, total motility, rapid linear progressive motility, normal sperm morphology and sperm viability for Indian fertile men are 2.88 ± 0.77 ml, 81.08 ± 29.21 million/ml, 66.37 ± 10.95%, 52.64 ± 15.78%, 56.68 ± 20.23% and 72.63 ± 8.31%, respectively, whereas in infertile these are 3.07 ± 1.27 ml, 37.94 ± 26.41 million/ml, 40.22 ± 13.76%, 26.79 ± 15.47%, 36.41 ± 21.66% and 55.25 ± 11.99%, respectively. The mean seminal parameter values were significantly lower (p < 0.001) in infertile as compared to fertile men, except semen volume. Semen parameters in Indian men have declined with time and the deterioration is quantitatively higher in the infertile group. The study also provides reference values for semen parameters in Indian men.
TL;DR: An extensive structure–activity relationship investigation pinpointed two compounds (R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model and exhibited minimal hERG inhibition.
Abstract: Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1-b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads (R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure–activity relationship investigation pinpointed two compounds (R-6 and pyridine R-136) with better solubility and pharmacokinet...
TL;DR: Four series of structurally related β-lactams, 2,5-pyrrolidinediones, azaspirodecatrienediones and dihydropyrroloquinoxalinetriones (DPQT) could be useful for the development of anti-obesity candidate drugs.