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author:("Singh, ajeeb")
1.  Improved Antidepressant Remission in Major Depression via a Pharmacokinetic Pathway Polygene Pharmacogenetic Report 
Major depressive disorder (MDD) is projected to be a leading cause of disability globally by 2030. Only a minority of patients remit with antidepressants. If assay of polymorphisms influencing central nervous system (CNS) bioavailability could guide prescribers to more effectively dose patients, remission rates may improve and the burden of disease from MDD reduce. Hepatic and blood brain barrier (BBB) polymorphisms appear to influence antidepressant CNS bioavailability.
A 12-week prospective double blind randomized genetically guided versus unguided trial of antidepressant dosing in Caucasian adults with MDD (n=148) was conducted.
Subjects receiving genetically guided prescribing had a 2.52-fold greater chance of remission (95% confidence interval [CI]=1.71–3.73, z=4.66, p<0.0001). The number needed to genotype (NNG)=3 (95% CI=1.7–3.5) to produce an additional remission.
These data suggest that a pharmacogenetic dosing report (CNSDose®) improves antidepressant efficacy. The effect size was sufficient that translation to clinical care may arise if results are independently replicated.
PMCID: PMC4540033  PMID: 26243841
Pharmacogenetics; Pharmacogenomics; Individualized medicine; Antidepressive agents; Major depression
2.  Effects of Persisting Emotional Impact from Child Abuse and Norepinephrine Transporter Genetic Variation on Antidepressant Efficacy in Major Depression: A Pilot Study 
Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and anti-depressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials.
Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history.
No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85–514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error.
The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.
PMCID: PMC4423165  PMID: 25912538
Abuse; Child; Antidepressants; Norepinephrine transporter; Remission
3.  A brief review of exercise, bipolar disorder, and mechanistic pathways 
Despite evidence that exercise has been found to be effective in the treatment of depression, it is unclear whether these data can be extrapolated to bipolar disorder. Available evidence for bipolar disorder is scant, with no existing randomized controlled trials having tested the impact of exercise on depressive, manic or hypomanic symptomatology. Although exercise is often recommended in bipolar disorder, this is based on extrapolation from the unipolar literature, theory and clinical expertise and not empirical evidence. In addition, there are currently no available empirical data on program variables, with practical implications on frequency, intensity and type of exercise derived from unipolar depression studies. The aim of the current paper is to explore the relationship between exercise and bipolar disorder and potential mechanistic pathways. Given the high rate of medical co-morbidities experienced by people with bipolar disorder, it is possible that exercise is a potentially useful and important intervention with regard to general health benefits; however, further research is required to elucidate the impact of exercise on mood symptomology.
PMCID: PMC4349127  PMID: 25788889
bipolar disorder; exercise; mechanistic pathways; depression; hypomania; neurogenesis
4.  Clinico-radiological profile and risk factors in patients with anthracosis 
Anthracosis is the black pigmentation of the mucosal lining of the tracheo-bronchial tree. The significance of this finding is not known and often ignored. The aim of the present study is to find the association of anthracosis with demographic variables, biomass fuel and occupational exposure, respiratory diseases, radiological pattern and functional morbidity.
Materials and Methods:
Enrolment of the subjects for the study was done at SMS hospital, Jaipur. Patients with anthracosis evident on bronchoscopy were included as the cases. Patients without anthracosis on bronchoscopy, matched according to age, gender and smoking habits, were included in the control group. Subjects in both the arms completed a questionnaire and also underwent computed tomography (CT) of the chest and six minute walk test (6MWT).
Thirty cases and 53 controls were included in the study. The patients with anthracosis presented with symptoms ranging from cough (76.65%), hemoptysis (46.6%), fever (26.6%), dyspnea (90%) and malaise (73.3%). Biomass fuel exposure for the cases was 35.13 ± 55.86 hours in a year and for the controls was 28.15 ± 40.09 hours in a year (P > 0.05). Stone mining was significantly associated with anthracosis (P < 0.05). CT chest revealed fibrosis (43.3%), consolidation (33.3%), cavitation (16.6%) and mass (46.6%) in the cases. Sixty percent of cases and 15% of controls were diagnosed to have either old or active pulmonary tuberculosis (P < 0.05).
Anthracosis is associated with pulmonary tuberculosis. Biomass exposure is not significantly associated with anthracosis. Post tubercular fibrosis is more common on CT chest of patients with anthracosis.
PMCID: PMC4372861  PMID: 25814792
Anthracofibrosis; anthracosis; biomass smoke; bronchoscopy; lung cancer; tuberculosis
5.  HgsDb: Haplogroups Database to understand migration and molecular risk assessment 
Bioinformation  2015;11(6):272-275.
HgsDb, a database is developed to organize the data under a single platform to facilitate easy access for researcher to get information on migration and molecular risk assessment. In past, human beings migrate from one place to other over the globe in search of food and better habitat, where they got adapted. These adaptations are visible in the form of change in color, facial pattern, average height, eye shape, hair texture, etc. This leads to origin of different race of human being. The adaptations are remarkable when move from equator to either poles. There are hundreds of different haplogroups reported on both maternal and paternal sites. This database provides overview of seventy-six major Haplogroup of mt-DNA and Y-DNA with their sub classes supplemented with structural information of individual Haplogroup responsible for various factor such molecular risk assessment, migration and origin. They help genealogist to gain deep insight information about their maternal and paternal patterns. , we had collected data from open source such as National Center for Biotechnology (NCBI), to develop this database for providing information, which Will helps the medical biology, molecular biology, genealogy and for designing personalized medicine.
PMCID: PMC4512000
Haplogroup; HgsDb; Molecular risk assessment; mt-DNA; Y-DNA
6.  Differentially expressed seed aging responsive heat shock protein OsHSP18.2 implicates in seed vigor, longevity and improves germination and seedling establishment under abiotic stress 
Small heat shock proteins (sHSPs) are a diverse group of proteins and are highly abundant in plant species. Although majority of these sHSPs were shown to express specifically in seed, their potential function in seed physiology remains to be fully explored. Our proteomic analysis revealed that OsHSP18.2, a class II cytosolic HSP is an aging responsive protein as its abundance significantly increased after artificial aging in rice seeds. OsHSP18.2 transcript was found to markedly increase at the late maturation stage being highly abundant in dry seeds and sharply decreased after germination. Our biochemical study clearly demonstrated that OsHSP18.2 forms homooligomeric complex and is dodecameric in nature and functions as a molecular chaperone. OsHSP18.2 displayed chaperone activity as it was effective in preventing thermal inactivation of Citrate Synthase. Further, to analyze the function of this protein in seed physiology, seed specific Arabidopsis overexpression lines for OsHSP18.2 were generated. Our subsequent functional analysis clearly demonstrated that OsHSP18.2 has ability to improve seed vigor and longevity by reducing deleterious ROS accumulation in seeds. In addition, transformed Arabidopsis seeds also displayed better performance in germination and cotyledon emergence under adverse conditions. Collectively, our work demonstrates that OsHSP18.2 is an aging responsive protein which functions as a molecular chaperone and possibly protect and stabilize the cellular proteins from irreversible damage particularly during maturation drying, desiccation and aging in seeds by restricting ROS accumulation and thereby improves seed vigor, longevity and seedling establishment.
PMCID: PMC4568394  PMID: 26442027
sHSP; chaperone; seed vigor; CDT; stress
7.  In silico analysis and modeling of putative T cell epitopes for vaccine design of Toscana virus 
3 Biotech  2014;5(4):497-503.
The sandfly fever Toscana virus is an important etiological agent known to cause human neurological infections in endemic Mediterranean countries during summer season. In the present study, prediction and modeling of T cell epitopes of Toscana virus (TOSV) antigenic proteins followed by the binding simulation studies of predicted highest binding scorers with their corresponding MHC class II alleles were done. Immunoinformatics was applied in computational vaccinology to analyze the viral proteins which generate possible outcomes to elicit vaccine for TOSV. Here, immunoinformatic tool ProPred was used to predict the promiscuous MHC class II epitopes of viral antigenic proteins. The molecular modeling of the selected epitopes as well as MHC alleles was done at CPH model 3.2 server. Molecular dynamics (MD) simulation studies were performed through the NAMD graphical user interface embedded in visual molecular dynamics. The epitope/peptide VKMMIVLNL of viral nucleoprotein as well as VMILGLLSS of viral glycoprotein has shown the highest binding score with the same DRB1*1104 MHC II allele. These two predicted peptides are highly potential to induce T cell-mediated immune response and are expected to be useful in designing epitope-based vaccines after further testing. The results signify that the nucleoprotein, glycoprotein or the combination of both could be useful for future development of a vaccine controlling the spread of this emerging virus that could pose a new threat for humans.
PMCID: PMC4522722
Toscana virus; ProPred; Structural modeling; Docking; Molecular dynamics; Vaccine design
8.  Atypical antipsychotic agents; Peas in a pod or chalk and cheese? 
BMC Medicine  2014;12:126.
With escalating health expenditure and a shrinking purse, there is increased focus on the cost efficacy of still patented versus generic medications in general, and for atypical antipsychotics in particular. In a recent BMC Medicine article, Godman and colleagues presented data indicating poor uptake of the off patent atypical antipsychotic risperidone, arguing for authorities to mandate its greater use. This is under the assumption of clinical equivalence of atypical antipsychotics. This commentary argues that there are clinically meaningful differences between atypical antipsychotics and important inter-individual heterogeneity in clinical response and tolerability. Access to a broad range of atypical antipsychotics enables clinicians to tailor care, taking consideration of differential efficacy and adverse effects profile in order to meet the needs of individual patients with improved real world effectiveness of treatment. Restriction of agent choice risks detracting from optimal clinical care, with possible poorer outcomes and greater costs of care. A balance between encouraging use of cheapest in class agent and allowing access to various atypical agents for tailored care is likely to produce optimal health outcomes.
Please see related article:
PMCID: PMC4243724
Atypical antipsychotics; Risperidone; Bipolar; Schizophrenia; Generic; Health economics
9.  SOX8 Regulates Permeability of the Blood-Testes Barrier That Affects Adult Male Fertility in the Mouse1 
Biology of Reproduction  2013;88(5):133.
Sertoli cells provide nutritional and physical support to germ cells during spermatogenesis. Sox8 encodes a member of the high mobility group of transcription factors closely related to Sox9 and Sox10. Sertoli cells express SOX8 protein, and its elimination results in an age-dependent dysregulation of spermatogenesis, causing adult male infertility. Among the claudin genes with altered expression in the Sox8−/− testes, was claudin-3, which is required for the regulation and maintenance of the blood-testes barrier (BTB). Because the BTB is critical in restricting small molecules in the luminal compartment of the seminiferous tubules, the aim of this study was to analyze the level of tight junction proteins (claudin-3, claudin-11, and occludin) and BTB permeability in Sox8−/− adult testes. The acetylation level of alpha-tubulin and microtubule organization was also evaluated because microtubules are critical in maintaining the microenvironment of the seminiferous epithelium. Western blot analysis shows that claudin-3 protein is decreased in Sox8−/− testes. Chromatin immunoprecipitation confirmed that SOX8 binds at the promoter region of claudin-3. Claudin-3 was localized to the Sertoli cell tight junctions of wild-type testes and significantly decreased in the Sox8−/− testes. The use of biotin tracers showed increased BTB permeability in the Sox8−/− adult testes. Electron microscopy analysis showed that microtubule structures were destabilized in the Sox8−/− testes. These results suggest that Sox8 is essential in Sertoli cells for germ cell differentiation, partly by controlling the microenvironment of the seminiferous epithelium.
PMCID: PMC4434911  PMID: 23595903
blood-testes barrier; male fertility; Sertoli cell; SOX8; testes; tight junction
10.  Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors 
BMC Genomics  2014;15(Suppl 1):S3.
Tuberculosis has become a major health problem being the second leading cause of death worldwide. Mycobacterium tuberculosis secretes a virulence factor, protein tyrosine phosphatase B (mPTPB) in the cytoplasm of host macrophage which suppresses its natural innate immune response and helps the pathogen survive and proliferate in the phagosome. The present study aims at indentifying potent inhibitors of mPTPB by using computational approaches of ligand based molecular modeling and docking studies.
A 3D QSAR model was developed using a set of benzofuran salicylic acid based mPTPB inhibitors with experimentally known IC50 values. The model was generated using the statistical method of principle component regression analysis in combination with step wise forward variable selection algorithm. It was observed that steric and hydrophobic descriptors positively contribute towards the inhibitory activity of the ligands. The developed model had a robust internal as well as external predictive power as indicated by the q2 value of 0.8920 and predicted r2 value of 0.8006 respectively. Hence, the generated model was used to screen a large set of naturally occurring chemical compounds and predict their biological activity to identify more potent natural compounds targeting mPTPB. The two top potential hits (with pIC50 value of 1.459 and 1.677 respectively) had a similar interaction pattern as that of the most potent compound (pIC50 = 1.42) of the congeneric series.
The contour plot provided a better understanding of the relationship between structural features of substituted benzofuran salicylic acid derivatives and their activities which would facilitate design of novel mPTPB inhibitors. The QSAR modeling was used to obtain an equation, correlating the important steric and hydrophobic descriptors with the pIC50 value. Thus, we report two natural compounds of inhibitory nature active against mPTPB enzyme of Mycobacterium tuberculosis. These inhibitors have the potential to evolve as lead molecules in the development of drugs for the treatment of tuberculosis.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-S1-S3) contains supplementary material, which is available to authorized users.
PMCID: PMC4046716  PMID: 24564493
QSAR; PTPB; Tuberculosis; Virtual screening; Tyrosine phosphatase; Inhibitor
11.  Virtual screening of phytochemicals to novel targets in Haemophilus ducreyi towards the treatment of Chancroid 
Bioinformation  2014;10(8):502-506.
Conventionally, drugs are discovered by testing chemically synthesized compounds against a battery of in vivo biological screens. Information technology and Omic science enabled us for high throughput screening of compound libraries against biological targets and hits are then tested for efficacy in cells or animals. Chancroid, caused by Haemophilus ducreyi is a public health problem and has been recognized as a cofactor for Human Immunodeficiency Virus (HIV) transmission. It facilitates HIV transmission by providing an accessible portal entry, promoting viral shedding, and recruiting macrophages as well as CD4 cells to the skin. So, there is a requirement to develop an efficient drug to combat Chancroid that can also diminish HIV infection. In-silico screening of potential inhibitors against the target may facilitate in detection of the novel lead compounds for developing an effective chemo preventive strategy against Haemophilus ducreyi. The present study has investigated the effects of approximately 1100 natural compounds that inhibit three vital enzymes viz. Phosphoenolpyruvate phosphotransferase, Acetyl-coenzyme A carboxylase and Fructose 1, 6-bisphosphatase of Haemophilus ducreyi in reference to a commercial drug Rifabutin. Results reveal that the lead compound uses less energy to bind to target. The lead compound parillin has also been predicted as less immunogenic in comparison to Rifabutin. Further, better molecular dynamics, pharmacokinetics, pharmacodynamics and ADME-T properties establish it as an efficient chancroid preventer.
PMCID: PMC4166769  PMID: 25258485
Haemophilus ducreyi; Chancroid; Rifabutin; Molecular docking; Molecular dynamics; RMSD
12.  Analysis of the SWI/SNF chromatin-remodeling complex during early heart development and BAF250a repression cardiac gene transcription during P19 cell differentiation 
Nucleic Acids Research  2013;42(5):2958-2975.
The regulatory networks of differentiation programs and the molecular mechanisms of lineage-specific gene regulation in mammalian embryos remain only partially defined. We document differential expression and temporal switching of BRG1-associated factor (BAF) subunits, core pluripotency factors and cardiac-specific genes during post-implantation development and subsequent early organogenesis. Using affinity purification of BRG1 ATPase coupled to mass spectrometry, we characterized the cardiac-enriched remodeling complexes present in E8.5 mouse embryos. The relative abundance and combinatorial assembly of the BAF subunits provides functional specificity to Switch/Sucrose NonFermentable (SWI/SNF) complexes resulting in a unique gene expression profile in the developing heart. Remarkably, the specific depletion of the BAF250a subunit demonstrated differential effects on cardiac-specific gene expression and resulted in arrhythmic contracting cardiomyocytes in vitro. Indeed, the BAF250a physically interacts and functionally cooperates with Nucleosome Remodeling and Histone Deacetylase (NURD) complex subunits to repressively regulate chromatin structure of the cardiac genes by switching open and poised chromatin marks associated with active and repressed gene expression. Finally, BAF250a expression modulates BRG1 occupancy at the loci of cardiac genes regulatory regions in P19 cell differentiation. These findings reveal specialized and novel cardiac-enriched SWI/SNF chromatin-remodeling complexes, which are required for heart formation and critical for cardiac gene expression regulation at the early stages of heart development.
PMCID: PMC3950667  PMID: 24335282
13.  Cnot1, Cnot2, and Cnot3 Maintain Mouse and Human ESC Identity and Inhibit Extraembryonic Differentiation 
Stem cells (Dayton, Ohio)  2012;30(5):910-922.
Embryonic stem cell (ESC) identity and self-renewal is maintained by extrinsic signaling pathways and intrinsic gene regulatory networks. Here, we show that three members of the Ccr4-Not complex, Cnot1, Cnot2, and Cnot3, play critical roles in maintaining mouse and human ESC identity as a protein complex and inhibit differentiation into the extraembryonic lineages. Enriched in the inner cell mass of blastocysts, these Cnot genes are highly expressed in ESC and downregulated during differentiation. In mouse ESCs, Cnot1, Cnot2, and Cnot3 are important for maintenance in both normal conditions and the 2i/LIF medium that sup ports the ground state pluripotency. Genetic analysis indicated that they do not act through known self-renewal pathways or core transcription factors. Instead, they repress the expression of early trophectoderm (TE) transcription factors such as Cdx2. Importantly, these Cnot genes are also necessary for the maintenance of human ESCs, and silencing them mainly lead to TE and primitive endoderm differ entiation. Together, our results indicate that Cnot1, Cnot2, and Cnot3 represent a novel component of the core self-renewal and pluripotency circuitry conserved in mouse and human ESCs.
PMCID: PMC3787717  PMID: 22367759
Ccr4-Not; Embryonic stem cell; Self-renewal; Pluripotency; Extraembryonic differentiation
14.  Sensory Neuron-Derived Eph Regulates Glomerular Arbors and Modulatory Function of a Central Serotonergic Neuron 
PLoS Genetics  2013;9(4):e1003452.
Olfactory sensory neurons connect to the antennal lobe of the fly to create the primary units for processing odor cues, the glomeruli. Unique amongst antennal-lobe neurons is an identified wide-field serotonergic neuron, the contralaterally-projecting, serotonin-immunoreactive deutocerebral neuron (CSDn). The CSDn spreads its termini all over the contralateral antennal lobe, suggesting a diffuse neuromodulatory role. A closer examination, however, reveals a restricted pattern of the CSDn arborization in some glomeruli. We show that sensory neuron-derived Eph interacts with Ephrin in the CSDn, to regulate these arborizations. Behavioural analysis of animals with altered Eph-ephrin signaling and with consequent arborization defects suggests that neuromodulation requires local glomerular-specific patterning of the CSDn termini. Our results show the importance of developmental regulation of terminal arborization of even the diffuse modulatory neurons to allow them to route sensory-inputs according to the behavioural contexts.
Author Summary
Serotonin, a major neuromodulatory transmitter, regulates diverse behaviours. Serotonergic dysfunction is implicated in various neuropsychological disorders, such as anxiety and depression, as well as in neurodegenerative disorders. In the central nervous systems, across taxa, serotonergic neurons are often small in number but connect to and act upon multiple brain circuits through their wide-field arborization pattern. We set out to decipher mechanisms by which wide-field serotonergic neurons differentially innervate their target-field to modulate behavior in a context-dependent manner. We took advantage of the sophisticated antennal lobe circuitry, the primary olfactory centre in the adult fruitfly Drosophila melanogaster. Olfactory sensory neurons and projection neurons connect in a partner-specific manner to create glomerular units in the antennal lobe for processing the sense of smell. Our analysis at a single-cell resolution reveals that a wide-field serotonergic neuron connects to all the glomeruli in the antennal lobe but exhibits the glomerular-specific differences in its innervation pattern. Our key finding is that Eph from sensory neurons regulates the glomerular-specific innervation pattern of the central serotonergic neuron, which in turn is essential for modulation of odor-guided behaviours in an odor-specific manner.
PMCID: PMC3630106  PMID: 23637622
15.  A consensus statement for safety monitoring guidelines of treatments for major depressive disorder 
This paper aims to present an overview of screening and safety considerations for the treatment of clinical depressive disorders and make recommendations for safety monitoring.
Data were sourced by a literature search using MEDLINE and a manual search of scientific journals to identify relevant articles. Draft guidelines were prepared and serially revised in an iterative manner until all co-authors gave final approval of content.
Screening and monitoring can detect medical causes of depression. Specific adverse effects associated with antidepressant treatments may be reduced or identified earlier by baseline screening and agent-specific monitoring after commencing treatment.
The adoption of safety monitoring guidelines when treating clinical depression is likely to improve overall physical health status and treatment outcome. It is important to implement these guidelines in the routine management of clinical depression.
PMCID: PMC3190838  PMID: 21888608
16.  Bmpr1a is required for proper migration of the AVE through regulation of Dkk1 expression in the pre-streak mouse embryo 
Developmental biology  2010;341(1):246-254.
Here, we report a novel mechanism regulating migration of the anterior visceral endoderm (AVE) by BMP signaling through BMPRIA. In Bmpr1a-deficient (Bmpr-null) embryos, the AVE does not migrate at all. In embryos with an epiblast-specific deletion of Bmpr1a (Bmpr1anull/flox; Sox2Cre embryos), the AVE cells migrate randomly from the distal end of embryos, resulting in an expansion of the AVE. Dkk1, which is normally expressed in the anterior proximal visceral endoderm (PxVE), is downregulated in Bmpr-null embryos, whereas it is circumferentially expressed in Bmpr1anull/flox; Sox2Cre embryos at E5.75–6.5. These results demonstrate an association of the position of Dkk1 expressing cells with direction of the migration of AVE. In Bmpr1anull/flox; Sox2Cre embryos, a drastic decrease of WNT signaling is observed at E6.0. Addition of WNT3A to the culture of Bmpr1anull/flox; Sox2Cre embryos at E5.5 restores expression patterns of Dkk1 and Cer1. These data indicate that BMP signaling in the epiblast induces Wnt3 and Wnt3a expression to maintain WNT signaling in the VE, resulting in downregulation of Dkk1 to establish the anterior expression domain. Thus, our results suggest that BMP signaling regulates the expression patterns of Dkk1 for anterior migration of the AVE.
PMCID: PMC2854289  PMID: 20211162
BMP signaling; AVE; Dkk1; Wnt3; Wnt3a
17.  Oral Bioavailability Enhancement of Exemestane from Self-Microemulsifying Drug Delivery System (SMEDDS) 
AAPS PharmSciTech  2009;10(3):906-916.
Limited aqueous solubility of exemestane leads to high variability in absorption after oral administration. To improve the solubility and bioavailability of exemestane, the self-microemulsifying drug delivery system (SMEDDS) was developed. SMEDDS comprises of isotropic mixture of natural or synthetic oil, surfactant, and cosurfactant, which, upon dilution with aqueous media, spontaneously form fine o/w microemulsion with less than 100 nm in droplet size. Solubility of exemestane were determined in various vehicles. Ternary phase diagrams were plotted to identify the efficient self-emulsification region. Dilution studies, droplet size, and zeta potential of the formulations were investigated. The release of exemestane from SMEDDS capsules was studied using USP dissolution apparatus in different dissolution media and compared the release of exemestane from a conventional tablet. Oral pharmacokinetic study was performed in female Wistar rats (n = 8) at the dose of 30 mg kg−1. The absorption of exemestane from SMEDDS form resulted in about 2.9-fold increase in bioavailability compared with the suspension. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as exemestane by the oral route.
PMCID: PMC2802159  PMID: 19609837
bioavailability enhancement; exemestane; microemulsion; SMEDDS
18.  Exemestane Loaded Self-Microemulsifying Drug Delivery System (SMEDDS): Development and Optimization 
AAPS PharmSciTech  2008;9(2):628-634.
The purpose of this research work was to formulate and characterize self-micro emulsifying drug delivery system containing exemestane. The solubility of exemestane was determined in various vehicles. Pseudo ternary phase diagram was used to evaluate the micro-emulsification existence area. SMEDDS formulations were tested for micro-emulsifying properties, and the resultant formulations loaded with exemestane (ME1, ME2, ME3, ME4 and ME5) were investigated for clarity, phase separation, globule size and shape, zeta potential, effect of various diluents and dilutions, thermodynamic and thermal stability. From the results it is concluded that increase in droplet size is proportional to the concentration of oil in SMEDDS formulation. Minor difference in the droplet size and zeta potential was observed by varying the diluents (deionized water and 0.1 N HCl) and dilutions (1:10, 1:50 and 1:100). Formulations, which were found to be thermodynamically stable (ME1, ME2, ME3 and ME4), were subjected to stability studies as per International Conference on Harmonization (ICH) guidelines. No significant variations were observed in the formulations over a period of 3 months at accelerated and long-term conditions. TEM photographs of microemulsions formulations further conformed the spherical shape of globules. Among the various SMEDDS formulations, ME4 offer the advantages of good clarity systems at high oil content and thus offer good solubilization of exemestane. Thus this study indicates that the SMEDDS can be used as a potential drug carrier for dissolution enhancement of exemestane and other lipophilic drug(s).
PMCID: PMC2976939  PMID: 18473177
aromatase inhibitors; exemestane; microemulsion; SMEDDS
19.  Influences of Reduced Expression of Maternal Bone Morphogenetic Protein 2 on Embryonic Development 
Bone morphogenetic protein 2 (BMP2) was originally found by its osteoinductive ability, and recent genetic analyses have revealed that it plays critical roles during early embryogenesis, cardiogenesis, decidualization as well as skeletogenesis. During a course of evaluation of the conditional allele for Bmp2, we found that the presence of a neo cassette, a selection marker needed for gene targeting events in embryonic stem cells, in the 3’ untranslated region of exon 3 of Bmp2, reduced the expression levels of Bmp2 both in embryonic and maternal tissues. Some of the embryos that were genotyped as transheterozygous for the floxed allele with the neo cassette over the conventional null allele (fn/−) showed a lethal phenotype including defects in cephalic neural tube closure and ventral abdominal wall closure. Embryos exhibiting these abnormalities were increased when genotypes of the pregnant females were different; when expression levels of Bmp2 in maternal tissues were lower, a larger proportion of fn/− embryos exhibit these abnormalities. These results suggest that the expression levels of Bmp2 together in both in embryonic and maternal tissues influence the normal neural tube closure and body wall closure with different thresholds.
PMCID: PMC2632600  PMID: 18769073
BMP2; hypomorphic; neural tube closure; decidualization; omphalocele
20.  Metamorphosis of an identified serotonergic neuron in the Drosophila olfactory system 
Neural Development  2007;2:20.
Odors are detected by sensory neurons that carry information to the olfactory lobe where they connect to projection neurons and local interneurons in glomeruli: anatomically well-characterized structures that collect, integrate and relay information to higher centers. Recent studies have revealed that the sensitivity of such networks can be modulated by wide-field feedback neurons. The connectivity and function of such feedback neurons are themselves subject to alteration by external cues, such as hormones, stress, or experience. Very little is known about how this class of central neurons changes its anatomical properties to perform functions in altered developmental contexts. A mechanistic understanding of how central neurons change their anatomy to meet new functional requirements will benefit greatly from the establishment of a model preparation where cellular and molecular changes can be examined in an identified central neuron.
In this study, we examine a wide-field serotonergic neuron in the Drosophila olfactory pathway and map the dramatic changes that it undergoes from larva to adult. We show that expression of a dominant-negative form of the ecdysterone receptor prevents remodeling. We further use different transgenic constructs to silence neuronal activity and report defects in the morphology of the adult-specific dendritic trees. The branching of the presynaptic axonal arbors is regulated by mechanisms that affect axon growth and retrograde transport. The neuron develops its normal morphology in the absence of sensory input to the antennal lobe, or of the mushroom bodies. However, ablation of its presumptive postsynaptic partners, the projection neurons and/or local interneurons, affects the growth and branching of terminal arbors.
Our studies establish a cellular system for studying remodeling of a central neuromodulatory feedback neuron and also identify key elements in this process. Understanding the morphogenesis of such neurons, which have been shown in other systems to modulate the sensitivity and directionality of response to odors, links anatomy to the development of olfactory behavior.
PMCID: PMC2129096  PMID: 17958902

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