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1.  Growth Inhibition and Apoptosis Induction by (+)-Cyanidan-3-ol in Hepatocellular Carcinoma 
PLoS ONE  2013;8(7):e68710.
The objective of this study was to evaluate the cytotoxicity of (+)-cyanidan-3-ol (CD-3) in human hepatocellular carcinoma cell line (HepG2) and chemopreventive potential against hepatocellular carcinoma (HCC) in Balb/c mice. The HepG2 cell line was treated with CD-3 at various concentrations and the proliferation of the HepG2 cells was measure by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT), sulforhodamine B (SRB) and lactate dehydrogenase (LDH) assays. Cell apoptosis was detected by Hoechst 33258 (HO), Acridine orange/ethylene dibromide (AO/EB) staining, DNA fragmentation analysis and the apoptosis rate was detected by flow cytometry. The HCC tumor model was established in mice by injecting N-nitrosodiethylamine/carbon tetrachloride (NDEA/CCl4) and the effect of CD-3 on tumor growth in-vivo was studied. The levels of liver injury markers, tumor markers, and oxidative stress were measured. The expression levels of apoptosis-related genes in in-vitro and in vivo models were determined by RT-PCR and ELISA. The CD-3 induced cell death was considered to be apoptotic by observing the typical apoptotic morphological changes under fluorescent microscopy and DNA fragmentation analysis. Annexin V/PI assay demonstrated that apoptosis increased with increase in the concentration of CD-3. The expression levels of apoptosis-related genes that belong to bcl-2 and caspase family were increased and AP-1 and NF-κB activities were significantly suppressed by CD-3. Immunohistochemistry data revealed less localization of p53, p65 and c-jun in CD-3 treated tumors as compared to localization in NDEA/CCl4 treated tumors. Taken together, our data demonstrated that CD-3 could significantly inhibit the proliferation of HepG2 cells in-vitro and suppress HCC tumor growth in-vivo by apoptosis induction.
doi:10.1371/journal.pone.0068710
PMCID: PMC3722203  PMID: 23894334
2.  Optimization of Procedures for Isolation of Mycobacteria from Soil and Water Samples Obtained in Northern India 
For isolation of environmental mycobacteria, a decontamination procedure has been standardized by which treatment with 3% sodium dodecyl sulfate plus 4% NaOH (15 and 30 min for rapid and slow growers, respectively) is followed by incubation with 2% cetrimide (5 and 15 min for fast- and slow-growing mycobacteria, respectively); this procedure was found to completely eliminate contamination with other organisms and resulted in the isolation of only mycobacteria.
doi:10.1128/AEM.70.6.3751-3753.2004
PMCID: PMC427771  PMID: 15184184
3.  A Comparative Study of Eustachian Tube Functions in Normal and Diseased Ears with Tympanometry and Videonasopharyngoscopy 
Eustachian tube is a bony and fibrocartilagenous tube extending from the antero-inferior part of middle ear cleft to lateral wall of the nasopharynx. Its main functions are ventilation of middle ear to equalize the middle ear pressure with atmospheric pressure and mucociliary clearance. The functioning of eustachian tube has a direct impact on normal middle ear function. As a corollary, dysfunction of eustachian tube inevitably leads to retraction of the tympanic membrane initially and sterile effusion and subsequent conductive deafness later. Secretory otitis media today is the most common cause of conductive deafness in children with an intact ear drum. Evaluation of function of eustachian tube assumes paramount importance in this scenario. To evaluate eustachian tube functions in normal and diseased ears with tympanometry and videonasopharyngoscopy and to compare the tympanometric tests of eustachian tube function with videonasopharyngoscopy and to assess their reliability. The study was conducted at Army hospital (R&R) Delhi Cantt from October 2005 to April 2007. Hundred (100) ears were examined and were divided into two groups, the control group with normal tympanic membrane on otoscopy and case group with complaints of diminished hearing and intact but retracted tympanic membrane. Their eustachian tube function was evaluated by tympanometric tests and videonasopharyngoscopy. Thereafter a comparison was made between the two. The study revealed that videonasopharyngoscopy was highly accurate and reliable test for eustachian tube function as compared to tympanometry. Slow motion video analysis of eustachian tube dynamics is a useful tool for further understanding the pathophysiology of tubal dysfunction.
doi:10.1007/s12070-011-0312-9
PMCID: PMC3889352  PMID: 24427699
Eustachian tube; Tympanometry; Videonasopharyngoscopy; Visual analogue score
4.  Discovery of Triazine Mimetics As Potent Antileishmanial Agents 
ACS Medicinal Chemistry Letters  2013;4(11):1108-1113.
The World Health Organization has classified the leishmaniasis as a major tropical disease. The discovery of new compounds for leishmaniasis is therefore a pressing concern for the anti-infective research program. We have synthesized 19 compounds of triazine dimers as novel antileishmanial agents. Most of the synthesized derivatives exhibited better activity against intracellular amastigotes (IC50 ranging from 0.77 to 10.32 μM) than the control, pentamidine (IC50 = 13.68 μM), and are not toxic to Vero cells. Compounds 14 and 15 showed significant in vivo inhibition of 74.41% and 62.64%, respectively, in L. donovani/hamster model. Moreover, expansion of Th1-type and suppression of Th2-type immune responses proved that compound 14 stimulates mouse macrophages to prevent the progression of leishmania parasite. The molecular docking studies involving PTR1 protein PDB further validated the concepts involved in the design of these compounds. Among the investigated analogues, compound 14 has emerged as the potential one to enlarge the scope of the study.
doi:10.1021/ml400317e
PMCID: PMC4027224  PMID: 24900613
L. donovani; triazine; pentamidine; in vitro/in vivo; pteridine reductase 1
5.  Role of Gist and PHOG Features in Computer-Aided Diagnosis of Tuberculosis without Segmentation 
PLoS ONE  2014;9(11):e112980.
Purpose
Effective diagnosis of tuberculosis (TB) relies on accurate interpretation of radiological patterns found in a chest radiograph (CXR). Lack of skilled radiologists and other resources, especially in developing countries, hinders its efficient diagnosis. Computer-aided diagnosis (CAD) methods provide second opinion to the radiologists for their findings and thereby assist in better diagnosis of cancer and other diseases including TB. However, existing CAD methods for TB are based on the extraction of textural features from manually or semi-automatically segmented CXRs. These methods are prone to errors and cannot be implemented in X-ray machines for automated classification.
Methods
Gabor, Gist, histogram of oriented gradients (HOG), and pyramid histogram of oriented gradients (PHOG) features extracted from the whole image can be implemented into existing X-ray machines to discriminate between TB and non-TB CXRs in an automated manner. Localized features were extracted for the above methods using various parameters, such as frequency range, blocks and region of interest. The performance of these features was evaluated against textural features. Two digital CXR image datasets (8-bit DA and 14-bit DB) were used for evaluating the performance of these features.
Results
Gist (accuracy 94.2% for DA, 86.0% for DB) and PHOG (accuracy 92.3% for DA, 92.0% for DB) features provided better results for both the datasets. These features were implemented to develop a MATLAB toolbox, TB-Xpredict, which is freely available for academic use at http://sourceforge.net/projects/tbxpredict/. This toolbox provides both automated training and prediction modules and does not require expertise in image processing for operation.
Conclusion
Since the features used in TB-Xpredict do not require segmentation, the toolbox can easily be implemented in X-ray machines. This toolbox can effectively be used for the mass screening of TB in high-burden areas with improved efficiency.
doi:10.1371/journal.pone.0112980
PMCID: PMC4229306  PMID: 25390291
7.  MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer 
Oncotarget  2014;5(17):7599-7609.
Pancreatic cancer has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MUC13, a transmembrane mucin is highly involved in pancreatic cancer progression. Thus, understanding its regulatory molecular mechanisms may offer new avenue of therapy for prevention/treatment of pancreatic cancer. Herein, we report a novel microRNA (miR-145)-mediated mechanism regulating aberrant MUC13 expression in pancreatic cancer. We report that miR-145 expression inversely correlates with MUC13 expression in pancreatic cancer cells and human tumor tissues. miR-145 is predominantly present in normal pancreatic tissues and early Pancreatic Ductal Adenocarcinoma (PDAC) precursor lesions (PanIN I) and is progressively suppressed over the course of development from PanIN II/III to late stage poorly differentiated PDAC. We demonstrate that miR-145 targets 3′ untranslated region of MUC13 and thus downregulates MUC13 protein expression in cells. Interestingly, transfection of miR-145 inhibits cell proliferation, invasion and enhances gemcitabine sensitivity. It causes reduction of HER2, P-AKT, PAK1 and an increase in p53. Similar results were found when MUC13 was specifically inhibited by shRNA directed at MUC13. Additionally, intratumoral injections of miR-145 in xenograft mice inhibited tumor growth via suppression of MUC13 and its downstream target, HER2. These results suggest miR-145 as a novel regulator of MUC13 in pancreatic cancer.
PMCID: PMC4202147  PMID: 25277192
Pancreatic cancer; MUC13; MicroRNA; Tumor suppressor; Diagnostics; Therapeutics
8.  Novel Curcumin Loaded Magnetic Nanoparticles for Pancreatic Cancer Treatment 
Molecular cancer therapeutics  2013;12(8):1471-1480.
Curcumin (CUR), a naturally occurring polyphenol derived from the root of Curcuma longa, has demonstrated potent anti-cancer and cancer prevention activity in a variety of cancers. However, the clinical translation of curcumin has been significantly hampered due to its extensive degradation, suboptimal pharmacokinetics and poor bioavailability. To address these clinically relevant issues, we have developed a novel curcumin loaded magnetic nanoparticle (MNP-CUR) formulation. Herein, we have evaluated the in vitro and in vivo therapeutic efficacy of this novel MNP-CUR formulation in pancreatic cancer. Human pancreatic cancer cells (HPAF-II and Panc-1) exhibited efficient internalization of the MNP-CUR formulation in a dose dependent manner. As a result, the MNP-CUR formulation effectively inhibited growth of HPAF-II and Panc-1 cells in cell proliferation and colony formation assays. The MNP-CUR formulation suppressed pancreatic tumor growth in an HPAF-II xenograft mice model and improved mice survival by delaying tumor growth. The growth inhibitory effect of MNP-CUR formulation was correlated with the suppression of PCNA, Bcl-xL, Mcl-1, MUC1, Collagen I and enhanced membrane β-catenin expression. MNP-CUR formulation did not show any sign of hemotoxicity and was stable after incubation with human serum proteins. Additionally, the MNP-CUR formulation improved serum bioavailability of curcumin in mice up to 2.5 fold as compared to free curcumin. Biodistribution studies demonstrate that a significant amount of MNP-CUR formulation was able to reach the pancreatic xenograft tumor(s) which suggests its clinical translational potential. In conclusion, this study suggests that our novel MNP-CUR formulation can be valuable for the treatment of pancreatic cancer.
doi:10.1158/1535-7163.MCT-12-1227
PMCID: PMC3965353  PMID: 23704793
magnetic nanoparticles; curcumin; chemoprevention; pancreatic cancer; nanomedicine
9.  Variation in alpha radioactivity of plants with the use of different fertilizers and radon measurement in fertilized soil samples 
Background
People are exposed to ionizing radin from the radionuclides that are present in different types of natural sources, of which phosphate fertilizer is one of the most important sources. Fertilizers are commonly used in agricultural field worldwide to enhance the crop yield.
Materials and methods
In the present investigation, a control study was carried out on the lady’s finger plants grown in earthen pots. To observe the effect of fertilizers their equal amounts were added to the soil just before the plantation. The alpha track densities were measured using solid state nuclear track detectors (SSNTDs), a sensitive detector for alpha particles.
Results
The measured alpha track densities (T cm−2d−1) in lady’s finger plants on top and bottom face of leaves after 30, 50 and 70 days of plantation varied from 49 ± 11 to 206 ± 2.6, 49 ± 16 to 248 ± 16 and 57 ± 8.5 to 265 ± 32 respectively in various leaf samples.
Conclusions
The alpha track densities were found to vary with nature of fertilizers added to the soil and an increase was also observed with time. The alpha track densities were also measured in soil samples mixed with different fertilizers. The radon exhalation rates in various soil samples and soil to plant transfer factor (TF) of alpha tracks were also calculated.
doi:10.1186/2052-336X-12-70
PMCID: PMC3999460  PMID: 24812584
Radioactivity; Soil; Fertilizer; Plants; Alpha track density; Radon concentration
10.  ZKSCAN3 (ZNF306) is a Master Transcriptional Repressor of Autophagy 
Molecular cell  2013;50(1):16-28.
Summary
Autophagy constitutes a major cell protective mechanism eliminating damaged components and maintaining energy homoeostasis via recycling nutrients under normal/stressed conditions. Although the core components of autophagy have been well studied, regulation of autophagy at the transcriptional level is poorly understood. Herein, we establish ZKSCAN3, a zinc-finger family DNA-binding protein, as a transcriptional repressor of autophagy. Silencing of ZKSCAN3 induced autophagy and increased lysosome biogenesis. Importantly, we show that ZKSCAN3 represses transcription of a large gene set (>60) integral to, or regulatory for, autophagy and lysosome biogenesis/function and a subset of these genes, including Map1lC3b and Wipi2 represent direct targets. Interestingly, ZKSCAN3 and TFEB are oppositely regulated by starvation and in turn oppositely regulate lysosomal biogenesis and autophagy, suggesting that they act in conjunction. Altogether, our study uncovers an autophagy master-switch regulating the expression of a transcriptional network of genes integral to autophagy and lysosome biogenesis/function.
doi:10.1016/j.molcel.2013.01.024
PMCID: PMC3628091  PMID: 23434374
11.  Experimental Induction of Type 2 Diabetes in Aging-Accelerated Mice Triggered Alzheimer-Like Pathology and Memory Deficits 
Alzheimer’s disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-β, dysregulated tau-phosphorylating glycogen synthase kinase 3β, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD.
doi:10.3233/JAD-131238
PMCID: PMC3941701  PMID: 24121970
Alzheimer’s disease; amyloid-β; diabetes; glycogen synthase kinase-3β; learning and memory; pathological aging of the brain; senescence-accelerated mice; synaptophysin; tau
12.  Modelling and Optimization Studies on a Novel Lipase Production by Staphylococcus arlettae through Submerged Fermentation 
Enzyme Research  2013;2013:353954.
Microbial enzymes from extremophilic regions such as hot spring serve as an important source of various stable and valuable industrial enzymes. The present paper encompasses the modeling and optimization approach for production of halophilic, solvent, tolerant, and alkaline lipase from Staphylococcus arlettae through response surface methodology integrated nature inspired genetic algorithm. Response surface model based on central composite design has been developed by considering the individual and interaction effects of fermentation conditions on lipase production through submerged fermentation. The validated input space of response surface model (with R2 value of 96.6%) has been utilized for optimization through genetic algorithm. An optimum lipase yield of 6.5 U/mL has been obtained using binary coded genetic algorithm predicted conditions of 9.39% inoculum with the oil concentration of 10.285% in 2.99 hrs using pH of 7.32 at 38.8°C. This outcome could contribute to introducing this extremophilic lipase (halophilic, solvent, and tolerant) to industrial biotechnology sector and will be a probable choice for different food, detergent, chemical, and pharmaceutical industries. The present work also demonstrated the feasibility of statistical design tools integration with computational tools for optimization of fermentation conditions for maximum lipase production.
doi:10.1155/2013/353954
PMCID: PMC3880713  PMID: 24455210
13.  Evaluation of a New Lipase from Staphylococcus sp. for Detergent Additive Capability 
BioMed Research International  2013;2013:374967.
Lipases are the enzymes of choice for laundry detergent industries owing to their triglyceride removing ability from the soiled fabric which eventually reduces the usage of phosphate-based chemical cleansers in the detergent formulation. In the present study, a partially purified bacterial lipase from Staphylococcus arlettae JPBW-1 isolated from the rock salt mine has been assessed for its triglyceride removing ability by developing a presoak solution so as to use lipase as an additive in laundry detergent formulations. The effects of selected surfactants, commercial detergents, and oxidizing agents on lipase stability were studied in a preliminary evaluation for its further usage in the industrial environment. Partially purified lipase has shown good stability in presence of surfactants, commercial detergents, and oxidizing agents. Washing efficiency has been found to be enhanced while using lipase with 0.5% nonionic detergent than the anioinic detergent. The wash performance using 0.5% wheel with 40 U lipase at 40°C in 45 min results in maximum oil removal (62%) from the soiled cotton fabric. Hence, the present study opens the new era in enzyme-based detergent sector for formulation of chemical-free detergent using alkaline bacterial lipase.
doi:10.1155/2013/374967
PMCID: PMC3782757  PMID: 24106703
14.  Alterations in mitochondrial DNA copy number and the activities of electron transport chain complexes and pyruvate dehydrogenase in the frontal cortex from subjects with autism 
Translational Psychiatry  2013;3(9):e299-.
Autism is a neurodevelopmental disorder associated with social deficits and behavioral abnormalities. Recent evidence suggests that mitochondrial dysfunction and oxidative stress may contribute to the etiology of autism. This is the first study to compare the activities of mitochondrial electron transport chain (ETC) complexes (I–V) and pyruvate dehydrogenase (PDH), as well as mitochondrial DNA (mtDNA) copy number in the frontal cortex tissues from autistic and age-matched control subjects. The activities of complexes I, V and PDH were most affected in autism (n=14) being significantly reduced by 31%, 36% and 35%, respectively. When 99% confidence interval (CI) of control group was taken as a reference range, impaired activities of complexes I, III and V were observed in 43%, 29% and 43% of autistic subjects, respectively. Reduced activities of all five ETC complexes were observed in 14% of autistic cases, and the activities of multiple complexes were decreased in 29% of autistic subjects. These results suggest that defects in complexes I and III (sites of mitochondrial free radical generation) and complex V (adenosine triphosphate synthase) are more prevalent in autism. PDH activity was also reduced in 57% of autistic subjects. The ratios of mtDNA of three mitochondrial genes ND1, ND4 and Cyt B (that encode for subunits of complexes I and III) to nuclear DNA were significantly increased in autism, suggesting a higher mtDNA copy number in autism. Compared with the 95% CI of the control group, 44% of autistic children showed higher copy numbers of all three mitochondrial genes examined. Furthermore, ND4 and Cyt B deletions were observed in 44% and 33% of autistic children, respectively. This study indicates that autism is associated with mitochondrial dysfunction in the brain.
doi:10.1038/tp.2013.68
PMCID: PMC3784762  PMID: 24002085
autism; electron transport chain; mitochondrial DNA; mitochondrial dysfunction; oxidative stress; pyruvate dehydrogenase
15.  Brain Transit and Ameliorative Effects of Intranasally Delivered Anti-Amyloid-β Oligomer Antibody in 5XFAD Mice 
Alzheimer’s disease (AD) is a global health crisis with limited treatment options. Despite major advances in neurotherapeutics, poor brain penetration due to the blood-brain barrier continues to pose a big challenge in overcoming the access of therapeutics to the central nervous system. In that regard, the non-invasive intranasal route of brain targeting is gaining considerable attention. The nasal mucosa offers a large surface area, rapid absorption, and avoidance of first-pass metabolism increasing drug bioavailability with less systemic side effects. Intranasal delivery is known to utilize olfactory, rostral migratory stream, and trigeminal routes to reach the brain. This investigation confirmed that intranasal delivery of oligomeric amyloid-β antibody (NU4) utilized all three routes to enter the brain with a resident time of 96 hours post single bolus intranasal administration, and showed evidence of perikaryal and parenchymal uptake of NU4 in 5XFAD mouse brain, confirming the intranasal route as a non-invasive and efficient way of delivering therapeutics to the brain. In addition, this study demonstrated that intranasal delivery of NU4 antibody lowered cerebral amyloid-β and improved spatial learning in 5XFAD mice.
doi:10.3233/JAD-122419
PMCID: PMC3722071  PMID: 23542865
Alzheimer’s immunotherapy; amyloid-β oligomer antibody; brain transit; cerebral amyloid-β immunocytochemistry; intranasal delivery; olfactory pathway; rostral migratory stream pathway; spatial acquisition learning; trigeminal pathway
16.  Vacuum Assisted Closure Therapy versus Standard Wound Therapy for Open Musculoskeletal Injuries 
Advances in Orthopedics  2013;2013:245940.
Background. This study was performed to evaluate the results of vacuum assisted wound therapy in patients with open musculoskeletal injuries. Study Design and Setting. Prospective, randomized, and interventional at tertiary care hospital, from 2011 to 2012. Materials and Methods. 30 patients of open musculoskeletal injuries underwent randomized trial of vacuum assisted closure therapy versus standard wound therapy around the upper limb and lower limb. Mean patient age was 39 ± 18 years (range, 18 to 76 years). Necrotic tissues were debrided before applying VAC therapy. Dressings were changed every 3 or 4 days. For standard wound therapy, debridement followed by daily dressings was done. Data Management and Statistical Analysis. The results obtained were subjected to statistical analysis. Results. The size of soft tissue defects reduced more than 5 mm to 25 mm after VAC (mean decrease of 26.66%), whereas in standard wound therapy, reduction in wound size was less than 5 mm. A free flap was needed to cover exposed bone and tendon in one case in standard wound therapy group. No major complication occurred that was directly attributable to treatment. Conclusion. Vacuum assisted wound therapy was found to facilitate the rapid formation of healthy granulation tissue on open wounds in the upper limb and lower limb, thus to shorten healing time and minimize secondary soft tissue defect coverage procedures.
doi:10.1155/2013/245940
PMCID: PMC3710616  PMID: 23878741
17.  Consensus Paper: Pathological Role of the Cerebellum in Autism 
Cerebellum (London, England)  2012;11(3):777-807.
There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.
doi:10.1007/s12311-012-0355-9
PMCID: PMC3677555  PMID: 22370873
cerebellum; autism
18.  Alternatively-spliced extra domain A of fibronectin promotes acute inflammation and brain injury following cerebral ischemia in mice 
Background and purpose
The fibronectin isoform containing the alternatively-spliced extra domain A (EDA+-FN) is normally absent from the circulation, but plasma levels of EDA+-FN can become markedly elevated in several human pathological conditions associated with inflammation including ischemic stroke. It remains unknown whether EDA+-FN contributes to stroke pathogenesis or is simply an associative marker. Several in vitro studies suggest that EDA+-FN can activate toll-like receptor 4 (TLR4), an innate immune receptor that triggers pro-inflammatory responses. We undertook a genetic approach in mice to investigate the ability of EDA+-FN to mediate inflammatory brain damage in a focal cerebral ischemia/reperfusion injury model.
Methods
We used genetically modified EDA+/+ mice, which constitutively express EDA+-FN. Extent of injury, neurological outcome and inflammatory mechanisms were assessed following one hour cerebral ischemia/23 hour reperfusion injury and compared to wild-type (WT) mice.
Results
We found that EDA+/+ mice developed significantly larger infarcts and severe neurological deficits that was associated with significant increased neutrophil and macrophage infiltration as quantitated by immunohistochemistry. Additionally, we found upregulation of NF-κB, COX-2, and inflammatory cytokines TNFα, IL-1β and IL-6 in the EDA+/+ mice compared to WT mice. Interestingly, increased brain injury and neurological deficits were largely abrogated in EDA+/+ mice by treatment with a specific TLR4 inhibitor.
Conclusions
These findings provide the first evidence that EDA+-FN promotes inflammatory brain injury following ischemic stroke and suggest that the elevated levels of plasma EDA+-FN observed in chronic inflammatory conditions could worsen injury and outcome in patients following acute stroke.
doi:10.1161/STROKEAHA.111.635516
PMCID: PMC3335936  PMID: 22363055
Fibronectin; Inflammation; Cerebral ischemia; mice
19.  Differences Between the Pattern of Developmental Abnormalities in Autism Associated with Duplications 15q11.2-q13 and Idiopathic Autism 
The purpose of this study was to identify differences in patterns of developmental abnormalities between the brains of individuals with autism of unknown etiology and those of individuals with duplications of chromosome 15q11.2-q13 [dup(15)] and autism, and to identify alterations that may contribute to seizures and sudden death in the latter. Brains of 9 subjects with dup(15), 10 with idiopathic autism, and 7 controls were examined. In the dup(15) cohort, 7 subjects (78%) had autism, 7 (78%) had seizures, and 6 (67%) had experienced sudden unexplained death. Subjects with dup(15) autism were microcephalic, with mean brain weights 300 g less (1,177 g) than those of subjects with idiopathic autism (1,477 g; p < 0.001). Heterotopias in the alveus, CA4, and dentate gyrus and dysplasia in the dentate gyrus were detected in 89% of dup(15) autism cases but in only 10% idiopathic autism cases (p < 0.001). By contrast, cerebral cortex dysplasia was detected in 50% of subjects with idiopathic autism and in no dup(15) autism cases (p < 0.04). The different spectrum and higher prevalence of developmental neuropathological findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death.
doi:10.1097/NEN.0b013e318251f537
PMCID: PMC3612833  PMID: 22487857
Autism; Chromosome 15q11.2-q13 duplication; Developmental brain alterations; Seizures; Sudden unexpected death
20.  A study of malocclusion and orthodontic treatment needs according to dental aesthetic index among school children of a hilly state of India 
Background:
The documentation of magnitude of malocclusion in terms of prevalence and severity has not been done till date in Himachal Pradesh, India.
Aims:
To assess the prevalence of malocclusion and orthodontic treatment needs (OTNs) among 9-and 12-year-old school children by using the Dental Aesthetic Index (DAI) in the state.
Materials and Methods:
A cross-sectional study was conducted among 1188 children from randomly selected schools. The survey was done according to the Oral Health Assessment Form (modified). DAI was used to assess the severity of malocclusion, along with collection of demographic data.
Results:
The overall prevalence of malocclusion was 12.5% and required orthodontic treatment, whereas 87.5% did not require treatment. A severe malocclusion for which treatment was highly desirable was recorded in 3.1%; 8% had a definite malocclusion for which treatment was elective. Only about 1.3% had a handicapping malocclusion that needed mandatory treatment. Almost equal proportions of males and females were affected with malocclusion with the means 20 ± 4.6 and 19.9 ± 4.9, respectively (P < 0.641). The prevalence and severity of malocclusion was more in 12-year age group than in 9-year age group (P = 0.002**). There was an increase in the proportion of malocclusion among older children: In 12-year age group, 15.7% with mean 20.5 ± 5.1 and in 9-year-old children, 8.9% with the mean 19.3 ± 4.1 were in the need of orthodontic treatment.
Conclusion:
Severity and treatment needs, both are important factors in public health planning.
doi:10.4103/2231-0762.115706
PMCID: PMC3894101  PMID: 24478978
Dental Aesthetic Index; malocclusion; orthodontic treatment needs; World Health Organization
21.  Abnormal Intracellular Accumulation and Extracellular Aβ Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders 
PLoS ONE  2012;7(5):e35414.
Background
It has been shown that amyloid ß (Aβ), a product of proteolytic cleavage of the amyloid β precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type–specific amount.
Methodology/Principal Findings
In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Aβ load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Aβ load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly N-terminally truncated. Increased intraneuronal accumulation of Aβ17–40/42 in children and adults suggests a life-long enhancement of APP processing with α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced α-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Aβ1–40/42 detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques.
Conclusions/Significance
The higher prevalence of excessive Aβ accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.
doi:10.1371/journal.pone.0035414
PMCID: PMC3342283  PMID: 22567102
22.  Curcumin-loaded magnetic nanoparticles for breast cancer therapeutics and imaging applications 
Background
The next generation magnetic nanoparticles (MNPs) with theranostic applications have attracted significant attention and will greatly improve nanomedicine in cancer therapeutics. Such novel MNP formulations must have ultra-low particle size, high inherent magnetic properties, effective imaging, drug targeting, and drug delivery properties. To achieve these characteristic properties, a curcumin-loaded MNP (MNP-CUR) formulation was developed.
Methods
MNPs were prepared by chemical precipitation method and loaded with curcumin (CUR) using diffusion method. The physicochemical properties of MNP-CUR were characterized using dynamic light scattering, transmission electron microscopy, and spectroscopy. The internalization of MNP-CUR was achieved after 6 hours incubation with MDA-MB-231 breast cancer cells. The anticancer potential was evaluated by a tetrazolium-based dye and colony formation assays. Further, to prove MNP-CUR results in superior therapeutic effects over CUR, the mitochondrial membrane potential integrity and reactive oxygen species generation were determined. Magnetic resonance imaging capability and magnetic targeting property were also evaluated.
Results
MNP-CUR exhibited individual particle grain size of ~9 nm and hydrodynamic average aggregative particle size of ~123 nm. Internalized MNP-CUR showed a preferential uptake in MDA-MB-231 cells in a concentration-dependent manner and demonstrated accumulation throughout the cell, which indicates that particles are not attached on the cell surface but internalized through endocytosis. MNP-CUR displayed strong anticancer properties compared to free CUR. MNP-CUR also amplified loss of potential integrity and generation of reactive oxygen species upon treatment compared to free CUR. Furthermore, MNP-CUR exhibited superior magnetic resonance imaging characteristics and significantly increased the targeting capability of CUR.
Conclusion
MNP-CUR exhibits potent anticancer activity along with imaging and magnetic targeting capabilities. This approach can be extended to preclinical and clinical use and may have importance in cancer treatment and cancer imaging in the future. Further, if these nanoparticles can functionalize with antibody/ligands, they will serve as novel platforms for multiple biomedical applications.
doi:10.2147/IJN.S29290
PMCID: PMC3356199  PMID: 22619526
magnetic nanoparticles; drug delivery systems; magnetic resonance imaging; nanomedicine; cancer therapeutics; biomedical applications
23.  Reduced Activity of Protein Kinase C in the Frontal Cortex of Subjects with Regressive Autism: Relationship with Developmental Abnormalities 
Autism is a neurodevelopmental disorder with unknown etiology. In some cases, typically developing children regress into clinical symptoms of autism, a condition known as regressive autism. Protein kinases are essential for G-protein-coupled receptor-mediated signal transduction, and are involved in neuronal functions, gene expression, memory, and cell differentiation. Recently, we reported decreased activity of protein kinase A (PKA) in the frontal cortex of subjects with regressive autism. In the present study, we analyzed the activity of protein kinase C (PKC) in the cerebellum and different regions of cerebral cortex from subjects with regressive autism, autistic subjects without clinical history of regression, and age-matched control subjects. In the frontal cortex of subjects with regressive autism, PKC activity was significantly decreased by 57.1% as compared to age-matched control subjects (p = 0.0085), and by 65.8% as compared to non-regressed autistic subjects (p = 0.0048). PKC activity was unaffected in the temporal, parietal and occipital cortices, and in the cerebellum in both autism groups, i.e., regressive and non-regressed autism as compared to control subjects. These results suggest brain region-specific alteration of PKC activity in the frontal cortex of subjects with regressive autism. Further studies showed a negative correlation between PKC activity and restrictive, repetitive and stereotyped pattern of behavior (r= -0.084, p = 0.0363) in autistic individuals, suggesting involvement of PKC in behavioral abnormalities in autism. These findings suggest that regression in autism may be attributed, in part, to alterations in G-protein-coupled receptor-mediated signal transduction involving PKA and PKC in the frontal cortex.
doi:10.7150/ijbs.4742
PMCID: PMC3432855  PMID: 22949890
Autism; behavior; protein kinase C; protein kinases; regression; signal transduction.
24.  Interaction of curcumin nanoformulations with human plasma proteins and erythrocytes 
Background
Recent studies report curcumin nanoformulation(s) based on polylactic-co-glycolic acid (PLGA), β-cyclodextrin, cellulose, nanogel, and dendrimers to have anticancer potential. However, no comparative data are currently available for the interaction of curcumin nanoformulations with blood proteins and erythrocytes. The objective of this study was to examine the interaction of curcumin nanoformulations with cancer cells, serum proteins, and human red blood cells, and to assess their potential application for in vivo preclinical and clinical studies.
Methods
The cellular uptake of curcumin nanoformulations was assessed by measuring curcumin levels in cancer cells using ultraviolet-visible spectrophotometry. Protein interaction studies were conducted using particle size analysis, zeta potential, and Western blot techniques. Curcumin nanoformulations were incubated with human red blood cells to evaluate their acute toxicity and hemocompatibility.
Results
Cellular uptake of curcumin nanoformulations by cancer cells demonstrated preferential uptake versus free curcumin. Particle sizes and zeta potentials of curucumin nanoformulations were varied after human serum albumin adsorption. A remarkable capacity of the dendrimer curcumin nanoformulation to bind to plasma protein was observed, while the other formulations showed minimal binding capacity. Dendrimer curcumin nanoformulations also showed higher toxicity to red blood cells compared with the other curcumin nanoformulations.
Conclusion
PLGA and nanogel curcumin nanoformulations appear to be very compatible with erythrocytes and have low serum protein binding characteristics, which suggests that they may be suitable for application in the treatment of malignancy. These findings advance our understanding of the characteristics of curcumin nanoformulations, a necessary component in harnessing and implementing improved in vivo effects of curcumin.
Video abstract
Video
doi:10.2147/IJN.S25534
PMCID: PMC3225220  PMID: 22128249
nanoparticle; curcumin; chemotherapy; cellular uptake; protein binding; hemocompatibility
25.  Brain Region–Specific Decrease in the Activity and Expression of Protein Kinase A in the Frontal Cortex of Regressive Autism 
PLoS ONE  2011;6(8):e23751.
Autism is a severe neurodevelopmental disorder that is characterized by impaired language, communication, and social skills. In regressive autism, affected children first show signs of normal social and language development but eventually lose these skills and develop autistic behavior. Protein kinases are essential in G-protein-coupled, receptor-mediated signal transduction and are involved in neuronal functions, gene expression, memory, and cell differentiation. We studied the activity and expression of protein kinase A (PKA), a cyclic AMP–dependent protein kinase, in postmortem brain tissue samples from the frontal, temporal, parietal, and occipital cortices, and the cerebellum of individuals with regressive autism; autistic subjects without a clinical history of regression; and age-matched developmentally normal control subjects. The activity of PKA and the expression of PKA (C-α), a catalytic subunit of PKA, were significantly decreased in the frontal cortex of individuals with regressive autism compared to control subjects and individuals with non-regressive autism. Such changes were not observed in the cerebellum, or the cortices from the temporal, parietal, and occipital regions of the brain in subjects with regressive autism. In addition, there was no significant difference in PKA activity or expression of PKA (C-α) between non-regressive autism and control groups. These results suggest that regression in autism may be associated, in part, with decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling.
doi:10.1371/journal.pone.0023751
PMCID: PMC3166116  PMID: 21909354

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