Recent Approaches of Intranasal to Brain Drug Delivery System

While the intranasal administration of drugs to the brain has been gaining both research attention and regulatory success over the past several years, key fundamental and translational challenges remain to fully leveraging the promise of this drug delivery pathway for improving the treatment of various neurological and psychiatric illnesses. In response, this review highlights the current state of understanding of the nose-to-brain drug delivery pathway and how both biological and clinical barriers to drug transport using the pathway can been addressed, as illustrated by demonstrations of how currently approved intranasal sprays leverage these pathways to enable the design of successful therapies. Moving forward, aiming to better exploit the understanding of this fundamental pathway, we also outline the development of nanoparticle systems that show improvement in delivering approved drugs to the brain and how engineered nanoparticle formulations could aid in breakthroughs in terms of delivering emerging drugs and therapeutics while avoiding systemic adverse effects

Microbiome diversity in African American, European American, and Egyptian colorectal cancer patients

Purpose: Although there is an established role for microbiome dysbiosis in the pathobiology of colorectal cancer (CRC), CRC patients of various race/ethnicities demonstrate distinct clinical behaviors. Thus, we investigated microbiome dysbiosis in Egyptian, African American (AA), and European American (EA) CRC patients. Patients and methods: CRCs and their corresponding normal tissues from Egyptian (n = 17) patients of the Alexandria University Hospital, Egypt, and tissues from AA (n = 18) and EA (n = 19) patients at the University of Alabama at Birmingham were collected. DNA was isolated from frozen tissues, and the microbiome composition was analyzed by 16S rRNA sequencing. Differential microbial abundance, diversity, and metabolic pathways were identified using linear discriminant analysis (LDA) effect size analyses. Additionally, we compared these profiles with our previously published microbiome data derived from Kenyan CRC patients. Results:Differential microbiome analysis of CRCs across all racial/ethnic groups showed dysbiosis. There were high abundances of Herbaspirillum and Staphylococcus in CRCs of Egyptians, Leptotrichia in CRCs of AAs, Flexspiria and Streptococcus in CRCs of EAs, and Akkermansia muciniphila and Prevotella nigrescens in CRCs of Kenyans (LDA score \u3e4, adj. p-value Conclusions: Our findings showed altered mucosa-associated microbiome profiles of CRCs and their metabolic pathways across racial/ethnic groups. These findings provide a basis for future studies to link racial/ethnic microbiome differences with distinct clinical behaviors in CRC

Atomic Absorption Spectroscope, Methanolic Extracts Correspondence to Author:

ABSTRACT: Achyranthes aspera (Amaranthaceae) is an important medicinal herb found as a weed throughout India. It has been used in almost all the traditional system of medicine, ayurveda, unani, and sidha from the ancient time. It serves as a folk medicine in traditional uses. In present study, the methanolic extract and aqueous extracts of leaf, stem, inflorescence and roots of Achyranthes aspera was screened. The Physio-Chemical Parameters of Achyranthes aspera like determination of moisture content, total ash content, acid insoluble ash content, water soluble ash content and solvent extractive values were done. Qualitative phytochemicals revealed the presence of alkaloids, saponins, flavonoids and glycosides in each extract. In A.aspera extract the moisture content, total ash content, insoluble ash content in stem and roots was more than leaf and inflorescence and water soluble ash content was found highest in inflorescence followed by stem then leaf and least in roots

Molecular Subtyping and Survival Analysis of Osteosarcoma Reveals Prognostic Biomarkers and Key Canonical Pathways

Osteosarcoma (OS) is a common bone malignancy in children and adolescents. Although histological subtyping followed by improved OS treatment regimens have helped achieve favorable outcomes, a lack of understanding of the molecular subtypes remains a challenge to characterize its genetic heterogeneity and subsequently to identify diagnostic and prognostic biomarkers for developing effective treatments. In the present study, global analysis of DNA methylation, and mRNA and miRNA gene expression in OS patient samples were correlated with their clinical characteristics. The mucin family of genes, MUC6, MUC12, and MUC4, were found to be highly mutated in the OS patients. Results revealed the enrichment of molecular pathways including Wnt signaling, Calcium signaling, and PI3K-Akt signaling in the OS tumors. Survival analyses showed that the expression levels of several genes such as RAMP1, CRIP1, CORT, CHST13, and DDX60L, miRNAs and lncRNAs were associated with survival of OS patients. Molecular subtyping using Cluster-Of-Clusters Analysis (COCA) for mRNA, lncRNA, and miRNA expression; DNA methylation; and mutation data from the TARGET dataset revealed two distinct molecular subtypes, each with a distinctive gene expression profile. Between the two subtypes, three upregulated genes, POP4, HEY1, CERKL, and seven downregulated genes, CEACAM1, ABLIM1, LTBP2, ISLR, LRRC32, PTPRF, and GPX3, associated with OS metastasis were found to be differentially regulated. Thus, the molecular subtyping results provide a strong basis for classification of OS patients that could be used to develop better prognostic treatment strategies

Mitochondrial DNA Polymerase POLG1 Disease Mutations and Germline Variants Promote Tumorigenic Properties.

Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of POLG1, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic properties

Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma

Abstract Background Colorectal adenocarcinomas are characterized by abnormal mitochondrial DNA (mtDNA) copy number and genomic instability, but a molecular interaction between mitochondrial and nuclear genome remains unknown. Here we report the discovery of increased copies of nuclear mtDNA (NUMT) in colorectal adenocarcinomas, which supports link between mtDNA and genomic instability in the nucleus. We name this phenomenon of nuclear occurrence of mitochondrial component as numtogenesis. We provide a description of NUMT abundance and distribution in tumor versus matched blood-derived normal genomes. Methods Whole-genome sequence data were obtained for colon adenocarcinoma and rectum adenocarcinoma patients participating in The Cancer Genome Atlas, via the Cancer Genomics Hub, using the GeneTorrent file acquisition tool. Data were analyzed to determine NUMT proportion and distribution on a genome-wide scale. A NUMT suppressor gene was identified by comparing numtogenesis in other organisms. Results Our study reveals that colorectal adenocarcinoma genomes, on average, contains up to 4.2-fold more somatic NUMTs than matched normal genomes. Women colorectal tumors contained more NUMT than men. NUMT abundance in tumor predicted parallel abundance in blood. NUMT abundance positively correlated with GC content and gene density. Increased numtogenesis was observed with higher mortality. We identified YME1L1, a human homolog of yeast YME1 (yeast mitochondrial DNA escape 1) to be frequently mutated in colorectal tumors. YME1L1 was also mutated in tumors derived from other tissues. We show that inactivation of YME1L1 results in increased transfer of mtDNA in the nuclear genome. Conclusions Our study demonstrates increased somatic transfer of mtDNA in colorectal tumors. Our study also reveals sex-based differences in frequency of NUMT occurrence and that NUMT in blood reflects NUMT in tumors, suggesting NUMT may be used as a biomarker for tumorigenesis. We identify YME1L1 as the first NUMT suppressor gene in human and demonstrate that inactivation of YME1L1 induces migration of mtDNA to the nuclear genome. Our study reveals that numtogenesis plays an important role in the development of cancer

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Not AvailableThis study was conducted to understand the behaviour of ten rice genotypes for different water deficit stress levels. The spectroscopic hyperspectral reflectance data in the range of 350–2500 nm was recorded and relative water content (RWC) of plants was measured at different stress levels. The optimal wavebands were identified through spectral indices, multivariate techniques and neural network technique, and prediction models were developed. The new water sensitive spectral indices were developed and existing water band spectral indices were also evaluated with respect to RWC. These indices based models were efficient in predicting RWC with R2 values ranging from 0.73 to 0.94. The contour plotting using the ratio spectral indices (RSI) and normalized difference spectral indices (NDSI) was done in all possible combinations within 350–2500 nm and their correlations with RWC were quantified to identify the best index. Spectral reflectance data was also used to develop partial least squares regression (PLSR) followed by multiple linear regression (MLR) and Artificial Neural Networks (ANN), support vector machine regression (SVR) and random forest (RF) models to calculate plant RWC. Among these multivariate models, PLSR-MLR was found to be the best model for prediction of RWC with R2 as 0.98 and 0.97 for calibration and validation respectively and Root mean square error of prediction (RMSEP) as 5.06. The results indicate that PLSR is a robust technique for identification of water deficit stress in the crop. Although the PLSR is robust technique, if PLSR extracted optimum wavebands are fed into MLR, the results are found to be improved significantly. The ANN model was developed with all spectral reflectance bands. The 43 developed model didn’t produce satisfactory results. Therefore, the model was developed 44 with PLSR selected optimum wavebands as independent x variables and PLSR-ANN model 45 was found better than the ANN model alone. The study successfully conducts a comparative 46 analysis among various modelling approaches to quantify water deficit stress. The methodology developed would help to identify water deficit stress more accurately by predicting RWC in the crops.Not Availabl