Parkinson's disease (PD) is a progressive and incurable neurodegenerative disorder. Although numerous genetic and environmental factors have been linked to the aetiology of PD the underlying ...pathobiology remains poorly understood, hampering the development of improved therapies. Transcriptomics has the potential to reveal significant insights into disease processes. In this review, we focused on published transcriptomics studies on PD with the aim of summarizing studies and identifying common biological pathways. A total of 96 articles were identified as follows: 12 meta‐analyses, 21 re‐analyses of existing data and 63 original studies. Of the 63 original studies, 33 were performed on brain tissue, 26 on blood, three on cerebrospinal fluid and one on skin. In the brain studies, altered pathways identified included those involved in dopamine metabolism, mitochondrial function, oxidative stress, protein degradation, neuroinflammation, vesicular transport and synaptic transmission. Studies on blood samples revealed alterations in pathways involved in immune function, inflammation, RNA processing, protein chaperones, mitochondrial function and programmed cell death. Limitations of these studies include small sample sizes (generally <40 cases/40 controls) and the application of widely varying statistical analysis and parameters. Only eight studies used the RNA‐Seq technique. This review highlights the need for harmonization of transcriptomic approaches and the statistical analyses, and for the data to be deposited into publicly available databases in a standardized format for meta‐analyses. Notably, the concordance of several pathways such as mitochondrial function, protein degradation and inflammation, identified in both blood and brain tissues, suggests that the disease process is systemic and not restricted to neurological tissues.
A review of 96 articles on genome‐wide transcriptomic studies in Parkinson's disease revealed several overlapping and non‐overlapping pathways. The need for harmonization of statistical analyses, and for the data to be deposited into databases in a standardized format for meta‐analyses, is highlighted. Processes such as mitochondrial function, protein degradation and inflammation, identified in both blood and brain tissues, suggest that the disease process is systemic.
An aortic aneurysm is a dilatation in which the aortic diameter is ≥3.0 cm. If left untreated, the aortic wall continues to weaken and becomes unable to withstand the forces of the luminal blood ...pressure resulting in progressive dilatation and rupture, a catastrophic event associated with a mortality of 50-80%. Smoking and positive family history are important risk factors for the development of abdominal aortic aneurysms (AAA). Several genetic risk factors have also been identified. On the histological level, visible hallmarks of AAA pathogenesis include inflammation, smooth muscle cell apoptosis, extracellular matrix degradation and oxidative stress. We expect that large genetic, genomic, epigenetic, proteomic and metabolomic studies will be undertaken by international consortia to identify additional risk factors and biomarkers, and to enhance our understanding of the pathobiology of AAA. Collaboration between different research groups will be important in overcoming the challenges to develop pharmacological treatments for AAA.
Abstract
Intracranial aneurysms, also called cerebral aneurysms, are dilatations in the arteries that supply blood to the brain. Rupture of an intracranial aneurysm leads to a subarachnoid ...hemorrhage, which is fatal in about 50% of the cases. Intracranial aneurysms can be repaired surgically or endovascularly, or by combining these two treatment modalities. They are relatively common with an estimated prevalence of unruptured aneurysms of 2%-6% in the adult population, and are considered a complex disease with both genetic and environmental risk factors. Known risk factors include smoking, hypertension, increasing age, and positive family history for intracranial aneurysms. Identifying the molecular mechanisms underlying the pathogenesis of intracranial aneurysms is complex. Genome-wide approaches such as DNA linkage and genetic association studies, as well as microarray-based mRNA expression studies, provide unbiased approaches to identify genetic risk factors and dissecting the molecular pathobiology of intracranial aneurysms. The ultimate goal of these studies is to use the information in clinical practice to predict an individual's risk for developing an aneurysm or monitor its growth or rupture risk. Another important goal is to design new therapies based on the information on mechanisms of disease processes to prevent the development or halt the progression of intracranial aneurysms.
Collagen alpha-1(III) chain, also known as the alpha 1 chain of type III collagen, is a protein that in humans is encoded by the COL3A1 gene. Three alpha 1 chains are required to form the type III ...collagen molecule which has a long triple-helical domain. Type III collagen, an extracellular matrix protein, is synthesized by cells as a pre-procollagen. It is found as a major structural component in hollow organs such as large blood vessels, uterus and bowel. Other functions of type III collagen include interaction with platelets in the blood clotting cascade and it is also an important signaling molecule in wound healing. Mutations in the COL3A1 gene cause the vascular type of Ehlers-Danlos syndrome (vEDS; OMIM 130050). It is the most serious form of EDS, since patients often die suddenly due to a rupture of large arteries. Inactivation of the murine Col3a1 gene leads to a shorter life span in homozygous mutant mice. The mice die prematurely from a rupture of major arteries mimicking the human vEDS phenotype. The biochemical and cellular effects of COL3A1 mutations have been studied extensively. Most of the glycine mutations lead to the synthesis of type III collagen with reduced thermal stability, which is more susceptible for proteinases. Intracellular accumulation of this normally secreted protein is also found. Ultrastructural analyses have demonstrated dilated rough endoplasmic reticulum and changes in the diameter of collagen fibers. Other clinical conditions associated with type III collagen are several types of fibroses in which increased amounts of type III collagen accumulate in the target organs.
•Type III collagen is a structural component of blood vessels, uterus and bowel.•Type III collagen regulates type I collagen fibril formation.•Mutations in COL3A1 cause vascular Ehlers-Danlos syndrome.•Mutations in COL3A1 can also cause frontoparietal polymicrogyria.•Accumulation of type III collagen is found in fibrotic diseases.
The African Esophageal Squamous Cell Carcinoma (ESCC) corridor, which spans from Ethiopia down to South Africa, is an esophageal cancer hotspot. Disproportionately high incidence and mortality rates ...of esophageal cancer have been reported from this region. The aim of this study was to systematically assess the evidence on environmental and life-style risk factors associated with ESCC in African populations.
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and carried out a comprehensive search of all African published studies up to March 2023 using PubMed, Embase, Scopus, and African Index Medicus databases.
We identified 45 studies with measures of association odds ratio (OR), relative risk (RR), and 95% confidence intervals (95%CI), which reported on several environmental and lifestyle risk factors for ESCC in Africa. We performed a meta-analysis on 38 studies investigating tobacco, alcohol use, combined tobacco and alcohol use, polycyclic aromatic hydrocarbon exposure, hot food and beverages consumption (which served as a proxy for esophageal injury through exposure to high temperature), and poor oral health. We found significant associations between all the risk factors and ESCC development. Analysis of fruit and vegetable consumption showed a protective effect. Using population attributable fraction (PAF) analysis, we calculated the proportion of ESCC attributable to tobacco (18%), alcohol use (12%), combined tobacco and alcohol use (18%), polycyclic aromatic hydrocarbon exposure (12%), hot food and beverages intake (16%), poor oral health (37%), and fruit and vegetable consumption (-12%).
Tobacco smoking and alcohol consumption were the most studied risk factors overall. Areas where there is an emerging body of evidence include hot food and beverages and oral health. Concurrently, new avenues of research are also emerging in PAH exposure, and diet as risk factors. Our results point to a multifactorial etiology of ESCC in African populations with further evidence on prevention potential.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Infiltration of macrophages and apoptosis of vascular smooth muscle cells (VSMCs) promote the development of abdominal aortic aneurysm (AAA). Previously, we demonstrated that global Notch1 deficiency ...prevents the formation of AAA in a mouse model. Herein, we sought to explore the cell-specific roles of Notch1 in AAA development.
Cell-specific Notch1 haploinsufficient mice, generated on Apoe-/- background using Cre-lox technology, were infused with angiotensin II (1000 ng/min/kg) for 28 days. Notch1 haploinsufficiency in myeloid cells (n = 9) prevented the formation of AAA attributed to decreased inflammation. Haploinsufficiency of Notch1 in SMCs (n = 14) per se did not prevent AAA formation, but histoarchitectural traits of AAA including elastin degradation and aortic remodeling, were minimal in SMC-Notch1+/-;Apoe-/- mice compared to Apoe-/- mice (n = 33). Increased immunostaining of the contractile SMC-phenotype markers and concomitant decreased expression of synthetic SMC-phenotype markers were observed in the aortae of SMC-Notch1+/-;Apoe-/- mice. Expression of connective tissue growth factor (CTGF), a matrix-associated protein that modulates the synthetic VSMC phenotype, increased in the abdominal aorta of Apoe-/- mice and in the adventitial region of the abdominal aorta in human AAA. Notch1 haploinsufficiency decreased the expression of Ctgf in the aorta and in vitro cell culture system. In vitro studies on SMCs using the Notch1 intracellular domain (NICD) plasmid, dominant negative mastermind-like (dnMAML), or specific siRNA suggest that Notch1, not Notch3, directly modulates the expression of CTGF.
Our data suggest that lack of Notch1 in SMCs limits dilation of the abdominal aorta by maintaining contractile SMC-phenotype and preventing matrix-remodeling.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Esophageal squamous cell carcinoma (ESCC), one of the most aggressive cancers, is endemic in Sub-Saharan Africa, constituting a major health burden. It has the most divergence in cancer incidence ...globally, with high prevalence reported in East Asia, Southern Europe, and in East and Southern Africa. Its etiology is multifactorial, with lifestyle, environmental, and genetic risk factors. Very little is known about the role of genetic factors in ESCC development and progression among African populations. The study aimed to systematically assess the evidence on genetic variants associated with ESCC in African populations.
We carried out a comprehensive search of all African published studies up to April 2019, using PubMed, Embase, Scopus, and African Index Medicus databases. Quality assessment and data extraction were carried out by two investigators. The strength of the associations was measured by odds ratios and 95% confidence intervals.
Twenty-three genetic studies on ESCC in African populations were included in the systematic review. They were carried out on Black and admixed South African populations, as well as on Malawian, Sudanese, and Kenyan populations. Most studies were candidate gene studies and included DNA sequence variants in 58 different genes. Only one study carried out whole-exome sequencing of 59 ESCC patients. Sample sizes varied from 18 to 880 cases and 88 to 939 controls. Altogether, over 100 variants in 37 genes were part of 17 case-control genetic association studies to identify susceptibility loci for ESCC. In these studies, 25 variants in 20 genes were reported to have a statistically significant association. In addition, eight studies investigated changes in cancer tissues and identified somatic alterations in 17 genes and evidence of loss of heterozygosity, copy number variation, and microsatellite instability. Two genes were assessed for both genetic association and somatic mutation.
Comprehensive large-scale studies on the genetic basis of ESCC are still lacking in Africa. Sample sizes in existing studies are too small to draw definitive conclusions about ESCC etiology. Only a small number of African populations have been analyzed, and replication and validation studies are missing. The genetic etiology of ESCC in Africa is, therefore, still poorly defined.
Abstract Factor H is a 155 kDa sialic acid containing glycoprotein that plays an integral role in the regulation of the complement-mediated immune system that is involved in microbial defense, immune ...complex processing, and programmed cell death. These events take place primarily in fluid phase and on the cell surface and are particularly important in the context of distinguishing self from non-self. Activation of the complement system occurs within seconds and results in a proteolytic cascade eventually forming the membrane attack complex leading to cell lysis. Factor H protects host cells from injury resulting from unrestrained complement activation. Mutations and SNPs (single nucleotide polymorphisms) in Factor H have been implicated in a variety of human conditions including age-related macular degeneration (AMD), atypical hemolytic uremic syndrome, and membranoproliferative glomuleronephritis type II or dense deposit disease. It should not be surprising that these seemingly unrelated diseases involving mutations in Factor H may share common features. Because the immune process involves, in part, an inflammatory response and common or similar surface antigens, it is also not unexpected to observe features of inflammation, including deposition of bioactive complement fragments such as C3a and C5a, a cellular influx of immune related cells such as lymphocytes, and the potential for multiple organ involvement. We review recent developments in molecular genetics; SNPs, including Y402H; the three-dimensional structure; and mass spectroscopy of Factor H as it relates to the pathogenesis of eye disease. In addition, we discuss the concepts of molecular mimicry, sequestered or hidden antigens, and antigenic cross reactivity, and propose that AMD should not simply be considered to be an eye disease, but rather a systemic vascular disease where the eye has the ability to self regulate a local immune response. Identification of the initial event or inciting antigen has yet to be determined and will significantly advance the understanding of the pathogenesis of AMD.
Abdominal aortic aneurysms are a common disorder with an incompletely understood etiology. We used Illumina and Affymetrix microarray platforms to generate global gene expression profiles for both ...aneurysmal (AAA) and non-aneurysmal abdominal aorta, and identified genes that were significantly differentially expressed between cases and controls.
Affymetrix and Illumina arrays included 18,057 genes in common; 11,542 (64%) of these genes were considered to be expressed in either aneurysmal or normal abdominal aorta. There were 3,274 differentially expressed genes with a false discovery rate (FDR) </= 0.05. Many of these genes were not previously known to be involved in AAA, including SOST and RUNX3, which were confirmed using Q-RT-PCR (Pearson correlation coefficient for microarray and Q-RT-PCR data = 0.89; p-values for differences in expression between AAA and controls for SOST: 4.87 x 10-4 and for RUNX3: 4.33 x 10-5). Analysis of biological pathways, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), indicated extreme overrepresentation of immune related categories. The enriched categories included the GO category Immune Response (GO:0006955; FDR = 2.1 x 10-14), and the KEGG pathways natural killer cell mediated cytotoxicity (hsa04650; FDR = 5.9 x 10-6) and leukocyte transendothelial migration (hsa04670; FDR = 1.1 x 10-5).
Previous studies have provided evidence for the involvement of the immune system in AAA. The current expression analysis extends these findings by demonstrating broad coordinate gene expression in immunological pathways. A large number of genes involved in immune function were differentially expressed in AAA, and the pathway analysis gave these results a biological context. The data provide valuable insight for future studies to dissect the pathogenesis of human AAA. These pathways might also be used as targets for the development of therapeutic agents for AAA.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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