Pathogenesis Of Multifactorial Diseases Research Articles

Secrets and lies of host-microbial interactions: MHC restriction and trans-regulation of T cell trafficking conceal the role of microbial agents on the edge between health and multifactorial/complex diseases.

Here we critically discuss data supporting the view that microbial agents (pathogens, pathobionts or commensals alike) play a relevant role in the pathogenesis of multifactorial diseases, but their role is concealed by the rules presiding over T cell antigen recognition and trafficking. These rules make it difficult to associate univocally infectious agents to diseases' pathogenesis using the paradigm developed for canonical infectious diseases. (Cross-)recognition of a variable repertoire of epitopes leads to the possibility that distinct infectious agents can determine the same disease(s). There can be the need for sequential infection/colonization by two or more microorganisms to develop a given disease. Altered spreading of infectious agents can determine an unwanted activation of T cells towards a pro-inflammatory and trafficking phenotype, due to differences in the local microenvironment. Finally, trans-regulation of T cell trafficking allows infectious agents unrelated to the specificity of T cell to modify their homing to target organs, thereby driving flares of disease. The relevant role of microbial agents in largely prevalent diseases provides a conceptual basis for the evaluation of more specific therapeutic approaches, targeted to prevent (vaccine) or cure (antibiotics and/or Biologic Response Modifiers) multifactorial diseases.

The role of polymorphic variants of the glutathione-S-transferase genes in the pathogenesis of multifactorial diseases

The role of polymorphic variants of the glutathione-S-transferase genes in the pathogenesis of multifactorial diseases

Current Status and Prospects of the Single-Cell Sequencing Technologies for Revealing the Pathogenesis of Pregnancy-Associated Disorders.

Single-cell RNA sequencing (scRNA-seq) is a method that focuses on the analysis of gene expression profile in individual cells. This method has been successfully applied to answer the challenging questions of the pathogenesis of multifactorial diseases and open up new possibilities in the prognosis and prevention of reproductive diseases. In this article, we have reviewed the application of scRNA-seq to the analysis of the various cell types and their gene expression changes in normal pregnancy and pregnancy complications. The main principle, advantages, and limitations of single-cell technologies and data analysis methods are described. We discuss the possibilities of using the scRNA-seq method for solving the fundamental and applied tasks related to various pregnancy-associated disorders. Finally, we provide an overview of the scRNA-seq findings for the common pregnancy-associated conditions, such as hyperglycemia in pregnancy, recurrent pregnancy loss, preterm labor, polycystic ovary syndrome, and pre-eclampsia.

Contribution of polymorphic variants of the NFKB1 transcription factor gene to the development of multifactorial diseases with an infammatory component

NFKB1 — a product of the same-name gene – is a transcription factor that regulates the expression of target genes which encode a wide range of proteins with properties essential for functioning of the body. Numerous studies confrmed the NFKB1 gene's contribution of the polymorphism to the processes of adaptation to climatic and geographical conditions, protection from infectious agents, as well as the pathogenesis of multifactorial diseases. In the materials supplied with the article is a summary of the results of published population-genetic and cohort studies of NFKB1. Summary data on the requencies of NFKB1 gene alleles (rs28362491, rs230521, rs4648068, rs3774937, rs3774959) in the population of Europe, Africa, South and East Asia, America, Eastern Russia and Siberia (according to the open databases from 1000 Genomes and Siberian projects) illustrates the pronounced genetic differentiation of world populations by polymorphic variants of NFKB1, which indirectly confrms their selective role. The signifcance of the aforementioned polymorphisms in the etiology and pathogenesis in a number of socially signifcant nosological forms was studied according to an analysis of materials from articles posted on NCBI platform from 2008 to 2021. As a result of deconstructing the data, it was found that changes in the structure of the promoter (del) and introns (SNP polymorphism) are able to modify the activity of the transcription factor NFKB1, through a change in the expression of the gene and the activity of its product. This information forms an ambiguous picture of associations of the NFKB1 gene polymorphic variants with oncological (ovarian, stomach, breast, bladder, colorectal cancer, Hodgkin's lymphoma, melanoma), cardiovascular (coronary heart disease, acute coronary syndrome, myocardial infarction, varicose veins), autoimmune and chronic infammatory diseases (obesity, chronic hepatitis, rheumatoid arthritis, Behcet's disease, psoriasis, acute infammatory reactions to the graft). Ambiguity of the established associative relations could be due to the modifying infuence of ethnic and population characteristics, as well as intensity of the infuence of phlogogenic factors. Nevertheless, the summarized data and generalizations published in the materials of the article can be used in development of a strategy for basic and screening studies in context of the etiology and pathogenesis of multifactorial diseases.

The role of genes of the second phase of detoxification of xenobiotics in the pathogenesis of multifactorial diseases

The genetic status of a person is currently assigned a major role in the pathogenesis, diagnosis and treatment of various diseases. The most important genetic factors that have been attached great importance to are the genes of the glutathione-S-transferase family (GSTs). The genes of the glutathione-S-transferase family belong to the second phase of detoxification of xenobiotics and their altered activity leads to the development of many pathological conditions. GSTM, GSTT, GSTP are considered to be the most polymorphic. The issues of the participation of polymorphic GSTs in the development of infectious, allergic and oncological diseases, disorders of the reproductive system, as well as in the development of Alzheimer's disease are discussed in the article.

Clinical Genealogical and Epigenetic Examination of Patients with Juvenile Epiphysiolysis of the Femoral Head

Summary. Slipped capital femoral epiphysis (SCFE) is a multifactorial disease caused by a number of factors, and each of them can be triggered in its occurrence. Modern research is increasingly pointing to the leading role of epigenetic structures in the origin and course of this group of diseases. In recent years, the most promising area is the study of the role of microRNAs as an epigenetic factor that plays a leading role in the pathogenesis of multifactorial diseases.
 Objective: to develop a methodology for genetic genealogical examination of patients with juvenile epiphysiolysis of the femoral head.
 Materials and Methods. The study material was 26 patients with SCFE (15 girls and 11 boys) in different periods of sexual development: prepuberty – 7 patients, induction of puberty – 12 patients, and puberty and postpuberty – 7 patients. A questionnaire developed by us was used for clinical and genealogical research of the patients. The material for the epigenetic study, namely the study of microRNA-21 expression in patients with SCFE, was venous blood.
 Results. The expression of microRNA-21 in the blood of patients with SCFE is different (average expression is 0.86 conventional units) from those of healthy donors (average 0.393 conventional units) of the same age (p<0.05). Analysis of dependence on the period of sexual development revealed statistical differences in indicators depending on the group (p<0.05). No dependence of the level of microRNA-21 expression in patients with SCFE on sex and the period before or after surgery (p>0.05) was revealed. The obtained data on the probability of the influence of hereditary factors on the occurrence of SCFE are statistically significant (p<0.05).
 Conclusions. Our results of epigenetic and clinical genealogical research of patients with SCFE showed a high probability of influence of hereditary and epigenetic factors on the occurrence and course of this disease.

Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na+ channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFβ signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF.

Immunomodulatory factors gene polymorphisms in chronic periodontitis: an overview

BackgroundChronic periodontitis (CP), defines as destruction of the supporting tissues of the teeth and resorption of the alveolar bone. It is widespread in human populations and represent an important problem for public health. CP results from inflammatory mechanisms created by the interaction between environmental and host genetic factors that confer the individual susceptibility to the disease.AimThe aim of the current study was to explore and summarize some functional biomarkers that are associated with CP susceptibility.MethodsCP is considered to be a multifactorial disease. The pathogenesis of multifactorial diseases is characterized by various biological pathways. The studies revealed that polymorphisms were associated with susceptibility to periodontal diseases. In other word, genetic variations can change the development of CP. However, there are some conflicting results, because there are different variations in frequency of some alleles in any populations. Therefore, we conducted the current review to completely understanding the special biomarkers for CP.ResultsThere is some evidence that SNPs in the IL-1α, IL-1β, IL1RN, IL-6, IL-10, TNF-α, TGF-β1, IFN-γ and VDR may be associated with CP susceptibility.ConclusionIn conclusion, numerous studies have reported the host genetic factors associated with CP susceptibility and related traits. Therefore, it is prevail to study the multiple SNPs and their effects to find the useful diagnosis methods. The current study will investigate the relationship between polymorphisms in cytokine genes and the susceptibility to the chronic periodontitis.

The Therapeutic Potential of Stem Cells for Bronchopulmonary Dysplasia: "It's About Time" or "Not so Fast" ?

Objective: While the survival of extremely premature infants has improved over the past decades, the rate of complications – especially for bronchopulmonary dysplasia (BPD) – remains un-acceptably high. Over the past 50 years, no safe therapy has had a substantial impact on the incidence and severity of BPD.Methods: This may stem from the multifactorial disease pathogenesis and the increasing lung imma-turity. Mesenchymal Stromal Cells (MSCs) display pleiotropic effects and show promising results in neonatal rodents in preventing or rescuing lung injury without adverse effects. Early phase clinical trials are now underway to determine the safety and efficacy of this therapy in extremely premature infants.Results and Conclusion: This review summarizes our current knowledge about MSCs, their mecha-nism of action and the results of preclinical studies that provide the rationale for early phase clinical trials and discuss remaining gaps in our knowledge

Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease

The pathophysiology of glomerular lesions of membranous nephropathy (MN), including seldom-reported IgG4-related disease, is still elusive. Unlike in idiopathic MN where IgG4 prevails, in this patient IgG3 was predominant in glomerular deposits in the absence of circulating anti-phospholipase A2 receptor antibodies, suggesting a distinct pathologic process. Here we documented that IgG4 retrieved from the serum of our propositus reacted against carbonic anhydrase II (CAII) at the podocyte surface. In patient's biopsy, glomerular CAII staining increased and co-localized with subepithelial IgG4 deposits along the capillary walls. Patient's IgG4 caused a drop in cell pH followed by mitochondrial dysfunction, excessive ROS production and cytoskeletal reorganization in cultured podocytes. These events promoted mitochondrial superoxide-dismutase-2 (SOD2) externalization on the plasma membrane, becoming recognizable by complement-binding IgG3 anti-SOD2. Among patients with IgG4-related disease only sera of those with IgG4 anti-CAII antibodies caused low intracellular pH and mitochondrial alterations underlying SOD2 externalization. Circulating IgG4 anti-CAII can cause podocyte injury through processes of intracellular acidification, mitochondrial oxidative stress and neoantigen induction in patients with IgG4 related disease. The onset of MN in a subset of patients could be due to IgG4 antibodies recognizing CAII with consequent exposure of mitochondrial neoantigen in the context of multifactorial pathogenesis of disease.

Association of polymorphisms of the ADIPOQ, ADIPOR1 and ADIPOR2 genes with type 2 diabetes mellitus

The study of hereditary predisposition to multifactorial diseases is essential for diagnosis and selection of the optimal treatment. The study of polymorphisms of candidate genes whose products are involved in the pathogenesis of multifactorial diseases is of great clinical importance. Aim. The aim of this study was to investigate the association of rs2241766 and rs1501299 polymorphisms in the ADIPOQ gene, rs2275737 and rs2275738 polymorphisms in the ADIPOR1 gene and rs11061971 and rs16928751 polymorphisms in the ADIPOR2 gene with the development of type 2 diabetes mellitus (T2DM) in the Russian population. Materials and methods. The study included a group of 500 patients with T2DM diagnosed based on standard diagnostic criteria (T2DM+). The control group (T2DM-) was a random sample of 500 patients with no evidence of the disease and was matched to the T2DM+ group for gender, age and body mass index. The determination of alleles and genotypes was performed using real-time polymerase chain reaction with TaqMan probes. The X2 test and contingency tables were used to compare the distribution of allele and genotype frequencies. A p-value of

The Role of microRNAs in Mitochondria: Small Players Acting Wide.

MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that act as post-transcriptional gene regulators. They can inhibit target protein-coding genes, through repressing messenger RNA (mRNA) translation or promoting their degradation. miRNAs were initially found to be originated from nuclear genome and exported to cytosol; where they exerted most of their actions. More recently, miRNAs were found to be present specifically in mitochondria; even originated there from mitochondrial DNA, regulating in a direct manner genes coding for mitochondrial proteins, and consequently mitochondrial function. Since miRNAs are recognized as major players in several biological processes, they are being considered as a key to better understand, explain, and probably prevent/cure not only the pathogenesis of multifactorial diseases but also mitochondrial dysfunction and associated diseases. Here we review some of the molecular mechanisms purported for miRNA actions in several biological processes, particularly the miRNAs acting in mitochondria or in mitochondria-related mechanisms.

Rheumatic Diseases and Obesity: Adipocytokines as Potential Comorbidity Biomarkers for Cardiovascular Diseases

Inflammation has been recognized as a common trait in the pathogenesis of multifactorial diseases including obesity, where a low-grade inflammation has been established and may be responsible for the cardiovascular risk related to the disease. Obesity has also been associated with the increased incidence and a worse outcome of rheumatoid arthritis (RA) and osteoarthritis (OA). RA is characterized by systemic inflammation, which is thought to play a key role in accelerated atherosclerosis and in the increased incidence of cardiovascular disease, an important comorbidity in patients with RA. The inflammatory process underlying the cardiovascular risk both in obesity and RA may be mediated by adipocytokines, a heterogeneous group of soluble proteins mainly secreted by the adipocytes. Many adipocytokines are mainly produced by white adipose tissue. Adipocytokines may also be involved in the pathogenesis of OA since a positive association with obesity has been found for weight-bearing and nonweight-bearing joints, suggesting that, in addition to local overload, systemic factors may contribute to joint damage. In this review we summarize the current knowledge on experimental models and clinical studies in which adipocytokines were examined in obesity, RA, and OA and discuss the potential of adipocytokines as comorbidity biomarkers for cardiovascular risk.

Genome, epigenome and transcriptome analyses of a pair of monozygotic twins discordant for systemic lupus erythematosus

Information to distinguish genetic and environmental factors in the pathogenesis of multifactorial diseases can be obtained by investigation of disease development in monozygotic twins. Recent reports have shown that there are genomic and epigenomic differences between monozygotic twins. Genomic/epigenomic and gene expression analyses were performed in monozygotic twins discordant for systemic lupus erythematosus (SLE) to find the genes playing important roles in SLE pathogenesis. Single nucleotide polymorphism (SNP) and copy number variation (CNV) typing, CpG methylation and gene expression were analyzed. The discordances in SNPs and CNVs were not confirmed. Both CpG methylation and gene expression levels were different for 10 genes. There were no genomic differences between monozygotic twins discordant for SLE, but epigenomic and gene expression differences were detected. These findings provide information for better understanding of SLE pathogenesis.

A comparative analysis of the molecular genetic processes in the pathogenesis of psoriasis and Crohn’s disease

A comparative bioinformatics analysis of the molecular genetic processes in the pathogenesis of multifactorial diseases—psoriasis and Crohn’s disease—was performed using the results of microarray experiments deposited with the GEO DataSets database. A number of genes and molecular genetic processes common to both pathologies were found. The involvement of several transcription factors, including AP-1 transcription factors, in the pathogeneses of both psoriasis and Crohn’s disease was postulated.

Selenium status alters tumour differentiation but not incidence or latency of pancreatic adenocarcinomas in Ela-TGF- p53+/ mice

Genetic predisposition and environmental factors act in concert in the pathogenesis of multi-factorial diseases. Selenoproteins represent fundamental antioxidative systems for the maintenance of cellular redox homeostasis, which is altered in various disease processes. Optimal function of selenoproteins requires availability of sufficient amounts of the essential trace element selenium, but in many countries the nutritive selenium supply is regarded insufficient. Supplemental selenium has been shown to have cancer-protective effects in a variety of experimental settings and clinical studies. Pancreatic carcinoma has so far not been tested as an end-point in such studies. We thus investigated the influence of supplemental nutritive selenium on pancreatic carcinogenesis in selenium-deficient animals by use of a genetically defined disease model. Over a period of 800 days, all animals (n = 131) in the study developed tumours. Within this time, the mean total tumour latency was not influenced by the selenium status (471 versus 472 days). Also, the mean latency of pancreatic carcinomas (n = 83) was not influenced (464 versus 466 days). In contrast, the percentage of pancreatic tumors within all tumours was lower in the selenium-deficient group (55 versus 70%). A highly significant difference in the differentiation grade of the pancreatic tumours was evident between the two groups: selenium-deficient mice (n = 33) developed predominantly undifferentiated anaplastic carcinomas (26 anaplastic versus 7 differentiated), whereas in the selenium-supplemented group (n = 50) mainly well-differentiated carcinomas were detected (20 anaplastic versus 30 differentiated). These data point at a new role of the trace element selenium in carcinogenesis.

Transcription Factor Profile by Degenerate RT-PCR/SSCP - Application in 3T3-L1 Adipocyte Treated with TNF- α -

Background: Several high-throughput gene analysis techniques - differential display PCR, suppression subtraction hybridization (SSH), serial analysis of gene expression (SAGE), and DNA microarray - have permitted transcriptome profiling to understand the molecular pathogenesis of multifactorial diseases. But these techniques are of no great utility regarding feasibility, reproducibility, cost, and the amount of material required for analysis. To establish more practical method for transcription factor transcriptome profiling, we combined degenerate reverse transcriptase-polymerase chain reaction (RT-PCR) and single strand conformational polymorphism (SSCP) technique. Methods: We categorized 417 human/mouse transcription factor mRNA into 92 small groups according to homology with ClustalW method and established 92 degenerate RT-PCR including common motives of the 92 small groups with the software program of CODEHOP, Primer Premier, Amplify 1.2. Further analysis on the amplified PCR products was performed by SSCP. This system was applied for the evaluation of changes on transcription factor transcriptome of differentiated 3T3-L1 adipocyte treated with TNF-α. Results: 82 groups and 52 groups showed amplification of PCR before and after TNF-α treatment respectively and 24 groups showed significant amplification difference after TNF-α treatment. After TNF-α treatment for 48 hours, mRNA expressions of group 7, 30, and 33 which include adipocyte related transcription factors such as CEBP-α, RXR-α, PPAR-γ were downregulated and mRNA expression of group 8 including preadipocyte abundant CEBP-β was upregulated. These results are largely concordant with the results analyzed by oligonucleotide microarray. Randomly selected single PCR bands of group 28 and 75 on agarose electrophoresis displayed additional multiple bands by SSCP and necessitated addition of this technique to degenerate RT-P CR for further analysis. Conclusion: It could be suggested that degenerate RT-PCR/SSCP is practical method and could be used as a screening test for transcriptome profiling of various disease states with further validation study. (J Kor Diabetes Assoc 31:410~420, 2007)

Molecular profiling of temporal lobe epilepsy: comparison of data from human tissue samples and animal models

The advent of gene chip technology and the era of functional genomics have initially been accompanied by huge anticipations to quickly unravel the molecular pathogenesis of multifactorial diseases. Expectations have, today, given way to some concerns about this non-hypothesis driven approach. However, the careful and controlled application of expression microarrays in concert with refined bioinformatic tools may provide novel insights in major disorders particularly of highly complex organs such as the central nervous system (CNS). Epilepsies are among the most frequent CNS disorders affecting approximately 1.5% of the population worldwide. In temporal lobe epilepsy (TLE), the seizure origin typically involves the hippocampal formation, a structure located in the mesial temporal lobe. Many TLE patients develop pharmacoresistance, i.e. seizures can no more be controlled by antiepileptic drugs. In order to achieve seizure control, surgical removal of the epileptogenic focus has been established as successful therapeutic strategy. Hippocampal biopsy tissue of pharmacoresistant TLE patients represents an excellent substrate to analyze molecular mechanisms related to structural and cellular reorganization in epilepsy. The complexity of alterations in TLE hippocampi suggests numerous genes and signaling cascades to be involved in the pathogenesis. By microarrays, genome wide expression profiles can be constituted from TLE tissues. However, hippocampi of pharmacoresistant TLE patients represent an advanced stage of the disease. Early stages of epilepsy development are not available for functional genome analysis in humans. Animal models of TLE appear particularly helpful to study molecular mechanisms of highly dynamic processes such as the development of hyperexcitability and pharmacoresistance. In this review, we summarize recent data of gene expression profiles in human and experimental TLE and discuss the relevance of novel tools for bioinformatic analysis and data mining.

Gene-environment interaction: a central concept in multifactorial diseases.

Unlike the rare and severe genetic defects that cause monogenic diseases, the genetic factors that modulate the individual susceptibility to multifactorial diseases (cardiovascular diseases, cancers, diabetes, etc.) are common, functionally different, forms of genes (polymorphisms), which generally have a modest effect at an individual level but, because of their high frequency in the population, can be associated with a high attributable risk. Environmental factors can reveal or facilitate the phenotypic expression of such susceptibility genes. Indeed, in common diseases genetic effects can be considerably amplified in the presence of triggering factors. There is now accumulating evidence that most of the susceptibility genes for common diseases do not have a primary aetiological role in predisposition to disease, but rather act as response modifiers to exogenous factors such as stress, environment, disease, drug intake. A better characterisation of the interactions between environmental and genetic factors constitute a key issue in the understanding of the pathogenesis of multifactorial diseases. The present paper will review three examples of gene-environment interactions in the field of CHD.