Mechanisms Of Disease Development Research Articles

Plasma Myostatin Increases with Age in Male Youth and Negatively Correlates with Vitamin D in Severe Pediatric Obesity.

Obesity already causes non-communicable diseases during childhood, but the mechanisms of disease development are insufficiently understood. Myokines such as myostatin and irisin are muscle-derived factors possibly involved in obesity-associated diseases. This explorative study aims to investigate whether myostatin and irisin are associated with metabolic parameters, including the vitamin D status in pediatric patients with severe obesity. Clinical, anthropometric and laboratory data from 108 patients with severe obesity (>97th percentile) aged between 9 and 19 years were assessed. Myostatin, its antagonist follistatin, and irisin, were measured from plasma by ELISA. Myostatin concentrations, particularly in males, positively correlated with age and pubertal stage, as well as metabolic parameters such as insulin resistance. Irisin concentrations correlated positively with HDL and negatively with LDL cholesterol values. For follistatin, the associations with age and pubertal stage were inverse. Strikingly, a negative correlation of myostatin with serum vitamin D levels was observed that remained significant after adjusting for age and pubertal stage. In conclusion, there is an independent association of low vitamin D and elevated myostatin levels. Further research may focus on investigating means to prevent increased myostatin levels in interventional studies, which might open several venues to putative options to treat and prevent obesity-associated diseases.

Family Financial Pressure in Childhood and Telomere Length in Early Adolescence: A Prospective Study.

Much research on children in high-risk environments has focused on the biological consequences of maltreatment, adversity, and trauma. Whether other early-life stress sources such as family financial hardship are implicated in the cellular mechanism of disease development remains unclear. This study investigated the long-term effect of childhood exposure to family financial pressure on telomere length. It involved two waves of data collection occurring when participants reached Grade 3 (W1) and 7 (W2), respectively. In W1, parents reported family demographics and perceived financial stressors and pressure. In W2, participants provided buccal swab samples for measurement of their telomere length. Data from 92 participants (Mage in W2 = 13.2 years; 56.5% male) were analyzed. The main type of stressors reported by parents who perceived high family financial pressure in W1 were child-level stressors including affordability of their medical and educational expenses. Participants exposed to high parent-perceived family financial pressure in W1 had shorter telomeres in W2 when compared to those exposed to low parent-perceived family financial pressure (β = −0.61, p = 0.042). Subgroup analyses revealed stronger associations in girls than boys. These findings reveal an important spillover effect between parental financial perceptions and stress and children’s health at the cellular level.

Application of Micro-Engineered Kidney, Liver, and Respiratory System Models to Accelerate Preclinical Drug Testing and Development.

Developing novel drug formulations and progressing them to the clinical environment relies on preclinical in vitro studies and animal tests to evaluate efficacy and toxicity. However, these current techniques have failed to accurately predict the clinical success of new therapies with a high degree of certainty. The main reason for this failure is that conventional in vitro tissue models lack numerous physiological characteristics of human organs, such as biomechanical forces and biofluid flow. Moreover, animal models often fail to recapitulate the physiology, anatomy, and mechanisms of disease development in human. These shortfalls often lead to failure in drug development, with substantial time and money spent. To tackle this issue, organ-on-chip technology offers realistic in vitro human organ models that mimic the physiology of tissues, including biomechanical forces, stress, strain, cellular heterogeneity, and the interaction between multiple tissues and their simultaneous responses to a therapy. For the latter, complex networks of multiple-organ models are constructed together, known as multiple-organs-on-chip. Numerous studies have demonstrated successful application of organ-on-chips for drug testing, with results comparable to clinical outcomes. This review will summarize and critically evaluate these studies, with a focus on kidney, liver, and respiratory system-on-chip models, and will discuss their progress in their application as a preclinical drug-testing platform to determine in vitro drug toxicology, metabolism, and transport. Further, the advances in the design of these models for improving preclinical drug testing as well as the opportunities for future work will be discussed.

Myeloid neoplasms and clonal hematopoiesis from the RUNX1 perspective.

RUNX1 is a critical transcription factor for the emergence of definitive hematopoiesis and the precise regulation of adult hematopoiesis. Dysregulation of its regulatory network causes aberrant hematopoiesis. Recurrent genetic alterations in RUNX1, including chromosomal translocations and mutations, have been identified in both inherited and sporadic diseases. Recent genomic studies have revealed a vast mutational landscape surrounding genetic alterations in RUNX1. Accumulating pieces of evidence also indicate the leukemogenic role of wild-type RUNX1 in certain situations. Based on these efforts, part of the molecular mechanisms of disease development as a consequence of dysregulated RUNX1-regulatory networks have become increasingly evident. This review highlights the recent advances in the field of RUNX1 research and discusses the critical roles of RUNX1 in hematopoiesis and the pathobiological function of its alterations in the context of disease, particularly myeloid neoplasms, and clonal hematopoiesis.

Validation of a food-frequency questionnaire to assess methyl-group donor intake in preschoolers.

The FFQ is a tool with a moderate validity and reproducibility to estimate the consumption of dietary methyl-group donors in preschoolers. This tool might be used in future research epidemiological studies including preschoolers. • Poor dietary habits during childhood have been associated with chronic disease in adulthood. • Methyl-group donors are important for DNA methylation, which is the underlying mechanism of disease development. • For the first time, a food-frequency questionnaire that can assess the intake of methione, folate, choline, and betaine has been developed and validated for the use in preschoolers.

Radiation-induced oral mucositis — radiation-induced oral mucositis: pathogenesis, risk factors, clinical manifestations, prevention, and treatment

This study presents the modern concepts of pathogenesis, risk factors, etiology, clinical manifestations, prevention, and treatment of oropharyngeal mucositis, one of the main complications of radiation therapy for head and neck region cancer. The leading role in the mechanisms of disease development belongs to rapidly dividing cells of the basal layer of the oropharyngeal mucous membrane. This damage is due to both direct (excitation and ionization) and indirect (accumulation of active oxygen and nitrogen compounds, activation of transcription factors, hyperfunction of pro-inflammatory cytokines, etc.) action of ionizing radiation on the most important biological molecules and supramolecular structures (polynucleotides, nucleoproteins, phospholipids, etc.). The main risk factors for mucositis include the localization and size of the tumor, the amount of radiation dose to the oral region, and individual body characteristics (young age, pernicious habits, metal structures of dentures, a history of periodontal disease, etc.). The disease severity is described from mild (erythema and moderate pain that does not require analgesia) to severe (ulceration, hemorrhage, necrosis, and other symptoms) to establishment necessary prescription of effective means of pathogenetic and symptomatic therapy. The main means and methods of prevention of radiation-induced mucositis include the following: non-steroidal anti-inflammatory drug benzydamine, means of protection against oxidative stress glutamine, and drugs with a complex stimulating effect on wound healing processes. Drug therapy for mucositis involves the use of benzydamine; the tricyclic antidepressant doxepin; and a gel consisting of polyvinylpyrrolidone (Belclaiz), mucolytic acetylcysteine. When non-narcotic analgesics are ineffective, low doses of opiates (fentanyl, morphine, and methadone) are used in oral, transdermal, or parenteral dosage forms, as well as low-intensity laser therapy. The most important components of the etiopathogenetic therapy of the disease include antiviral drugs (acyclovir and valacyclovir) and fungicides (clotrimazole, fluconazole, and itraconazole). Enteral nutrition difficulty indicates nasogastric or nasojejunal tube usage, and in more serious cases, surgical methods such as gastro- or jejunostomy.

Genetics: Genome-wide data processing for polygenic risk scores.

Comprehensive genomic profiling in Alzheimer's disease (AD) and other dementias will become pivotal in selecting targeted therapies based on an individual risk profile. The Genetics working group addresses this challenge by bringing together genetic data from over 25 cohorts to establish disease risk profiles using polygenic risk sores. Comparable work in other diseases, such as breast or prostate cancer, have shown enhanced utility for clinicians in predicting the development and progression of these diseases, by integrating polygenic risk scores into risk models. These links are, however, currently underexploited for clinical diagnostic practice in AD and dementia. Genetic data from collaborating DPUK cohorts will be used to address the genetic variability of dementia. Using genetic expertise led from the UK DRI, genetic information will be linked with clinical presentation at different stages of dementia and integrated with additional factors, such as geographical and ethnic diversity, to fully capture heterogeneity of common dementias. To achieve high diagnostic accuracy, genetic risk scoring will be linked with other phenotypes, biomarkers, clinical and environmental information, and tested for its prediction accuracy in specific groups of people targeting specific functional mechanisms of disease development. Analyses will be conducted within the DPUK Data Portal. This project will establishing a technological platform and best practices for national and international collaboration between clinicians, geneticists, biostatisticians, data scientists and wet lab scientists. The project will 1) unify and harmonise all genetic data available via the DPUK Data Portal; 2) derive genetic risk scores with the latest genome-wide association results for all DPUK cohorts in a unified way; 3) integrate genetic risk scores with clinical data with the aim to obtain a complete map linking genetic profiles and disease manifestations across the entire spectrum of dementia. By maximally exploiting demographic, clinical, and research data and linking them to individual genetic risk scores, this project will establish a roadmap towards precision medicine for Alzheimer's disease and other dementias. The unified genetic data across cohorts available in DPUK, will be an aid to refine inclusion criteria for future clinical trials and ultimately translate into guidance for personalized healthcare decisions.

Novel associations between inflammation-related proteins and adiposity: A targeted proteomics approach across four population-based studies

Chronic low-grade inflammation has been proposed as a linking mechanism between obesity and the development of inflammation-related conditions such as insulin resistance and cardiovascular disease. Despite major advances in the last 2 decades, the complex relationship between inflammation and obesity remains poorly understood. Therefore, we aimed to identify novel inflammation-related proteins associated with adiposity. We investigated the association between BMI and waist circumference and 72 circulating inflammation-related proteins, measured using the Proximity Extension Assay (Olink Proteomics), in 3,308 participants of four independent European population-based studies (KORA-Fit, BVSII, ESTHER, and Bialystok PLUS). In addition, we used body fat mass measurements obtained by Dual-energy X-ray absorptiometry (DXA) in the Bialystok PLUS study to further validate our results and to explore the relationship between inflammation-related proteins and body fat distribution. We found 14 proteins associated with at least one measure of adiposity across all four studies, including four proteins for which the association is novel: DNER, SLAMF1, RANKL, and CSF-1. We confirmed previously reported associations with CCL19, CCL28, FGF-21, HGF, IL-10RB, IL-18, IL-18R1, IL-6, SCF, and VEGF-A. The majority of the identified inflammation-related proteins were associated with visceral fat as well as with the accumulation of adipose tissue in the abdomen and the trunk. In conclusion, our study provides new insights into the immune dysregulation observed in obesity that might help uncover pathophysiological mechanisms of disease development.

A roadmap for multi-omics data integration using deep learning.

High-throughput next-generation sequencing now makes it possible to generate a vast amount of multi-omics data for various applications. These data have revolutionized biomedical research by providing a more comprehensive understanding of the biological systems and molecular mechanisms of disease development. Recently, deep learning (DL) algorithms have become one of the most promising methods in multi-omics data analysis, due to their predictive performance and capability of capturing nonlinear and hierarchical features. While integrating and translating multi-omics data into useful functional insights remain the biggest bottleneck, there is a clear trend towards incorporating multi-omics analysis in biomedical research to help explain the complex relationships between molecular layers. Multi-omics data have a role to improve prevention, early detection and prediction; monitor progression; interpret patterns and endotyping; and design personalized treatments. In this review, we outline a roadmap of multi-omics integration using DL and offer a practical perspective into the advantages, challenges and barriers to the implementation of DL in multi-omics data.

Emotional and cognitive representation of COVID-19 among Polish adults during the peak of the second wave of the pandemic

Introduction: This paper presents the results of cognitive and emotional representation of COVID-19 in the sample of adult Poles during the peak of the second wave of the pandemic (November–December 2020). Aims: The study was designed to investigate the mental and emotional representation of COVID-19 in adult Poles. It was hypothesised that the representation would have a different structure depending on gender, age, education as well as personal experience of COVID-19 or other medical conditions. Methods: The survey was carried out in November and December 2020, and involved two hundred Polish adults aged 17 to 58 years (Mage = 32.59, SD = 10.19). The subjects were surveyed via the Google Forms web survey platform. A link to the survey was sent to the participants on Facebook. Results: Three in four respondents were found to believe that COVID-19 indeed existed, and that a virus was the most important cause of the problem. According to nearly one in two respondents, the effects of the disease were exaggerated by the mass media. On average, the respondents tend to believe that the severity of the disease may be controlled by one’s behaviour. The emotional representation of COVID-19 reflected predominantly negative emotions. The respondents were convinced that the disease led to significant consequences affecting the domains of personal life and work. Discussion: According to many participants, the effects of the disease are overestimated in media reports. The lack of knowledge about neurological and neuropsychological complications suggests that this aspect of the disease is insufficiently emphasised in the mass media during the second wave of the pandemic. Conclusions: Individual variables and experience of COVID-19 affect one’s cognitive and emotional representation of the disease and one’s beliefs concerning the mitigation of risks. This means that any future information related to COVID-19, and the promotion of knowledge concerning the possible mechanisms of disease development, must be conveyed in a way adjusted to gender and age as well as the level of education.

Identification of Hub Genes and Potential ceRNA Networks of Diabetic Nephropathy by Weighted Gene Co-Expression Network Analysis.

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients, and is the main cause of end-stage renal disease. The exact molecular mechanism of DN is not fully understood. The aim of this study was to identify novel biomarkers and mechanisms for DN disease progression by weighted gene co-expression network analysis (WGCNA). From the GSE142153 dataset based on the peripheral blood monouclear cells (PBMC) of DN, we identified 234 genes through WGCNA and differential expression analysis. Gene Ontology (GO) annotations mainly included inflammatory response, leukocyte cell-cell adhesion, and positive regulation of proteolysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways mostly included IL-17 signaling pathway, MAPK signaling pathway, and PPAR signaling pathway in DN. A total of four hub genes (IL6, CXCL8, MMP9 and ATF3) were identified by cytoscape, and the relative expression levels of hub genes were also confirmed by RT-qPCR. ROC curve analysis determined that the expression of the four genes could distinguish DN from controls (the area under the curve is all greater than 0.8), and Pearson correlation coefficient analysis suggested that the expression of the four genes was related to estimated glomerular filtration rate (eGFR) of DN. Finally, through database prediction and literature screening, we constructed lncRNA-miRNA-mRNA network. We propose that NEAT1/XIST/KCNQ1T1-let-7b-5p-IL6, NEAT1/XIST-miR-93-5p-CXCL8 and NEAT1/XIST/KCNQ1T1-miR-27a-3p/miR-16-5p-ATF3 might be potential RNA regulatory pathways to regulate the disease progression of early DN. In conclusion, we identified four hub genes, namely, IL6, CXCL8, MMP9, and ATF3, as markers for early diagnosis of DN, and provided insight into the mechanisms of disease development in DN at the transcriptome level.

Cal'MAM'ity at the Endoplasmic Reticulum-Mitochondrial Interface: A Potential Therapeutic Target for Neurodegeneration and Human Immunodeficiency Virus-Associated Neurocognitive Disorders.

The endoplasmic reticulum (ER) is a multifunctional organelle and serves as the primary site for intracellular calcium storage, lipid biogenesis, protein synthesis, and quality control. Mitochondria are responsible for producing the majority of cellular energy required for cell survival and function and are integral for many metabolic and signaling processes. Mitochondria-associated ER membranes (MAMs) are direct contact sites between the ER and mitochondria that serve as platforms to coordinate fundamental cellular processes such as mitochondrial dynamics and bioenergetics, calcium and lipid homeostasis, autophagy, apoptosis, inflammation, and intracellular stress responses. Given the importance of MAM-mediated mechanisms in regulating cellular fate and function, MAMs are now known as key molecular and cellular hubs underlying disease pathology. Notably, neurons are uniquely susceptible to mitochondrial dysfunction and intracellular stress, which highlights the importance of MAMs as potential targets to manipulate MAM-associated mechanisms. However, whether altered MAM communication and connectivity are causative agents or compensatory mechanisms in disease development and progression remains elusive. Regardless, exploration is warranted to determine if MAMs are therapeutically targetable to combat neurodegeneration. Here, we review key MAM interactions and proteins both in vitro and in vivo models of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. We further discuss implications of MAMs in HIV-associated neurocognitive disorders (HAND), as MAMs have not yet been explored in this neuropathology. These perspectives specifically focus on mitochondrial dysfunction, calcium dysregulation and ER stress as notable MAM-mediated mechanisms underlying HAND pathology. Finally, we discuss potential targets to manipulate MAM function as a therapeutic intervention against neurodegeneration. Future investigations are warranted to better understand the interplay and therapeutic application of MAMs in glial dysfunction and neurotoxicity.

High-Throughput and Real-Time Monitoring of Single-Cell Extracellular pH Based on Polyaniline Microarrays.

Real-time monitoring of extracellular pH (pHe) at the single-cell level is critical for elucidating the mechanisms of disease development and investigating drug effects, with particular importance in cancer cells. However, there are still some challenges for analyzing and measuring pHe due to the strong heterogeneity of cancer cells. Thus, it is necessary to develop a reliable method with good selectivity, reproducibility, and stability for achieving the pHe heterogeneity of cancer cells. In this paper, we report a high-throughput, real-time measuring technique based on polyaniline (PANI) microelectrode arrays for monitoring single-cell pHe. The PANI microelectrode array not only has a high sensitivity (57.22 mV/pH) ranging from pH 6.0 to 7.6 but also exhibits a high reliability (after washing, the PANI film was still smooth, dense, and with a sensitivity of 55.9 mV/pH). Our results demonstrated that the pHe of the cancer cell region is lower than that of the surrounding blank region, and pHe changes of different cancer cells exhibit significant cellular heterogeneity during cellular respiration and drug stimulation processes.

Current state of the obesity research: genetic aspects, the role of microbiome, and susceptibility to COVID-19

Obesity affects over 700 million people worldwide and its prevalence keeps growing steadily. The problem is particularly relevant due to the increased risk of COVID-19 complications and mortality in obese patients. Obesity prevalence increase is often associated with the influence of environmental and behavioural factors, leading to stigmatization of people with obesity due to beliefs that their problems are caused by poor lifestyle choices. However, hereditary predisposition to obesity has been established, likely polygenic in nature. Morbid obesity can result from rare mutations having a significant effect on energy metabolism and fat deposition, but the majority of patients does not present with monogenic forms. Microbiome low diversity significantly correlates with metabolic disorders (inflammation, insulin resistance), and the success of weight loss (bariatric) surgery. However, data on the long-term consequences of bariatric surgery and changes in the microbiome composition and genetic diversity before and after surgery are currently lacking. In this review, we summarize the results of studies of the genetic characteristics of obesity patients, molecular mechanisms of obesity, contributing to the unfavourable course of coronavirus infection, and the evolution of their microbiome during bariatric surgery, elucidating the mechanisms of disease development and creating opportunities to identify potential new treatment targets and design effective personalized approaches for the diagnosis, management, and prevention of obesity.

Predictive value of m5C regulatory gene expression in pancreatic adenocarcinoma

Pancreatic adenocarcinoma (PAAD) is the most malignant digestive tumor. The global incidence of pancreatic cancer has been rapidly trending upwards, necessitating an exploration of potential prognostic biomarkers and mechanisms of disease development. One of the most prevalent RNA modifications is 5-methylcytosine (m5C); however, its contribution to PAAD remains unclear. Data from The Cancer Genome Atlas (TCGA) database, including genes, copy number variations (CNVs), and simple nucleotide variations (SNVs), were obtained in the present study to identify gene signatures and prognostic values for m5C regulators in PAAD. Regulatory gene m5C changes were significantly correlated with TP53, BRCA1, CDKN2A, and ATM genes, which play important roles in PAAD pathogenesis. In particular, there was a significant relationship between m5C regulatory gene CNVs, especially in genes encoding epigenetic “writers”. According to m5C-regulated gene expression in clinically graded cases, one m5C-regulated genes, DNMT3A, showed both a strong effect on CNVs and a significant correlation between expression level and clinical grade (P < 0.05). Furthermore, low DNMT3A expression was not only associated with poor PAAD patient prognosis but also with the ribosomal processing. The relationship between low DNMT3A expression and poor prognosis was confirmed in an International Cancer Genome Consortium (ICGC) validation dataset.

CD99 and polymeric immunoglobulin receptor peptides deregulation in critical COVID-19: A potential link to molecular pathophysiology?

Identification of significant changes in urinary peptides may enable improved understanding of molecular disease mechanisms. We aimed towards identifying urinary peptides associated with critical course of COVID‐19 to yield hypotheses on molecular pathophysiological mechanisms in disease development. In this multicentre prospective study urine samples of PCR‐confirmed COVID‐19 patients were collected in different centres across Europe. The urinary peptidome of 53 patients at WHO stages 6–8 and 66 at WHO stages 1–3 COVID‐19 disease was analysed using capillary electrophoresis coupled to mass spectrometry. 593 peptides were identified significantly affected by disease severity. These peptides were compared with changes associated with kidney disease or heart failure. Similarities with kidney disease were observed, indicating comparable molecular mechanisms. In contrast, convincing similarity to heart failure could not be detected. The data for the first time showed deregulation of CD99 and polymeric immunoglobulin receptor peptides and of known peptides associated with kidney disease, including collagen and alpha‐1‐antitrypsin. Peptidomic findings were in line with the pathophysiology of COVID‐19. The clinical corollary is that COVID‐19 induces specific inflammation of numerous tissues including endothelial lining. Restoring these changes, especially in CD99, PIGR and alpha‐1‐antitripsin, may represent a valid and effective therapeutic approach in COVID‐19, targeting improvement of endothelial integrity.

СОВРЕМЕННОЕ СОСТОЯНИЕ ИССЛЕДОВАНИЙ В ОБЛАСТИ ОЖИРЕНИЯ: ГЕНЕТИЧЕСКИЕ АСПЕКТЫ, РОЛЬ МИКРОБИОМА И ПРЕДРАСПОЛОЖЕННОСТЬ К COVID-19

Obesity affects over 700 million people worldwide and its prevalence keeps growing steadily. The problem is particularly relevant due to the increased risk of COVID-19 complications and mortality in obese patients. Obesity prevalence increase is often associated with the influence of environmental and behavioural factors, leading to stigmatization of people with obesity due to beliefs that their problems are caused by poor lifestyle choices. However, hereditary predisposition to obesity has been established, likely polygenic in nature. Morbid obesity can result from rare mutations having a significant effect on energy metabolism and fat deposition, but the majority of patients does not present with monogenic forms. Microbiome low diversity significantly correlates with metabolic disorders (inflammation, insulin resistance), and the success of weight loss (bariatric) surgery. However, data on the long-term consequences of bariatric surgery and changes in the microbiome composition and genetic diversity before and after surgery are currently lacking. In this review, we summarize the results of studies of the genetic characteristics of obesity patients, molecular mechanisms of obesity, contributing to the unfavourable course of coronavirus infection, and the evolution of their microbiome during bariatric surgery, elucidating the mechanisms of disease development and creating opportunities to identify potential new treatment targets and design effective personalized approaches for the diagnosis, management, and prevention of obesity.

Successful Genetic Screening and Creating Awareness of Familial Hypercholesterolemia and Other Heritable Dyslipidemias in the Netherlands.

The genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the government was terminated in 2014, the approach had proven its effectiveness and had built the foundation for the development of more sophisticated diagnostic tools, clinical collaborations, and new molecular-based treatments for FH patients. As such, the community was driven to continue the program, insurance companies were convinced to collaborate, and multiple approaches were launched to find new index cases with FH. Additionally, the screening was extended, now also including other heritable dyslipidemias. For this purpose, a diagnostic next-generation sequencing (NGS) panel was developed, which not only comprised the culprit LDLR, APOB, and PCSK9 genes, but also 24 other genes that are causally associated with genetic dyslipidemias. Moreover, the NGS technique enabled further optimization by including pharmacogenomic genes in the panel. Using such a panel, more patients that are prone to cardiovascular diseases are being identified nowadays and receive more personalized treatment. Moreover, the NGS output teaches us more and more about the dyslipidemic landscape that is less straightforward than we originally thought. Still, continuous progress is being made that underlines the strength of genetics in dyslipidemia, such as discovery of alternative genomic pathogenic mechanisms of disease development and polygenic contribution.

Molecular Pathways Involved in the Development of Congenital Erythrocytosis.

Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

Parkinson’s disease: epidemiology and pathogenesis

This review presents data on the etiology, epidemiology, and pathogenesis of Parkinsons disease from National Center for Biotechnology Information (NCBI), eLibrary, CyberLeninka, and from monographs and textbooks. The prevalence, classification, genetic variability, main pathogenetic links, and potential disease development mechanisms are described. Both classic Parkinsons disease and variable manifestations of parkinsonism are considered. The factors that contribute to disease progression and inhibit its development are described. The main hypotheses of the pathogenetic mechanisms of Parkinsons disease are presented. These are protein misfolding, mitochondrial dysfunction, impaired protein purification systems, neuroinflammation, and pathology of the gut-brain axis.