Involvement In Various Diseases Research Articles

MATR3's Role beyond the Nuclear Matrix: From Gene Regulation to Its Implications in Amyotrophic Lateral Sclerosis and Other Diseases.

Matrin-3 (MATR3) was initially discovered as a component of the nuclear matrix about thirty years ago. Since then, accumulating studies have provided evidence that MATR3 not only plays a structural role in the nucleus, but that it is also an active protein involved in regulating gene expression at multiple levels, including chromatin organization, DNA transcription, RNA metabolism, and protein translation in the nucleus and cytoplasm. Furthermore, MATR3 may play a critical role in various cellular processes, including DNA damage response, cell proliferation, differentiation, and survival. In addition to the revelation of its biological role, recent studies have reported MATR3's involvement in the context of various diseases, including neurodegenerative and neurodevelopmental diseases, as well as cancer. Moreover, sequencing studies of patients revealed a handful of disease-associated mutations in MATR3 linked to amyotrophic lateral sclerosis (ALS), which further elevated the gene's importance as a topic of study. In this review, we synthesize the current knowledge regarding the diverse functions of MATR3 in DNA- and RNA-related processes, as well as its involvement in various diseases, with a particular emphasis on ALS.

The Significance of Key Proteins in the RAS Signaling Pathway: Implications for Cancer and Therapeutic Targets

The RAS signaling pathway is a crucial cell transduction pathway central to transmitting signals from outside the cell to the cell nucleus and influencing fundamental biological mechanisms like cell growth, division, and specialization. This signaling pathway has recently received much attention in scientific research because of its involvement in various diseases, especially carcinogenesis. Our study identified the significance of crucial proteins in the RAS signaling cascade in cancer development and progression. We found that proteins such as PDGFRB, PDGFB, IGF1, HRAS, HGF, FGF10, and ABL1 are involved in various types of cancer and could serve as potential therapeutic targets. Misregulation of these proteins may result in unregulated cell proliferation and contribute to cancer development and maintenance. The study also emphasizes the importance of oncogenes in cancer development, with RAS being identified as a pivotal oncogene. In addition, the findings indicate several proteins, including PDGFRA, NRAS, HRAS, CSF1R, KIT, MET, ABL1, FGFR2, FGFR3, and KRAS, function as oncogenes and are related to different forms of cancer and diseases. Targeted therapies for these proteins are being investigated in various cancer types, including gastrointestinal stromal tumors, chronic myelogenous leukemia, and bladder cancer. Moreover, we identified NF1 as a critical tumor suppressor gene essential in regulating cellular proliferation. Mutations in the NF1 gene lead to neurofibromatosis category 1. This paper emphasizes the significance of crucial proteins implicated in the RAS signaling pathway in cancer growth and advancement. Understanding the complexity of these proteins and their dysregulation could offer essential insights into the progression of practical treatment approaches that enhance and refine cancer therapies. These findings provide promising avenues for further research and advances in cancer treatment and give us hope for better outcomes in the fight against this challenging disease.

"Oh, Dear We Are in Tribble": An Overview of the Oncogenic Functions of Tribbles 1.

Pseudokinases are catalytically inactive proteins in the human genome that lack the ability to transfer phosphate from ATP to their substrates. The Tribbles family of pseudokinases contains three members: Tribbles 1, 2, and 3. Tribbles 1 has recently gained importance because of its involvement in various diseases, including cancer. It acts as a scaffolding protein that brings about the degradation of its substrate proteins, such as C/EBPα/β, MLXIPL, and RAR/RXRα, among others, via the ubiquitin proteasome system. It also serves as an adapter protein, which sequesters different protein molecules and activates their downstream signaling, leading to processes, such as cell survival, cell proliferation, and lipid metabolism. It has been implicated in cancers such as AML, prostate cancer, breast cancer, CRC, HCC, and glioma, where it activates oncogenic signaling pathways such as PI3K-AKT and MAPK and inhibits the anti-tumor function of p53. TRIB1 also causes treatment resistance in cancers such as NSCLC, breast cancer, glioma, and promyelocytic leukemia. All these effects make TRIB1 a potential drug target. However, the lack of a catalytic domain renders TRIB1 "undruggable", but knowledge about its structure, conformational changes during substrate binding, and substrate binding sites provides an opportunity to design small-molecule inhibitors against specific TRIB1 interactions.

Necroptosis and Its Involvement in Various Diseases.

Necroptosis is a regulated form of cell death involved in the development of various pathological conditions. In contrast to apoptosis, plasma membrane rupture (PMR) occurs in cells in the relatively early stage of necroptosis; therefore, necroptosis induces a strong inflammatory response. Stimuli, including tumor necrosis factor (TNF), interferon (IFN)α/β, lipopolysaccharide, polyI:C, and viral infection, induce the formation of necrosomes that lead to membrane rupture and the release of intracellular contents, termed danger-associated molecular patterns (DAMPs). DAMPs are the collective term for molecules that normally reside in the cytoplasm or nucleus in living cells without inducing inflammation but induce strong inflammatory responses when released outside cells. Recent studies have provided a better understanding of the mechanisms underlying PMR and the release of DAMPs. Moreover, necroptosis is involved in various pathological conditions, and mutations in necroptosis-related genes can cause hereditary autoinflammatory syndromes. Thus, manipulating necroptosis signaling pathways may be useful for treating diseases involving necroptosis.

Hsa_circ_0105040 promotes Cutbacterium acnes biofilm induced inflammation via sponge miR-146a in human keratinocyte

Acne is a chronic inflammatory skin disease, and the pathogenesis of acne induced by Cutibacterium acnes (C.acnes) is not well understood. Recently, circular RNAs (circRNAs) have attracted much attention because of its involvement in various diseases. However, the mechanisms by which circRNAs regulated acne have rarely been reported. We identified several differentially expressed circRNAs by sequencing patient-derived acne tissues. Among them, hsa_circ_0105040 was determined to be low expressed in acne tissues and localized in the cytoplasm of human primary keratinocytes. We established a C.acnes biofilms model of acne in vitro and showed that hsa_circ_0105040 promoted inflammation via MAPK and NF-κB pathway. Mechanistically, hsa_circ_0105040 could directly bind to miR-146a and inhibit the expression of miR-146a. Moreover, hsa_circ_0105040 promoted the expression of IRAK1 and TRAF6 by sponging miR-146a, thereby elevating the level of inflammation in acne. Collectively, our data suggested that hsa_circ_0105040- miR-146a -IRAK1/TRAF6 axis was involved in regulating the inflammatory response in acne, which provided a potential therapeutic target for acne and a novel insight into the pathogenesis of inflammatory acne.

The role and potential therapeutic targets of astrocytes in central nervous system demyelinating diseases.

Astrocytes play vital roles in the central nervous system, contributing significantly to both its normal functioning and pathological conditions. While their involvement in various diseases is increasingly recognized, their exact role in demyelinating lesions remains uncertain. Astrocytes have the potential to influence demyelination positively or negatively. They can produce and release inflammatory molecules that modulate the activation and movement of other immune cells. Moreover, they can aid in the clearance of myelin debris through phagocytosis and facilitate the recruitment and differentiation of oligodendrocyte precursor cells, thereby promoting axonal remyelination. However, excessive or prolonged astrocyte phagocytosis can exacerbate demyelination and lead to neurological impairments. This review provides an overview of the involvement of astrocytes in various demyelinating diseases, emphasizing the underlying mechanisms that contribute to demyelination. Additionally, we discuss the interactions between oligodendrocytes, oligodendrocyte precursor cells and astrocytes as therapeutic options to support myelin regeneration. Furthermore, we explore the role of astrocytes in repairing synaptic dysfunction, which is also a crucial pathological process in these disorders.

TXNIP: A key protein in the cellular stress response pathway and a potential therapeutic target.

Thioredoxin-interacting protein (TXNIP), which is also known as thioredoxin-binding protein 2 (TBP2), directly interacts with the major antioxidant protein thioredoxin (TRX) and inhibits its antioxidant function and expression. However, recent studies have demonstrated that TXNIP is a multifunctional protein with functions beyond increasing intracellular oxidative stress. TXNIP activates endoplasmic reticulum (ER) stress-mediated nucleotide-binding oligomerization domain (NOD)-like receptor protein-3 (NLRP3) inflammasome complex formation, triggers mitochondrial stress-induced apoptosis, and stimulates inflammatory cell death (pyroptosis). These newly discovered functions of TXNIP highlight its role in disease development, especially in response to several cellular stress factors. In this review, we provide an overview of the multiple functions of TXNIP in pathological conditions and summarize its involvement in various diseases, such as diabetes, chronic kidney disease, and neurodegenerative diseases. We also discuss the potential of TXNIP as a therapeutic target and TXNIP inhibitors as novel therapeutic drugs for treating these diseases.

"HLA-C: evolution, epigenetics, and pathological implications in the major histocompatibility complex".

HLA-C, a gene located within the major histocompatibility complex, has emerged as a prominent target in biomedical research due to its involvement in various diseases, including cancer and autoimmune disorders; even though its recent addition to the MHC, the interaction between HLA-C and KIR is crucial for immune responses, particularly in viral infections. This review provides an overview of the structure, origin, function, and pathological implications of HLA-C in the major histocompatibility complex. In the last decade, we systematically reviewed original publications from Pubmed, ScienceDirect, Scopus, and Google Scholar. Our findings reveal that genetic variations in HLA-C can determine susceptibility or resistance to certain diseases. However, the first four exons of HLA-C are particularly susceptible to epigenetic modifications, which can lead to gene silencing and alterations in immune function. These alterations can manifest in diseases such as alopecia areata and psoriasis and can also impact susceptibility to cancer and the effectiveness of cancer treatments. By comprehending the intricate interplay between genetic and epigenetic factors that regulate HLA-C expression, researchers may develop novel strategies for preventing and treating diseases associated with HLA-C dysregulation.

Cathepsin K in Pathological Conditions and New Therapeutic and Diagnostic Perspectives.

Cathepsin K (CatK) is a part of the family of cysteine proteases involved in many important processes, including the degradation activity of collagen 1 and elastin in bone resorption. Changes in levels of CatK are associated with various pathological conditions, primarily related to bone and cartilage degradation, such as pycnodysostosis (associated with CatK deficiency), osteoporosis, and osteoarthritis (associated with CatK overexpression). Recently, the increased secretion of CatK is being highly correlated to vascular inflammation, hypersensitivity pneumonitis, Wegener granulomatosis, berylliosis, tuberculosis, as well as with tumor progression. Due to the wide spectrum of diseases in which CatK is involved, the design and validation of active site-specific inhibitors has been a subject of keen interest in pharmaceutical companies in recent decades. In this review, we summarized the molecular background of CatK and its involvement in various diseases, as well as its clinical significance for diagnosis and therapy.

Postsystolic shortening and early systolic lengthening for early detection of myocardial involvement in patients with systemic lupus erythematosus.

Cardiac involvement predicts a poor prognosis in patients with systemic lupus erythematosus (SLE). Two-dimensional speckle-tracking echocardiography (2D-STE) are used to identify subclinical myocardial involvement in various diseases. This study objected to evaluate postsystolic shortening (PSS) and early systolic lengthening (ESL) by 2D-STE for early detection of myocardial involvement in patients with SLE. A total of 121 patients with preserved left ventricular ejection fraction (LVEF) in SLE and 30 healthy controls underwent standard 2D-STE in our study. According to SLE disease activity index (SLEDAI), we divided SLE patients into two groups: the group of inactive disease (SLEDAI ≤ 4) and active disease (SLEDAI ≥ 5). The maximum of postsystolic strain index (PSImax ) and early systolic strain index (ESImax ) were acquired from 17 segments of left ventricular (LV). We also compared the PSImax and ESImax of basal, medial, and apical segments between SLE patients and controls. Compared with healthy controls and the group of SLEDAI ≤ 4, the group of SLEDAI ≥ 5 had higher PSImax and ESImax value of global LV and basal segments. The absolute value of global longitudinal strain (GLS) had no difference between the group of active disease and inactive disease. Multivariate analysis demonstrated that PSS was independently associated with SLEDAI and diabetes mellitus. Detection of PSS and ESL enable to identify LV systolic impairment in SLE patients at an early stage.

Integrative Conformational Ensembles of Sic1 Using Different Initial Pools and Optimization Methods

Intrinsically disordered proteins play key roles in regulatory protein interactions, but their detailed structural characterization remains challenging. Here we calculate and compare conformational ensembles for the disordered protein Sic1 from yeast, starting from initial ensembles that were generated either by statistical sampling of the conformational landscape, or by molecular dynamics simulations. Two popular, yet contrasting optimization methods were used, ENSEMBLE and Bayesian Maximum Entropy, to achieve agreement with experimental data from nuclear magnetic resonance, small-angle X-ray scattering and single-molecule Förster resonance energy transfer. The comparative analysis of the optimized ensembles, including secondary structure propensity, inter-residue contact maps, and the distributions of hydrogen bond and pi interactions, revealed the importance of the physics-based generation of initial ensembles. The analysis also provides insights into designing new experiments that report on the least restrained features among the optimized ensembles. Overall, differences between ensembles optimized from different priors were greater than when using the same prior with different optimization methods. Generating increasingly accurate, reliable and experimentally validated ensembles for disordered proteins is an important step towards a mechanistic understanding of their biological function and involvement in various diseases.

Possible Glutathione Peroxidase 4-Independent Reduction of Phosphatidylcholine Hydroperoxide: Its Relevance to Ferroptosis.

Ferroptosis is mainly caused by iron-mediated peroxidation of phospholipids and has recently attracted attention due to its involvement in various diseases. At the center of it is supposedly the inability of glutathione peroxidase 4 (GPX4) to reduce excess peroxidized phospholipids (e.g., phosphatidylcholine hydroperoxide (PCOOH)) that trigger ferroptosis. However, the involvement of enzymes other than GPX4 in ferroptosis is scarcely known. To elucidate this matter, we evaluated the uptake of PCOOH in a GPX4 knockout (KO) human hepatoma cell line HepG2 generated using CRISPR-Cas9. After confirming that GPX4 expression in the KO cells was below the detection limit, we cultured both wild-type (WT) and GPX4 KO HepG2 cells in a medium containing 50 μM PCOOH for 1-8 hours. By analyzing the level of PCOOH and its reduction product (phosphatidylcholine hydroxide, PCOH) in cells using liquid chromatography-tandem mass spectrometry, we detected the cellular uptake of PCOOH. On top of this, we detected a large amount of PCOH not only in WT HepG2 but also in GPX4 KO HepG2, thus indicating the notable involvement of enzymes other than GPX4 (e.g., other GPX family, glutathione S-transferase, thioredoxin, or peroxiredoxin) in reducing PCOOH. Further corroboration of these findings hopefully leads to the development of novel methods to prevent ferroptosis-related diseases by targeting enzymes other than GPX4.

A comprehensive review of online resources for microRNA-diseases associations: the state of the art.

MicroRNAs (miRNAs) as small 19- to 24-nucleotide noncoding RNAs regulate several mRNA targets and signaling pathways. Therefore, miRNAs are considered key regulators in cellular pathways as well as various pathologies. There is substantial interest in the relationship between disease and miRNAs, which made that one of the important research topics. Interestingly, miRNAs emerged as an attractive approach for clinical application, not only as biomarkers for diagnosis and prognosis or in the prediction of therapy response but also as therapeutic tools. For these purposes, the identification of crucial miRNAs in disease is very important. Databases provided valuable experimental and computational miRNAs-disease information in an accessible and comprehensive manner, such as miRNA target genes, miRNA related in signaling pathways and miRNA involvement in various diseases. In this review, we summarized miRNAs-disease databases in two main categories based on the general or specific diseases. In these databases, researchers could search diseases to identify critical miRNAs and developed that for clinical applications. In another way, by searching particular miRNAs, they could recognize in which disease these miRNAs would be dysregulated. Despite the significant development that has been done in these databases, there are still some limitations, such as not being updated and not providing uniform and detailed information that should be resolved in future databases. This survey can be helpful as a comprehensive reference for choosing a suitable database by researchers and as a guideline for comparing the features and limitations of the database by developer or designer. Short abstract We summarized miRNAs-disease databases that researchers could search disease to identify critical miRNAs and developed that for clinical applications. This survey can help choose a suitable database for researchers.

The discovery of group 2 innate lymphoid cells has changed the concept of type 2 immune diseases.

Group 2 innate lymphoid cells (ILC2s), discovered in 2010, have been recognized as immune cells with unique functions and their involvement in various diseases has been clarified. Before 2010, the antigen-specific response was a primary focus of immunology research, and immune responses were considered almost equivalent to biological responses to foreign antigens. However, with the emergence of ILC2s, the importance of ‘antigen-independent responses’ was confirmed, and this concept has permeated basic and clinical research as well as drug development. When ILC2s were discovered, their function in the acute phase of diseases garnered attention because of their rapid and potent type 2 immune response. However, several studies have revealed that the main role of ILC2s is more closely related to the chronicity of diseases, such as allergy and fibrosis, than to the induction of diseases. In this review, we discuss how ILC2 research has affected the concept of ‘Taishitsu’, a Japanese term describing the overall nature of an individual as determined by the interaction of genetic and acquired predisposition.

Approaching transglutaminase from Streptomyces bacteria over three decades.

Transglutaminases are protein cross-linking and protein-modifying enzymes that have attracted considerable interest due to their causal involvement in various diseases and versatility in industrial applications. In particular, microbial transglutaminases (MTG) from Streptomyces bacteria have managed in recent years to evolve from simple food additives to specialized enzymes for the site-directed modification of therapeutic proteins. The review summarizes relevant studies from the beginning dealing with the occurrence, production, structure, catalysis, and substrate molecules of MTG enzymes. It also addresses biotechnological procedures with MTG from S. mobaraensis (SmMTG) as the most prominent representative in focus. Reassessment of the available data revealed unexpected insights into catalysis of SmMTG and other transglutaminases, suggesting selection of glutamine donor proteins by subsites at the front vestibule and the existence of distinct lysine pockets. Flexibility of the SmMTG-accessible glutamine donor substrate regions seems to be more important than the glutamine environment. Nevertheless, residues in close vicinity to glutamines also determine interaction with the SmMTG subsites. The apparent lack of subsites for lysine donor proteins suggests self-assembly of the substrate proteins prior to enzymatic cross-linking. The study of natural substrate proteins, especially their mutual interaction, is proposed to further illuminate catalysis of SmMTG. To this end, structure and function of the characterized substrate proteins from S. mobaraensis are discussed in conclusion.

Role of Fibulins in Embryonic Stage Development and Their Involvement in Various Diseases.

The extracellular matrix (ECM) plays an important role in the evolution of early metazoans, as it provides structural and biochemical support to the surrounding cells through the cell–cell and cell–matrix interactions. In multi-cellular organisms, ECM plays a pivotal role in the differentiation of tissues and in the development of organs. Fibulins are ECM glycoproteins, found in a variety of tissues associated with basement membranes, elastic fibers, proteoglycan aggregates, and fibronectin microfibrils. The expression profile of fibulins reveals their role in various developmental processes such as elastogenesis, development of organs during the embryonic stage, tissue remodeling, maintenance of the structural integrity of basement membrane, and elastic fibers, as well as other cellular processes. Apart from this, fibulins are also involved in the progression of human diseases such as cancer, cardiac diseases, congenital disorders, and chronic fibrotic disorders. Different isoforms of fibulins show a dual role of tumor-suppressive and tumor-promoting activities, depending on the cell type and cellular microenvironment in the body. Knockout animal models have provided deep insight into their role in development and diseases. The present review covers details of the structural and expression patterns, along with the role of fibulins in embryonic development and disease progression, with more emphasis on their involvement in the modulation of cancer diseases.

Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros.

NIMA-related kinase 1 (Nek1) has lately garnered attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response. Despite its involvement in various diseases and its potential as a cancer drug target, no directed medicinal chemistry efforts toward inhibitors against this dark kinase are published. Here, we report the structure-guided design of a potent small-molecule Nek1 inhibitor, starting from a scaffold identified by kinase cross-screening analysis. Seven lead compounds were identified in silico and evaluated for their inhibitory activity. The top compound, 10f, was further profiled for efficacy, toxicity, and bioavailability in a zebrafish polycystic kidney disease model. Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. Compound 10f displayed insignificant inhibition in 48 of 50 kinases in a selectivity test panel. The findings provide a powerful tool to further elucidate the function and pharmacology of this neglected kinase.

Nicotinic acetylcholine receptors: Diversity and physiological importance for neurodegenerative disorders and development of organophosphate antidotes

The communication between the nervous and other systems in the organism is carried out by the transmission of nerve impulses. Diverse neurotransmitters are released into the synaptic cleft and bind to the specific receptors at the neighbouring cell to transmit the signal further. One of such receptors are nicotinic acetylcholine receptors (nAChR), integrated membrane proteins (ligand-gated ion channels) activated by the binding of a neurotransmitter acetylcholine. nAChR's main characteristic is their diversity, as they consist of five of the same or mutually different subunits, which contribute to the specific receptors properties and biological activity. During the assembly of a pentameric protein structure, various combinations of subunits are linked together. After the discovery of nAChR’s involvement in various diseases, they became an important therapeutic target, for example in the treatment of neurodegenerative diseases (Alzheimer's and Parkinson's) and in the treatment of organophosphorus compound poisoning. This paper presents an overview of current knowledge on nicotinic receptors and an accompanying discussion on diseases, poisonings, potential drugs and treatments is given.

Brain Diffusion Tensor Imaging Findings in Hashimoto's Thyroiditis.

Hashimoto's thyroiditis (HT) is a type of autoimmune thyroid disease. Diffusion tensor imaging (DTI) can evaluate microstructural brain involvement in various diseases. We aimed to investigate whether there were any DTI differences in patients with HT, and the relationship between DTI values and disease duration time and thyroid peroxidase antibodies (TPOAb) levels. We prospectively included 36 patients with HT (mean age 41.6 ± 13.8 years, range 18-64 years) and 18 age and sex-matched healthy control subjects (mean age 41.6 ± 13.1 years, range 18-63 years). All patients were euthyroid at the time of imaging. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values of 15 distinct neuroanatomical locations were measured and compared. FA values of the patients with HT were lower in cingulum, globus pallidus (GP), cerebellar white matter (CWM) than the control (P = .019, .002, and <.001, respectively). MD values of the CWM in patients were higher than the control (P = .008). AD values of patients with HT were lower in the cingulum, posterior limbs of the internal capsule, GP, and putamen (P = .038, .038, .030, and .045, respectively). RD values of cingulum and CWM in HT were higher than controls (P <.001 and P = .011, respectively). There was a negative relationship between the FA values of PLIC and a positive relationship between the MD values of the corona radiata and TPOAb levels were detected. The current DTI study presented microstructural changes in the neurocognitive-related areas that may be related to accompanying neurological findings in HT.

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications.

Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high-efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive-oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria-targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed.