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Autism spectrum disorder (ASD) is known as a group of neurodevelopmental conditions including stereotyped and repetitive behaviors, besides social and sensorimotor deficits. Anatomical and functional evidence indicates atypical maturation of the striatum. Astrocytes regulate the maturation and plasticity of synaptic circuits, and impaired calcium signaling is associated with repetitive behaviors and atypical social interaction. Spontaneous calcium transients (SCT) recorded in the striatal astrocytes of the rat were investigated in the preclinical model of ASD by prenatal exposure to valproic acid (VPA). Our results showed sensorimotor delay, augmented glial fibrillary acidic protein -a typical intermediate filament protein expressed by astrocytes- and diminished expression of GABAA-ρ3 through development, and increased frequency of SCT with a reduced latency that resulted in a diminished amplitude in the VPA model. The convulsant picrotoxin, a GABAA (γ-aminobutyric acid type A) receptor antagonist, reduced the frequency of SCT in both experimental groups but rescued this parameter to control levels in the preclinical ASD model. The amplitude and latency of SCT were decreased by picrotoxin in both experimental groups. Nipecotic acid, a GABA uptake inhibitor, reduced the mean amplitude only for the control group. Nevertheless, nipecotic acid increased the frequency but diminished the latency in both experimental groups. Thus, we conclude that striatal astrocytes exhibit SCT modulated by GABAA-mediated signaling, and prenatal exposure to VPA disturbs this tuning. [ABSTRACT FROM AUTHOR]

Keratin intermediate filaments confer structural stability to epithelial tissues, but the reason this simple mechanical function requires a protein family with 54 isoforms is not understood. During skin wound healing, a shift in keratin isoform expression alters the composition of keratin filaments. If and how this change modulates cellular functions that support epidermal remodeling remains unclear. We report an unexpected effect of keratin isoform variation on kinase signal transduction. Increased expression of wound-associated keratin 6A, but not of steady-state keratin 5, potentiated keratinocyte migration and wound closure without compromising mechanical stability by activating myosin motors to increase contractile force generation. These results substantially expand the functional repertoire of intermediate filaments from their canonical role as mechanical scaffolds to include roles as isoform-tuned signaling scaffolds that organize signal transduction cascades in space and time to influence epithelial cell state. [Display omitted] • During skin wound healing, the isoform composition of keratin filaments changes • Wound-associated keratin isoforms organize cellular signals to activate myosin • Keratin isoform-dependent signaling is separable from canonical mechanical function Nanes et al. explore why the seemingly simple mechanical function of keratin intermediate filaments requires a protein family with 54 isoforms. They find that skin wound healing triggers a change in keratin isoform expression not to alter force resistance but to organize signals activating myosin and promoting cell motility. [ABSTRACT FROM AUTHOR]

Background and Objectives: Glial fibrillary acidic protein (GFAP) is a type III intermediate filament protein primarily produced by cells in the central nervous system (CNS) and other major organs such as the kidneys. This study investigated whether serum GFAP could be used to estimate cross-sectional vasculitis activity presented via the Birmingham vasculitis activity score (BVAS) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Materials and Methods: This study included 74 patients with AAV. Clinical and laboratory data at diagnosis including BVAS and C-reactive protein (CRP) were reviewed. During follow-up, all-cause mortality and end-stage kidney disease (ESKD) were considered poor outcomes. Serum GFAP was measured from sera collected and stored at diagnosis. Results: The median age of the 74 patients was 63.5 years. Serum GFAP was inversely correlated with the cross-sectional BVAS (r = −0.373) and CRP (r = −0.320). It was also significantly correlated with general (r = −0.237) and renal (r = −0.335) manifestations among BVAS systemic items, and furthermore, among minor items of renal manifestation, correlating with sum scores for proteinuria (r = −0.409) and haematuria (r = −0.305). Additionally, compared with patients with serum GFAP > 194.9 pg/mL, those with serum GFAP ≤ 194.9 pg/mL showed a higher risk for progression to ESKD (relative risk 3.150) and a significantly lower cumulative ESKD-free survival rate. Conclusions: This study demonstrated the clinical potential of serum GFAP at diagnosis for predicting not only cross-sectional vasculitis activity through the anticipation of the extent of renal involvement but also future progression to ESKD in patients with AAV. [ABSTRACT FROM AUTHOR]

Glial cells of the peripheral nervous system (PNS) are one of the major focuses of modern neurobilogy. This review aims to summarize our own and literature data on the expression and distribution patterns of glial fibrillary acidic protein (GFAP) in PNS glial cells, specifically, in the enteric nervous system, dorsal root ganglia, and peripheral nerves. A comparative study of different PNS gliocyte populations shows that GFAP, a key intermediate filament protein, has different distribution patterns in these cells. Analysis of the literature demonstrates that although this protein is widely employed as a molecular marker of glial activation, there is still a lack of understanding of the exact mechanisms behind its involvement in glial reactivity. The described features of GFAP-expressing gliocytes in different parts of the PNS reveals a functional polymorphism of this protein. Its ability to be expressed in PNS gliocytes in response to injury requires further investigation. [ABSTRACT FROM AUTHOR]

Objective: To screen the host interaction proteins of the severe fever with thrombocytopenia syndrome virus (SFTSV) nonstructural protein (NSs) by immunoprecipitation combined with mass spectrometry analysis, to discuss the functions, subcellular localization, and biological pathways of these interaction proteins, and to provide the basis for clarifying the replication and pathogenic mechanism of SFTSV. Methods: The eukaryotic expression vectors pSFTSV-NSs-Flag (experimental group) and Flag-CMV-3 (negative group) were transfected into the human embryonic kidney 293T cells, and contorl group (no treatment) was set up. The lysates of the cells in various groups were collected, and the expression and localization of SFTSV NSs in the host cells were verified by indirect immunofluorescence and Western blotting methods. The protein lysates were treated with protein A/G and immunoprecipitation was used to enrich host proteins binding to NSs. The captured interaction proteins were initially analyzed by silver staining and Coomassie brilliant blue staining to observe the differential protein bands in various groups; liquid chromatography-tandem mass spectrometry was used to obtain the information of protein sequences; the reliable proteins were retained and searched by UniProt database; Gene Ontology (GO) functional enrichment analysis, IPR, eukaryotic orthologous groups (KOGs) functional annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis, subcellular localization, and transcription factor (TF) functional annotation were used to determine the subcellular structure, gene functions, and biological processes of the interaction proteins. Results: The immunofluorescence results showed that the SFTSV NSs expressed a single specific band at relative molecular mass 33 000 and was localized in the cytoplasm in a granular inclusion body-like manner. The silver staining and Coomassie brilliant blue staining results showed there were significant differential protein bands between experimental group and negative group. The mass spectrometry results identified 46 potential interaction proteins. The GO functional enrichment analysis, KOGs functional annotation, and KEGG signaling pathway enrichment analysis results showed that the biological pathways related to viral translation, cellular metabolism, and protein transport were enriched with a considerable number of proteins. Eight annotated proteins had intermediate filament domains. The highest percentage of subcellular localization was cytoplasmic proteins, consistent with the NSs localization site. The TF functional annotation analysis results showed one protein from the NF-Y family. Conclusion: The interaction proteins play roles in assisting the proper protein folding, participating in the cribosome translation, and forming the cytoskeleton, which may be involved in antiviral replication. These proteins can be used as candidate proteins for further study on the replication mechanism of SFTSV. [ABSTRACT FROM AUTHOR]

Keratins are typical intermediate filament proteins of the epithelium that exhibit highly specific expression patterns related to the epithelial type and stage of cellular differentiation. They are important for cytoplasmic stability and epithelial integrity and are involved in various intracellular signaling pathways. Several keratins are associated with enamel formation. However, information on their expression patterns during tooth development remains lacking. In this study, we analyzed the spatiotemporal expression of keratin family members during tooth development using single‐cell RNA‐sequencing (scRNA‐seq) and microarray analysis. scRNA‐seq datasets from postnatal Day 1 mouse molars revealed that several keratins are highly expressed in the dental epithelium, indicating the involvement of keratin family members in cellular functions. Among various keratins, keratin 5 (Krt5), keratin 14 (Krt14), and keratin 17 (Krt17) are highly expressed in the tooth germ; KRT17 is specifically expressed in the stratum intermedium (SI) and stellate reticulum (SR). Depletion of Krt17 did not affect cell proliferation in the dental epithelial cell line SF2 but suppressed their differentiation ability. These results suggest that Krt17 is essential for SI cell differentiation. Furthermore, scRNA‐seq results indicated that Krt5, Krt14, and Krt17 exhibited distinct expression patterns in ameloblast, SI, and SR cells. Our findings contribute to the elucidation of novel mechanisms underlying tooth development. [ABSTRACT FROM AUTHOR]

Keratin intermediate filaments form dynamic filamentous networks, which provide mechanical stability, scaffolding, and protection against stress to epithelial cells. Keratins and other intermediate filaments have been increasingly linked to the regulation of mitochondrial function and homeostasis in different tissues and cell types. While deletion of keratin 8 (K8–/–) in mouse colon elicits a colitis-like phenotype, epithelial hyperproliferation, and blunted mitochondrial ketogenesis, the role of K8 in colonocyte mitochondrial function and energy metabolism is unknown. We used two K8 knockout mouse models and CRISPR/Cas9 K8–/– colorectal adenocarcinoma Caco-2 cells to answer this question. The results show that K8–/– colonocyte mitochondria in vivo are smaller and rounder and that mitochondrial motility is increased in K8–/– Caco-2 cells. Furthermore, K8−/− Caco-2 cells displayed diminished mitochondrial respiration and decreased mitochondrial membrane potential compared with controls, whereas glycolysis was not affected. The levels of mitochondrial respiratory chain complex proteins and mitochondrial regulatory proteins mitofusin-2 and prohibitin were decreased both in vitro in K8–/– Caco-2 cells and in vivo in K8–/– mouse colonocytes, and reexpression of K8 into K8–/– Caco-2 cells normalizes the mitofusin-2 levels. Mitochondrial Ca2+ is an important regulator of mitochondrial energy metabolism and homeostasis, and Caco-2 cells lacking K8 displayed decreased levels and altered dynamics of mitochondrial matrix and cytoplasmic Ca2+. In summary, these novel findings attribute an important role for colonocyte K8 in stabilizing mitochondrial shape and movement and maintaining mitochondrial respiration and Ca2+ signaling. Further, how these metabolically compromised colonocytes are capable of hyperproliferating presents an intriguing question for future studies. NEW & NOTEWORTHY: In this study, we show that colonocyte intermediate filament protein keratin 8 is important for stabilizing mitochondria and maintaining mitochondrial energy metabolism, as keratin 8-deficient colonocytes display smaller, rounder, and more motile mitochondria, diminished mitochondrial respiration, and altered Ca2+ dynamics. Changes in fusion-regulating proteins are rescued with reexpression of keratin 8. These alterations in colonocyte mitochondrial homeostasis contribute to keratin 8-associated colitis pathophysiology. [ABSTRACT FROM AUTHOR]

Background: Nestin is an intermediate filament first reported in neuroepithelial stem cells. Nestin expression could be found in a variety of tissues throughout all systems of the body, especially during tissue development and tissue regeneration processes. Aim of Review: This review aimed to summarize and discuss current studies on the distribution, contribution and regulation of nestin+ cells in different systems of the body, to discuss the feasibility of using nestin as a marker of multilineage stem/progenitor cells, and better understand the potential roles of nestin+ cells in tissue development, regeneration and pathological processes. Key Scientific Concepts of Review: This review highlights the potential of nestin as a marker of multilineage stem/progenitor cells, and as a key factor in tissue development and tissue regeneration. The article discussed the current findings, limitations, and potential clinical implications or applications of nestin+ cells. Additionally, it included the relationship of nestin+ cells to other cell populations. We propose potential future research directions to encourage further investigation in the field.

Islet β-cell dysfunction is an underlying factor for type I diabetes (T1D) development. Insulin sensing and secretion are tightly regulated in β-cells at multiple subcellular levels. The epithelial intermediate filament (IF) protein keratin (K) 8 is the main β-cell keratin, constituting the filament network with K18. To identify the cell-autonomous functions of K8 in β-cells, mice with targeted deletion of β-cell K8 (K8flox/flox; Ins-Cre) were analyzed for islet morphology, ultrastructure, and integrity, as well as blood glucose regulation and streptozotocin (STZ)-induced diabetes development. Glucose transporter 2 (GLUT2) localization was studied in β-cells in vivo and in MIN6 cells with intact or disrupted K8/K18 filaments. Loss of β-cell K8 leads to a major reduction in K18. Islets without β-cell K8 are more fragile, and these β-cells display disjointed plasma membrane organization with less membranous E-cadherin and smaller mitochondria with diffuse cristae. Lack of β-cell K8 also leads to a reduced glucose-stimulated insulin secretion (GSIS) response in vivo, despite undisturbed systemic blood glucose regulation. K8flox/flox, Ins-Cre mice have a decreased sensitivity to STZ compared with K8 wild-type mice, which is in line with decreased membranous GLUT2 expression observed in vivo, as GLUT2 is required for STZ uptake in β-cells. In vitro, MIN6 cell plasma membrane GLUT2 is rescued in cells overexpressing K8/K18 filaments but mistargeted in cells with disrupted K8/K18 filaments. β-Cell K8 is required for islet and β-cell structural integrity, normal mitochondrial morphology, and GLUT2 plasma membrane targeting, and has implications on STZ sensitivity as well as systemic insulin responses. NEW & NOTEWORTHY: Keratin 8 is the main cytoskeletal protein in the cytoplasmic intermediate filament network in β-cells. Here for the first time, we assessed the β-cell autonomous mechanical and nonmechanical roles of keratin 8 in β-cell function. We demonstrated the importance of keratin 8 in islet and β-cell structural integrity, maintaining mitochondrial morphology and GLUT2 plasma membrane targeting. [ABSTRACT FROM AUTHOR]

Background: Function of thyroid gland is regulated by the axis hypothalamic- pituitarythyroid through these hormones: Thyrotrophin releasing hormone (TRH), thyroid stimulating hormone (TSH), tetraiodothyronine hormone (T4) and triiodothyronine hormone (T3). Thyroid disorders(hyperthyroidism or hypothyroidism) are common around the world and are common diseases in Iraq. Thyroid disorders are states that initially affect on amount of hormones that produced by the thyroid, and affects on all physiological systems including central nervous system, cardiovascular system, blood, and others. Afamin (AFM) is an 87 Kilodalton (kDa) glycoprotein that shares 55% of the amino acid sequence of albumin and contains 15% of carbohydrates. Vimentin (VIM) is a protein among 70 types of intermediate filaments, including Vimentin, Keratin, Desmin and Lamin. Vimentin is a cytoskeleton is an intermediate filament protein that makes up the nucleus and muscle cells. Aimes of study: We aimed to evaluate levels of Afamin, Vimentin and number of biochemical variables (TRH,TSH,T3 and T4) with Body mass index (BMI) in females patients with thyroid disorders. Methods: The study groups include 30 women with hyperthyroidism, 30 women with hypothyroidism and a control group of 30 healthy women with ages between(18-45) years, From September 2023 until March 2024. Protein assays include Afamin, Vimentin levels and number of biochemical variables( TRH,TSH,T3 and T4) in females patients with thyroid disorders . Results: The results of current study showed a significant increase at (P≤ 0.05) in AFM (227.67 ± 32.31), VIM(40.00 ± 4.39) levels with TRH(225.04± 57.08), TSH (11.71 ± 2.77) and BMI (29.70 ± 2.86) in patients with hypothyroidism group compared to (hyperthyroidism and healthy) groups. Levels of T3 (0.76 ± 0.14) and T4 (3.33 ± 0.79) showed a significant decrease at (P≤0.05) in hypothyroidism group compared to hyperthyroidism and healthy groups, While TSH (0.25 ± 0.08) levels showed a significant decrease at (P≤ 0.05) in hyperthyroidism group compared to hypothyroidism group and healthy group. Concentrations of T4 (13.42 ± 1.36) with T3 (2.16 ± 0.42) showed a significant increase at (P≤ 0.05) in hyperthyroidism group compared to hypothyroidism and healthy groups. Conclusions: We conclude from results of current study that high levels of AFM and VIM are associated with high levels of TRH,TSH and BMI in hypothyroidism group . Serum levels of AFM and VIM may be a new biomarkers for detecting and monitoring thyroid disorders, and may be an important useful clinical tools for detecting and monitoring thyroid disturbances. [ABSTRACT FROM AUTHOR]

[Display omitted] • This review summarized and discussed current studies on the distribution, contribution and regulation of nestin+ cells in different systems of the body. • This review highlighted the potential of nestin as a marker of multilineage stem/progenitor cells, and recommended nestin as a key factor in tissue development and tissue regeneration. • The article discussed the current findings, limitations, and potential clinical implications or applications of nestin+ cells. Additionally, it included the relationship of nestin+ cells to other cell populations. Nestin is an intermediate filament first reported in neuroepithelial stem cells. Nestin expression could be found in a variety of tissues throughout all systems of the body, especially during tissue development and tissue regeneration processes. This review aimed to summarize and discuss current studies on the distribution, contribution and regulation of nestin+ cells in different systems of the body, to discuss the feasibility of using nestin as a marker of multilineage stem/progenitor cells, and better understand the potential roles of nestin+ cells in tissue development, regeneration and pathological processes. This review highlights the potential of nestin as a marker of multilineage stem/progenitor cells, and as a key factor in tissue development and tissue regeneration. The article discussed the current findings, limitations, and potential clinical implications or applications of nestin+ cells. Additionally, it included the relationship of nestin+ cells to other cell populations. We propose potential future research directions to encourage further investigation in the field. [ABSTRACT FROM AUTHOR]

Background: The intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly associated with cancer metastatic potential, the exact role of vimentin in cancer metastasis and the underlying mechanism of its pro-metastatic functions remain unclear. Results: This study revealed that vimentin can enhance integrin β1 surface expression and induce integrin-dependent clustering of cells, shielding them against anoikis cell death. The increased integrin β1 surface expression in suspended cells was caused by vimentin-mediated protection of the internal integrin β1 pool against lysosomal degradation. Additionally, cell detachment was found to induce vimentin Ser38 phosphorylation, allowing the translocation of internal integrin β1 to the plasma membrane. Furthermore, the use of an inhibitor of p21-activated kinase PAK1, one of the kinases responsible for vimentin Ser38 phosphorylation, significantly reduced cancer metastasis in animal models. Conclusions: These findings suggest that vimentin can act as an integrin buffer, storing internalized integrin β1 and releasing it when needed. Overall, this study provides insights regarding the strong correlation between vimentin expression and cancer metastasis and a basis for blocking metastasis using this novel therapeutic mechanism. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrowderived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN. [ABSTRACT FROM AUTHOR]

Exudate plays a crucial role in wound healing, but an excessive amount can lead to over-hydration of tissue and aggravating the infection and the injury. On the other hand, inadequate exudate can cause scarring and hinder healing. Traditional wound dressings are unable to regulate exudate levels based on the specific needs of the wound. To address this issue, a liquid-gated trilayered fibrous wound dressing capable of pumping fluid in a temperature-dependent manner is developed. This dressing comprises a hydrophilic cotton layer, a thermo-sensitive (TPPU) layer, and a hydrophobic layer of polyurethane (PU) nanofibers. The TPPU layer is constituted by nanofibers that are composed of an upper critical solution temperature (UCST)-type polymer, PU, and silver nanoparticles. The intermediate TPPU layer exhibits changes in its wettability upon heating, adjusting the thickness of the hydrophobic layer and ultimately achieving the appropriate structure for guiding spontaneous fluid transport. The positive effect of this novel dressing on diabetic wounds is observed, as it enhanced epithelialization and collagen synthesis while reducing inflammation, ultimately accelerating the wound healing process. This dressing has the potential to provide a groundbreaking solution for managing exudate, achieving moisture balance and promoting wound healing in clinical settings. [ABSTRACT FROM AUTHOR]

This document is a list of references for various scientific articles related to cellular homeostasis, intervertebral disc degeneration, and the role of specific proteins and receptors in these processes. The articles cover topics such as the protective effects of hypoxia-inducible factor-1α signaling pathway in intervertebral disc degeneration, the role of P2X7 receptors in inflammation and osteoarthritis, and the impact of nuclear lamins on cellular function. These articles provide valuable insights into the mechanisms and potential therapeutic approaches for intervertebral disc degeneration. [Extracted from the article]

Intermediate filaments (IFs), being traditionally the least studied component of the cytoskeleton, have begun to receive more attention in recent years. IFs are found in different cell types and are specific to them. Accumulated data have shifted the paradigm about the role of IFs as structures that merely provide mechanical strength to the cell. In addition to this role, IFs have been shown to participate in maintaining cell shape and strengthening cell adhesion. The data have also been obtained that point out to the role of IFs in a number of other biological processes, including organization of microtubules and microfilaments, regulation of nuclear structure and activity, cell cycle control, and regulation of signal transduction pathways. They are also actively involved in the regulation of several aspects of intracellular transport. Among the intermediate filament proteins, vimentin is of particular interest for researchers. Vimentin has been shown to be associated with a range of diseases, including cancer, cataracts, Crohn's disease, rheumatoid arthritis, and HIV. In this review, we focus almost exclusively on vimentin and the currently known functions of vimentin intermediate filaments (VIFs). This is due to the structural features of vimentin, biological functions of its domains, and its involvement in the regulation of a wide range of basic cellular functions, and its role in the development of human diseases. Particular attention in the review will be paid to comparing the role of VIFs with the role of intermediate filaments consisting of other proteins in cell physiology. [ABSTRACT FROM AUTHOR]

The endometrial epithelium and underlying stroma undergo profound changes to support and limit embryo adhesion and invasion, which occur in the secretory phase of the menstrual cycle during the window of implantation. This coincides with a peak in progesterone and estradiol production. We hypothesized that the interplay between hormone-induced changes in the mechanical properties of the endometrial epithelium and stroma supports this process. To study it, we used hormone-responsive endometrial adenocarcinoma-derived Ishikawa cells growing on substrates of different stiffness. We showed that Ishikawa monolayers on soft substrates are more tightly clustered and uniform than on stiff substrates. Probing for mechanical alterations, we found accelerated stress–relaxation after apical nanoindentation in hormone-stimulated monolayers on stiff substrates. Traction force microscopy furthermore revealed an increased number of foci with high traction in the presence of estradiol and progesterone on soft substrates. The detection of single cells and small cell clusters positive for the intermediate filament protein vimentin and the progesterone receptor further underscored monolayer heterogeneity. Finally, adhesion assays with trophoblast-derived AC-1M-88 spheroids were used to examine the effects of substrate stiffness and steroid hormones on endometrial receptivity. We conclude that the extracellular matrix and hormones act together to determine mechanical properties and, ultimately, embryo implantation. [ABSTRACT FROM AUTHOR]

Severe cardiac remodeling leading to heart failure in individuals harboring pathogenic LMNA variants, known as cardiolaminopathy, poses a significant clinical challenge. Currently, there is no effective treatment for lamin-related diseases. Exploring the intricate molecular landscape underlying this condition, with a specific focus on abnormal mechanotransduction, will propel our understanding of cardiolaminopathy. The LMNA gene undergoes alternative splicing to create A-type lamins, a part of the intermediate filament protein family. A-type lamins are located underneath the nuclear envelope, and given their direct interaction with chromatin, they serve as mechanosensory of the cell by interacting with the cytoskeleton and safeguarding the transcriptional program of cells. Nucleated cells in the cardiovascular system depend on precise mechanical cues for proper function and adaptation to stress. Mechanosensitive signaling pathways are essential in regulating mechanotransduction. They play a pivotal role in various molecular and cellular processes and commence numerous downstream effects, leading to transcriptional activation of target genes involved in proliferation, migration, and (anti-)apoptosis. Most pathways are known to be regulated by kinases, and this area remains largely understudied in cardiomyopathies. Heart failure is linked to disrupted mechanotransduction, where LMNA mutations affect nuclear integrity, impacting the response to extracellular matrix signals and the environment. The Hippo pathway, anchored by YAP1/WWTR1, emerges as a central player by orchestrating cellular responses to mechanical signals. However, the involvement of Hippo and YAP1/WWTR1 in cardiolaminopathy is unclear and likely mutation- and tissue-specific, warranting further investigation. Here, we highlight the involvement of multiple signaling pathways in mechanotransduction in cardiolaminopathy. We delve into (non-)canonical functions of key signaling components, which may hold critical clues for understanding disease pathogenesis. In summary, we comprehensively examine the mechanobiology of A-type lamins, the role of mechanosensitive signaling pathways, and their intricate interplay in the pathogenesis of cardiolaminopathy. A better understanding of these mechanisms is paramount for developing targeted therapies and interventions for individuals afflicted with this debilitating cardiac condition. Prior studies overlooked accurate gene nomenclature in protein and pathway names. Our review addresses this gap, ensuring precision by aligning names with correct gene nomenclature. Plain English Summary: Mutations in the A-type lamin gene (LMNA) can cause a laminopathy. A specific manifestation of this disease leads to cardiolaminopathy, a serious heart condition. The lamin network, located at the inner nuclear membrane, is a central player in transforming forces within cells. As cells move and function, they rely on the ability to sense and respond to these forces, a process named mechanosensing and -response. This review provides an overview of the key molecular pathways involved in the development of heart failure. The molecular mechanisms underlying LMNA cardiomyopathy are poorly understood because the interaction between the signaling pathways is challenging to elucidate. Deciphering these pathways is key to understanding the underlying mechanisms of disease and finding novel targets to alter the pathways and lessen the symptoms of diseases. [ABSTRACT FROM AUTHOR]

Vimentin, an intermediate filament protein primarily recognized for its intracellular role in maintaining cellular structure, has recently garnered increased attention and emerged as a pivotal extracellular player in immune regulation and host–pathogen interactions. While the functions of extracellular vimentin were initially overshadowed by its cytoskeletal role, accumulating evidence now highlights its significance in diverse physiological and pathological events. This review explores the multifaceted role of extracellular vimentin in modulating immune responses and orchestrating interactions between host cells and pathogens. It delves into the mechanisms underlying vimentin's release into the extracellular milieu, elucidating its unconventional secretion pathways and identifying critical molecular triggers. In addition, the future perspectives of using extracellular vimentin in diagnostics and as a target protein in the treatment of diseases are discussed. [ABSTRACT FROM AUTHOR]

Background Information: Lamins are type V intermediate filament proteins underlying the inner nuclear membrane which provide structural rigidity to the nucleus, tether the chromosomes, maintain nuclear homeostasis, and remain dynamically associated with developmentally regulated regions of the genome. A large number of mutations particularly in the LMNA gene encoding lamin A/C results in a wide array of human diseases, collectively termed as laminopathies. Dilated Cardiomyopathy (DCM) is one such laminopathic cardiovascular disease which is associated with systolic dysfunction of left or both ventricles leading to cardiac arrhythmia which ultimately culminates into myocardial infarction. Results: In this work, we have unraveled the epigenetic landscape to address the regulation of gene expression in mouse myoblast cell line in the context of the missense mutation LMNA 289A

This document provides concise summaries of several research studies in the fields of dermatology and immunology. The studies explore the role of different immune cells in the development and progression of various skin conditions, such as psoriasis, atopic dermatitis, vitiligo, and allergic contact dermatitis. The findings of these studies offer valuable insights into the underlying mechanisms of these conditions and may contribute to the development of new treatment options. The document emphasizes the importance of understanding the immune system's role in skin diseases and highlights potential therapeutic targets for further investigation. [Extracted from the article]

Background: The network of intermediate filament proteins underlying the inner nuclear membrane forms the nuclear lamina. Lamins have been associated with important cellular functions: DNA replication, chromatin organization, differentiation of the cell, apoptosis and in maintenance of nuclear structure. Little is known regarding the etiopathogenesis of adhesive capsulitis (AC); recently, a dysregulating fibrotic response starting from a subpopulation has been described within the fibroblast compartment, which suddenly turns on an activated phenotype. Considering the key role of A-type lamins in the regulation of cellular stability and function, our aim was to compare the lamin A/C expression between patients with AC and healthy controls. Materials and methods: A case–control study was performed between January 2020 and December 2021. Tissue samples excised from the rotator interval were analysed for lamin A/C expression by immunohistochemistry. Patients with AC were arbitrarily distinguished according to the severity of shoulder flexion limitation: ≥ 90° and < 90°. Controls were represented by samples obtained by normal rotator interval excised from patients submitted to shoulder surgery. The intensity of staining was graded, and an H-score was assigned. Statistical analysis was performed (Chi-square analysis; significance was set at alpha = 0.05). Results: We enrolled 26 patients [12 male and 14 female, mean age (SD): 52.3 (6.08)] and 15 controls [6 male and 9 female, mean age (SD): 57.1 (5.3)]. The expression of lamin A/C was found to be significantly lower in the fibroblasts of patients with adhesive capsulitis when compared with controls (intensity of staining: p: 0.005; H-score: 0.034); no differences were found regarding the synoviocytes (p: > 0.05). Considering only patients with AC, lamin A/C intensity staining was found to be significantly higher in samples where acute inflammatory infiltrate was detected (p: 0.004). No significant changes in levels of lamin A/C expression were documented between the mild and severe adhesive capsulitis severity groups. Conclusions: Our study demonstrated that the activity of lamin A/C in maintaining nuclear structural integrity and cell viability is decreased in patients with adhesive capsulitis. The phase of the pathogenetic process (freezing and early frozen) is the key factor for cell functionality. On the contrary, the clinical severity of adhesive capsulitis plays a marginal role in nuclear stability. Level of evidence: III. [ABSTRACT FROM AUTHOR]

Many biochemical, immunological, and neuropsychiatric changes are associated with end-stage renal disease (ESRD). Neuronal damage biomarkers such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), S100 calcium-binding protein B (S100B), ionized calcium-binding adaptor molecule-1 (IBA1), and myelin basic protein (MBP) are among the less-studied biomarkers of ESRD. We examined the associations between these neuro-axis biomarkers, inflammatory biomarkers, e.g., C-reactive protein (CRP), interleukin (IL-6), IL-10, and zinc, copper, and neuropsychiatric symptoms due to ERSD. ELISA techniques were used to measure serum levels of neuronal damage biomarkers in 70 ESRD patients, and 46 healthy controls. ESRD patients have higher scores of depression, anxiety, fatigue, and physiosomatic symptoms than healthy controls. Aberrations in kidney function tests and the number of dialysis interventions are associated with the severity of depression, anxiety, fibro-fatigue and physiosomatic symptoms, peripheral inflammation, nestin, and NFL. Serum levels of neuronal damage biomarkers (NFL, MBP, and nestin), CRP, and interleukin (IL)-10 are elevated, and serum zinc is decreased in ESRD patients as compared with controls. The neuronal damage biomarkers NFL, nestin, S100B and MBP are associated with the severity of one or more neuropsychiatric symptom domains. Around 50 % of the variance in the neuropsychiatric symptoms is explained by NFL, nestin, S00B, copper, and an inflammatory index. The severity of renal dysfunction and/or the number of dialysis interventions may induce peripheral inflammation and, consequently, neurotoxicity to intermediate filament proteins, astrocytes, and the blood-brain barrier, leading to the neuropsychiatric symptoms of ESRD. • ESRD patients have higher scores of depression, anxiety, and fatigue. • Kidney function decline and dialysis treatments cause peripheral inflammation. • NFL, MBP, and nestin are associated with the severity of neuropsychiatric symptoms. • Serum levels of NFL, MBP, nestin, CRP, and IL-10 are elevated in ESRD patients. [ABSTRACT FROM AUTHOR]

Glial fibrillary acidic protein (GFAP), an intracellular type III intermediate filament protein, provides structural support and maintains the mechanical integrity of astrocytes. It is predominantly found in the astrocytes which are the most abundant subtypes of glial cells in the brain and spinal cord. As a marker protein of astrocytes, GFAP may exert a variety of physiological effects in neurological diseases. For example, previous published literatures showed that autoimmune GFAP astrocytopathy is an inflammatory disease of the central nervous system (CNS). Moreover, the studies of GFAP in brain tumors mainly focus on the predictive value of tumor volume. Furthermore, using biomarkers in the early setting will lead to a simplified and standardized way to estimate the poor outcome in traumatic brain injury (TBI) and ischemic stroke. Recently, observational studies revealed that cerebrospinal fluid (CSF) GFAP, as a valuable potential diagnostic biomarker for neurosyphilis, had a sensitivity of 76.60% and specificity of 85.56%. The reason plasma GFAP could serve as a promising biomarker for diagnosis and prediction of Alzheimer's disease (AD) is that it effectively distinguished AD dementia from multiple neurodegenerative diseases and predicted the individual risk of AD progression. In addition, GFAP can be helpful in differentiating relapsing–remitting multiple sclerosis (RRMS) versus progressive MS (PMS). This review article aims to provide an overview of GFAP in the prediction of clinical progression in neuroinflammation, brain tumors, TBI, ischemic stroke, genetic disorders, neurodegeneration and other diseases in the CNS and to explore the potential therapeutic methods. [ABSTRACT FROM AUTHOR]

Keratins are epithelial intermediate filament proteins that play a crucial role in cellular stress protection, with K8 being the most abundant in the colon. The intestinal epithelial-specific K8-deficient mouse model (K8flox/flox;Villin-Cre) exhibits characteristics of inflammatory bowel disease, including diarrhea, crypt erosion, hyperproliferation, and decreased barrier function. Nevertheless, the order in which these events occur and whether they are a direct cause of K8 loss or a consequence of one event inducing another remains unexplored. Increased knowledge about early events in the disruption of colon epithelial integrity would help to understand the early pathology of inflammatory and functional colon disorders and develop preclinical models and diagnostics of colonic diseases. Here, we aimed to characterize the order of physiological events after Krt8 loss by utilizing K8flox/flox;Villin-CreERt2 mice with tamoxifen-inducible Krt8 deletion in intestinal epithelial cells, and assess stool analysis as a noninvasive method to monitor real-time gene expression changes following Krt8 loss. K8 protein was significantly decreased within a day after induction, followed by its binding partners, K18 and K19 from day 4 onward. The sequential colonic K8 downregulation in adult mice leads to immediate diarrhea and crypt elongation with activation of proliferation signaling, followed by crypt loss and increased neutrophil activity within 6-8 days, highlighting impaired water balance and crypt elongation as the earliest colonic changes upon Krt8 loss. Furthermore, epithelial gene expression patterns were comparable between colon tissue and stool samples, demonstrating the feasibility of noninvasive monitoring of gut epithelia in preclinical research utilizing Cre-LoxP-based intestinal disease models. NEW & NOTEWORTHY: Understanding the order in which physiological and molecular events occur helps to recognize the onset of diseases and improve their preclinical models. We utilized Cre-Lox-based inducible keratin 8 deletion in mouse intestinal epithelium to characterize the earliest events after keratin 8 loss leading to colitis. These include diarrhea and crypt elongation, followed by erosion and neutrophil activity. Our results also support noninvasive methodology for monitoring colon diseases in preclinical models. [ABSTRACT FROM AUTHOR]

Intermediate filaments constitute the most heterogeneous class among the major classes of cytoskeletal proteins of mammalian cells. The 40 or more intermediate filament proteins have been classified into five types which show very specific rules of expression in specialized cell types. This study aimed to investigate the immunohistochemical distribution of cytokeratins (CKs) 8, 18, and 19 as well as the intermediate filaments vimentin, laminin, and desmin in bovine and ovine tongues. Immunohistochemical staining was performed for CKs 8, 18, 19, vimentin, laminin, and desmin. Our results revealed similar immunostaining intensity and distribution among various CKs, contrasting with distinct patterns for vimentin, laminin, and desmin. Immunoreactions were primarily localized in serous acini and ductal epithelium for cytokeratins, while vimentin and laminin were evident in connective tissue, endothelium, serous acini, and desmin in striated and smooth muscles. This study highlighted the absence of CKs 8, 18, 19, vimentin, and desmin in the lingual epithelium of bovine and ovine tongues. These findings enabled the classification of epithelial cells based on their specific cytokeratin patterns. Furthermore, vimentin was identified in mesodermal tissues and organs, desmin in muscle tissue, and laminin played crucial roles in basement membrane formation, nerve tissue regeneration, innervation of epithelial taste buds, and tissue separation and connection. Our findings provide essential insights into intermediate filament dynamics at the cellular and tissue levels. They serve as a foundation for future studies using systematic molecular biological techniques in this field. [ABSTRACT FROM AUTHOR]

Synaptopodin-2 (SYNPO2) is a protein associated with the Z-disc in striated muscle cells. It interacts with α-actinin and filamin C, playing a role in Z-disc maintenance under stress by chaperone-assisted selective autophagy (CASA). In smooth muscle cells, SYNPO2 is a component of dense bodies. Furthermore, it has been proposed to play a role in tumor cell proliferation and metastasis in many different kinds of cancers. Alternative transcription start sites and alternative splicing predict the expression of six putative SYNPO2 isoforms differing by extended amino- and/or carboxy-termini. Our analyses at mRNA and protein levels revealed differential expression of SYNPO2 isoforms in cardiac, skeletal and smooth muscle cells. We identified synemin, an intermediate filament protein, as a novel binding partner of the PDZ-domain in the amino-terminal extension of the isoforms mainly expressed in cardiac and smooth muscle cells, and demonstrated colocalization of SYNPO2 and synemin in both cell types. A carboxy-terminal extension, mainly expressed in smooth muscle cells, is sufficient for association with dense bodies and interacts with α-actinin. SYNPO2 therefore represents an additional and novel link between intermediate filaments and the Z-discs in cardiomyocytes and dense bodies in smooth muscle cells, respectively. In pathological skeletal muscle samples, we identified SYNPO2 in the central and intermediate zones of target fibers of patients with neurogenic muscular atrophy, and in nemaline bodies. Our findings help to understand distinct functions of individual SYNPO2 isoforms in different muscle tissues, but also in tumor pathology. [ABSTRACT FROM AUTHOR]

This article discusses the role of nestin, a protein, in driving airway smooth muscle (ASM) hyperplasia and airway remodeling in asthma. The study found that nestin expression is upregulated in asthmatic ASM cells and tissues. By using mouse models and in vitro experiments, the researchers demonstrated that nestin plays a crucial role in ASM hyperplasia and airway remodeling. The study also suggests that nestin may interact with other proteins, such as 14-3-3 and mTOR, to induce ASM proliferation. These findings provide insights into the mechanisms underlying asthma and may have implications for future therapeutic approaches. [Extracted from the article]

Pachyonychia congenita (PC) is a rare genetic disorder characterized by thickened and dystrophic nails, painful palmoplantar keratoderma, and glandular cysts. This study focuses on a Chinese patient with PC who has a mutation in the KRT16 gene. The patient presented with hyperkeratotic lesions, nail changes, and other symptoms. The findings highlight the variable nature of PC patients with the same genetic genotype and the potential for phenotypic variations. This research provides insights into the pathogenesis of PC and the role of the KRT16 gene. [Extracted from the article]

The advancement of tumor cell metastasis is significantly influenced by epithelial-to-mesenchymal transition (EMT), and metastasis is a prominent contributor to the mortality of patients diagnosed with colorectal cancer (CRC). AT-rich interactive domain-containing protein 1A (ARID1A), which acts as a tumor suppressor, frequently exhibits a loss-of-function mutation in metastatic CRC tissues. However, the underlying molecular mechanisms of ARID1A relating to EMT remain poorly understood. The present study aimed to clarify the association between ARID1A and EMT regulation in human CRC cells. The investigation into the loss of ARID1A expression in tissues from patients with CRC was performed using immunohistochemistry. Furthermore, ARID1A-overexpressing SW48 cells were established using lentiviruses carrying human full-length ARID1A. The results revealed that overexpression of ARID1A induced cellular morphological changes by promoting the tight junction molecule zonula occludens 1 (ZO-1) and the adherens junction molecule E-cadherin, whereas it decreased the intermediate filament protein vimentin. The results of reverse transcription-quantitative PCR also confirmed that ARID1A overexpression upregulated the mRNA expression levels of TJP1/ZO-1 and CDH1/E-cadherin, and downregulated VIM/vimentin and zinc finger E-box binding homeobox 1 expression, which are considered epithelial and mesenchymal markers, respectively. In addition, the overexpression of ARID1A in CRC cells resulted in a suppression of cell motility and migratory capabilities. The present study also demonstrated that the tumor suppressor ARID1A was commonly absent in CRC tissues. Notably, ARID1A overexpression could reverse the EMT-like phenotype and inhibit cell migration through alterations in EMT-related markers, leading to the inhibition of malignant progression. In conclusion, ARID1A may serve as a biomarker and therapeutic target in the clinical management of metastatic CRC. [ABSTRACT FROM AUTHOR]

Defective protein degradation is one of the primary contributors in the pathogenesis of neuromuscular diseases. Muscle cells rely on the ubiquitin-proteasome system for the degradation of most muscle proteins via the addition of the ubiquitin 'recognition' tag onto the cellular targets by E3-ligases such as Cullin-3 (Cul3). Our work has shown that loss of Cul3 in muscle cells in vitro impairs their differentiation, while its deletion in mouse skeletal muscles results in postnatal lethality marked with severe myopathy. Cul3 knockout (KO) muscles showed reduced fibers size and revealed positive Gomori Trichrome stain protein aggregates; resembling of nemaline bodies found in nemaline myopathy (NM) patients. Additionally, the proteome analysis revealed unexpected accumulation of non-muscle alpha-actinins 1 and 4 within the tissue. We further explored the nature of these protein aggregates in Cul3 KO diaphragms and tongues. However, immunofluorescence analyses of KO muscles showed no evidence of alpha-actinin containing aggregates. Analysis of electron microscopic images also revealed that aggregates in Cul3 KO muscles did not originate from expanded Z-discs or thin filament structures, typically associated with nemaline bodies. However, we did observe changes to the sarcomere organization. Specifically, significant increases in Z-disc widths and sarcomere lengths were found in KO muscles. In addition, Cul3 KO muscles showed deregulation of sarcomeric and intermediate filament protein levels, such as myosin, sarcomeric alpha-actinin, desmin or filamin C. Despite histological analyses of Cul3 KO muscles sharing similarities with features of NM patients features, the nature of these protein aggregates remains elusive. Nevertheless, Cul3 KO muscles show accumulation of non-muscle actinins, altered sarcomere structure, and deregulation of sarcomeric protein levels. [ABSTRACT FROM AUTHOR]

By analyzing the expression patterns of inner root sheath (IRS) specific genes during different developmental stages of hair follicle (HF) in Tan sheep embryos and at birth, this study aims to reveal the influence of the IRS on crimped wool. Skin tissues from the scapular region of male Tan sheep were collected at 85 days (E85) and 120 days (E120) of fetal development, and at 0 days (D0), 35 days (D35), and 60 days (D60) after birth, with four samples at each stage. Real-time quantitative polymerase chain reaction (RT-qPCR) was employed to determine the relative expression levels of IRS type I keratin genes (KRT25, KRT26, KRT27, KRT28), type II keratin genes (KRT71, KRT72, KRT73, KRT74), and the trichohyalin gene (TCHH) in the skin of Tan sheep at different stages. Results showed that the expression levels of all IRS-specific genes peaked at D0, with the expression of all genes significantly higher than at E85 (P < 0.01), except for KRT73 and TCHH. The expression levels of KRT25, KRT26, and KRT72 were also significantly higher than at E120 (P < 0.01). Furthermore, the expression levels of KRT27, KRT28, KRT71, and KRT74 were significantly higher than both at E120 and D35 (P < 0.01). The expression levels of other genes at different stages showed no significant difference (P > 0.05). Conclusion: The IRS-specific genes exhibit the highest expression levels in Tan sheep at the neonatal stage. The expression levels of KRT71, KRT72, and TCHH, which are consistent with the pattern of wool crimp, may influence the morphology of the IRS and thereby affect the crimp of Tan sheep wool., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)