Search Results (16)

The cytoskeleton has been described as a regulator of adrenal physiology and tumour behaviour. In the adrenal cortex, both cytoskeletal filaments, by mediating cholesterol transfer to mitochondria, and their binding proteins, such as cofilin and diaphanous-related formin 1 (DIAPH1), have been implicated in modulating steroidogenic processes. Beyond hormone production, the cytoskeleton participates in oncogenic signalling and contributes to the acquisition of malignant behaviour in adrenocortical carcinoma (ACC). Cytoskeleton-associated proteins such as filamin A (FLNA), fascin-1 (FSCN1), RASSF1A, and the guanine nucleotide exchange factor VAV2 are involved in signal transduction, cell cycle regulation, and cytoskeletal remodelling. In ACC, dysregulation of the expression or activity of these proteins correlates with ACC aggressiveness, including increased proliferation, motility, and invasion as well as poor prognosis, making them attractive candidates for targeted therapeutic strategies. To date, no review has systematically addressed the role of cytoskeleton and its binding partners in both adrenal physiological regulation and pathological context. This review is the first to provide a comprehensive overview of cytoskeletal involvement in adrenal cortex function and cancer, highlighting emerging molecular players and their possible therapeutic implications. Full article

Receptor for advanced glycation end-products (RAGE) activation by hyperglycemia-induced AGE (advanced glycation end-products) accumulation is likely to play a crucial role in the development of complications such as diabetic peripheral neuropathy (DPN). RAGE signaling is mediated via its cytosolic tail. Through its cytosolic tail, RAGE recruits diaphanous-related formin 1 (Diaph1), a protein involved in actin filament organization. Disruption of RAGE–Diaph1 interactions using small molecules alleviates diabetic complications in mice; however, the role of Diaph1 in DPN progression has not been rigorously tested. In this study, we employed a Diaph1 knockout mouse (DKO) to investigate the role of Diaph1 in DPN progression. Herein, we demonstrate that, at the systemic level, CRISPR deletion of Diaph1 fails to ameliorate diabetes-induced weight loss in mice. Within the sciatic nerve (SCN), the lack of Diaph1 failed to prevent hyperglycemia-induced loss of β-actin in the nerve fibers. At a morphological level, the lack of Diaph1 leads to a partial rescue in DPN. While we observed improvements in axonal and fiber diameters in diabetic DKO mice, the g-ratio (an indicator of myelination) and myelin invaginations displayed incomplete rescue. Furthermore, the lack of Diaph1 failed to rescue motor or sensory nerve conduction defects resulting from hyperglycemia over 6 months. Overall, our data thus indicate that the complete loss of Diaph1 is insufficient to halt the progression of DPN. However, across a range of parameters including blood glucose levels, body weight measurements, axon and fiber diameters, and nerve conduction velocity, DKO diabetic mice show improvement when compared to wild-type diabetic mice. Full article

Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s (HD) diseases. And while all these diseases seem to have different genetic and environmental components, growing evidence shows that they share common underlying pathological features such as increased neuroinflammation and excessive oxidative stress. RAGE, the receptor for advanced glycation end-products, is a signal transduction receptor, and its activation triggers an increase in proinflammatory molecules, oxidative stressors, and cytokines. Diaph1, protein diaphanous homolog 1, is an actin modulator and an intracellular ligand of RAGE. Studies demonstrated that RAGE and Diaph1 act together, and their downstream signaling pathways play a role in neurodegeneration. Here, based on current evidence and our own research, we provide an overview of the RAGE–Diaph1 signaling and discuss the therapeutic potential of targeted therapy aimed at RAGE–Diaph1 signaling inhibition in the prevention and treatment of neurodegenerative diseases. Full article

Background: Uniparental disomy (UPD) is the inheritance of both copies of a chromosome from a single parent, leading to distinct genetic conditions. Maternal UPD of chromosome 6 (UPD(6)mat) is extremely rare, with few molecularly confirmed cases reported. Methods: We report a prematurely born female with isodisomic UPD(6)mat, presenting with intrauterine growth restriction (IUGR), developmental delay, autism spectrum disorder, dysmorphic features, and a sacrococcygeal teratoma. In addition, we reviewed 24 confirmed UPD(6)mat cases to assess clinical patterns in prenatal findings, birth outcomes, and postnatal features. Results: Trio whole-exome sequencing revealed complete isodisomy of chromosome 6 and a de novo heterozygous DIAPH2 variant of uncertain significance. In the literature review, IUGR was present in 87% of cases, with most individuals born small for gestational age and preterm. Failure to thrive and neurodevelopmental issues were also frequent. While the exact molecular basis remains unknown, imprinting disturbances—similar to those in UPD(6)pat—and cryptic trisomy 6 mosaicism, particularly in heterodisomy, are the most likely mechanisms. No specific gene or consistent epigenetic abnormality has been identified. Conclusions: This study aims to enhance the understanding of the genetic and phenotypic spectrum of UPD(6)mat, improving diagnostic and management approaches for this ultra-rare genetic disorder. We propose a detailed list of clinical assessments and tests to be performed following the detection of maternal uniparental disomy of chromosome 6. Full article

Copy number variation (CNV) serves as a crucial source of genomic variation and significantly aids in the mining of genomic information in cattle. This study aims to analyze re–sequencing data from Chinese Hainan yellow cattle, to uncover breed CNV information, and to elucidate the resources of population genetic variation. We conducted whole–genome sequencing on 30 Chinese Hainan yellow cattle, thus generating 814.50 Gb of raw data. CNVs were called using CNVnator software, and subsequent filtering with Plink and HandyCNV yielded 197,434 high–quality CNVs and 5852 CNV regions (CNVRs). Notably, the proportion of deleted sequences (81.98%) exceeded that of duplicated sequences (18.02%), with the lengths of CNVs predominantly ranging between 20 and 500 Kb This distribution demonstrated a decrease in CNVR count with increasing fragment length. Furthermore, an analysis of the population genetic structure using CNVR databases from Chinese, Indian, and European commercial cattle breeds revealed differences between Chinese Bos indicus and Indian Bos indicus. Significant differences were also observed between Hainan yellow cattle and European commercial breeds. We conducted gene annotation for both Hainan yellow cattle and European commercial cattle, as well as for Chinese Bos indicus and Indian Bos indicus, identifying 206 genes that are expressed in both Chinese and Indian Bos indicus. These findings may provide valuable references for future research on Bos indicus. Additionally, selection signatures analysis based on Hainan yellow cattle and three European commercial cattle breeds identified putative pathways related to heat tolerance, disease resistance, fat metabolism, environmental adaptation, candidate genes associated with reproduction and the development of sperm and oocytes (CABS1, DLD, FSHR, HSD17B2, KDM2A), environmental adaptation (CNGB3, FAM161A, DIAPH3, EYA4, AAK1, ERBB4, ERC2), oxidative stress anti–inflammatory response (COMMD1, OXR1), disease resistance (CNTN5, HRH4, NAALADL2), and meat quality (EHHADH, RHOD, GFPT1, SULT1B1). This study provides a comprehensive exploration of CNVs at the molecular level in Chinese Hainan yellow cattle, offering theoretical support for future breeding and selection programs aimed at enhancing qualities of this breed. Full article

Endometrial cancer (EC) is the most common gynecological malignancy. EC is associated with metabolic disorders that may promote non-enzymatic glycation and activate the receptor for advanced glycation end-products (RAGE) signaling pathways. Thus, we assumed that RAGE and its ligands may contribute to EC. Of particular interest is the interaction between diaphanous-related formin 1 (Diaph1) and RAGE during the progression of human cancers. Diaph1 is engaged in the proper organization of actin cytoskeletal dynamics, which is crucial in cancer invasion, metastasis, angiogenesis, and axonogenesis. However, the detailed molecular role of RAGE in EC remains uncertain. In this review, we discuss epigenetic factors that may play a key role in the RAGE-dependent endometrial pathology. We propose that DNA methylation may regulate the activity of the RAGE pathway in the uterus. The accumulation of negative external factors, such as hyperglycemia, inflammation, and oxidative stress, may interfere with the DNA methylation process. Therefore, further research should take into account the role of epigenetic mechanisms in EC progression. Full article

Autosomal dominant non-syndromic hearing loss (HL) typically occurs when only one dominant allele within the disease gene is sufficient to express the phenotype. Therefore, most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent, although de novo mutations should be considered in all cases of negative family history. To date, more than 50 genes and 80 loci have been identified for autosomal dominant non-syndromic HL. DFNA22 (MYO6 gene), DFNA8/12 (TECTA gene), DFNA20/26 (ACTG1 gene), DFNA6/14/38 (WFS1 gene), DFNA15 (POU4F3 gene), DFNA2A (KCNQ4 gene), and DFNA10 (EYA4 gene) are some of the most common forms of autosomal dominant non-syndromic HL. The characteristics of autosomal dominant non-syndromic HL are heterogenous. However, in most cases, HL tends to be bilateral, post-lingual in onset (childhood to early adulthood), high-frequency (sloping audiometric configuration), progressive, and variable in severity (mild to profound degree). DFNA1 (DIAPH1 gene) and DFNA6/14/38 (WFS1 gene) are the most common forms of autosomal dominant non-syndromic HL affecting low frequencies, while DFNA16 (unknown gene) is characterized by fluctuating HL. A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants. Full article

Hearing relies on the proper functioning of auditory hair cells and on actin-based cytoskeletal structures. Diaphanous-related formins (DRFs) are evolutionarily conserved cytoskeletal proteins that regulate the nucleation of linear unbranched actin filaments. They play key roles during metazoan development, and they seem particularly pivotal for the correct physiology of the reproductive and auditory systems. Indeed, in Drosophila melanogaster, a single diaphanous (dia) gene is present, and mutants show sterility and impaired response to sound. Vertebrates, instead, have three orthologs of the diaphanous gene: DIAPH1, DIAPH2, and DIAPH3. In humans, defects in DIAPH1 and DIAPH3 have been associated with different types of hearing loss. In particular, heterozygous mutations in DIAPH1 are responsible for autosomal dominant deafness with or without thrombocytopenia (DFNA1, MIM #124900), whereas regulatory mutations inducing the overexpression of DIAPH3 cause autosomal dominant auditory neuropathy 1 (AUNA1, MIM #609129). Here, we provide an overview of the expression and function of DRFs in normal hearing and deafness. Full article

Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand–receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for dysfunction in hyperglycemia observed in both type 1 and type 2 diabetes. Recent evidence indicates that RAGE ligands, acting as damage-associated molecular patterns molecules, or DAMPs, through RAGE may impact interferon signaling pathways, specifically through upregulation of IRF7 (interferon regulatory factor 7), thereby heralding and evoking pro-inflammatory effects on vulnerable tissues. Although successful targeting of RAGE in the clinical milieu has, to date, not been met with success, recent approaches to target RAGE intracellular signaling may hold promise to fill this critical gap. This review focuses on recent examples of highlights and updates to the pathobiology of RAGE and DIAPH1 in diabetic complications. Full article

F-Actin remodeling is important for the spread of HIV via cell–cell contacts; however, the mechanisms by which HIV corrupts the actin cytoskeleton are poorly understood. Through live cell imaging and focused ion beam scanning electron microscopy (FIB-SEM), we observed F-Actin structures that exhibit strong positive curvature to be enriched for HIV buds. Virion proteomics, gene silencing, and viral mutagenesis supported a Cdc42-IQGAP1-Arp2/3 pathway as the primary intersection of HIV budding, membrane curvature and F-Actin regulation. Whilst HIV egress activated the Cdc42-Arp2/3 filopodial pathway, this came at the expense of cell-free viral release. Importantly, release could be rescued by cell–cell contact, provided Cdc42 and IQGAP1 were present. From these observations, we conclude that a proportion out-going HIV has corrupted a central F-Actin node that enables initial coupling of HIV buds to cortical F-Actin to place HIV at the leading cell edge. Whilst this initially prevents particle release, the maturation of cell–cell contacts signals back to this F-Actin node to enable viral release & subsequent infection of the contacting cell. Full article

Almost 25 years have passed since a mutation of a formin gene, DIAPH1, was identified as being responsible for a human inherited disorder: a form of sensorineural hearing loss. Since then, our knowledge of the links between formins and disease has deepened considerably. Mutations of DIAPH1 and six other formin genes (DAAM2, DIAPH2, DIAPH3, FMN2, INF2 and FHOD3) have been identified as the genetic cause of a variety of inherited human disorders, including intellectual disability, renal disease, peripheral neuropathy, thrombocytopenia, primary ovarian insufficiency, hearing loss and cardiomyopathy. In addition, alterations in formin genes have been associated with a variety of pathological conditions, including developmental defects affecting the heart, nervous system and kidney, aging-related diseases, and cancer. This review summarizes the most recent discoveries about the involvement of formin alterations in monogenic disorders and other human pathological conditions, especially cancer, with which they have been associated. In vitro results and experiments in modified animal models are discussed. Finally, we outline the directions for future research in this field. Full article

AIM, DIAPH2, PTPRD and HIC1 are the cell glycoprotein, which play an important role in the occurrence and development of tumors. This study was designed to assess the association between DIAPH2, PTPRD and HIC1 SNPs and laryngeal cancer risk. PATIENTS AND METHODS: This study including 267 patients with histologically confirmed laryngeal cancer and 157 controls. The relationship between genetic variations DIAPH2 (rs6620138), PTPRD (rs3765142) and HIC1 (rs9901806) and the onset of laryngeal cancer were investigated. Statistical analysis to calculate the relationship between DIAPH2, PTPRD and HIC1 genes polymorphism and pathogenesis of laryngeal cancer. RESULTS: The results showed that rs6620138 DIAPH2 polymorphism could increase the onset risk of laryngeal cancer. Statistically significant differences in allele distribution of rs6620138 DIAPH2 and rs9901806 HIC1 in the case and control groups subgroups. CONCLUSIONS: This study results suggested that genetic variation of rs6620138 DIAPH2 polymorphism is related to the susceptibility to laryngeal cancer. Our results provide a basis to begin basic research on the role of DIAPH2 gene in the pathogenesis of laryngeal cancer. Full article

Phenanthriplatin is a new monofunctional platinum(II) complex that binds only one strand of DNA and acts by blocking gene transcription, but its effect on gene regulation has not been characterized relative to the traditional platinum-based complex, cisplatin. A549 non-small cell lung cancer and IMR90 lung fibroblast cells were treated with cisplatin, phenanthriplatin, or a control and then their RNA transcripts were subjected to next generation sequencing analysis. DESeq2 and CuffDiff2 were used to identify up- and downregulated genes and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used to identify pathways and functions. We found that phenanthriplatin may regulate the genes GPRC5a, TFF1, and TNFRSF10D, which act through p53 to control apoptosis, differently or to a greater extent than cisplatin, and that it, unlike cisplatin, could upregulate ATP5MD, a gene which signals through the Wnt/β catenin pathway. Furthermore, phenanthriplatin caused unique or enhanced effects compared to cisplatin on genes regulating the cytoskeleton, cell migration, and proliferation, e.g., AGAP1, DIAPH2, GDF15, and THSD1 (p < 0.05; q < 0.05). Phenanthriplatin may modulate some oncogenes differently than cisplatin potentially leading to improved clinical outcome, but this monofunctional complex should be carefully matched with cancer gene data to be successfully applied in chemotherapy. Full article

Cell division is essential for the maintenance of life and involves chromosome segregation and subsequent cytokinesis. The processes are tightly regulated at both the spatial and temporal level by various genes, and failures in this regulation are associated with oncogenesis. Here, we investigated the gene responsible for defects in cell division by using murine temperature-sensitive (ts) mutant strains, tsFT101 and tsFT50 cells. The ts mutants normally grow in a low temperature environment (32 °C) but fail to divide in a high temperature environment (39 °C). Exome sequencing and over-expression analyses identified Diaph3, a member of the formin family, as the cause of the temperature sensitivity observed in tsFT101 and tsFT50 cells. Interestingly, Diaph3 knockout cells showed abnormality in cytokinesis at 39 °C, and the phenotype was rescued by re-expression of Diaph3 WT, but not Diaph1 and Diaph2, other members of the formin family. Furthermore, Diaph3 knockout cells cultured at 39 °C showed a significant increase in the level of acetylated α-tubulin, an index of stabilized microtubules, and the level was reduced by Diaph3 expression. These results suggest that Diaph3 is required for cytokinesis only under high temperature conditions. Therefore, our study provides a new insight into the mechanisms by which regulatory factors of cell division function in a temperature-dependent manner. Full article

Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in these processes. However, the role of formin-like 1 (FMNL1) in cancer remains unclear. We studied FMNL1 expression in glioblastoma samples using immunohistochemistry. We sought to analyze the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from The Cancer Genome Atlas and analyzed using gene set enrichment analysis (GSEA). FMNL1 was an independent predictor of poor prognosis in a cohort of 217 glioblastoma multiforme cases (p < 0.001). FMNL1 expression was significantly higher in the mesenchymal subtype. FMNL1 upregulation and downregulation were associated with mesenchymal and proneural markers in the GSEA, respectively. These data highlight the important role of FMNL1 in the neural-to-mesenchymal transition. Conversely, FMNL1 downregulation suppressed glioblastoma multiforme cell migration and invasion via DIAPH1 and GOLGA2, respectively. FMNL1 downregulation also suppressed actin fiber assembly, induced morphological changes, and diminished filamentous actin. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression. Full article