Search Results (101)

Aberrant DNA methylation has been shown to be a fingerprint characteristic in human colorectal tumors. In this study, we hypothesize that investigating global DNA methylation could offer potential candidates for clinical application in CRC. The epigenome-wide association analysis was conducted in both the tumor area (N = 27) and the adjacent tumor-free (NAT) area (N = 15). We found 78,935 differentially methylated CpG sites (DMCs) (FDR < 0.05), 42,888 hypomethylated and 36,047 hypermethylation showing overall hypomethylation. Gene ontology and KEGG analysis of differentially methylated genes showed significant enrichment in developmental genes, as well as in genes involved in metabolic processes and the cell cycle, such as the TFGβ and cAMP signaling pathways. Through filtered analysis, we identified TNXB as the most epigenetically dysregulated gene, hypomethylated and downregulated in CRC (both with p < 0.001) and associated with poor overall survival. In the functional analysis, TNXB was epigenetically regulated in a dose-dependent manner, suggesting a potential role in CRC. The epigenetic dysregulation and functional role of TNXB in CRC could have clinical implications, serving as indicators of malignant potential, with adverse effects associated with disease origin and progression in CRC. Full article

In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of Aβ42, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer’s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., Aβ42, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an “amoeboid-like phenotype”), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo™ Red E. coli BioParticles™ phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (ΔΨm), response to ATP-induced transient intracellular Ca²⁺ influx, cell polarization (cluster of differentiation 68 (CD68)/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-α). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca²⁺ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-α. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD. Full article

Colorectal cancer remains a leading malignancy. As the aberrant activation of Wnt/β-catenin signaling causes colorectal cancer, Wnt/β-catenin signaling inhibitors are potential candidates for colorectal cancer treatment. Our drug screening platform identified ursolic acid (UA), a triterpenoid with various biological activities, as a potential anticancer drug because it inhibits the T-cell factor (TCF)/β-catenin-mediated transcriptional activity. Here, we discovered that UA inhibited Wnt signaling by reducing the Wnt reporter activity and Wnt target gene expression, leading to a delay in cell cycle progression and the suppression of cell proliferation. Stepwise epistatic analyses suggested that UA functions on β-catenin protein stability in Wnt signaling. Further studies revealed that UA reduced β-catenin protein levels by Western blotting and immunofluorescent staining and induced autophagy by microtubule-associated protein 1 light chain 3 beta (LC3B) punctate staining. The cotreatment with UA and the autophagy inhibitors chloroquine and wortmannin recovered the β-catenin protein levels. Therefore, UA was confirmed to induce β-catenin degradation by the autophagy–lysosomal degradation system through inhibition in the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (protein kinase B; AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Our results not only highlight the potential of UA in Wnt-driven colorectal cancer therapy but also provide a workable Wnt signaling termination approach for the treatment of other Wnt-related diseases. Full article

This review paper highlights the importance of educating current and future professionals about epigenetic mechanisms and recognizing epigenetics as a crucial model for protection against ionizing radiation. Two basic models for radiation-induced DNA damage are currently in use. The association between mutations and chromosomal aberrations provides a framework for analyzing risks at low radiation doses and exposure to small doses. However, there is no monitoring of epigenetic changes in professionals exposed to low doses of ionizing radiation. Epigenetic events regulate gene activity and expression not only during cell development and differentiation but also in response to environmental stimuli, such as ionizing radiation. Furthermore, the potential occurrence of malignant and hereditary diseases at low doses of ionizing radiation is linearly correlated and is considered a scientifically accepted assumption, despite recognized scientific limitations associated with this assessment. The aim of this review is to integrate novel and intriguing radiobiological paradigms regarding the effects of ionizing radiation on DNA methylation and epigenetic regulation of the DNA molecule. Several hypothesized biological responses to ionizing radiation are examined, linking them to epigenetic mechanisms involved in health risk assessment for professionals. The second part of the review includes published research related to epigenetics, supplementation, and virus reactivation in the context of epigenetic modifications of the DNA molecule. We hypothesize that different cycles lead to changes in the epigenome, which may be associated with the reactivation of certain viruses and the deficiency of specific dietary elements. These findings are linked to minimal deficiencies in vitamin B12 and folic acid, which may contribute to epigenomic changes. This aspect is crucial for the immune status of individuals working in high-risk environments. Full article

Tribbles Pseudokinase 3 (TRIB3) is a negative regulator of cellular signaling, particularly the PI3K-Akt and NF-κB pathways. Aberrant TRIB3 expressions have been reported in a number of cancers, but its role in tumor growth and progression remains controversial since both oncogenic and tumor suppressive activities have been reported. The goal of this study is to understand the roles of TRIB3 in prostate cancers through bioinformatic queries of public databases and experimental evaluations through gain-of-function and loss-of-function approaches. Here we report that there was increased TRIB3 gene expression with a Z-score over 2, relative to normal samples, in 26% of prostate cancers. Increased TRIB3 expression was associated with increased mutation counts and aneuploidy scores of prostate cancers. Increased TRIB3 expression was also associated with reduced progression-free or disease-free survival of prostate cancer patients. However, our experiments found that increased TRIB3 expression actually had an antiproliferative effect and increased cell cycle arrest at the G2/M phase. Depletion of the endogenous TRIB3 expression enhanced cell proliferation and reduced the level of Cdc25C phosphatase. Our results suggest that although TRIB3 expression was increased in prostate cancers in association with increased genomic instabilities, TRIB3 actually promoted cell cycle arrest and reduced tumor cell proliferation. Full article

The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases. Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest. It acts as a powerful defense mechanism against normal organ development and aging-related diseases. On the other hand, the accumulation of senescent cells without their proper removal contributes to the development or worsening of cancer and age-related diseases. A correlation was recently reported between the Hippo pathway and cellular senescence, which preserves tissue homeostasis. This review is the first to describe the close relationship between aging and the Hippo pathway, and provides insights into the mechanisms of aging and the development of age-related diseases. In addition, it describes advanced findings that may lead to the development of tissue regeneration therapies and drugs targeting rejuvenation. Full article

Cell division cycle 6 (CDC6) is essential for the initiation of DNA replication in eukaryotic cells and contributes to the development of various human tumors. Polycystic ovarian syndrome (PCOS) is a reproductive endocrine disease in women of childbearing age, with a significant risk of endometrial cancer (EC). However, the role of CDC6 in the progression of PCOS to EC is unclear. Therefore, we examined CDC6 expression in patients with PCOS and EC. We evaluated the relationship between CDC6 expression and its prognostic value, potential biological functions, and immune infiltrates in patients with EC. In vitro analyses were performed to investigate the effects of CDC6 knockdown on EC proliferation, migration, invasion, and apoptosis. CDC6 expression was significantly upregulated in patients with PCOS and EC. Moreover, this protein caused EC by promoting the aberrant infiltration of macrophages into the immune microenvironment in patients with PCOS. A functional enrichment analysis revealed that CDC6 exerted its pro-cancer and pro-immune cell infiltration functions via the PI3K-AKT pathway. Moreover, it promoted EC proliferation, migration, and invasion but inhibited apoptosis. This protein significantly reduced EC survival when mutated. These findings demonstrate that CDC6 regulates the progression of PCOS to EC and promotes immune infiltration. Full article

A shared hallmark of age-related neurodegenerative diseases is the chronic activation of innate immune cells, which actively contributes to the neurodegenerative process. In Alzheimer’s disease, this inflammatory milieu exacerbates both amyloid and tau pathology. A similar abnormal inflammatory response has been reported in Parkinson’s disease, with elevated levels of cytokines and other inflammatory intermediates derived from activated glial cells, which promote the progressive loss of nigral dopaminergic neurons. Understanding the causes that support this aberrant inflammatory response has become a topic of growing interest and research in neurodegeneration, with high translational potential. It has been postulated that the phenotypic shift of immune cells towards a proinflammatory state combined with the presence of immunogenic cell death fuels a vicious cycle in which mitochondrial dysfunction plays a central role. Mitochondria and mitochondria-generated reactive oxygen species are downstream effectors of different inflammatory signaling pathways, including inflammasomes. Dysfunctional mitochondria are also recognized as important producers of damage-associated molecular patterns, which can amplify the immune response. Here, we review the major findings highlighting the role of mitochondria as a checkpoint of neuroinflammation and immunogenic cell deaths in neurodegenerative diseases. The knowledge of these processes may help to find new druggable targets to modulate the inflammatory response. Full article

Background: Transactivation Response Element RNA-binding Protein (TRBP2) is a double-stranded RNA-binding protein widely known for its critical contribution to RNA interference (RNAi), a conserved mechanism of gene-expression regulation mediated through small non-coding RNA moieties (ncRNAs). Nevertheless, TRBP2 has also proved to be involved in other molecular pathways and biological processes, such as cell growth, organism development, spermatogenesis, and stress response. Mutations or aberrant expression of TRBP2 have been previously associated with diverse human pathologies, including Alzheimer’s disease, cardiomyopathy, and cancer, with TRBP2 playing an essential role(s) in proliferation, invasion, and metastasis of tumor cells. Methods: Hence, the present study aims to investigate, via employment of advanced flow cytometry, immunofluorescence, cell transgenesis and bioinformatics technologies, new, still elusive, functions and properties of TRBP2, particularly regarding its cell cycle-specific control during cancer cell division. Results: We have identified a novel, mitosis-dependent regulation of TRBP2 protein expression, as clearly evidenced by the lack of its immunofluorescence-facilitated detection during mitotic phases, in several human cancer cell lines of different tissue origin. Notably, the obtained TRBP2-downregulation patterns seem to derive from molecular mechanisms that act independently of oncogenic activities (e.g., malignancy grade), metastatic capacities (e.g., low versus high), and mutational signatures (e.g., p53^−/− or p53^ΔΥ126) of cancer cells. Conclusions: Taken together, we herein propose that TRBP2 serves as a novel cell cycle-dependent regulator, likely exerting mitosis-suppression functions, and, thus, its mitosis-specific downregulation can hold strong promise to be exploited for the efficient and successful prognosis, diagnosis, and (radio-/chemo-)therapy of diverse human malignancies, in the clinic. Full article

Amyloid-beta peptide (Aβ) is a neurotoxic constituent of senile plaques in the brains of Alzheimer’s disease (AD) patients. The detailed mechanisms by which protein kinase C-delta (PKCδ) contributes to Aβ toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, we found that inhibition of Aβ25-35-induced PKCδ increased cell viability with restoration of neuronal morphology. Using cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) as the respective markers for the G1-, S-, and G2/M-phases, PKCδ inhibition mitigated cell cycle reentry (CCR) and subsequent caspase-3 cleavage induced by both Aβ25-35 and Aβ1-42 in the post-mitotic cortical neurons. Upstream of PKCδ, signal transducers and activators of transcription (STAT)-3 mediated PKCδ induction, CCR, and caspase-3 cleavage upon Aβ exposure. Downstream of PKCδ, aberrant neuronal CCR was triggered by overactivating cyclin-dependent kinase-5 (CDK5) via calpain2-dependent p35 cleavage into p25. Finally, PKCδ and CDK5 also contributed to Aβ25-35 induction of p53-upregulated modulator of apoptosis (PUMA) in cortical neurons. Together, we demonstrated that, in the post-mitotic neurons exposed to Aβs, STAT3-dependent PKCδ expression triggers calpain2-mediated p35 cleavage into p25 to overactivate CDK5, thus leading to aberrant CCR, PUMA induction, caspase-3 cleavage, and ultimately apoptosis. Full article

The highly conserved Notch pathway, a pillar of juxtacrine signaling, orchestrates intricate intercellular communication, governing diverse developmental and homeostatic processes through a tightly regulated cascade of proteolytic cleavages. This pathway, culminating in the migration of the Notch intracellular domain (NICD) to the nucleus and the subsequent activation of downstream target genes, exerts a profound influence on a plethora of molecular processes, including cell cycle progression, lineage specification, cell–cell adhesion, and fate determination. Accumulating evidence underscores the pivotal role of Notch dysregulation, encompassing both gain and loss-of-function mutations, in the pathogenesis of numerous human diseases. This review delves deep into the multifaceted roles of Notch signaling in cellular dynamics, encompassing proliferation, differentiation, polarity maintenance, epithelial–mesenchymal transition (EMT), tissue regeneration/remodeling, and its intricate interplay with other signaling pathways. We then focus on the emerging landscape of Notch aberrations in gynecological pathologies predisposing individuals to infertility. By highlighting the exquisite conservation of Notch signaling in Drosophila and its power as a model organism, we pave the way for further dissection of disease mechanisms and potential therapeutic interventions through targeted modulation of this master regulatory pathway. Full article

Erythropoiesis is initiated with the transformation of multipotent hematopoietic stem cells into committed erythroid progenitor cells in the erythroblastic islands of the bone marrow in adults. These cells undergo several stages of differentiation, including erythroblast formation, normoblast formation, and finally, the expulsion of the nucleus to form mature red blood cells. The erythropoietin (EPO) pathway, which is activated by hypoxia, induces stimulation of the erythroid progenitor cells and the promotion of their proliferation and survival as well as maturation and hemoglobin synthesis. The regulation of erythropoiesis is a complex and dynamic interaction of a myriad of factors, such as transcription factors (GATA-1, STAT5), cytokines (IL-3, IL-6, IL-11), iron metabolism and cell cycle regulators. Multiple microRNAs are involved in erythropoiesis, mediating cell growth and development, regulating oxidative stress, erythrocyte maturation and differentiation, hemoglobin synthesis, transferrin function and iron homeostasis. This review aims to explore the physiology of steady-state erythropoiesis and to outline key mechanisms involved in ineffective erythropoiesis linked to anemia, chronic inflammation, stress, and hematological malignancies. Studying aberrations in erythropoiesis in various diseases allows a more in-depth understanding of the heterogeneity within erythroid populations and the development of gene therapies to treat hematological disorders. Full article

Breast cancer (BC) is a complex disease driven by a combination of genetic mutations and epigenetic modifications. In particular, the overexpression of BET family proteins (BETs) has emerged as a key epigenetic aberration contributing to BC pathogenesis. CBL0137 (CBL), a small-molecule compound, has shown promise as an inhibitor of BETs in HeLa TI cells. In this study, we aimed to assess the anticancer effects of CBL in vitro and evaluate its impact on the expression of BETs in BC cells. Cells of three subtypes of BC (MCF7, MDA-MB-231, SKBR3) were used in this study. Cytotoxic effects were analyzed using the MTT assay. Effects on cell cycle and apoptosis were assessed using FACS with PI and FITC-Annexin staining. The level of BETs (BRD2, BRD3, BRD4) was determined by Western blotting. CBL demonstrated a significant reduction in BС cell viability with an IC50 value of approximately 1 μM for all cell lines after 72h of exposure and 20 μM after 24h. CBL treatment resulted in an increase in cells in the G2/M phase in MCF7 and SKBR3 cells after 24h and 72h of action, as well as in MDA-MB-231 cells after 24h. In MCF7 cells, the influence of CBL led to apoptotic changes characterized by a slight elevation in the early apoptotic population. Treatment of MDA-MB-231 cells with CBL resulted in a decrease in the expression of BRD2, BRD3, and BRD4 proteins, while treatment of MCF7 cells led to a reduction in BRD3 and BRD4 protein levels. No significant changes in the amount of BET proteins were observed in SKBR3 cells. In conclusion, the presented data offer valuable insights into the mechanisms of action of CBL, providing a basis for further investigation into its therapeutic potential in BC treatment. This research was funded by the RSF (no. 21-75-10163). Full article

Cancers and neurological disorders are two major types of diseases in humans. We developed the concept called the “Aberrant Cell Cycle Disease (ACCD)” due to the accumulating evidence that shows that two different diseases share the common mechanism of aberrant cell cycle re-entry. The aberrant cell cycle re-entry is manifested as kinase/oncoprotein activation and tumor suppressor (TS) inactivation, which are associated with both tumor growth in cancers and neuronal death in neurological disorders. Therefore, some cancer therapies (e.g., kinase/oncogene inhibition and TS elevation) can be leveraged for neurological treatments. MicroRNA (miR/miRNA) provides a new style of drug-target binding. For example, a single tumor suppressor miRNA (TS-miR/miRNA) can bind to and decrease tens of target kinases/oncogenes, producing much more robust efficacy to block cell cycle re-entry than inhibiting a single kinase/oncogene. In this review, we summarize the miRNAs that are altered in both cancers and neurological disorders, with an emphasis on miRNA drugs that have entered into clinical trials for neurological treatment. Full article

The Chlamydiae phylum is comprised of obligate intracellular bacteria including human pathogens such as Chlamydia trachomatis and lesser-known Chlamydia-related bacteria like Waddlia chondrophila or Simkania negevensis. Despite broad differences, these bacteria share a similar development including a persistent state induced using stressors such as immune responses, nutrient starvation, or penicillin introduction. In microbiology, this persistent state is identified by enlarged bacteria, called aberrant bodies, which are unable to divide but are able to survive and resume the developmental cycle upon clearance of the stressor. Clinically, chlamydial persistence is thought to be linked to chronic disease and long-term infections with pathogenic strains. This review aims to share and discuss the latest discoveries made on the little-known mechanisms that take place during stress response. The results indicate that an inter-linked homeostasis between iron and tryptophan is required for effective bacterial proliferation. During stress, Chlamydiae attempt to compensate by inducing tight regulations of the tryptophan and iron acquisition operons. These compensations allow bacterial survival but result in the halting of cell division. As cell division is tightly linked to peptidoglycan synthesis and regulation, treatment with β-lactamase inhibitors can also exhibit an aberrant body phenotype. Full article