Breast cancer (BC) is a leading cause of cancer-related deaths among women worldwide. Neoadjuvant therapy (NAT) is increasingly being used to reduce tumor burden prior to surgical resection. However, ...current techniques for assessing tumor response have significant limitations. Additionally, drug resistance is commonly observed, raising a need to identify biomarkers that can predict treatment sensitivity and survival outcomes. Circulating microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have been shown to play a significant role in cancer progression as tumor inducers or suppressors. The expression of circulating miRNAs has been found to be significantly altered in breast cancer patients. Moreover, recent studies have suggested that circulating miRNAs can serve as non-invasive biomarkers for predicting response to NAT. Therefore, this review provides a brief overview of recent studies that have demonstrated the potential of circulating miRNAs as biomarkers for predicting the clinical response to NAT in BC patients. The findings of this review will strengthen future research on developing miRNA-based biomarkers and their translation into medical practice, which could significantly improve the clinical management of BC patients undergoing NAT.
Androgenetic alopecia is a highly prevalent condition mainly affecting men. This complex trait is related to aging and genetics; however, multiple other factors, for example, lifestyle, are also ...involved. Despite its prevalence, the underlying biology of androgenetic alopecia remains elusive, and thus advances in its treatment have been hindered. Herein, we review the functional anatomy of hair follicles and the cell signaling events that play a role in follicle cycling. We also discuss the pathology of androgenetic alopecia and the known molecular mechanisms underlying this condition. Additionally, we describe studies comparing the transcriptional differences in hair follicles between balding and non-balding scalp regions. Given the genetic contribution, we also discuss the most significant risk variants found to be associated with androgenetic alopecia. A more comprehensive understanding of this pathology may be generated through using multi-omics approaches.
Recent studies have revealed the heterogeneous nature of astrocytes; however, how diverse constituents of astrocyte-lineage cells are regulated in adult spinal cord after injury and contribute to ...regeneration remains elusive. We perform single-cell RNA sequencing of GFAP-expressing cells from sub-chronic spinal cord injury models and identify and compare with the subpopulations in acute-stage data. We find subpopulations with distinct functional enrichment and their identities defined by subpopulation-specific transcription factors and regulons. Immunohistochemistry, RNAscope experiments, and quantification by stereology verify the molecular signature, location, and morphology of potential resident neural progenitors or neural stem cells in the adult spinal cord before and after injury and uncover the populations of the intermediate cells enriched in neuronal genes that could potentially transition into other subpopulations. This study has expanded the knowledge of the heterogeneity and cell state transition of glial progenitors in adult spinal cord before and after injury.
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•scRNA-seq revealed GFAP+ populations with distinct functional enrichment and dynamics•Regulatory network analysis predicted regulons defining specific subpopulations•Laminectomy sham surgery was sufficient to induce the activation of astrocyte-lineage cells•This study unveiled additional sources/pools of resident progenitors in adult spinal cord
Wei et al. report the identification of the subpopulations of GFAP-expressing cells in healthy and injured adult spinal cords using single-cell RNA-seq. Bioinformatic and functional investigations of these subpopulations revealed the signature, location, morphology, and proliferation and differentiation abilities of the resident progenitors in the spinal cord.
Oligodendrocytes, responsible for axon ensheathment, are critical for central nervous system (CNS) development, function, and diseases. OLIG2 is an important transcription factor (TF) that acts ...during oligodendrocyte development and performs distinct functions at different stages. Previous studies have shown that lncRNAs (long non-coding RNAs; > 200 bp) have important functions during oligodendrocyte development, but their roles have not been systematically characterized and their regulation is not yet clear.
We performed an integrated study of genome-wide OLIG2 binding and the epigenetic modification status of both coding and non-coding genes during three stages of oligodendrocyte differentiation in vivo: neural stem cells (NSCs), oligodendrocyte progenitor cells (OPCs), and newly formed oligodendrocytes (NFOs). We found that 613 lncRNAs have OLIG2 binding sites and are expressed in at least one cell type, which can potentially be activated or repressed by OLIG2. Forty-eight of them have increased expression in oligodendrocyte lineage cells. Predicting lncRNA functions by using a "guilt-by-association" approach revealed that the functions of these 48 lncRNAs were enriched in "oligodendrocyte development and differentiation." Additionally, bivalent genes are known to play essential roles during embryonic stem cell differentiation. We identified bivalent genes in NSCs, OPCs, and NFOs and found that some bivalent genes bound by OLIG2 are dynamically regulated during oligodendrocyte development. Importantly, we unveiled a previously unknown mechanism that, in addition to transcriptional regulation via DNA binding, OLIG2 could self-regulate through the 3' UTR of its own mRNA.
Our studies have revealed the missing links in the mechanisms regulating oligodendrocyte development at the transcriptional level and after transcription. The results of our research have improved the understanding of fundamental cell fate decisions during oligodendrocyte lineage formation, which can enable insights into demyelination diseases and regenerative medicine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for ...the lysosomal enzyme β-glucocerebrosidase (β-GCase), considered the main genetic risk factor for sporadic PD. The loss of β-GCase activity results in the formation of α-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to α-synuclein (α-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the β-GCase, β-galactosidase (β-gal), β-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, β-GAL, β-HEX, CTSD, PSAP, Saposin C and α-Syn protein levels by Western-blot. We found a 20% reduced β-GCase and β-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of α-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of α-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the β-GCase activity, resulting in the accumulation of α-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD.
Hyperoxia−hypoxia exposure is a proposed cause of alveolar developmental arrest in bronchopulmonary dysplasia in preterm infants, where mitochondrial reactive oxygen species and oxidative stress ...vulnerability are increased. The aryl hydrocarbon receptor (AhR) is one of the main activators of the antioxidant enzyme system that protects tissues and systems from damage. The present study aimed to determine if the activation of the AhR signaling pathway by prenatal administration of indole-3-carbinol (I3C) protects rat pups from hyperoxia–hypoxia-induced lung injury. To assess the activation of protein-encoding genes related to the AhR signaling pathway (Cyp1a1, Cyp1b1, Ugt1a6, Nqo1, and Gsta1), pup lungs were excised at 0, 24, and 72 h after birth, and mRNA expression levels were quantified by reverse transcription-quantitative polymerase chain reaction assays (RT-qPCR). An adapted Ratner's method was used in rats to evaluate radial alveolar counts (RACs) and the degree of fibrosis. The results reveal that the relative expression of AhR-related genes in rat pups of prenatally I3C-treated dams was significantly different from that of untreated dams. The RAC was significantly lower in the hyperoxia–hypoxia group (4.0 ± 1.0) than that in the unexposed control group (8.0 ± 2.0; P < 0.01). When rat pups of prenatally I3C-treated dams were exposed to hyperoxia–hypoxia, an RAC recovery was observed, and the fibrosis index was similar to that of the unexposed control group. A cytokine antibody array revealed an increase in the NF-κB signaling cascade in I3C-treated pups, suggesting that the pathway could regulate the inflammatory process under the stimulus of this compound. In conclusion, the present study demonstrates that I3C prenatal treatment activates AhR-responsive genes in pup’s lungs and hence attenuates lung damage caused by hyperoxia–hypoxia exposure in newborns.
Currently, there are no effective treatments for glioma or for neurodegenerative diseases because of, in part, our limited understanding of the pathophysiology and cellular heterogeneity of these ...diseases. Mounting evidence suggests that astrocytes play an active role in the pathogenesis of these diseases by contributing to a diverse range of pathophysiological states. In a previous study, five molecularly distinct astrocyte subpopulations from three different brain regions were identified. To further delineate the underlying diversity of these populations, we obtained mouse brain region-specific gene signatures for both protein-coding and long non-coding RNA and found that these astrocyte subpopulations are endowed with unique molecular signatures across diverse brain regions. Additional gene set and single-sample enrichment analyses revealed that gene signatures of different subpopulations are differentially correlated with glioma tumors that harbor distinct genomic alterations. To the best of our knowledge, this is the first study that links transcriptional profiles of astrocyte subpopulations with glioma genomic mutations. Furthermore, our results demonstrated that subpopulations of astrocytes in select brain regions are associated with specific neurodegenerative diseases. Overall, the present study provides a new perspective for understanding the pathophysiology of glioma and neurodegenerative diseases and highlights the potential contributions of diverse astrocyte populations to normal, malignant, and degenerative brain functions.
Systematic study of the regulatory mechanisms of Hematopoietic Stem Cell and Progenitor Cell (HSPC) self-renewal is fundamentally important for understanding hematopoiesis and for manipulating HSPCs ...for therapeutic purposes. Previously, we have characterized gene expression and identified important transcription factors (TFs) regulating the switch between self-renewal and differentiation in a multipotent Hematopoietic Progenitor Cell (HPC) line, EML (Erythroid, Myeloid, and Lymphoid) cells. Herein, we report binding maps for additional TFs (SOX4 and STAT3) by using chromatin immunoprecipitation (ChIP)-Sequencing, to address the underlying mechanisms regulating self-renewal properties of lineage-CD34+ subpopulation (Lin-CD34+ EML cells). Furthermore, we applied the Assay for Transposase Accessible Chromatin (ATAC)-Sequencing to globally identify the open chromatin regions associated with TF binding in the self-renewing Lin-CD34+ EML cells. Mass spectrometry (MS) was also used to quantify protein relative expression levels. Finally, by integrating the protein-protein interaction database, we built an expanded transcriptional regulatory and interaction network. We found that MAPK (Mitogen-activated protein kinase) pathway and TGF-β/SMAD signaling pathway components were highly enriched among the binding targets of these TFs in Lin-CD34+ EML cells. The present study integrates regulatory information at multiple levels to paint a more comprehensive picture of the HSPC self-renewal mechanisms.
Mutations in LRRK2 and GBA1 are key contributors to genetic risk of developing Parkinson's disease (PD). To investigate how LRRK2 kinase activity interacts with GBA and contributes to lysosomal ...dysfunctions associated with the pathology of PD. The activity of the lysosomal enzyme β-Glucocerebrosidase (GCase) was assessed in a human neuroglioma cell model treated with two selective inhibitors of LRKK2 kinase activity (LRRK2-in-1 and MLi-2) and a GCase irreversible inhibitor, condutirol-beta-epoxide (CBE), under 24 and 72 h experimental conditions. We observed levels of GCase activity comparable to controls in response to 24 and 72 h treatments with LRRK2-in-1 and MLi-2. However, GBA protein levels increased upon 72 h treatment with LRRK2-in-1. Moreover, LC3-II protein levels were increased after both 24 and 72 h treatments with LRRK2-in-1, suggesting an activation of the autophagic pathway. These results highlight a possible regulation of lysosomal function through the LRRK2 kinase domain and suggest an interplay between LRRK2 kinase activity and GBA. Although further investigations are needed, the enhancement of GCase activity might restore the defective protein metabolism seen in PD.
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