Zbp1 gene: a modulator of multiple aging hallmarks as potential therapeutic target for age-related diseases.

The Zbp1 gene has recently emerged as a potential therapeutic target for age-related diseases. Multiple studies have reported that Zbp1 plays a key role in regulating several aging hallmarks, including cellular senescence, chronic inflammation, DNA damage response, and mitochondrial dysfunction. Regarding cellular senescence, Zbp1 appears to regulate the onset and progression of senescence by controlling the expression of key markers such as p16INK4a and p21CIP1/WAF1. Similarly, evidence suggests that Zbp1 plays a role in regulating inflammation by promoting the production of pro-inflammatory cytokines, such as IL-6 and IL-1ß, through activation of the NLRP3 inflammasome. Furthermore, Zbp1 seems to be involved in the DNA damage response, coordinating the cellular response to DNA damage by regulating the expression of genes such as p53 and ATM. Additionally, Zbp1 appears to regulate mitochondrial function, which is crucial for energy production and cellular homeostasis. Given the involvement of Zbp1 in multiple aging hallmarks, targeting this gene represents a potential strategy to prevent or treat age-related diseases. For example, inhibiting Zbp1 activity could be a promising approach to reduce cellular senescence and chronic inflammation, two critical hallmarks of aging associated with various age-related diseases. Similarly, modulating Zbp1 expression or activity could also improve DNA damage response and mitochondrial function, thus delaying or preventing the development of age-related diseases. Overall, the Zbp1 gene appears to be a promising therapeutic target for age-related diseases. In the current review, we have discussed the molecular mechanisms underlying the involvement of Zbp1 in aging hallmarks and proposed to develop effective strategies to target this gene for therapeutic purposes.

Common factors among three types of cells aged in mice.

The greatest risk factor for the formation of numerous significant chronic disorders is aging. Understanding the core molecular underpinnings of aging can help to slow down the inevitable process. Systematic study of gene expression or DNA methylation data is possible at the transcriptomics and epigenetics levels. DNA methylation and gene expression are both affected by aging. Gene expression is an important element in the aging of Homo sapiens. In this work, we evaluated the expression of differentially expressed genes (DEGs), proteins, and transcription factors (TFs) in three different types of cells in mice: antibody-secreting cells, cardiac mesenchymal stromal cells, and skeletal muscle cells. The goal of this article is to uncover a common cause during aging among these cells in order to increase understanding about establishing complete techniques for preventing aging and improving people's quality of life. We conducted a comprehensive network-based investigation to establish which genes and proteins are shared by the three different types of aged cells. Our findings clearly indicated that aging induces gene dysregulation in immune, pharmacological, and apoptotic pathways. Furthermore, our research developed a list of hub genes with differential expression in aging responses that should be investigated further to discover viable anti-aging treatments.

Identification and profiling of conserved microRNAs in different developmental stages of crown imperial (Fritillaria imperialis L.) using high-throughput sequencing.

BACKGROUND: Novel strategies for improvement of ornamental plants and their properties relay on miRNA control of differential plant gene expression modulation. Still, in response to the same abiotic stresses, some conserved miRNA families show different expression patterns in different plant species. In parallel, the use of deep sequencing technologies reveals new levels of complexity of regulatory networks in plants through identification of new miRNAs. METHODS AND RESULTS: Fritillaria imperialis plants were collected from their natural habitats in Koohrang, Chaharmahal va Bakhtiari, Iran. Several tissues including stamen, pistil, petal, sepal, leaf, stem, bulb and fruit were collected during three developmental stages (stem elongation, flower development and seed head stages). Using RNAseq and qRT-PCR approach, this research revealed 21 conserved miRNAs, matching 15 miRNA families, in Fritilaria imperialis. CONCLUSIONS: The expression of seven conserved miRNAs (Fim-miR156b, Fim-miR159, Fim-miR166a-5p, Fim-miR169d-5p, Fim-miR171c, Fim-miR393 and Fim-miR396e-3p) was further investigated in different tissues and three developmental stages, suggesting different roles for these miRNAs during growth and development of crown imperial. Gained knowledge from this research can open the door to find efficient ways to secure crown imperial survival, preservation and utilization and if proven useful may be applied in other plant species as well.

Dissecting the molecular responses of lentil to individual and combined drought and heat stresses by comparative transcriptomic analysis.

Lentil cultivation could be challenged by combined heat and drought stress in semi-arid regions. We used RNA-seq approach to profile transcriptome changes of Lens culinaris exposed to individual and combined heat and drought stresses. It was determined that most of the differentially expressed genes observed in response to combined stress, could not be identified by analysis of transcriptome exposed to corresponding individual stresses. Interestingly, this study results revealed that the expression of ribosome generation and protein biosynthesis and starch degradation pathways related genes were uniquely up-regulated under the combined stress. Although multiple genes related to antioxidant activity were up-regulated in response to all stresses, variation in types and expression levels of these genes under the combined stress were higher than that of individual stresses. Using this comparative approach, for the first time, we reported up-regulation of several TF, CDPK, CYP, and antioxidant genes in response to combined stress in plants.

The clinical significance of circulating DSCAM-AS1 in patients with ER-positive breast cancer and construction of its competitive endogenous RNA network.

Long Non-Coding RNAs (lncRNAs), with diagnostic and therapeutic applications in malignancies, are newly described tumour-related molecules. Here, we reported the importance of circulating DSCAM-AS1 as the biomarker to detect Estrogen Receptor (ER)-positive breast cancer (BC) cases. Moreover, the expression of a BC-associated lncRNAs, namely DSCAM-AS1, was measured in tumoural and Paired Adjacent Non-Tumoral (PANT) tissue, as well as plasma, using Real-Time Polymerase Chain Reaction (RT-PCR). Besides, the correlations between gene expression and the clinicopathological features were analyzed. The diagnostic power of circulating DSCAM-AS1 in BC was estimated using the Area Under the Curve (AUC) value. Furthermore, we studied the DSCAM-AS1 associated with the network of competitive endogenous RNA (ceRNA) in BC using the literature review and in silico analysis. We found a significant increase in the expression levels of lncRNA in the tumour (P < 0.001) and in plasma (P < 0.001) of ER-positive BC patients. The sensitivity and specificity of DSCAM-AS1 in plasma for detection of BC from healthy controls were 100 and 97%, respectively (AUC = 0.98, P < 0.001). Accordingly, we suggest an elevated level of circulating DSCAM-AS1 as a candidate biomarker of ER-positive BC patients. Moreover, perturbation of DSCAM-AS1, as a ceRNA, acts in the tumor progression and drug resistance by affecting different cell signaling.

Identification of genes involved in steroid alkaloid biosynthesis in Fritillaria imperialis via de novo transcriptomics.

Crown imperial (CI) has been used in traditional medicine. Today it is known that such beneficial effects are due to its richness in steroidal alkaloids (SA). Using de novo transcriptomics, orthologues/paralogues finder, phylogenetic analysis and tissue- and developmental stage-specific expression analysis, we identified ten genes and several TFs involved in the biosynthesis of SA in CI. The comparative analysis of ten genes expression profiles revealed the possibility of their co-regulation, which may imply the possibility of their organization in metabolic gene clusters. Having in mind convergent evolution of steroidal biosynthetic pathways in flowering plants and records of convergent evolution of specific proteins, observed expression patterns open a reasonable interest to investigate the possibility of the existence of genes cluster organization in SA pathway in the family Liliaceae or at least in some species of genus Fritillaria. Obtained results support transcriptomics as useful approach in elucidating genes underlying complex biochemical pathways.

Dynamics changes in the transcription factors during early human embryonic development.

Development of an embryo from a single cell, zygote, to multicellular morulae requires activation of hundreds of genes that were mostly inactivated before fertilization. Inevitably, transcription factors (TFs) would be involved in modulating the drastic changes in gene expression pattern observed at all preimplantation stages. Despite many ongoing efforts to uncover the role of TFs at the early stages of embryogenesis, still many unanswered questions remained that need to be explored. This could be done by studying the expression pattern of multiple genes obtained by high-throughput techniques. In the current study, we have identified a set of TFs that are involved in the progression of the zygote to blastocyst. Global gene expression patterns of consecutive stages were compared and differences documented. Expectedly, at the early stages of development, only a few sets of TFs differentially expressed while at the later stages hundreds of TFs appear to be upregulated. Interestingly, the expression levels of many TFs show an oscillation pattern during development indicating a need for their precise expression. A significant shift in gene expression was observed during the transition from four- to eight-cell stages, an indication of zygote genome activation. Additionally, we have found 11 TFs that were common in all stages including ATF3, EN1, IFI16, IKZF3, KLF3, NPAS3, NR2F2, RUNX1, SOX2, ZBTB20, and ZSCAN4. However, their expression patterns did not follow similar trends in the steps studied. Besides, our findings showed that both upregulation and active downregulation of the TFs expression is required for successful embryogenesis. Furthermore, our detailed network analysis identified the hub TFs for each transition. We found that HNF4A, FOXA2, and EP300 are the three most important elements for the first division of zygote.

A comparative system-level analysis of the neurodegenerative diseases.

Neurodegenerative diseases are disorders in the central nervous system with consequent progressive neurological symptoms including behavioral and cognitive disabilities. Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, multiple sclerosis, and schizophrenia are the most important and abundant neurodegenerative diseases that affect different parts of the brain. Detailed studies unveiled the molecular mechanisms and pathways affected in each of these disorders. The role of many genes has been documented in the onset and progression of each disease. Although many system-level approaches have been used to understand the exact cause of these diseases, there is no comparative analysis in this regard. Despite all differences in the molecular basis of these diseases, overlapping symptoms might indicate the involvement of the similar pathways and processes. Here, we have applied a system biology approach to uncover many aspects of main neurodegenerative diseases using microarray data obtained from 118 cases of postmortem brain samples. Our analysis has identified key genes that might contribute to the status of diseases. We have also compared the involved biological process and pathway between different disease to find possible similar mechanisms that exist in all of them. We also predicted potentially important transcription factors in each disease and predicted the core gene regulatory networks. We have provided a list of possible new key regulators that could be further explored and also discussed the role of these hub genes. The results of this study would be useful to develop new diagnostic strategies and also to find new drug targets.

Regulatory networks upon neurogenesis induction in PC12 cell line by small molecules.

Alteration in the normal regulatory pathway of differentiation can lead to the induction of programmed cell death. Accordingly, some chemicals like staurosporine, nerve growth factor, pituitary adenylate cyclase activating peptide, and trimethyltin are shown to be able to induce differentiation in vitro, via different mechanisms in the PC12 cell line. Hence, understanding the details of the molecular mechanisms of differentiation induction by these small molecules are important for further application of these molecules in neurogenesis. Therefore, we sought to determine these signaling pathways, using gene regulatory networks analysis. Then, we have conducted a comparative analysis of the alterations in the gene expression pattern of the PC12 cell lines in response to these chemicals at the early stages. Based on the comparative analysis and previous knowledge, we have proposed the affected pathways during differentiation and apoptosis. Our findings could be useful in the development of protocols to reprogramming of neurons by such small molecules with high efficiency.

Interaction of long noncoding RNA MEG3 with miRNAs: A reciprocal regulation.

The competitive endogenous RNA (ceRNA) hypothesis suggests that a long noncoding RNA (lncRNA) can function as sinks for pools of microRNAs (miRNAs); thereby, in the presence of ceRNA, messenger RNAs (mRNAs) targeted by specific miRNAs can liberate and translate to protein. Maternally expressed gene 3 (MEG3) is a lncRNA, which its expression has been detected in various normal tissues, while it is lost or downregulated in human tumors. The MEG3 is an imprinted gene which, is methylated and suppressed by DNA methyltransferases (DNMTs) family. Also, miRNAs are involved in the regulation of MEG3 gene expression. Interestingly, the lncRNA MEG3 (lnc-MEG3), as a ceRNA affects various cell processes such as proliferation, apoptosis, and angiogenesis by sponging miRNAs. These miRNAs, in turn, regulate different mRNAs in different pathways. This review focuses on the interaction between lnc-MEG3 and experimentally validated miRNAs. In addition, the discussion supplemented by some data obtained from mirPath (v.3) and TarBase (v.8) databanks to provide more details about the pathways affected by this ceRNA.

Dissection of Regulatory Elements During Direct Conversion of Somatic Cells Into Neurons.

A revolutionary approach that involves direct conversion of somatic cells into almost any other types of cells showed promising results for regenerative medicine. Currently, producing valuable cell types including neurons, cardiomyocytes, and hepatocytes through direct conversion of somatic cells appear to be a feasible option for regenerative medicine. The process involves inducing the cells by chemical cocktails or by expression of different types of transcription factors. In this concept, in vitro neurogenesis considered to be able to produce neuron cells to replace damaged neurons especially in Alzheimer and Parkinson disease. However, early successful experiments followed by major drawbacks such as low differentiation efficiency in producing neurons and detection of various undesirable types of cells in the culture. Therefore, there is not a single optimized common protocol for producing high quality neurons in vitro so far. This is partly due to the lack of our understanding about the precise cellular, genetic, and molecular mechanisms underlying neurogenesis via direct conversion. In the current work, we have employed meta-analysis tools and extensive gene regulatory network analysis on the high throughput gene expression data obtained from previous reprogramming protocols to identify central gene regulatory components involved in direct conversion of fibroblasts into neurons. Our results identified miR-9, miR-30 as the most important miRNA and TP53, MYC, JUN, SP1, and SMAD2 considered to be the most important transcription factors. These findings would be useful for direct targeting these hub regulatory elements in order to increase the efficacy and specificity of the conversion protocols. J. Cell. Biochem. 118: 3158-3170, 2017. © 2017 Wiley Periodicals, Inc.

In silico search and biological validation of microRNAs related to drought response in peach and almond.

Plant responses to drought stress are regulated at the transcriptional and post-transcriptional levels through noncoding endogenous microRNAs. These microRNAs play key roles in gene expression, mainly by down-regulating target mRNAs. In this work, an in silico search and validation for microRNAs related to drought response in peach ('G.H. Hill'), almond ('Sefied') and an interspecific peach-almond hybrid ('GN 15') has been performed. We used qPCR to analyse the gene expression of several miRNAs described as being related to drought response in peach, including miR156, miR159, miR160, miR167, miR171, miR172, miR398, miR403, miR408, miR842 and miR2275 under mild and severe water deficit. These miRNAs were in silico selected on the basis of previous works, their conservation in plants and their drought response. qPCR analysis confirmed the implication of these miRNAs in the dehydration stress response in the three assayed genotypes. Comparison of miRNA expression patterns in the three evaluated genotypes indicated that the hybrid GN 15 showed higher expression levels of specific miRNAs which should be related to the observed drought tolerance. mRNA target transcripts of the miRNAs studied were predicted using the Rose database, which includes transcription factors that regulate plant growth and development. In addition, results showed that the promoter region contains responsive elements to hormone-mediated regulatory elements. Network analysis not only unravelled the interaction between miRNAs and their predicted gene targets but also highlighted the roles of miRNAs in response to drought stress.

Signaling and Gene Regulatory Networks Governing Definitive Endoderm Derivation From Pluripotent Stem Cells.

The generation of definitive endoderm (DE) from pluripotent stem cells (PSCs) is a fundamental stage in the formation of highly organized visceral organs, such as the liver and pancreas. Currently, there is a need for a comprehensive study that illustrates the involvement of different signaling pathways and their interactions in the derivation of DE cells from PSCs. This study aimed to identify signaling pathways that have the greatest influence on DE formation using analyses of transcriptional profiles, protein-protein interactions, protein-DNA interactions, and protein localization data. Using this approach, signaling networks involved in DE formation were constructed using systems biology and data mining tools, and the validity of the predicted networks was confirmed experimentally by measuring the mRNA levels of hub genes in several PSCs-derived DE cell lines. Based on our analyses, seven signaling pathways, including the BMP, ERK1-ERK2, FGF, TGF-beta, MAPK, Wnt, and PIP signaling pathways and their interactions, were found to play a role in the derivation of DE cells from PSCs. Lastly, the core gene regulatory network governing this differentiation process was constructed. The results of this study could improve our understanding surrounding the efficient generation of DE cells for the regeneration of visceral organs. J. Cell. Physiol. 231: 1994-2006, 2016. © 2016 Wiley Periodicals, Inc.

Inhibitory effect of ibuprofen on tumor survival and angiogenesis in gastric cancer cell.

Numerous epidemiological studies have suggested effectiveness of long-term and regular use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, in preventing and treatment of certain cancers including prostate, colon, breast, lung, and gastric cancers. We have studied the potential anti-turmeric effect of ibuprofen in adenocarcinoma gastric cell line (AGS). The effects of ibuprofen were investigated on cell proliferation, apoptosis, angiogenesis, and expression of stemness marker genes using real-time RT-PCR, DNA laddering, and tube formation assays via ECM gel and human umbilical vein endothelial cells (HUVECs). Annexin-V-FLUOS and propidium iodide (PI) were used to stain the apoptotic cells. Our findings indicate that ibuprofen at the concentrations of 100, 200, 300, 400, and 500 µM is able to reduce the cancerous characteristics of the AGS cells by inducing apoptosis, inhibition of cell proliferation, and angiogenesis. Real-time RT-PCR showed that ibuprofen altered the expression of several genes including Akt, P53, PCNA, Bax, and Bcl2 in the AGS cells. In addition, reduction in CD44 and OCT3/4 transcript levels revealed that ibuprofen reduces the stemness of the AGS cells and therefore it could be used as a potential anti-tumor drug.

Unraveling molecular similarities between colorectal polyps and colorectal cancer: a systems biology approach.

BACKGROUND/AIMS: Colorectal cancer (CRC) and colorectal polyps are intimately linked, with polyps acting as precursors to CRC. Understanding the molecular mechanisms governing their development is crucial for advancing diagnosis and treatment. Employing a systems biology approach, we investigated the molecular similarities between polyp and CRC. METHODS: We analyzed gene expression profiles, protein-protein interactions, transcription factors, and gene ontology to identify common differentially expressed genes (DEGs) and unravel shared molecular pathways. RESULTS: Our analysis revealed 520 commonly dysregulated genes in polyps and CRC, serving as potential biomarkers and pivotal contributors to disease progression. Gene ontology analysis elucidated distinct biological processes associated with upregulated and downregulated DEGs in both conditions, highlighting common pathways, including signal transduction, cell adhesion, and positive regulation of cell proliferation. Moreover, protein-protein interaction networks shed light on subnetworks involved in rRNA processing, positive regulation of cell proliferation, mRNA splicing, and cell division. Transcription factor analysis identified major regulators and differentially expressed transcription factors in polyp and CRC. Notably, we identified common differentially expressed transcription factors, including ZNF217, NR3C1, KLF5, GATA6, and STAT3, with STAT3 and NR3C1 exhibiting increased expression. CONCLUSIONS: This comprehensive analysis enriches our understanding of the molecular mechanisms underlying polyp formation and CRC development, providing potential targets for further investigation and therapeutic intervention. Our findings contribute substantively to crafting personalized strategies for refining the diagnosis and treatment of polyps and CRC.

Cell-cell communication in stem cells and cancer: Alone but in touch.

BACKGROUND: Cellular communication and signaling pathways are fundamental regulators of stem cell and cancer cell behaviors. This review explores the intricate interplay of these pathways in governing cellular behaviors, focusing on their implications for diseases, particularly cancer. OBJECTIVES: This comprehensive review aims to elucidate the significance of cellular signaling pathways in regulating the behavior of stem cells and cancer cells. It delves into the alterations in these pathways, their impact on cell fate, and their implications for developing diseases, notably cancer. The objective is to underscore the importance of understanding these signaling pathways for developing targeted therapeutic strategies. METHODS: The review critically analyzes existing literature and research findings concerning the roles of signaling pathways in stem cell behavior regulation, emphasizing their parallels and disparities in cancer cells. It synthesizes information on both direct and indirect modes of cell communication to delineate the complexity of signaling networks. RESULTS: Direct and indirect modes of cell communication intricately regulate the complex signaling pathways governing stem cell behaviors, influencing differentiation potential and tissue regeneration. Alterations in these pathways significantly impact stem cell fate, contributing to disease pathogenesis, including cancer. Understanding these signaling cascades offers insights into developing targeted therapies, particularly cancer treatment. CONCLUSION: Understanding the regulation of signaling pathways in stem cells and the specialized subset of cancer stem cells holds promise for innovative therapeutic approaches. By targeting aberrant signaling pathways, tailored interventions may improve treatment outcomes. This review underscores the critical role of signaling pathways in cellular behaviors, offering a pathway toward developing novel, more effective therapies for diverse diseases and disorders.

Identification of common factors among fibrosarcoma, rhabdomyosarcoma, and osteosarcoma by network analysis.

Sarcoma cancers are uncommon malignant tumors, and there are many subgroups, including fibrosarcoma (FS), which mainly affects middle-aged and older adults in deep soft tissues. Rhabdomyosarcoma (RMS), on the other hand, is the most common soft-tissue sarcoma in children and is located in the head and neck area. Osteosarcomas (OS) is the predominant form of primary bone cancer among young adults, primarily resulting from sporadically random mutations. This frequently results in the dissemination of cancer cells to the lungs, commonly known as metastasis. Mesodermal cells are the origin of sarcoma cancers. In this study, a rather radical approach has been applied. Instead of comparing homogenous cancer types, we focus on three main subtypes of sarcoma: fibrosarcoma, rhabdomyosarcoma, and osteosarcoma, and compare their gene expression with normal cell groups to identify the differentially expressed genes (DEGs). Next, by applying protein-protein interaction (PPI) network analysis, we determine the hub genes and crucial factors, such as transcription factors (TFs), affected by these types of cancer. Our findings indicate a modification in a range of pathways associated with cell cycle, extracellular matrix, and DNA repair in these three malignancies. Results showed that fibrosarcoma (FS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) had 653, 1270, and 2823 differentially expressed genes (DEGs), respectively. Interestingly, there were 24 DEGs common to all three types. Network analysis showed that the fibrosarcoma network had two sub-networks identified in FS that contributed to the catabolic process of collagen via the G-protein coupled receptor signaling pathway. The rhabdomyosarcoma network included nine sub-networks associated with cell division, extracellular matrix organization, mRNA splicing via spliceosome, and others. The osteosarcoma network has 13 sub-networks, including mRNA splicing, sister chromatid cohesion, DNA repair, etc. In conclusion, the common DEGs identified in this study have been shown to play significant and multiple roles in various other cancers based on the literature review, indicating their significance.

The Epigenetic Regulation of Quiescent in Stem Cells.

This review article discusses the epigenetic regulation of quiescent stem cells. Quiescent stem cells are a rare population of stem cells that remain in a state of cell cycle arrest until activated to proliferate and differentiate. The molecular signature of quiescent stem cells is characterized by unique epigenetic modifications, including histone modifications and deoxyribonucleic acid (DNA) methylation. These modifications play critical roles in regulating stem cell behavior, including maintenance of quiescence, proliferation, and differentiation. The article specifically focuses on the role of histone modifications and DNA methylation in quiescent stem cells, and how these modifications can be dynamically regulated by environmental cues. The future perspectives of quiescent stem cell research are also discussed, including their potential for tissue repair and regeneration, their role in aging and age-related diseases, and their implications for cancer research. Overall, this review provides a comprehensive overview of the epigenetic regulation of quiescent stem cells and highlights the potential of this research for the development of new therapies in regenerative medicine, aging research, and cancer biology.

A comprehensive analysis of transcriptomic data for comparison of plants with different photosynthetic pathways in response to drought stress.

The main factor leading to a decrease in crop productivity is abiotic stresses, particularly drought. Plants with C4 and CAM photosynthesis are better adapted to drought-prone areas than C3 plants. Therefore, it is beneficial to compare the stress response of plants with different photosynthetic pathways. Since most crops are C3 and C4 plants, this study focused on conducting an RNA-seq meta-analysis to investigate and compare how C3 and C4 plants respond to drought stress at the gene expression level in their leaves. Additionally, the accuracy of the meta-analysis results was confirmed with RT-qPCR. Based on the functional enrichment and network analysis, hub genes related to ribosomal proteins and photosynthesis were found to play a potential role in stress response. Moreover, our findings suggest that the low abundant amino acid degradation pathway, possibly through providing ATP source for the TCA cycle, in both groups of plants and the activation of the OPPP pathway in C4 plants, through providing the electron source required by this plant, can help to improve drought stress tolerance.