Frontiers in Cell and Developmental Biology
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Published By Frontiers Media Sa

Updated Friday, 03 December 2021

Peijie Wu ◽  
Ling Qiao ◽  
Han Yu ◽  
Hui Ming ◽  
Chao Liu ◽  

Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos, which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α-naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.

Yang Wang ◽  
Jing Tan ◽  
Lu Wang ◽  
Gaiqin Pei ◽  
Hongxin Cheng ◽  

Cardiovascular and cerebrovascular diseases are a serious threaten to the health of modern people. Understanding the mechanism of occurrence and development of cardiovascular and cerebrovascular diseases, as well as reasonable prevention and treatment of them, is a huge challenge that we are currently facing. The miR-125 family consists of hsa-miR-125a, hsa-miR-125b-1 and hsa-miR-125b-2. It is a kind of miRNA family that is highly conserved among different species. A large amount of literature shows that the lack of miR-125 can cause abnormal development of the cardiovascular system in the embryonic period. At the same time, the miR-125 family participates in the occurrence and development of a variety of cardiovascular and cerebrovascular diseases, including myocardial ischemia, atherosclerosis, ischemia-reperfusion injury, ischemic stroke, and heart failure directly or indirectly. In this article, we summarized the role of the miR-125 family in the development and maturation of cardiovascular system, the occurrence and development of cardiovascular and cerebrovascular diseases, and its important value in the current fiery stem cell therapy. In addition, we presented this in the form of table and diagrams. We also discussed the difficulties and challenges faced by the miR-125 family in clinical applications.

Yuanyuan Li ◽  
Ning-Hua Mei ◽  
Gui-Ping Cheng ◽  
Jing Yang ◽  
Li-Quan Zhou

Mitochondrion plays an indispensable role during preimplantation embryo development. Dynamic-related protein 1 (DRP1) is critical for mitochondrial fission and controls oocyte maturation. However, its role in preimplantation embryo development is still lacking. In this study, we demonstrate that inhibition of DRP1 activity by mitochondrial division inhibitor-1, a small molecule reported to specifically inhibit DRP1 activity, can cause severe developmental arrest of preimplantation embryos in a dose-dependent manner in mice. Meanwhile, DRP1 inhibition resulted in mitochondrial dysfunction including decreased mitochondrial activity, loss of mitochondrial membrane potential, reduced mitochondrial copy number and inadequate ATP by disrupting both expression and activity of DRP1 and mitochondrial complex assembly, leading to excessive ROS production, severe DNA damage and cell cycle arrest at 2-cell embryo stage. Furthermore, reduced transcriptional and translational activity and altered histone modifications in DRP1-inhibited embryos contributed to impeded zygotic genome activation, which prevented early embryos from efficient development beyond 2-cell embryo stage. These results show that DRP1 inhibition has potential cytotoxic effects on mammalian reproduction, and DRP1 inhibitor should be used with caution when it is applied to treat diseases. Additionally, this study improves our understanding of the crosstalk between mitochondrial metabolism and zygotic genome activation.

Jeremy Kah Sheng Pang ◽  
Beatrice Xuan Ho ◽  
Woon-Khiong Chan ◽  
Boon-Seng Soh

Medical research in the recent years has achieved significant progress due to the increasing prominence of organoid technology. Various developed tissue organoids bridge the limitations of conventional 2D cell culture and animal models by recapitulating in vivo cellular complexity. Current 3D cardiac organoid cultures have shown their utility in modelling key developmental hallmarks of heart organogenesis, but the complexity of the organ demands a more versatile model that can investigate more fundamental parameters, such as structure, organization and compartmentalization of a functioning heart. This review will cover the prominence of cardiac organoids in recent research, unpack current in vitro 3D models of the developing heart and look into the prospect of developing physiologically appropriate cardiac organoids with translational applicability. In addition, we discuss some of the limitations of existing cardiac organoid models in modelling embryonic development of the heart and manifestation of cardiac diseases.

Minglei Zhao ◽  
Tingfang Mei ◽  
Bizhi Shang ◽  
Bin Zou ◽  
Qing Lian ◽  

Congenital cataract is one of the leading causes of blindness in children worldwide. About one-third of congenital cataracts are caused by genetic defects. LSS, which encodes lanosterol synthase, is a causal gene for congenital cataracts. LSS is critical in preventing abnormal protein aggregation of various cataract-causing mutant crystallins; however, its roles in lens development remain largely unknown. In our study, we generated a mouse model harboring Lss G589S mutation, which is homologous to cataract-causing G588S mutation in human LSS. LssG589S/G589S mice exhibited neonatal lethality at postal day 0 (P0), whereas these mice showed severe opacity in eye lens. Also, we found that cataract was formed at E17.5 after we examined the opacity of embryonic lens from E13.5 to E18.5. Moreover, disrupted lens differentiation occurred at E14.5 prior to formation of the opacity of eye lens, shown as delayed differentiation of lens secondary fiber and disordered lens fiber organization. In addition, RNA-seq analysis indicated that cholesterol synthesis signaling pathways were significantly downregulated. Overall, our findings provide clear evidence that a mouse model harboring a homozygous Lss G589S mutation can recapitulate human congenital cataract. Our study points out that LSS functions as a critical determinant of lens development, which will contribute to better understanding LSS defects in cataractogenesis and developing therapies for cataracts.

Bingyi Zhou ◽  
Deliang Liu ◽  
Yuyong Tan

Worldwide, cancer is the second leading cause of mortality after cardiovascular diseases. Among the numerous malignant tumors in human, digestive system cancers are the primary cause of morbidity and mortality. Acetylation and deacetylation are crucially involved in cancer occurrence and development; in addition, the deacetylation process is regulated by histone deacetylases (HDACs). Among the 18 human HDACs that have been reported, HDAC6 has been widely studied. There is upregulated HDAC6 expression in numerous types of tumor tissues and is closely associated with clinicopathological characteristics. Moreover, several HDAC6 inhibitors have been identified; furthermore, there has been extensive research on their ability to inhibit the growth of many tumors. This review summarizes the roles of HDAC6 in different primary digestive system malignancies.

Antonia Malinova ◽  
Lisa Veghini ◽  
Francisco X. Real ◽  
Vincenzo Corbo

Infidelity to cell fate occurs when differentiated cells lose their original identity and either revert to a more multipotent state or transdifferentiate into a different cell type, either within the same embryonic lineage or in an entirely different one. Whilst in certain circumstances, such as in wound repair, this process is beneficial, it can be hijacked by cancer cells to drive disease initiation and progression. Cell phenotype switching has been shown to also serve as a mechanism of drug resistance in some epithelial cancers. In pancreatic ductal adenocarcinoma (PDAC), the role of lineage infidelity and phenotype switching is still unclear. Two consensus molecular subtypes of PDAC have been proposed that mainly reflect the existence of cell lineages with different degrees of fidelity to pancreatic endodermal precursors. Indeed, the classical subtype of PDAC is characterised by the expression of endodermal lineage specifying transcription factors, while the more aggressive basal-like/squamous subtype is defined by epigenetic downregulation of endodermal genes and alterations in chromatin modifiers. Here, we summarise the current knowledge of mechanisms (genetic and epigenetic) of cell fate switching in PDAC and discuss how pancreatic organoids might help increase our understanding of both cell-intrinsic and cell-extrinsic factors governing lineage infidelity during the distinct phases of PDAC evolution.

Ana Coto-Montes ◽  
Laura González-Blanco ◽  
Eduardo Antuña ◽  
Iván Menéndez-Valle ◽  
Juan Carlos Bermejo-Millo ◽  

Biomarkers are essential tools for accurate diagnosis and effective prevention, but their validation is a pending challenge that limits their usefulness, even more so with constructs as complex as frailty. Sarcopenia shares multiple mechanisms with frailty which makes it a strong candidate to provide robust frailty biomarkers. Based on this premise, we studied the temporal evolution of cellular interactome in frailty, from independent patients to dependent ones. Overweight is a recognized cause of frailty in aging, so we studied the altered mechanisms in overweight independent elderly and evaluated their aggravation in dependent elderly. This evidence of the evolution of previously altered mechanisms would significantly support their role as real biomarkers of frailty. The results showed a preponderant role of autophagy in interactome control at both different functional points, modulating other essential mechanisms in the cell, such as mitochondrial capacity or oxidative stress. Thus, the overweight provoked in the muscle of the elderly an overload of autophagy that kept cell survival in apparently healthy individuals. This excessive and permanent autophagic effort did not seem to be able to be maintained over time. Indeed, in dependent elderly, the muscle showed a total autophagic inactivity, with devastating effects on the survival of the cell, which showed clear signs of apoptosis, and reduced functional capacity. The frail elderly are in a situation of weakness that is a precursor of dependence that can still be prevented if detection is early. Hence biomarkers are essential in this context.

Shilang Xiao ◽  
Xiaoming Liu ◽  
Lingzhi Yuan ◽  
Fen Wang

Background: Accumulating literature demonstrates that long noncoding RNAs (lncRNAs) are involved in ferroptosis and gastric cancer progression. However, the predictive value of ferroptosis-related lncRNAs for prognosis and therapeutic response is yet to be elucidated in gastric cancer (GC).Method: The transcriptomic data and corresponding clinical information of GC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database. The association between ferroptosis-related lncRNAs and ferroptosis regulators was analyzed by Spearman correlation analysis. Then, we established a risk predictive model based on the ferroptosis-related lncRNAs using multivariate Cox regression analysis. Furthermore, we performed correlation analysis for the risk score and characteristics of biological processes, immune landscape, stromal activity, genomic integrity, drug response, and immunotherapy efficacy.Results: We constructed a 17-ferroptosis-related-lncRNA signature via multivariate Cox analysis to divide patients into two groups: low- and high-risk groups. The low-risk group was linked to prolonged overall survival and relapse-free survival. The risk score had good predictive ability to predict the prognosis of GC patients compared with other clinical biomarkers. We found that the high-risk group was associated with activation of carcinogenetic signaling pathways, including stromal activation, epithelial-mesenchymal-transition (EMT) activation, and immune escape through integrated bioinformatics analysis. In contrast, the low-risk group was associated with DNA replication, immune-flamed state, and genomic instability. Additionally, through Spearman correlation analysis, we found that patients in the high-risk group may respond well to drugs targeting cytoskeleton, WNT signaling, and PI3K/mTOR signaling, and drugs targeting chromatin histone acetylation, cell cycle, and apoptosis regulation could bring more benefits for the low-risk group. The high-risk group was associated with poor immunotherapy efficacy.Conclusion: Our study systematically evaluated the role of ferroptosis-related lncRNAs in t tumor microenvironment, therapeutic response, and prognosis of GC. Risk score–based stratification could reflect the characteristic of biological processes, immune landscape, stromal activity, genomic stability, and pharmaceutical profile in GC patients. The ferroptosis-related lncRNA signature could serve as a reliable biomarker to predict prognosis and therapeutic response of patients with GC.

Na Wang ◽  
Qian Yang ◽  
Jialin Wang ◽  
Rui Shi ◽  
Ming Li ◽  

Sexual size dimorphism (SSD) is the difference in segments or body size between sexes prevalent in various species. Understanding the genetic architecture of SSD has remained a significant challenge owing to the complexity of growth mechanisms and the sexual influences among species. The Chinese tongue sole (Cynoglossus semilaevis), which exhibits a female-biased SSD and sex reversal from female to pseudomale, is an ideal model for exploring SSD mechanism at the molecular level. The present study aimed to integrate transcriptome and methylome analysis to unravel the genetic and epigenetic changes in female, male, and pseudomale C. semilaevis. The somatotropic and reproductive tissues (brain, liver, gonad, and muscle) transcriptomes were characterized by RNA-seq technology. Transcriptomic analysis unravelled numerous differentially expressed genes (DEGs) involved in cell growth and death-related pathways. The gonad and muscle methylomes were further employed for screening differentially methylated genes (DMGs). Relatively higher DNA methylation levels were observed in the male and pseudomale individuals. In detail, hypermethylation of the chromosome W was pronounced in the pseudomale group than in the female group. Furthermore, weighted gene co-expression network analysis showed that turquoise and brown modules positively and negatively correlated with the female-biased SSD, respectively. A combined analysis of the module genes and DMGs revealed the female-biased mRNA transcripts and hypomethylated levels in the upstream and downstream regions across the cell cycle-related genes. Moreover, the male and pseudomale-biased gene expression in the hippo signaling pathway were positively correlated with their hypermethylation levels in the gene body. These findings implied that the activation of the cell cycle and the inhibition of the hippo signaling pathway were implicated in C. semilaevis female-biased SSD. In addition, the dynamic expression pattern of the epigenetic regulatory factors, including dnmt1, dnmt3a, dnmt3b, and uhrf1, among the different sexes correspond with their distinct DNA methylation levels. Herein, we provide valuable clues for understanding female-biased SSD in C. semilaevis.

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