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Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing technology is the ideal tool of the future for treating diseases by permanently correcting deleterious base mutations or disrupting disease-causing genes with great precision and efficiency. A variety of efficient Cas9 variants and derivatives have been developed to cope with the complex genomic changes that occur during diseases. However, strategies to effectively deliver the CRISPR system to diseased cells in vivo are currently lacking, and nonviral vectors with target recognition functions may be the focus of future research. Pathological and physiological changes resulting from disease onset are expected to serve as identifying factors for targeted delivery or targets for gene editing. Diseases are both varied and complex, and the choice of appropriate gene-editing methods and delivery vectors for different diseases is important. Meanwhile, there are still many potential challenges identified when targeting delivery of CRISPR/Cas9 technology for disease treatment. This paper reviews the current developments in three aspects, namely, gene-editing type, delivery vector, and disease characteristics. Additionally, this paper summarizes successful examples of clinical trials and finally describes possible problems associated with current CRISPR applications.

Aminoacyl-tRNA synthetases (ARSs) are widely found in organisms, which can activate amino acids and make them bind to tRNA through ester bond to form the corresponding aminoyl-tRNA. The classic function of ARS is to provide raw materials for protein biosynthesis. Recently, emerging evidence demonstrates that ARSs play critical roles in controlling inflammation, immune responses, and tumorigenesis as well as other important physiological and pathological processes. With the recent development of genome and exon sequencing technology, as well as the discovery of new clinical cases, ARSs have been reported to be closely associated with a variety of cardiovascular diseases (CVDs), particularly angiogenesis and cardiomyopathy. Intriguingly, aminoacylation was newly identified and reported to modify substrate proteins, thereby regulating protein activity and functions. Sensing the availability of intracellular amino acids is closely related to the regulation of a variety of cell physiology. In this review, we summarize the research progress on the mechanism of CVDs caused by abnormal ARS function and introduce the clinical phenotypes and characteristics of CVDs related to ARS dysfunction. We also highlight the potential roles of aminoacylation in CVDs. Finally, we discuss some of the limitations and challenges of present research. The current findings suggest the significant roles of ARSs involved in the progress of CVDs, which present the potential clinical values as novel diagnostic and therapeutic targets in CVD treatment., Graphical abstract, Zou et al. reviewed the functional roles of aminoacyl-tRNA synthetases (ARSs) in cardiovascular diseases (CVDs) and discussed the involved molecular mechanisms. These reviews provide important insights into the potential value of ARS and provide potential diagnosis biomarker or therapeutic targets for CVDs, especially for angiogenesis and cardiomyopathy.

Our previous studies have shown that the Adipose‐derived mesenchymal stem cells (ADSCs) can regulate metastasis and development of ovarian cancer. However, its specific mechanism has yet to be fully revealed. In this study, an RNA‐seq approach was adopted to compare the differences in mRNA levels in ovarian cancer cells being given or not given ADSCs. The mRNA level of paired box 8 (PAX8) changed significantly and was confirmed as an important factor in tumour‐inducing effect of ADSCs. In comparison with the ovarian cancer cells cultured in the common growth medium, those cultured in the medium supplemented with ADSCs showed a significant increase of the PAX8 level. Moreover, the cancer cell growth could be restricted, even in the ADSC‐treated group (P

Background The treatment and prevention of perinatal venous thromboembolism (VTE) are challenging because of the potential for both fetal and maternal complications. Methods This study developed a rapid assessment scale for VTE and evaluate its validity based on Delphi-AHP (Analytic Hierarchy Process) method in China. The research was conducted by literature retrieval and two rounds of Delphi expert consultation. The item pools of the scale were developed and a questionnaire was designed according to literature retrieval published between 2010 and 2020. A survey was conducted among experts from 25 level A hospitals in China, and data of experts’ opinions were collected and analyzed by the Delphi method. Results A perinatal VTE risk assessment scale was formed, including 5 first-level items, 20 s-level items and 40 third-level items. The response rates in the two rounds of expert consultation were 97.4% and 98.0%, and the authoritative coefficients were 0.89 and 0.92. The coefficients of variation ranged from 0.04 to 0.28. Conclusions The scale is significantly valid and reliable with a high authority and coordination degree, and it can be used to assess the risk of perinatal VTE and initiate appropriate thrombophylactic interventions in China.

Accumulating evidence shows that tRNA-derived fragments are a novel class of functional small non-coding RNA; however, their roles in aortic dissection (AD) are still unknown. In this study, we found that 5′-tiRNA-Cys-GCA was significantly downregulated in human and mouse models of aortic dissection. The abnormal proliferation, migration, and phenotypic transition of vascular smooth muscle cells (VSMCs) played a crucial role in the initiation and progression of aortic dissection, with 5′-tiRNA-Cys-GCA as a potential phenotypic switching regulator, because its overexpression inhibited the proliferation and migration of VSMCs and increased the expression of contractile markers. In addition, we verified that signal transducer and activator of transcription 4 (STAT4) was a direct downstream target of 5′-tiRNA-Cys-GCA. We found that the STAT4 upregulation in oxidized low-density lipoprotein (ox-LDL)-treated VSMCs, which promoted cell proliferation, migration, and phenotypic transformation, was reversed by 5′-tiRNA-Cys-GCA. Furthermore, 5′-tiRNA-Cys-GCA treatment reduced the incidence and prevented the malignant process of angiotensin II- and β-aminopropionitrile-induced AD in mice. In conclusion, our findings reveal that 5′-tiRNA-Cys-GCA is a potential regulator of the AD pathological process via the STAT4 signaling pathway, providing a novel clinical target for the development of future treatment strategies for aortic dissection., Graphical abstract, Zong et al. explored the functional roles of 5′-tiRNA-Cys-GCA as a regulator of phenotypic transition of VSMC by targeting the STAT4 and discussed its protective roles in the onset and progression of aortic dissection. This study provides important insights into the potential value of tiRNAs and provides potential diagnosis biomarker or therapeutic targets for AD.

tsRNAs are small fragments of RNAs with specific lengths that are generated by particular ribonucleases, such as dicer and angiogenin (ANG), clipping on the rings of transfer RNAs (tRNAs) in specific cells and tissues under specific conditions. Depending on where the splicing site is, tsRNAs can be segmented into two main types, tRNA‐derived stress‐induced RNAs (tiRNAs) and tRNA‐derived fragments (tRFs). Many studies have shown that tsRNAs are functional molecules, not the random degradative products of tRNAs. Notably, due to their regulatory mechanism in regulating mRNA stability, transcription, ribosomal RNA (rRNA) synthesis and RNA reverse transcription, tsRNAs are significantly involved in the cell function, such as cell proliferation, migration, cycle and apoptosis, as well as the occurrence and development of a variety of diseases. In addition, tsRNAs may represent a new generation of clinical biomarkers or therapeutic targets because of their stable structures, high conservation and widely distribution, particularly in the peripheral tissues, bodily fluids and exosomes. In this review, we describe the generation, function and mechanism of tsRNAs and illustrate the current research progress of tsRNAs in various diseases, highlight their potentials as biomarkers and therapeutic targets in clinical application. Although our understanding of tsRNAs is still in infancy, the application prospects shown in this field deserve further exploration., tsRNAs are generated under stress condition which are functional molecules. Due to their regulatory mechanism in regulating mRNA stability, transcription, ribosomal RNA (rRNA) synthesis and RNA reverse transcription, tsRNAs are significantly involved in the cellular function, including cell proliferation, migration, cell cycle and apoptosis, as well as the occurrence and development of a variety of diseases.

Backgrounds Chronic inflammation in retinal pigment epithelial (RPE) cells is related to the pathogenesis of retinal inflammatory blind causing diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). Nepetin, a natural flavonoid compound, has shown potent anti-inflammatory activities but has not been studied on ocular resident cells yet. Here, we assess the ability of Nepetin to alleviate the inflammatory responses of ARPE-19 cells induced by interleukin (IL)-1β. Methods The secretion and mRNA expression of inflammatory cytokines IL-6, IL-8 and monocyte chemoattractant protein-1 (MCP-1) induced by IL-1β are measured by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR) respectively. To clarify the underlying action mechanism, we examine the effect of Nepetin on activation of nuclear factor of kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways using Western blot. Results Nepetin can significantly decrease the three inflammatory mediators at both protein and mRNA level in a dose-dependent manner. Western blot results show that Nepetin can decrease the nuclear translocation of p65 through suppressing phosphorylation of inhibitor of nuclear factor kappa B (IκB) and IκB kinase (IKK). Also, Nepetin can decrease the phosphorylation of extracellular signal-regulated kinases (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38 MAPK. Conclusions Taken together, Nepetin abolishes IL-1β-induced IL-6, IL-8 and MCP-1 secretion and mRNA expression by repressing the activation of NF-κB and MAPKs. These results indicate that Nepetin shows potential to be used for prevention and treatment of inflammatory retinal diseases or as a lead compound.

Deer antlers are amazing natural appendages that grow faster than any other known mammalian bone. Antler growth occurs at the tip and is initially cartilage, which is later replaced by bone tissue. However, little is known regarding the precise role of cooperation between cell lineages and functional genes in regulating antler growth, and molecular mechanisms responsible for rapid growth remain elusive. In this study, we use an RNA-Seq approach to elucidate the full spectrum of cell lineages, functional genes, and their cooperative interactions during antler growth. We identify Sox9 as a pivotal transcription factor during chondrogenesis and skeletal development expressed in the chondrocyte lineage from the multipotent mesenchymal precursor stage through most subsequent cell differentiation stages with a particularly strong activity in proliferating and prehypertrophic chondrocytes. Furthermore, we analyze the miRNA expression patterns at initial growth stage and rapid growth stage and identify several miRNAs that involve in regulating antler chondrogenesis and rapid growth. Among these miRNAs, miR-140 plays pivotal role during antler growth by targeting Sox9 and vice versa.

As a potent chemotherapeutic agent, doxorubicin (DOX) is widely used for the treatment of a variety of cancers However, its clinical utility is limited by dose-dependent cardiotoxicity, and pathogenesis has traditionally been attributed to the formation of reactive oxygen species (ROS). Accordingly, the prevention of DOX-induced cardiotoxicity is an indispensable goal to optimize therapeutic regimens and reduce morbidity. Acetylation is an emerging and important epigenetic modification regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs). Despite extensive studies of the molecular basis and biological functions of acetylation, the application of acetylation as a therapeutic target for cardiotoxicity is in the initial stage, and further studies are required to clarify the complex acetylation network and improve the clinical management of cardiotoxicity. In this review, we summarize the pivotal functions of HDACs and HATs in DOX-induced oxidative stress, the underlying mechanisms, the contributions of noncoding RNAs (ncRNAs) and exercise-mediated deacetylases to cardiotoxicity. Furthermore, we describe research progress related to several important SIRT activators and HDAC inhibitors with potential clinical value for chemotherapy and cardiotoxicity. Collectively, a comprehensive understanding of specific roles and recent developments of acetylation in doxorubicin-induced cardiotoxicity will provide a basis for improved treatment outcomes in cancer and cardiovascular diseases., Graphical abstract Image 1, Highlights • Cardiotoxicity caused by DOX is an important problem to be urgently solved in cancer treatment. • HDACs and HATs mediated-cell death, oxidative stress and inflammation plays a pivotal role in DOX-induced cardiotoxicity. • Noncoding RNA mediates HDACs to provide novel insights for the development of treatments for DOX-induced cardiotoxicity. • SIRT activators and HDAC inhibitors are promising drug approaches to attenuate DOX-induced cardiotoxicity.

This paper studies a group of female sex workers and their ambivalent experiences of home in Dongguan, China’s so-called sin city, before the local government technically cracked down on the city’s...

Background Our previous study showed that human omental adipose-derived stem cells (ADSCs) promote ovarian cancer growth and metastasis. In this study, the role of autophagy in the ovarian cancer-promoting effects of omental ADSCs was further determined. Methods The growth and invasion of ovarian cancer cells were detected by CCK-8 and Transwell assays, respectively. The autophagy of ovarian cancer cells transfected with MRFP-GFP-LC3 adenoviral vectors was evaluated by confocal microscopy and western blot assay. Transfection of STAT3 siRNA was used to inhibit the expression of STAT3. Results Our results show that autophagy plays a vital role in ovarian cancer and is promoted by ADSCs. Specifically, we show that proliferation and invasion are correlated with autophagy induction by ADSCs in two ovarian cancer cell lines under hypoxic conditions. Mechanistically, ADSCs activate the STAT3 signalling pathway, thereby promoting autophagy. Knockdown of STAT3 expression using siRNA decreased hypoxia-induced autophagy and decreased the proliferation and metastasis of ovarian cancer cells. Conclusion Taken together, our data indicate that STAT3-mediated autophagy induced by ADSCs promotes ovarian cancer growth and metastasis.

Antler growth is a unique event compared to other growth and development processes in mammals. Antlers grow extremely fast during the rapid growth stage when growth rate peaks at 2 cm per day. Antler growth is driven by a specific endochondral ossification process in the growth center that is in the distal region of the antler tip. In this study, we used state-of-art RNA-seq technology to analyze the expression profiles of mRNAs and miRNAs during antler growth. Our results indicated that the expression levels of multiple genes involved in chondrogenesis and endochondral ossification, including Fn1, Sox9, Col2a1, Acan, Col9a1, Col11a1, Hapln1, Wwp2, Fgfr3, Comp, Sp7 and Ihh, were significantly increased at the rapid growth stage. Our results also indicated that there were multiple differentially expressed miRNAs interacting with differentially expressed genes with opposite expression patterns. Furthermore, some of the miRNAs, including miR-3072-5p, miR-1600, miR-34-5p, miR-6889-5p and miR-6729-5p, simultaneously interacted with and controlled multiple genes involved in the process of chondrogenesis and endochondral ossification. Therefore, we established a miRNA-mRNA regulatory network by identifying miRNAs and their target genes that were differentially expressed in the antler growth centers by comparing the rapid growth stage and the initial growth stage.

Deer antlers are amazing appendages with the fastest growth rate among mammalian organs. Antler growth is driven by the growth center through a modified endochondral ossification process. Thus, identification of signaling pathways functioning in antler growth center would help us to uncover the underlying molecular mechanism of rapid antler growth. Furthermore, exploring and dissecting the molecular mechanism that regulates antler growth is extremely important and helpful for identifying methods to enhance long bone growth and treat cartilage- and bone-related diseases. In this study, we build a comprehensive intercellular signaling network in antler growth centers from both the slow growth stage and rapid growth stage using a state-of-art RNA-Seq approach. This network includes differentially expressed genes that regulate the activation of multiple signaling pathways, including the regulation of actin cytoskeleton, calcium signaling, and adherens junction. These signaling pathways coordinately control multiple biological processes, including chondrocyte proliferation and differentiation, matrix homeostasis, mechanobiology, and aging processes, during antler growth in a comprehensive and efficient manner. Therefore, our study provides novel insights into the molecular mechanisms regulating antler growth and provides valuable and powerful insight for medical research on therapeutic strategies targeting skeletal disorders and related cartilage and bone diseases.

Endometrial cancer is the most common gynaecological cancer, and its incidence is increasing. Obesity is a well-recognized risk factor for endometrial cancer, and the mechanisms by which adipose tissue influences tumour development remain controversial. In this study, we examined the high IL-6 level in the ADSCs supernatant following treatment of endometrial cancer cell CM. Then, the activation of STAT3, a major tumourigenic IL-6 effector, was examined in ADSCs CM treated endometrial cancer cells. Conditioned ADSC medium was used to stimulate endometrial cancer cell growth in vitro. Similar to IL-6, ADSC-conditioned medium significantly promoted endometrial cancer growth and invasion. Furthermore, siRNA-mediated STAT3 inhibition in endometrial cancer cells decreased the ADSC-mediated promotion of cell proliferation and invasion. In addition, a subcutaneous nude mouse model of endometrial cancer was established to monitor the tumour-promoting effect of ADSCs. ADSC-conditioned medium promoted tumour growth, and STAT3 inhibition attenuated this effect. Based on these data, ADSCs promote endometrial cancer progression by the STAT3 signalling pathway.

BACKGROUND The study aimed to investigate the clinical value of velocity vector imaging (VVI) in assessing heart function in fetuses of pregnant women with thyroid dysfunction. The inter-observer and intra-observer variability was assessed for all VVI parameters observed. MATERIAL AND METHODS The participants were enrolled from singleton pregnant women with gestational ages ranging 24+0 to 40+1 weeks who visited the Department of Obstetrics and Gynecology at the Affiliated Hospital of Qingdao University, China, for prenatal care from July 2011 to February 2014. Digital 2-dimensional (2D) dynamic 4-chamber images of the heart were collected. A total of qualified 226 images from 125 fetuses of pregnant women with normal thyroid (control group), 64 fetuses of pregnant women with hypothyroidism (hypothyroidism group), and 37 fetuses of pregnant women with hyperthyroidism (hyperthyroidism group) were interrogated offline using VVI software. The echocardiographic parameters including the myocardium peak systolic velocity (Vs), peak diastolic velocity (Vd), peak systolic strain (S), peak systolic strain rate (SRs), peak diastolic strain rate (SRd) of RV and LV, were obtained from the velocity curves of 2D myocardial motion. The heart rate was measured using a virtual M-mode algorithm built into the software. RESULTS The study found that the longitudinal Vs and Vd of both ventricles in the control group gradually decreased from basal segments to apical segments and significantly increased over the gestation. S, SRs, and SRd of both ventricles remained stable after middle gestation. Compared with the control group, the hypothyroidism and hyperthyroidism groups exhibited significantly reduced S, SRs, and SRd, even for fetuses at 24-weeks gestation. There were no significant differences in global Vs and global Vd between the control group and the hyperthyroidism or hypothyroidism groups. CONCLUSIONS The thyroid dysfunction of pregnant women may damage fetal heart function, and VVI could be a sensitive technique to measure the variation of fetal heart function.

The Sika deer antler is well known for its unique ability to regenerate repeatedly and grow rapidly. Furthermore, it is a precious traditional Chinese medicine and has been widely used for more than 20 centuries. The major bioactive components within the antlers are water-soluble proteins, polypeptides, and free amino acids. Many studies have shown that water-soluble antler extracts play pivotal roles in wound healing, immune system modulation, anti-oxidation, and anti-inflammation. However, the exact effects on chondrocytes are still largely unknown. In this study, we prepared fresh, aqueous extracts from growing deer antlers in a rapid growth stage. We isolated the chondrocytes from neonatal mouse rib cartilage and investigated the effects of antler extracts on chondrocyte viability. We also used the RNA-Seq method to analyze the gene expression pattern under antler extract treatment. We demonstrated that fresh extracts from Sika deer antlers in a rapid growth stage significantly promoted chondrocyte viability and kept chondrocytes proliferating continuously, while blocking maturation and further differentiation. Additionally, our results indicated that antler extracts might serve as a potent anti-oxidant, anti-inflammatory agent, and immune modulator to boost the abilities of chondrocytes against oxidative, inflammatory, and immune stresses. Thus, this study has greatly deepened our current knowledge of the molecular control of antler extracts on chondrocytes. It has also shed light on possible new strategies to further prevent and treat diseases of cartilage and other related diseases.

Objective: To evaluate the value of two-dimensional strain rate imaging (STE) in detecting the alteration of regionally left ventricular long-axis systolic function in patients with slow coronary flow (SCF). Methods: 24 patients who were with SCF but without significant coronary artery stenosis in LAD were included in left anterior descending artery (LAD) group, and 15 patients with slow flow in right coronary artery (RCA) were included in RCA group, and 20 patients who were without significant coronary stenosis or abnormal corrected thrombolysis in myocardial infarction frame count (CTFC) were included in control group. CTFC was carried on 3 groups. Peak systolic strain rate (PSRs) were measured at basal, middle and apical segments in left ventricular walls, including the septal, lateral, inferior and anterior. Results: CTFC of left anterior descending coronary artery blood flow (39.88 ± 7.48) was significantly higher in LAD group than control group (19.84 ± 5.91, P

The health status of Naolihe Basin has already varied significantly affected by the climate change and human activity. Therefore, it is reasonably much important to analyze and evaluate the health status of river, which could provide basis for the comprehensive development and protection in the Naolihe Basin. So, this paper takes Baoqing country as the study region, uses the stable state, the harmonious degree and evolution rate to describe the health status, and establishes the health evaluation index system of water-based system in Baoqing country based on the concept of water-based system. The entropy method is used to the weight vector of steady state index and harmonious degree index, the TOPSIS was applied to analysis the health status of water-based system of Baoqing country during 2005 to 2009. The comprehensive evaluation result shows that the water-based system of Baoqing country is in the state of comparative healthy, the main reason is that water resources of the study area are relatively insufficient, and drinking water security and water consumption cannot obtain the complete guarantee, which leads to lower steady state.