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The response mechanism and interaction patterns of HIF-1α and p53 in animals in an hypoxic environment are crucial for their hypoxic tolerance and adaptation. Many studies have shown that underground rodents have better hypoxic adaptation characteristics. However, the mechanism by which HIF-1α and p53 in underground rodents respond to hypoxic environments compared with in ground rodents remains unclear. Further, whether a synergy between HIF-1α and p53 enables animals tolerate extremely hypoxic environments is unclear. We studied HIF-1α and p53 expression in the brain tissue and cell apoptosis in the hippocampal CA1 region during 6 hours of acute hypoxia (5% oxygen) in Lasiopodomys mandarinus (Milne-Edwards, 1871) and Lasiopodomys brandtii (Radde, 1861), two closely related small rodents with different life characteristics (underground and aboveground, respectively), using a comparative biology method to determine the mechanisms underlying their adaptation to this environment. Our results indicate that HIF-1α and p53 expression is more rapid in L. mandarinus than in L. brandtii under acute hypoxic environments, resulting in a significant synergistic effect in L. mandarinus. Correlation analysis revealed that HIF-1α expression and the apoptotic index of the hippocampal CA1 regions of the brain tissues of L. mandarinus and L. brandtii, both under hypoxia, were significantly negatively and positively correlated, respectively. Long-term existence in underground burrow systems could enable better adaptation to hypoxia in L. mandarinus than in L. brandtii. We speculate that L. mandarinus can quickly eliminate resulting damage via the synergistic effect of p53 and HIF-1α in response to acute hypoxic environments, helping the organism quickly return to a normal state after the stress.

N6-methyladenosine (m6A) is the most abundant inner RNA modification in eukaryotes. Due to the development of RNA sequencing technology, the distribution pattern of m6A in the transcriptome has been uncovered. Dynamically, the reversible N6-methylation is mediated by two types of proteins, which are classified as “writers” and “erasers”. Under the association of specific co-factors, writers show spatiotemporal N6-methyltransferase activity. Mechanically, m6A can be recognized by “reader” proteins or can directly modify RNA conformation, and it widely affects gene expression by mediating RNA stability, translation, splicing and export. m6A is involved in a series of physiology processes. Dysregulation of m6A is gradually defined as the pathogenesis of some diseases, e.g., cancer and cardiovascular disease. Therefore, a good understanding of m6A is essential for molecular biology and pathology research. In this article we systemically present an overview of the functions and mechanisms of identified m6A regulators. The discovered biological and pathological processes affected by m6A are also summarized. We hope that readers with related research interests benefit from our review.

Although the number of robotic hepatectomy (RH) performed is increasing, few studies have reported its efficacy in comparison with the conventional surgical modalities. The aim of this meta-analysis was to evaluate the perioperative results of RH vs. open hepatectomy (OH) and RH vs. laparoscopic hepatectomy (LH). We systematically searched for English papers published in PubMed (Medline), Embase, and Cochrane library before March 1, 2020. A total of 39 papers and 2999 patients were eventually included. Among the included patients, 1249, 1010, and 740 underwent RH, LH, and OH, respectively. Compared with OH, the operation time was significantly increased but the intraoperative blood loss, blood transfusion rate, incidence of severe complications, and length of postoperative hospitalization were significantly reduced in patients with RH. However, there was no significant difference in the use of Pringle maneuver and overall incidence of complications. Compared with LH, the operation time was significantly increased, and the intraoperative blood loss was also more in RH. However, there were no differences in blood transfusion rate, use of Pringle maneuver, incidence of complications, incidence of severe complications, and length of postoperative hospitalization between the two groups. A longer operation time remains the main shortcoming of RH. However, based on the perioperative clinical efficacy, we conclude that RH is comparable to LH but is better than OH for selected patients.

Aims In response to vascular injury, vascular smooth muscle cells (VSMC) may change from a contractile phenotype to a proliferative phenotype and consequently become conducive to neointima formation. Apoptosis repressor with caspase recruitment domain (ARC) was initially discovered as an endogenous apoptosis inhibitor, but whether ARC plays a role in VSMCs and whether it can participate in the regulation of atherosclerosis are unknown. Methods and results Protein and mRNA levels of ARC in tissues and cells were detected by western blot and quantitative real-time PCR. Immunofluorescence staining was used to detect the protein location, and immunohistochemistry was used to detect protein expression in tissues. VSMC proliferation was analysed using Cell Counting Kit-8 (CCK-8) and EdU assays, while migration was assessed by Transwell assay. Mechanistically, the direct binding between two proteins was verified by immunoprecipitation. We found that ARC expression was stimulated in VSMCs during cell proliferation. Our results also showed that ARC promoted cell proliferation and induced phenotypic modulation of VSMCs in vitro and vivo. Mechanistic studies demonstrated that ARC increased the nuclear localization of Yes associated protein (YAP) by binding to 14-3-3e and that ARC played a role in promoting cell proliferation and phenotypic modulation. Additionally, the transcription factor p53 negatively regulated ARC expression at the transcriptional level during cell proliferation and phenotypic modulation. Conclusions Our findings define a novel role for ARC in the phenotypic transition of proliferating VSMCs, which may provide a new strategy for regulating neointimal formation.

Glenoid bony lesions play a role in approximately half of anterior shoulder instability cases. The purpose of this study is to see if the anatomy of the coracoid affects the location of glenoid rim defects. We hypothesized that a prominent coracoid (lower and lateral) would be more likely to cause an anterior–inferior glenoid lesion, and a less prominent coracoid more prone to cause an anterior lesion. The null hypothesis being the absence of correlation. Fifty-one shoulder CT-scans from a prospective database, with 3D reconstruction, were analyzed. The position of glenoid lesions was identified using the validated clock method, identifying the beginning and end time. The size of bony glenoid defects was calculated using the validated glenoid ratio method. The position of the coracoid tip was measured in three orthogonal planes. Analysis included 25 right shoulders and 26 left shoulders in seven females and 41 males. The vertical position of the coracoid tip relative to the top of the glenoid was highly correlated to the location of the glenoid defect on the profile view (r = −0.625; 95% CI 0.423–0.768; p = 0.001). Thus, higher coracoids were associated with anterior lesions, while lower coracoids were associated with anterior–inferior lesions. A more laterally prominent coracoid was also correlated with anterior–inferior lesions (r = 0.433; 95% CI 0.179–0.633; p = 0.002). This study shows that coracoid anatomy affects the location of bony Bankart defects in anterior shoulder instability. Lower and laterally prominent coracoids are associated with anterior–inferior lesions. This variation in anatomy should be considered during pre-op planning for surgeries involving bone graft. Level 4 basic science.

Purpose To investigate the risk factors associated with retinal detachment recurrence after first vitrectomy in high myopic eyes with macular hole retinal detachment (MHRD). Methods Patients with high myopic eyes with MHRD who underwent pars plana vitrectomy and silicone oil (SO) tamponade with a follow-up period more than 12 months and more than 3 months after SO removal were included in this retrospective study. Logistic regression was performed to determine the risk factors associated with retinal re-detachment. Results A total of 45 eyes from 43 patients were included in this study (11 male and 34 female patients). The retinal re-detachment rate after the first removal of silicon oil was 35.5% (16/45) in a mean postoperative follow-up time of 35.64 ± 32.94 months. Complete macular atrophy on fundus photography (odds ratio (OR) = 17.021, 95% confidence interval (95% CI): 2.218-130.609, p = 0.006) was a risk factor for MHRD after SO removal, while internal limiting membrane (ILM) peeling (OR = 0.091, 95% CI: 0.013-0.633, p = 0.015) and duration of SO tamponade (OR = 0.667, 95% CI: 0.454-0.980, p = 0.039) were protective factors. Conclusion For high myopic eyes with MHRD, complete macular atrophy was a significant risk factor for retinal re-detachment after silicon oil removal. ILM peeling and the duration of silicon oil tamponade were protective factors.

Purpose To compare the anatomic results of optical coherence tomography angiography (OCTA)-guided half-dose photodynamic therapy (PDT) versus indocyanine green angiography (ICGA)-guided PDT in eyes with acute central serous chorioretinopathy. Methods This study is a prospective, single-center, noninferiority, double-masked, randomized, controlled clinical trial. Fifty-one eyes of 45 patients with acute central serous chorioretinopathy were recruited, and randomized to an ICGA-guided group and an OCTA-guided group. The primary outcome measures were the rates of complete subretinal fluid (SRF) resolution at 1 month and 3 months. Results Forty-six eyes of 40 patients finished the follow-up and were analyzed. In the OCTA-guided group, the SRF was completely resolved in 13 (56.5%) eyes within 1 month and in 21 (91.3%) eyes within 3 months. In the ICGA-guided group, the SRF was resolved in 16 (69.6%) of the eyes within 1 month and in 22 (95.7%) of the eyes by 3 months. Optical coherence tomography angiography-guided PDT was demonstrated noninferior to ICGA-guided PDT for SRF resolution rate at 3 months (P = 0.016), but not at 1 month (P = 0.311) for acute central serous chorioretinopathy patients. Subretinal fluid did not recur in any of the eyes in the OCTA-guided group, but did recur in 2 eyes (8.7%) of the ICGA-guided group during the 3-month follow-up period. Conclusion Optical coherence tomography angiography-guided PDT seemed to be noninferior to ICGA-guided PDT for resolution of SRF at 3 months in eyes with acute central serous chorioretinopathy.

Site-specific fluorescent labeling of RNA is crucial for obtaining the structural and dynamic information of RNAs by fluorescence techniques. Post-synthetic modification of RNA based on N-hydroxysuccinimide (NHS) coupling reaction is an economic, efficient and simple strategy to introduce fluorophore to samples. However, this strategy are not that frequently used in RNA molecules, and the reported reaction conditions and yields varied among different systems. This study results mainly focused on screening the reaction conditions (reactants concentrations, dimethylsulfoxide concentration, solution conditions, pH and reaction time) between NHS-linked fluorophore and aminoallyl-RNA (aa-RNA) to optimize the yield of fluorescent RNA up to 55%, doubled the initial yield. What’s more, as low as one tenth of fluorescent reagent was used in our protocol compared with the reported protocols, greatly reducing the experimental cost. The protocol can be applied as a general guide potentially for RNA labeling by NHS-ester coupling reaction., Graphical Abstract

Cadmium (Cd) is a well-known toxic metal element that is largely distributed in the environment. Cd causes toxicity to most organs. Accumulating evidence suggests that Cd exposure is associated with islet dysfunction and development of diabetes, but the association remains controversial. The aim of this study is to evaluate the possible effects of chronic Cd exposure on glucose metabolism in male C57BL/6 mice. Mice were intraperitoneally injected with CdCl2solution (1 mg.kg−1) twice a week for 24 weeks. Fasting blood glucose (FBG) levels and body weights were measured weekly. After 24 weeks, the intraperitoneal glucose tolerance test (IPGTT), intraperitoneal insulin tolerance test (IPITT), and fasting serum insulin (FSI) level test were performed. The insulin resistance index (HOMA-IR) and pancreaticβcell function index (HOMA-β) were calculated and analyzed. The expression of insulin receptor (IR) in mouse liver was detected by real-time PCR. Pancreatic tissue was collected for histological examination. The results demonstrated that FBG, IPGTT, HOMA-IR, and HOMA-βwere identical between Cd exposure and control mice. In contract, mean fasting serum insulin level, area under the curve (AUC) of IPITT, and IR expression in livers of Cd-exposed mice decreased significantly compared with control mice. Cd administration induced islet atrophy and decreased islet area. The results suggested that Cd exposure decreased insulin secretion and maintained glucose homeostasis in male C57BL/6 mice and that pancreatic functions should be monitored in populations chronically exposed to Cd.

Yogurt is a popular product worldwide partly because of the health-promoting effects of the probiotics that it contains. Probiotics with high survivability constitute a promising direction for fortified yogurt products. This study aimed to prepare Bifidobacterium breve-loaded yogurt with the bacteria surviving transit to the lower part of small intestine or colon. Bifidobacterium breve beads were prepared through an ion-crosslinking method using low methoxyl pectin as the encapsulating material. Features such as encapsulation efficiency and stability during storage and passage through the simulated gastrointestinal tract were studied in vitro. A commercial starter was used for yogurt fermentation, and B. breve with or without encapsulation was added as a probiotic supplement with the starter or 3 to 4 h after fermentation. The effects of B. breve beads on yogurt characteristics were evaluated after different fermentation processes: BC, milk fermented with marketed yogurt starter; UBFF, unencapsulated B. breve added to fresh milk and then fermented; EBFF, encapsulated B. breve added to fresh milk and then fermented; UBAF, unencapsulated B. breve added after fermentation with the starter; and EBAF, encapsulated B. breve beads added 3 to 4 h after fermentation with the starter. Evaluation was based on texture, electronic nose, and electronic tongue analyses. The particle size analysis of B. breve beads showed that they were uniform, mostly spherical, 1 to 1.5 mm in diameter with encapsulating efficiency higher than 99%. Following treatment with the simulated gastrointestinal tract conditions, the number of B. breve decreased by 1.76 and 4.82 log cfu/g for B. breve beads and unencapsulated B. breve, respectively. The EBAF group showed the lowest viscosity (2,235.67 cP) at d 0, and the lower postfermentation degree was reflected by the slow increase in yogurt viscosity. All groups kept a relatively stable pH during storage. The cohesiveness values of the EBAF and UBAF groups were significantly higher than those of the other groups. The trends in texture changes within the BC, UBFF, and EBFF groups were similar, and the UBAF and EBAF groups showed similar trends. In conclusion, B. breve beads showed good stability in vitro and improved yogurt characteristics by increasing the survival rate of the encapsulated cells. Good compatibility of low methoxyl pectin beads with yogurt was also observed.

The study investigated the effects of low cadmium (Cd) burden on the respiratory symptoms and pulmonary function in occupational workers. The study population consisted of 98 nickel-cadmium battery workers. Levels of urine cadmium, urinary creatinine (Cr), and data on the adverse respiratory symptoms and pulmonary function of the participants were measured and collected respectively. The urinary cadmium level in cadmium-exposed workers (n = 53) was within the normal range but greater than 2.4 times than those of the control group (n = 45). Compared with the control group, the cadmium-exposed workers had higher prevalence of all subjective respiratory symptoms studied in the study. The prevalence of cough (30%), phlegm (23%), and upper respiratory tract infection (URTI) (79%) in the exposure group was significantly (P

The purpose of this article is to compare optical coherence tomography angiography (OCTA) and indocyanine green angiography (ICGA) in patients with central serous chorioretinopathy (CSC). OCTA, ICGA and fluorescein angiography (FA) images of all enrolled patients were collected and compared. Abnormal areas were annotated on en face choriocapillaris OCTA and ICGA images and compared with each other. We found three main types of anomalies in choriocapillaris OCTA images: type A, coarse granulated high reflective area (61 eyes [92.4%]); type B, roundish dark halo around Type A (54 eyes [81.8%]); and type C, coarse granulated low reflective area (66 eyes [100%]). There were 54 eyes (81.8%) that exhibited all three types abnormalities, 7 (10.6%) had only type A and C abnormalities, and 5 (7.6%) had only type C abnormalities. The Mean JI of type A on OCTA and hyperfluorescence area on ICGA was 0.84 ± 0.15 and 0.82 ± 0.23 for grader 1 and 2, respectively. Type A area on OCTA had a statistically larger area than hyperfluorescence on ICGA (P = 0.01 [paired t-test]). In summary, abnormalities were found on OCTA images of CSC. Coarse granulated high reflective area in OCTA corresponded well with the hyper-permeability area in ICGA in most of the eyes.

Background To investigate the repeatability of superficial retinal vessel density measurements in healthy eyes with long axial length (AL) using optical coherence tomography angiography (OCTA). Methods There were 60 eyes of 31 volunteers enrolled in this cross-sectional observational study. All subjects underwent OCTA, AL and refraction test. The enrolled eyes were divided into the long AL group (26 mm ≤ AL

Background COVID-19 is a global pandemic that is affecting more than 200 countries worldwide. Efficient diagnosis and treatment are crucial to combat the disease. Computer-interpretable guidelines (CIGs) can aid the broad global adoption of evidence-based diagnosis and treatment knowledge. However, currently, no internationally shareable CIG exists. Objective The aim of this study was to establish a rapid CIG development and dissemination approach and apply it to develop a shareable CIG for COVID-19. Methods A 6-step rapid CIG development and dissemination approach was designed and applied. Processes, roles, and deliverable artifacts were specified in this approach to eliminate ambiguities during development of the CIG. The Guideline Definition Language (GDL) was used to capture the clinical rules. A CIG for COVID-19 was developed by translating, interpreting, annotating, extracting, and formalizing the Chinese COVID-19 diagnosis and treatment guideline. A prototype application was implemented to validate the CIG. Results We used 27 archetypes for the COVID-19 guideline. We developed 18 GDL rules to cover the diagnosis and treatment suggestion algorithms in the narrative guideline. The CIG was further translated to object data model and Drools rules to facilitate its use by people who do not employ the non-openEHR archetype. The prototype application validated the correctness of the CIG with a public data set. Both the GDL rules and Drools rules have been disseminated on GitHub. Conclusions Our rapid CIG development and dissemination approach accelerated the pace of COVID-19 CIG development. A validated COVID-19 CIG is now available to the public.

Background The coronavirus disease (COVID-19) was discovered in China in December 2019. It has developed into a threatening international public health emergency. With the exception of China, the number of cases continues to increase worldwide. A number of studies about disease diagnosis and treatment have been carried out, and many clinically proven effective results have been achieved. Although information technology can improve the transferring of such knowledge to clinical practice rapidly, data interoperability is still a challenge due to the heterogeneous nature of hospital information systems. This issue becomes even more serious if the knowledge for diagnosis and treatment is updated rapidly as is the case for COVID-19. An open, semantic-sharing, and collaborative-information modeling framework is needed to rapidly develop a shared data model for exchanging data among systems. openEHR is such a framework and is supported by many open software packages that help to promote information sharing and interoperability. Objective This study aims to develop a shared data model based on the openEHR modeling approach to improve the interoperability among systems for the diagnosis and treatment of COVID-19. Methods The latest Guideline of COVID-19 Diagnosis and Treatment in China was selected as the knowledge source for modeling. First, the guideline was analyzed and the data items used for diagnosis and treatment, and management were extracted. Second, the data items were classified and further organized into domain concepts with a mind map. Third, searching was executed in the international openEHR Clinical Knowledge Manager (CKM) to find the existing archetypes that could represent the concepts. New archetypes were developed for those concepts that could not be found. Fourth, these archetypes were further organized into a template using Ocean Template Editor. Fifth, a test case of data exchanging between the clinical data repository and clinical decision support system based on the template was conducted to verify the feasibility of the study. Results A total of 203 data items were extracted from the guideline in China, and 16 domain concepts (16 leaf nodes in the mind map) were organized. There were 22 archetypes used to develop the template for all data items extracted from the guideline. All of them could be found in the CKM and reused directly. The archetypes and templates were reviewed and finally released in a public project within the CKM. The test case showed that the template can facilitate the data exchange and meet the requirements of decision support. Conclusions This study has developed the openEHR template for COVID-19 based on the latest guideline from China using openEHR modeling methodology. It represented the capability of the methodology for rapidly modeling and sharing knowledge through reusing the existing archetypes, which is especially useful in a new and fast-changing area such as with COVID-19.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 virus, is now generating a global epidemic, leading to a severe public health emergency. Until April 12, 2020 around 1,700,954 confirmed cases and 105,633 deaths have been reported all over the world. The World Health Organization (WHO) has declared COVID-19 as a Public Health Emergency of International Concern. Under this circumstance, surgical activities should be carefully evaluated to avoid excessive occupation of limited medical resources, and to reduce the possibility of hospital infection. China has achieved an inspiring achievement on epidemic control. Here, we reviewed available studies on surgical activities during the outbreak, in combination with our current experience, with the aim of providing feasible suggestions on surgical issues during the COVID-19 pandemic.

Modifications of short RNAs at specific sites can be achieved commercially by solid-phase chemical synthesis method. However, labelling long RNAs is still challenging for the routine methods. Position-selective Labelling of RNA (PLOR) is a hybrid phase transcription method that allows to label RNAs at desired sites with great flexibility and decent efficiency. In principle, PLOR is a promising method for synthesis of long modified RNAs that are unable to be generated by solid-phase chemical synthesis and other methods. However, as a recently developed method, PLOR has been only applied to label a 71nt and a 104nt RNA, and the limited sequence applications of PLOR may hinder its potential usages. To extend PLOR to more RNAs, we tested the PLOR performances for various RNA sequences. Considering that the controlled transcriptional pauses at the initiation stage in PLOR may lead to different preferences on RNA sequences from in vitro transcription method, we here focused on identifying the effects of the 5ʹ-end and initiated lengths of RNA on PLOR. In addition, our work demonstrated that PLOR efficiencies also varied with linker sizes of DNA templates. This work can facilitate PLOR to be the choice of synthesizing long modified RNAs for more users in the near future.

microRNAs (miRNAs) are non‐coding RNAs that function as post‐transcriptional regulators of cardiac development and cardiovascular diseases. Single nucleotide polymorphisms (SNPs) in miRNA genes are a novel class of genetic variations in the human genome that confer the risk of cardiovascular diseases. Here, we identified a polymorphism A→G (rs3746444) in miR‐499 precursor (pre‐miR‐499) that affects the maturation of miR‐499‐5p and alters its antiapoptotic function by converting stable A‐U base pair to wobble G‐U base pair in pre‐miR‐499 secondary structure. Furthermore, our results showed that the concentrations of plasma miR‐499‐5p could be correlated with myocardial infarction (MI) and heart failure (HF) patients in comparison with control subjects and polymorphism rs3746444 in miR‐499 could influence its abundance in plasma. Finally, our results also showed that the variant of polymorphism in miR‐499 influenced the severity of the myocardial infarction significantly. This is the first report to highlight the biological significance of this polymorphism on the maturation of miR‐499‐5p and its antiapoptotic role during MI. These findings may pave a way to better understand the individual variability based on miRNA SNPs in heart diseases and may contribute to better treatment for disease severity on a personalized level.

The E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) functions as a putative tumor suppressor in non-small cell lung cancer (NSCLC) due to its regulation of a set of oncogenic proteins associated with cell proliferation and mitosis. Increasing efforts have been focused on the understanding of FBW7 in determining cell cycle progression and apoptosis induction, however, the correlation between FBW7 and tumor metastasis is not fully understood. In this study, we reported a potential anti-metastatic effect of FBW7 in non-small cell lung cancer (NSCLC). In this model, FBW7 inhibited cancer cell metastasis primarily by inducing ubiquitination and proteolysis of the transcriptional factor Snail, which suppressed E-cadherin cell tight junction protein expression. Loss of FBW7 would stabilize the Snail protein, thus, inhibit E-cadherin expression and promote metastasis in vitro and in vivo. Moreover, Snail ubiquitination and degradation were also achieved by pharmacological approach, in which the FBW7 agonist oridonin treatment led to Snail proteolysis. Furthermore, FBW7 silencing stabilized Snail protein and induced epithelial-to mesenchymal transition (EMT), and acquisition of migration and invasion properties in NSCLC. Overall, our study provides new insights into the FBW7-Snail axis in regulating cell migration and invasion, and suggests that targeting FBW7 may be a potent approach to inhibit metastasis in NSCLC.

Poorly differentiated colorectal cancers (CRCs) are more aggressive and lack targeted therapies. We and others previously reported the predominant role of tumor-suppressor NDRG2 in promoting CRC differentiation, but the underlying mechanism is largely unknown. Herein, we demonstrate that NDRG2 induction of CRC cell differentiation is dependent on the repression of E3 ligase Skp2 activity. In patients and Ndrg2 knockout mice, NDRG2 and Skp2 are negatively correlated and associated with cell differentiation stage. Further, NDRG2 suppression of Skp2 contributes to the inductions and stabilizations of p21 and p27, which are Skp2 target proteins for degradation. The reduction of either p21 or p27 levels by shRNA can decrease NDRG2-induced AKP activity and resume cell growth inhibition, thus both p21 and p27 are required for NDRG2 effect on the promotion of cell differentiation in CRCs. The mechanistic study shows that NDRG2 suppresses β-catenin nuclear translocation and decreases the occupancy of β-catenin/TCF complex on Skp2 promoter, potentially through dephosphorylating GSK-3β. By subjecting a series of NDRG2 deletion mutants to Skp2 expression, the loss of NH2-terminal domain can completely abolish NDRG2-dependent differentiation induction. Supporting the biological significance of the reciprocal relationship between NDRG2 and Skp2, an NDRG2low/Skp2high gene expression signature correlates with poor CRC patient outcome and could be considered as a diagnostic marker of CRCs.

Non-coding RNAs (ncRNAs) are considered major players in physiological and pathological processes based on their versatile regulatory roles in different diseases including cardiovascular disease. Circular RNAs (circRNAs), a newly discovered class of RNAs, constitute a substantial fraction of the mammalian transcriptome and are abundantly expressed in the cardiovascular system. However, the regulatory functions of these circRNAs in ischemic cardiac disease remain largely unknown. Here, we investigated the role of a circRNA transcribed from the sodium/calcium exchanger 1 (ncx1) gene, named circNCX1, in oxidative stress-induced cardiomyocyte apoptosis during ischemic myocardial injury. Methods: Divergent polymerase chain reaction (PCR) was conducted to amplify the circRNA. The circular structure of circNCX1 was verified by Sanger sequencing and RNase R digestion. The subcellular localization of circNCX1 was detected by fluorescence in situ hybridization (FISH). To test the expression pattern and function of circNCX1 during oxidative stress, H9c2 cells and neonatal rat cardiomyocytes were treated with H2O2 or hypoxia-reoxygenation (H/R). Mechanistically, the interaction of circNCX1 with miRNA was examined by AGO2-IP and RNA pull-down assays. The regulatory role of circNCX1 in target gene expression was tested by western blot and luciferase reporter assays. At the animal level, we constructed a myocardial ischemia-reperfusion (I/R) mouse model to analyze the effect of circNCX1 on heart function, cardiomyocyte apoptosis and cardiac remodeling. Results: circNCX1 was increased in response to reactive oxygen species (ROS) and promotes cardiomyocyte apoptosis by acting as an endogenous miR-133a-3p sponge. Due to competitive binding of circNCX1 to miR-133a-3p, the suppressive activity of pro-apoptotic gene cell death-inducing protein (CDIP1) by miR-133a-3p was reduced. Knockdown of circNCX1 in murine cardiomyocytes and heart tissues reduced the levels of CDIP1 and attenuated the apoptosis and I/R injury. Conclusions: Our findings reveal a novel regulatory pathway that comprises circNCX1, miR-133a-3p and CDIP1, that is involved in cardiomyocyte apoptosis. This pathway may serve as a potential therapeutic avenue for ischemic heart diseases.

β-glucan has been shown to increase non-specific immunity and resistance against infections or pathogenic bacteria in several fish species, but no information is available regarding its trans-generational effects to date. Here we clearly demonstrated that β-glucan enhanced the contents of immune-relevant molecules C3 and Bf in eggs of zebrafish, and the embryos derived from β-1,3 glucan-treated zebrafish were more resistant to bacterial challenge than control embryos. Moreover, the transferred C3 and Bf were directly associated with the antimicrobial defense of early embryos. In addition, feeding female zebrafish with β-glucan had little detrimental effects on the number of spawned eggs and their embryonic development. Collectively, these data show for the first time that β-glucan can be safely used to promote the non-specific immunity in offspring of fishes.

Gastric cancer (GC) is one of the most common malignant tumors in China and the third leading cause of cancer-related death. Parkin has been shown to be a tumor suppressor in a variety of malignancies, including GC. However, the mechanism of Parkin in GC remains unclear. In this study, the low expression of Parkin in GC cells and patient tumor tissues was observed, and Parkin inhibited proliferation and migration of GC cells. Additionally, doxorubicin (DOX) upregulated the expression of Parkin and promoted its anticancer effect. Forkhead box O3 (FOXO3a) is a crucial transcription factor that involves in the regulation of cancer cell proliferation, apoptosis, and metabolism. Here, we found that FOXO3a inhibits cell proliferation, migration, and promotes apoptosis in GC by regulating Parkin expression at the transcriptional level. In addition, Parkin inhibited cell proliferation, migration, and promoted apoptosis by inhibiting ATP-binding box protein E1 (ABCE1) expression. In summary, our results demonstrated a new regulatory axis of FOXO3a-Parkin-ABCE1 that modulated GC cell proliferation, migration, and apoptosis, and it can serve as a potential therapeutic target in GC.

Nanocellulose crystals (NCCs) were successfully prepared via acid hydrolysis from an abundant agricultural waste (tea stalk) in China. The effective factors for NCC yield were modeled by the response surface methodology (RSM). The RSM determined the reaction conditions (H2SO4 concentration, hydrolysis temperature, and reaction time) that optimized the yield of tea stalk NCCs (TNCCs). Under the optimized operating conditions, the fundamental properties of TNCCs were characterized via transmission electron microscopy (TEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), laser diffraction particle-size analyzer, and scanning probe microscopy (SPM). Wood NCCs (WNCCs) and microcrystalline NCCs (MNCCs) were simultaneously prepared from common wood and microcrystalline cellulose under the same conditions. The results show that TNCCs not only shows similar physical and chemical properties with WNCCs and MNCCs, but also has better stability. Therefore, this study offers novel routes for high-valued utilization of tea stalk and provides some theoretical guidance for utilizing cellulose obtained from tea stalk.

Necrosis is a key factor in myocardial injury during cardiac pathological processes, such as myocardial infarction (MI), ischemia/reperfusion (I/R) injury and heart failure. Increasing evidence suggests that several aspects of necrosis are programmed and tightly regulated, so targeting the necrosis process has become a new trend for myocardial protection. Multiple cellular signaling pathways have been implicated in necrotic cell death, such as the death receptor-mediated extrinsic and mitochondrial intrinsic pathways. However, the precise mechanisms underlying myocardial necrosis remain unclear. In this study, we showed that apoptosis repressor with caspase recruitment domain (ARC) participated in the mitochondrial intrinsic pathway and inhibited myocardial necrosis by preventing the opening of the mitochondrial permeability transition pore (mPTP). ARC attenuated necrotic cell death triggered by exposure to 500 μM hydrogen peroxide (H2O2) in the cardiomyocyte cell line H9c2. In mice, ARC ameliorated myocardial necrosis, reduced the myocardial infarct size and improved long-term heart function during I/R injury. Mechanistically, it has been shown that the inhibition of necrosis by ARC was dependent on its mitochondrial localization and that ARC prevented the opening of mPTP by targeting CypD, the main regulator of mPTP. In addition, ARC expression was negatively regulated by the transcription factor p53 at the transcriptional level during the necrosis process. These findings identified the novel role of ARC in myocardial necrosis and delineated the p53-ARC-CypD/mPTP necrosis pathway during ischemia- and oxidative stress-induced myocardial damage, which can provide a new strategy for cardiac protection., Graphical abstract fx1, Highlights • ARC attenuates necrosis both in cardiomyocytes exposed to H2O2 and in mouse hearts with ischemia/reperfusion injury. • The attenuation of necrosis by ARC depends on its mitochondrial localization and its inhibition of mPTP opening. • ARC targets CypD and prevents mPTP opening. • p53 regulates necrosis by suppression of ARC expression at the transcriptional level.

As a novel class of endogenous RNAs, circRNAs, have a covalently closed continuous loop, with neither a 5’to 3’polarity, nor a polyadenylated tail. Numerous circRNAs have been characterized by abundance, stabilization, conservation, and exhibit tissue/developmental stage-specific expression. Furthermore, circRNAs play vital roles in tumorigenesis and metastasis, such as functioning as a ceRNA or miRNA sponge, interacting with protein and encoding protein. Increasing evidence has revealed that it potentially serves as a required novel biomarker for cancer diagnosis. This review summarized the latest research on circRNAs, including its classification and biogenesis, mechanism and functions, as well as circRNAs in different cancers, as a potential biomarker.

The liver is the predominant metastatic site for several types of malignancies. Tumor-associated macrophages (TAMs) in the liver play crucial roles in the metastasis process. Shifting tumor-promoting M2-like TAMs toward the M1-like phenotype, which exerts tumor suppressor functions via phagocytosis and the secretion of inhibitory factors, may be a potential therapeutic strategy for liver cancer metastasis treatment.We first cloned NDRG2 (N-myc downstream-regulated gene 2) and verified its tumor suppressor role in multiple solid tumors, including colorectal cancer and hepatocellular carcinoma. However, its role in the tumor-associated liver microenvironment, especially in TAMs, has not been illustrated. By establishing a liver cancer metastasis model in wild-type (WT) and Ndrg2 knockout (Ndrg2−/−) mice, we found that the loss of the tumor suppressor Ndrg2 in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration in Ndrg2−/− mice. Interestingly, bone marrow (BM) transplantation revealed that BM-derived macrophages (BMDMs) rather than liver resident Kupffer cells were responsible for the inhibitory effect. We further demonstrated that loss of Ndrg2 influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression in Ndrg2−/− macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function of Ndrg2−/− macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.

Peroxisome proliferator-activated receptors (PPARs) play vital roles in cardiovascular pathophysiology, such as energy balance, cell proliferation/apoptosis, inflammatory response, and adipocyte differentiation. These vital roles make PPARs potential targets for therapeutic prevention of cardiovascular diseases (CVDs). Emerging evidence indicates that the crosstalk of microRNAs (miRNAs) and PPARs contributes greatly to CVD pathogenesis. PPARs are inhibited by miRNAs at posttranscriptional mechanisms in the progress of pulmonary hypertension and vascular dysfunction involving cell proliferation/apoptosis, communication, and normal function of endothelial cells and vascular smooth muscle cells. In the development of atherosclerosis and stroke, the activation of PPARs could change the transcripts of target miRNA through miRNA signalling. Furthermore, the mutual regulation of PPARs and miRNAs involves cell proliferation/apoptosis, cardiac remodeling, and dysfunction in heart diseases. In addition, obesity, an important cardiovascular risk, is modulated by the regulatory axis of PPARs/miRNAs, including adipogenesis, adipocyte dysfunction, insulin resistance, and macrophage polarization in adipose tissue. In this review, the crosstalk of PPARs and miRNAs and their emerging regulatory roles are summarized in the context of CVDs and risks. This provides an understanding of the underlying mechanism of the biological process related to CVD pathophysiology involving the interaction of PPARs and miRNAs and will lead to the development of PPARs/miRNAs as effective anti-CVD medications.

Our previous studies showed that Fibroblast growth factor receptor 3 (FGFR3) contributed to cell growth in lung cancer. However, the correlation between FGFR3 and tumor progression, coupled with the underlying mechanisms, are not fully understood. The clinical significance of FGFR3 was determined in two cohorts of clinical samples (n=22, n=78). A panel of biochemical assays and functional experiments was utilized to elucidate the underlying mechanisms and effects of FGFR3 and miR-24-3p on lung adenocarcinoma progression. Upregulated FGFR3 expression indicated an adverse prognosis for lung adenocarcinoma individuals and promoted metastatic potential of lung adenocarcinoma cells. Owing to the direct regulation towards FGFR3, miR-24-3p could interfere with the potential of proliferation, migration, and invasion in lung adenocarcinoma, following variations of EMT-related protein expression. As a significant marker of EMT, E-cadherin was negatively correlated with FGFR3, of which ectopic overexpression could neutralize the antitumour effects of miR-24-3p and reverse its regulatory effects on EMT markers. Taken together, these findings define a novel insight into the miR-24-3p/FGFR3 signaling axis in regulating lung adenocarcinoma progression and suggest that targeting the miR-24-3p/FGFR3 axis could be an effective and efficient way to prevent tumor progression.

Necrosis is an ancient topic which gains new attraction in the research area these years. There is no doubt that some necrosis can be regulated by genetic manipulation other than an accidental cell death resulting from physical or chemical stimuli. Recent advances in the molecular mechanism underlying the programmed necrosis show a fine regulation network which indicates new therapy targets in human diseases. Heart diseases seriously endanger our health and have high fatality rates in the patients. Cell death of cardiac myocytes is believed to be critical in the pathogenesis of heart diseases. Although necrosis is likely to play a more important role in cardiac cell death than apoptosis, apoptosis has been paid much attention in the past 30 years because it used to be considered as the only form of programmed cell death. However, recent findings of programmed necrosis and the related signalling pathways have broadened our horizon in the field of programmed cell death and promote new pharmacological application in the treatment of heart diseases. In this review, we summarize the advanced progress in these signalling pathways and discuss the pathos‐physiological relevance and therapeutic implication of targeting necrosis in heart diseases treatment.

Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α activity and of sorafenib resistance in hypoxic HCC cells. Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2α level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells. Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2–specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment. Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2–specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204–16. ©2018 AACR.

Circular RNAs (circRNAs) are a newly discovered type of RNA generated by back-splicing of precursor mRNA and found in many species. They are, expressed in a tissue-specific manner and fulfill regulatory activities in many biological processes. Recent research has revealed that circRNAs play critical roles in the development and pathologies of the cardiovascular system. Some of these circRNAs show aberrant expression and regulatory activities during heart disease including heart failure and cardiac infarction and hypertrophy. These findings suggest that circRNAs might be a suitable target for the treatment and prevention of heart disease. In this review, we summarize the latest research on the biogenesis and functions of circRNAs with emphasis on the regulatory roles of circRNAs in the development and pathologies of the cardiovascular system.

GH is known to play an important role in both growth promotion and osmoregulation in vertebrates. We have shown that amphioxus possesses a single GH-like hormone (GHl) gene encoding a functional protein capable of promoting growth. However, if GHl can mediate osmoregulation remains open. Here, we demonstrated clearly that GHl increased not only the survival rate of amphioxus but also the muscle moisture under high salinity. Moreover, GHl induced the expression of both the ion transporter Na+-K+-ATPase (NKA) and Na+-K+-2Cl−cotransporter (NKCC) in the gill as well as the mediator of GH action IGFl in the hepatic caecum, indicating that GHl fulfills this osmoregulatory activity through the same mechanisms of vertebrate GH. These results together suggest that the osmoregulatory activities of GH had emerged in the basal chordate amphioxus. We also proposed a new model depicting the origin of pituitary hormone family in vertebrates.

Osteosarcoma is the most common form of primary malignant bone tumor, with metastasis playing an essential role in determining a patient's prospects for survival. It is essential that new and better molecular targets that respond effectively to therapies and are predictive of the risk of tumor metastasis are identified. We have therefore undertaken the present prospective study to ascertain the clinical significance of circulating tumor cells (CTCs) in osteosarcoma patients. Peripheral blood was obtained from patients both pre- and post-surgery then processed using a CanPatrol™ system, an enrichment technique allowing isolation of CTCs by virtue of their size at baseline. Multiplex RNA in situ hybridization (RNA-ISH) was subsequently conducted to characterize the CTCs based on various molecular markers including MTA1, CD45, EpCAM, CK8, CK19, Vimentin and Twist. MTA1 expression was further validated by immunohistochemistry of the tumor tissue. Besides defining a diagnosis and prognosis for osteosarcoma patients, the correlation between CTC count and their molecular and clinicopathological characteristics was found to assist in the analysis of the response of patients to neoadjuvant chemotherapy. Our results revealed that the number of CTCs was significantly higher at baseline in metastatic patients than in those whose osteosarcomas were localized. The variation was attributed to the neoadjuvant chemotherapy treatment. A cut-off value of 7 CTCs/5 mL was found to effectively distinguish patients who had either a favorable or unfavorable prognosis. Notably, the ratio of mesenchymal CTCs at baseline was found to be higher in metastatic vs. localized osteosarcoma patients. In addition, the expression of MTA1 was higher in mesenchymal CTCs than the other CTC phenotypes. Furthermore, immunohistochemical analysis demonstrated a higher expression of MTA1 in tumor tissues from metastatic osteosarcoma patients. Taken together, our findings conclusively establish that the number and molecular phenotype of CTCs are predictive of tumor metastasis and the response of patients to neoadjuvant chemotherapy. Keywords: Circulating tumor cells, Metastasis-associated protein 1 (MTA1), Osteosarcoma, Prognosis, Tumor metastasis

Supplemental Digital Content is available in the text, Rationale: There is controversy regarding the optimal surgical approach for pancreatic lesions in the head of the pancreas. Duodenum-preserving pancreatic head resection compared with pancreaticoduodenectomy is technically more challenging, but preserves more functional pancreatic tissue. Patient concerns: A 25-year-old woman was admitted to our department on May 10, 2017. Computed tomographic's saw a 2.0 × 2.1-cm lesion located in the head of pancreas and its diagnosis was nonfunctional neuroendocrine tumors? The magnetic resonance cholangiopancreatography scan demonstrated a solitary 1.6 × 1.7-cm lesion located in the head of pancreas, and its diagnosis was tumor. The patient's condition was good and symptomless, without any disease history. Physical examination and routine blood investigations were normal. All pancreatic malignant tumor biological markers were negative. Diagnoses: Solid pseudopapillary neoplasm of pancreas. Interventions: Total laparoscopic head pancreatectomy with Roux-Y pancreaticojejunostomy was performed. Outcomes: The recovery was smooth after surgery. At the end of 20 months follow-up, she was well and showed no signs of recurrence. Lessons: The anatomy of the operation is clearer and easier than open surgery because of the magnification effect of laparoscopy. Total laparoscopic head pancreatectomy is safe, effective, and feasible for solid pseudopapillary neoplasm of pancreas, and it should be equally applicable to some other pancreatic cystic neoplasms and neuro-endocrine tumors.

Rationale There is controversy regarding the optimal surgical approach for pancreatic lesions in the center of the pancreas. Duodenum-preserving pancreatic cental resection compared with pancreaticoduodenectomy is technically more challenging, but preserves more functional pancreatic tissue. Patient concerns A 34-year-old woman was admitted to our department on March 15, 2017. Computed tomographic's and magnetic resonance cholangiopancreatography's diagnosis was a solitary tumor 3.0 × 2.2-cm lesion located in border between pancreatic neck and body. The patient's condition was good and symptomless, without any disease history. Physical examination and routine blood investigations were normal. All pancreatic malignant tumor biological markers were negative. Diagnoses Solid pseudopapillary neoplasm (SPN) of pancreas. Interventions Total laparoscopic central pancreatectomy with Roux-Y pancreaticojejunostomy was performed, and unscheduled open surgery was done for abdominal pain caused by intraperitoneal bleeding. Outcomes The recovery was smooth after unscheduled open surgery. At the end of 20 months follow-up, she was well and showed no signs of recurrence. Lessons The anatomy of the operation is clearer and easier than open surgery because of the magnification effect of laparoscopy. Total laparoscopic central pancreatectomy is safe, effective, feasible for SPN of pancreas, and it should be equally applicable to some other pancreatic cystic neoplasms and neuro-endocrine tumors. Suture is the best measure to prevent postoperative angiorhagia of intraperitoneal cavity.

Scope High fat (HF)-diet-induced insulin resistance is a major contributor to the pathogenesis of cardiovascular diseases. However, the molecular mechanisms that regulate cardiac insulin signaling are not fully understood. The regulatory role of tafazzin in the hearts of HF-diet-fed mice is investigated. Methods and results Mice are fed a HF diet or low fat (LF) diet for up to 24 weeks. After 24 weeks, it is found that HF-diet-induced cardiac dysfunction is linked to overexpression of the mitochondrial protein tafazzin. Increased tafazzin promotes mitochondrial fission and impairs insulin signaling, which is mediated by dynamin-related protein 1 (Drp-1) translocation from the cytosol to the mitochondria. Furthermore, knockdown of tafazzin with siRNA inhibits palmitic-acid-induced mitochondrial fission and restores insulin sensitivity. Moreover, miR-125b-5p as an upstream regulator targeting tafazzin is identified and palmitate-induced insulin resistance further rescued. Conclusion In HF-diet-fed mouse hearts, increased tafazzin contributes to insulin resistance via mediating Drp-1 translocation to the mitochondria, and a small non-coding RNA, miR-125b-5p, at least partially regulates this signaling pathway and alleviates insulin resistance.

Clinical trials testing the use of either autologous or allogeneic human bone marrow-derived mesenchymal stromal cells (MSC) as a cell-based pharmaceutical for suppression of autoimmune and alloimmune ailments are underway. Reported results from completed trials vary in effectiveness within and between studies without any clear mechanistic explanation. We propose that these discrepancies may arise from intrinsic variability in the immunosuppressive potential of each MSC donor source. Here, we demonstrate that tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-activated MSC derived from normal adult volunteers suppress T cell proliferation in vitro in a variegated manner, an observation linked to IFN-mediated indoleamine 2,3-dioxygenase (IDO) upregulation. We also demonstrate that MSC IDO activity is implicated in the differentiation of monocytes into interleukin (IL)-10-secreting M2 immunosuppressive macrophages (CD14(+)/CD206(+)). Those monocyte-derived M2 are in turn implicated in the suppression of T cell proliferation in an IL-10-independent manner, thus amplifying the immunosuppressive effect generated by MSC. In summary, the immune plasticity of IFN-γ and TNF-α licensed veto function of MSC vary among donors and defines a central role to inducible IDO activity and its bystander effect on lymphomyeloid immune effectors.

Autophagy, which is an evolutionarily conserved process according to the lysosomal degradation of cellular components, plays a critical role in maintaining cell homeostasis. Autophagy and mitochondria autophagy (mitophagy) contribute to the preservation of cardiac homeostasis in physiological settings. However, impaired or excessive autophagy is related to a variety of diseases. Recently, a close link between autophagy and cardiac disorders, including myocardial infarction, cardiac hypertrophy, cardiomyopathy, cardiac fibrosis, and heart failure, has been demonstrated. MicroRNAs (miRNAs) are a class of small non-coding RNAs with a length of approximately 21–22 nucleotides (nt), which are distributed widely in viruses, plants, protists, and animals. They function in mediating the post-transcriptional gene silencing. A growing number of studies have demonstrated that miRNAs regulate cardiac autophagy by suppressing the expression of autophagy-related genes in a targeted manner, which are involved in the pathogenesis of heart diseases. This review summarizes the role of microRNAs in cardiac autophagy and related cardiac disorders. Furthermore, we mainly focused on the autophagy regulation pathways, which consisted of miRNAs and their targeted genes.