Defective prelamin A processing promotes unconventional necroptosis driven by nuclear RIPK1.

Defects in the prelamin A processing enzyme caused by loss-of-function mutations in the ZMPSTE24 gene are responsible for a spectrum of progeroid disorders characterized by the accumulation of farnesylated prelamin A. Here we report that defective prelamin A processing triggers nuclear RIPK1-dependent signalling that leads to necroptosis and inflammation. We show that accumulated prelamin A recruits RIPK1 to the nucleus to facilitate its activation upon tumour necrosis factor stimulation in ZMPSTE24-deficient cells. Kinase-activated RIPK1 then promotes RIPK3-mediated MLKL activation in the nucleus, leading to nuclear envelope disruption and necroptosis. This signalling relies on prelamin A farnesylation, which anchors prelamin A to nuclear envelope to serve as a nucleation platform for necroptosis. Genetic inactivation of necroptosis ameliorates the progeroid phenotypes in Zmpste24-/- mice. Our findings identify an unconventional nuclear necroptosis pathway resulting from ZMPSTE24 deficiency with pathogenic consequences in progeroid disorder and suggest RIPK1 as a feasible target for prelamin A-associated progeroid disorders.

Autonomous Landing of Quadrotor Unmanned Aerial Vehicles Based on Multi-Level Marker and Linear Active Disturbance Reject Control.

Landing on unmanned surface vehicles (USV) autonomously is a critical task for unmanned aerial vehicles (UAV) due to complex environments. To solve this problem, an autonomous landing method is proposed based on a multi-level marker and linear active disturbance rejection control (LADRC) in this study. A specially designed landing board is placed on the USV, and ArUco codes with different scales are employed. Then, the landing marker is captured and processed by a camera mounted below the UAV body. Using the efficient perspective-n-point method, the position and attitude of the UAV are estimated and further fused by the Kalman filter, which improves the estimation accuracy and stability. On this basis, LADRC is used for UAV landing control, in which an extended state observer with adjustable bandwidth is employed to evaluate disturbance and proportional-derivative control is adopted to eliminate control error. The results of simulations and experiments demonstrate the feasibility and effectiveness of the proposed method, which provides an effective solution for the autonomous recovery of unmanned systems.

PANoptosis in cancer, the triangle of cell death.

BACKGROUND: PANoptosis is a novel form of programmed cell death (PCD) found in 2019 that is regulated by the PANoptosome. PANoptosis combines essential features of pyroptosis, apoptosis, and necroptosis, forming a "death triangle" of cells. While apoptosis, pyroptosis, and necroptosis have been extensively studied for their roles in human inflammatory diseases and many other clinical conditions, historically they were considered as independent processes. However, emerging evidence indicates that these PCDs exhibit cross talk and interactions, resulting in the development of the concept of PANoptosis. METHODS: In this review, we offer a concise summary of the fundamental mechanisms of apoptosis, pyroptosis, and necroptosis. We subsequently introduce the notion of PANoptosis and detail the assembly mechanism of the PANoptosome complex which is responsible for inducing cell death. We also describe some regulatory networks of PANoptosis. RESULTS: PANoptosis now has been associated with various human diseases including cancer. Although the exact function of PANoptosis in each tumor is not fully understood, it represents a prospective avenue for cancer therapy, offering promise for advancements in cancer therapy. CONCLUSIONS: In the future, in-depth study of PANoptosis will continue to help us in understanding the fundamental processes underlying cell death and provide scientific support for cancer research.

Multifunctional Multigate One-Transistor with Thin Advanced Materials, Logic-in-Memory, and Artificial Synaptic Behaviors.

The high device density and fabrication complexity have hampered the development of the electronics. The advanced designs, which could implement the functions of the circuits with higher device density but less fabrication complexity, are hence required. Meanwhile, the MoS2-based devices have recently attracted considerable attention owing to their advantages such as the ultrathin thickness. However, the MoS2-based multifunctional multigate one-transistor (MGT) designs with logic-in-memory and artificial synaptic functions have rarely been reported. Here, an MGT structure based on the MoS2 channel is proposed, with both the logic-in-memory and artificial synaptic behaviors and with more controllable processes than the manual transfer. The proposed MoS2-based MGT functions could be attributed to the semijunction mechanism and enhanced effect of the additional terminals with improved controllability. This study is the first to demonstrate that the neuromorphic computing, logic gate, and memory functions can all be achieved in a MoS2 MGT device without using any additional layers or plasticity to a transistor. The reported results provide a new strategy for developing brain-like systems and next-generation electronics using multifunctional designs and ultrathin materials.

An Array Magnetic Coupling Piezoelectric and Electromagnetic Energy Harvester for Rotary Excitation.

The energy of rotating machinery exists widely in the environment. It is of great significance to collect and utilize the energy of rotating machinery for sustainable development. In this paper, a novel piezoelectric and electromagnetic energy harvester, which is capable of generating electrical energy under rotary excitation, is proposed based on array magnetic coupling. The working principle of this kind of energy harvester is analyzed. And the energy output modeling of the harvester is developed and output results are simulated. Based on the experimental test platform built in the laboratory, the output characteristics of the piezoelectric and electromagnetic energy harvester are tested. Results show that the maximum output power of the proposed energy harvester reaches 182 mW when the excitation speed is 120 rpm. Furthermore, both the piezoelectric module and the electromagnetic module can reach the maximum output power at the excitation speed of 120 rpm.

C. tropicalis promotes CRC by down-regulating tumor cell-intrinsic PD-1 receptor via autophagy.

Background: The programmed cell death 1 (PD-1) receptor is an immune checkpoint molecule that induces immune tolerance and mediates the immune escape of tumor cells. It is mainly expressed in immune cells such as T cells, B cells and monocytes. In recent years, studies have shown that tumor cell-intrinsic PD-1 plays different roles in the development of melanoma, Liver cancer and lung cancer. However, the expression and function of PD-1 in colon cancer cells has not been reported. Our previous studies have found that Candida tropicalis (C. tropicalis) can promote CRC tumor growth and chemotherapy resistance to oxaliplatin by regulating mismatch repair system. Whether C. tropicalis participates in the progression of CRC and immunotherapy resistance through regulating the tumor cell-intrinsic PD-1 remains to be further elucidated. Methods & Results: In this study, we first found that high concentrations of C. tropicalis promote tumor growth in cell cultures and xenografts. In addition, we proved that colon cancer cell lines express PD-1 receptors. Knockdown of PD-1 enhanced SW480 viability in-vitro, while overexpression of PD-1 diminished cell viability. Moreover, blocking antibody against PD-1 promotes tumor growth both in SW480 cells and mice CRC xenografts in an adaptive immune-independent manner. We also demonstrated that high concentrations of C. tropicalis can down-regulate tumor cell-intrinsic PD-1 expression in colon cancer cells. CRC cell growth induced by C. tropicalis is partially offset in the presence of PD-1 overexpression. This shows that C. tropicalis promotes CRC progression via controlling the expression of tumor cell-intrinsic PD-1. Mechanistically, we found that C. tropicalis modulates the expression of PD-1 via increasing the autophagy traffic in colon cancer cells. Combining autophagy inhibitor with C. tropicalis treatment partly blocked the CRC tumor growth and reversed the downregulation of PD-1. Conclusion: This study shows that PD-1 is a tumor suppressor in CRC. C. tropicalis can down-regulate tumor cell-intrinsic PD-1 expression via enhancing tumor cells autophagy levels to promote CRC progression. It may provide a new idea and mechanism for answering why the immune monoclonal antibody treatment is ineffective in cancer patients.

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.

Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.

Adenosine monophosphate-activated protein kinase (AMPK) activity is stimulated to promote metabolic adaptation upon energy stress. However, sustained metabolic stress may cause cell death. The mechanisms by which AMPK dictates cell death are not fully understood. We report that metabolic stress promoted receptor-interacting protein kinase 1 (RIPK1) activation mediated by TRAIL receptors, whereas AMPK inhibited RIPK1 by phosphorylation at Ser415 to suppress energy stress-induced cell death. Inhibiting pS415-RIPK1 by Ampk deficiency or RIPK1 S415A mutation promoted RIPK1 activation. Furthermore, genetic inactivation of RIPK1 protected against ischemic injury in myeloid Ampkα1-deficient mice. Our studies reveal that AMPK phosphorylation of RIPK1 represents a crucial metabolic checkpoint, which dictates cell fate response to metabolic stress, and highlight a previously unappreciated role for the AMPK-RIPK1 axis in integrating metabolism, cell death, and inflammation.

LncRNA PVT1 influences breast cancer cells glycolysis through sponging miR-145-5p.

BACKGROUND: Long-non-coding RNA PVT1 (lncRNA PVT1) can be used as an oncogenic regulatory non-coding RNA (ncRNA) for many cancers. However, its function and mechanism in breast cancer (BRCA) are still not clearly elucidated. OBJECTIVE: We attempt to explain the mechanism of PVT1's role in breast cancer from different perspectives. METHODS: We analyzed the expression of PVT1 and its correlation with the breast cancer related clinical data in the The Cancer Genome Atlas (TCGA) database. We used PVT1 overexpression and knockdown lentivirus to infect breast cancer MDA-MB-231 cell line for cell function verification, in vitro using CCK-8 to measure proliferation, flow cytometry to measure apoptosis, transwell test to measure invasion and migration ability, detecting cell extracellular acidification rate (ECAR) to assess glycolysis metabolism and explore the biological functions of PVT1 in breast cancer cells. Transcriptome sequencing was used to analyze the changes of related genes in cells after overexpression of PVT1. In vivo we used a xenograft model to study the effect of PVT1 on breast cancer. RESULTS: PVT1 was up-regulated in breast cancer tissues and was positively correlated with the clinical stage of breast cancer patients. Overexpression of PVT1 in vitro promoted cell proliferation, migration and invasion, and promoted tumor growth in vivo. Knockdown of PVT1 led to the opposite biological consequence. Further bioinformatics analysis showed that PVT1 changes the glycolysis metabolism of tumors through regulation of glycolysis-related genes. In addition, the expression of miR-145-5p is negatively correlated with PVT1. We consider the possibility of PVT1 promoting cell proliferation and metastasis by regulating the aerobic glucose metabolism in breast cancer cells through sponging the miR-145-5p. CONCLUSION: Our results reveal a potential pathway for competing endogenous RNA to regulate breast cancer glucose metabolism. PVT1 regulates glycolysis related genes expression by competitively binding to endogenous miR-145-5p in breast cancer cells to change the metabolic phenotype. This may Provide new ideas for precise molecular therapy targets for breast cancer.

Surgical anatomy of the lingual lymph nodes: systematic literature analysis and proposition for topographic classification.

PURPOSE: Metastatic involvement of the lingual lymph nodes (LLNs) in oral cavity squamous cell cancer (SCC) has recently been proven to significantly reduce locoregional control and survival. Despite recent refinements in the detection of these lesions, the understanding of the LLN topographic anatomy among clinicians is limited. A proposition of a topographic division on LLN based on a comprehensive literature search and synthesis may be helpful in this condition. METHODS: A literature search and election based on contemporary PRISMA guidelines was performed for sources on LLN anatomy with special attention on their subdivision. RESULTS: Four topographic LLN subgroups were defined: median-between genioglossal and geniohyoid muscles; intermediate parahyoid-medial to the hyoglossal muscle, at the greater cornu of the hyoid bone; lateral sublingual (paraglandular) LLNs-at the sublingual salivary gland; lateral submandibular (paraglandular) LLNs -lateral to the hyoglossal muscle, at the deep surface of the submandibular salivary gland. CONCLUSION: The development and implementation of a unified anatomical topographic classification of LLN subgroups may be among the important conditions for improving the detection and treatment of LLN lesions.

Dectin3 protects against hepatocellular carcinoma by regulating glycolysis of macrophages.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the commonest cancer and is high in incidence. Besides, glycolysis has been proven to be a promoter in cancer progression. But the research related to glycolysis concentrates on tumor cells, and few are about macrophages. Dectin3 is a C-type Lectin receptor (CLR), expressed by myeloid lineage cells such as monocytes/macrophages, which can recognize pathogens and modulate immunity. We speculate that Dectin3 is involved in HCC by regulating the glycolysis in macrophages, which is meaningful. METHODS: Wild-type (WT) mice and Dectin3-/- mice were used to establish a mouse model of HCC and the progression of HCC was evaluated. Primary tumor associated macrophages (TAMs) were isolated from tumor tissues and the level of glycolysis was assessed. WT and Dectin3-/- tumor-bearing mice were treated with glycolysis inhibitors and the tumor progression was assessed. Culture supernatant derived from H22 cells was used to stimulate bone-marrow-derived macrophages (BMDMs). The level of glycolysis in BMDMs was subsequently detected. H22 cells and BMDMs were co-cultured and then the proliferation and apoptosis of H22 cells were evaluated. RESULTS: Compared with WT mice, tumor volume of Dectin3-/- mice increased, and the proportion of macrophages in tumor tissues increased, while the proportions of CD4+ and CD8+T cells decreased. Besides, the splenomegaly of Dectin3-/- mice was more serious. The level of glycolysis in macrophages of Dectin3-/- tumor-bearing mice was significantly up-regulated. After glycolysis inhibitor treatment, cancer progression of Dectin3-/- tumor-bearing mice slowed down, and the difference between WT mice and Dectin3-/- mice was significantly down-regulated. In addition, Dectin3 deficiency macrophages significantly promoted H22 cell proliferation and inhibited H22 cell apoptosis. CONCLUSION: Dectin3 can protect against HCC. Dectin3 contributes to the apoptosis of tumor cells and inhibits the proliferation of tumor cells by regulating the glycolysis of macrophages.

An Improved Bayesian Shrinkage Regression Algorithm for Genomic Selection.

Currently a hot topic, genomic selection (GS) has consistently provided powerful support for breeding studies and achieved more comprehensive and reliable selection in animal and plant breeding. GS estimates the effects of all single nucleotide polymorphisms (SNPs) and thereby predicts the genomic estimation of breeding value (GEBV), accelerating breeding progress and overcoming the limitations of conventional breeding. The successful application of GS primarily depends on the accuracy of the GEBV. Adopting appropriate advanced algorithms to improve the accuracy of the GEBV is time-saving and efficient for breeders, and the available algorithms can be further improved in the big data era. In this study, we develop a new algorithm under the Bayesian Shrinkage Regression (BSR, which is called BayesA) framework, an improved expectation-maximization algorithm for BayesA (emBAI). The emBAI algorithm first corrects the polygenic and environmental noise and then calculates the GEBV by emBayesA. We conduct two simulation experiments and a real dataset analysis for flowering time-related Arabidopsis phenotypes to validate the new algorithm. Compared to established methods, emBAI is more powerful in terms of prediction accuracy, mean square error (MSE), mean absolute error (MAE), the area under the receiver operating characteristic curve (AUC) and correlation of prediction in simulation studies. In addition, emBAI performs well under the increasing genetic background. The analysis of the Arabidopsis real dataset further illustrates the benefits of emBAI for genomic prediction according to prediction accuracy, MSE, MAE and correlation of prediction. Furthermore, the new method shows the advantages of significant loci detection and effect coefficient estimation, which are confirmed by The Arabidopsis Information Resource (TAIR) gene bank. In conclusion, the emBAI algorithm provides powerful support for GS in high-dimensional genomic datasets.

Gut fungi enhances immunosuppressive function of myeloid-derived suppressor cells by activating PKM2-dependent glycolysis to promote colorectal tumorigenesis.

BACKGROUND: Accumulating evidence implicates that gut fungi are associated with the pathogenesis of colorectal cancer (CRC). Our previous study has revealed that Candida tropicalis (C. tropicalis) promotes colorectal tumorigenesis by enhancing immunosuppressive function of myeloid-derived suppressor cells (MDSCs) and increasing accumulation of MDSCs, but the underlying mechanisms remain unestablished. METHODS: Bone marrow-derived MDSCs were stimulated with C. tropicalis. RNA-sequencing analysis was performed to screen the differentially expressed genes. Quantitative real-time PCR and western blot were used to measure the expression of related proteins. Co-culture assay of MDSCs and CD8+ T cells was used to determine the immunosuppressive ability of MDSCs. Metabolomic analysis was conducted to detect metabolic reprogramming of MDSCs. Aerobic glycolysis of MDSCs was assessed by extracellular acidification rate (ECAR), glucose consumption and lactate production. A CAC mouse model was induced by AOM and DSS to determine the therapeutic action of TEPP-46. IHC and immunofluorescence were performed to examine the expression of PKM2, PKM2 (p-Y105) and iNOS in human CRC-infiltrated MDSCs. RESULTS: C. tropicalis facilitates immunosuppressive function of MDSCs by increasing the expression of iNOS, COX2 and NOX2, production of nitric oxide (NO) and reactive oxygen species (ROS). Mechanistically, C. tropicalis facilitates the immunosuppressive function of MDSCs through the C-type lectin receptors Dectin-3 and Syk. C. tropicalis-enhanced immunosuppressive function of MDSCs is further dependent on aerobic glycolysis. On the one hand, NO produced by MDSCs enhanced aerobic glycolysis in a positive feedback manner. On the other hand, C. tropicalis promotes p-Syk binding to PKM2, which results in PKM2 Tyr105 phosphorylation and PKM2 nuclear translocation in MDSCs. Nuclear PKM2 interacts with HIF-1α and subsequently upregulates the expression of HIF-1α target genes encoding glycolytic enzymes, GLUT1, HK2, PKM2, LDHA and PDK1, which are required for the C. tropicalis-induced aerobic glycolysis of MDSCs. Blockade of PKM2 nuclear translocation attenuates C. tropicalis-mediated colorectal tumorigenesis. The high expression of PKM2, PKM2 (p-Y105) and iNOS in CRC-infiltrated MDSCs correlates with the development of human CRC. CONCLUSION: C. tropicalis enhances immunosuppressive function of MDSCs via Syk-PKM2-HIF-1α-glycolysis signaling axis, which drives CRC. Therefore, we identify the Syk-PKM2-HIF-1α-glycolysis signaling axis as a potential therapeutic target for CRC.

GSK3ß Exacerbates Myocardial Ischemia/Reperfusion Injury by Inhibiting Myc.

Myocardial ischemia/reperfusion (MI/R) injury is a life-threatening disease with high morbidity and mortality. Herein, the present study is conducted to explore the regulatory mechanism of GSK3ß in MI/R injury regarding cardiomyocyte apoptosis and oxidative stress. The MI/R injury mouse model and hypoxic reoxygenation (H/R) cell model were established. The expression pattern of GSK3ß, FTO, KLF5, and Myc was determined followed by their relation validation. Next, loss-of-function experiments were implemented to verify the effect of GSK3ß/FTO/KLF5/Myc on cardiomyocyte apoptosis and oxidative stress in the MI/R injury mouse model and H/R cell model. High expression of GSK3ß and low expression of FTO, KLF5, and Myc were observed in the MI/R injury mouse model and H/R cell model. GSK3ß promoted phosphorylation of FTO and KLF5, thus increasing the ubiquitination degradation of FTO and KLF5. A decrease of FTO and KLF5 was able to downregulate Myc expression, resulting in enhanced cardiomyocyte apoptosis and oxidative stress. These data together supported the crucial role that GSK3ß played in facilitating cardiomyocyte apoptosis and oxidative stress so as to accelerate MI/R injury, which highlights a promising therapeutic strategy against MI/R injury.

Irisin protects cardiomyocytes against hypoxia/reoxygenation injury via attenuating AMPK mediated endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress plays a central role in myocardial ischemia/reperfusion (I/R) injury. Irisin has been reported to have protective properties in ischemia disease. In this study, we aimed at investigating whether irisin could alleviate myocardial I/R injury by ER stress attenuation. The in vitro model of hypoxia/reoxygenation (H/R) was established, which resembles I/R in vivo. Cell viability and apoptosis were estimated. Expressions of cleaved caspase-3, cytochrome c, GRP78, pAMPK, CHOP, and eIF2α were assessed by western blot. Our results revealed that pre-treatment with irisin significantly decreased cytochrome c release from mitochondria and caspase-3 activation caused by H/R. Irsin also reduced apoptosis and increased cell viability. These effects were abolished by AMPK inhibitor compound C pre-treatment. Also, GRP78 and CHOP expressions were up-regulated in the H/R group compared to the control group; however, irisin attenuated their expression. The pAMPK level was significantly decreased compared to the control, and this effect could be partly reversed by metformin pre-treatment. These results suggest that ER stress is associated with cell viability decreasing and cardiomyocytes apoptosis induced by H/R. Irisin could efficiently protect cardiomyocytes from H/R-injury via attenuating ER stress and ER stress-induced apoptosis.

Accurate reconstruction of bone defects in orbital-maxillary-zygomatic (OMZ) complex with polyetheretherketone (PEEK).

PURPOSE: The aim of this study was to evaluate the safety and efficacy of using patient-specific polyetheretherketone (PEEK) for the reconstruction of patients with defects in orbital-maxillary-zygomatic (OMZ) complex. PATIENTS AND METHODS: This study included 12 patients who underwent primary/delayed reconstruction of defects in OMZ complex by using patient-specific PEEK implants. Postoperative appearance (facial and orbital symmetry) and function were assessed after 6 months. Ophthalmologic examinations including globe position, exophthalmos, and orbital volume measurement were also performed. A comparative analysis of the treatment outcomes between pre- and postoperation was performed, and a value of P < 0.05 was considered as significant. RESULTS: All patients underwent planned surgical procedure successfully. No obvious complications occurred. Facial symmetry and globe position were improved after surgery and the postoperative esthetic assessment was rated as excellent. The postoperative evaluation revealed that exophthalmos was 15.91 ± 1.80 mm, vertical position difference of eyeball 15.91 ± 1.80 mm, and orbital volume 15.91 ± 1.80 mm, respectively. There was a statistically significant difference in the mean values of exophthalmos, vertical position difference, and orbital volume among pre- and postoperation conditions, whereas there was no statistically significant difference between the reconstructed side and the unaffected side after surgery. CONCLUSION: With the aid of virtual surgical planning and individual custom-made surgical guides, patient-specific PEEK implantation can successfully reconstruct the complicated 3D structure of OMZ complex and shows excellent biocompatibility and clinical outcomes.

Single-Cell Quantitative Phenotyping via the Aptamer-Mounted Nest-PCR (Apt-nPCR).

Analyzing single-cell phenotypes is increasingly required in biomedical studies, for non-genetic understanding of cellular activities and the biological significance of rare cell subpopulations. However, as compared to the genotypic analysis, single-cell phenotype analysis is technically more challenging. Herein, a tractable method that allows quantitative phenotyping of single cell is developed in this work, termed as the aptamer-mounted nest-PCR (Apt-nPCR). In specific, only two rounds of PCR reactions are required to complete the analysis, where aptamers (short oligonucleotides that bind to specific target molecules) are used as the recognition elements to bind antigens and also as the templates of nPCR for multiplexed and quantitative detection. So, quantitative information of these target antigens can be revealed by quantitative PCR analysis of these aptamers, which can thus be used to interpret cell phenotypes in a quantitative-to-qualitative way. By addressing two technical issues that are involved in single-cell phenotype analysis─multiplexed detection plus high sensitivity, we have shown the availability of this method for single-cell phenotyping. Therefore, the Apt-nPCR method may represent a tractable method to facilitate the single-cell phenotype analysis, which can be used as a complementary method against these single-cell genotyping methods in our daily research.

Comprehensive Analysis of lncRNA and miRNA Regulatory Network Reveals Potential Prognostic Non-coding RNA Involved in Breast Cancer Progression.

Breast cancer is one of the most common malignant tumors in women and is the second leading cause of cancer deaths among women. The tumorigenesis and progression of breast cancer are not well understood. The existing researches have indicated that non-coding RNAs, which mainly include long non-coding RNA (lncRNA) and microRNA (miRNA), have gradually become important regulators of breast cancer. We aimed to screen the differential expression of miRNA and lncRNA in the different breast cancer stages and identify the key non-coding RNA using TCGA data. Based on series test of cluster (STC) analysis, bioinformatics analysis, and negatively correlated relationships, 122 lncRNAs, 67 miRNAs, and 119 mRNAs were selected to construct the regulatory network of lncRNA and miRNA. It was shown that the miR-93/20b/106a/106b family was at the center of the regulatory network. Furthermore, 6 miRNAs, 10 lncRNAs, and 15 mRNAs were significantly associated with the overall survival (OS, log-rank P < 0.05) of patients with breast cancer. Overexpressed miR-93 in MCF-7 breast cancer cells was associated with suppressed expression of multiple lncRNAs, and these downregulated lncRNAs (MESTIT1, LOC100128164, and DNMBP-AS1) were significantly associated with poor overall survival in breast cancer patients. Therefore, the miR-93/20b/106a/106b family at the core of the regulatory network discovered by our analysis above may be extremely important for the regulation of lncRNA expression and the progression of breast cancer. The identified key miRNA and lncRNA will enhance the understanding of molecular mechanisms of breast cancer progression. Targeting these key non-coding RNA may provide new therapeutic strategies for breast cancer treatment and may prevent the progression of breast cancer from an early stage to an advanced stage.

The Regulation Network and Clinical Significance of Circular RNAs in Breast Cancer.

Breast cancer is one of the most common malignant tumors in women worldwide. Circular RNA (circRNA) is a class of structurally stable non-coding RNA with a covalently closed circular structure. In recent years, with the development of high-throughput RNA sequencing, many circRNAs have been discovered and have proven to be clinically significant in the development and progression of breast cancer. Importantly, several regulators of circRNA biogenesis have been discovered. Here, we systematically summarize recent progress regarding the network of regulation governing the biogenesis, degradation, and distribution of circRNAs, and we comprehensively analyze the functions, mechanisms, and clinical significance of circRNA in breast cancer.

8-Formylophiopogonanone B antagonizes doxorubicin-induced cardiotoxicity by suppressing heme oxygenase-1-dependent myocardial inflammation and fibrosis.

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity.