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In recent decades, many serious respiratory infections have broken out all over the world, including SARS-CoV, MERS, and COVID-19. They are characterized by strong infectivity, rapid disease progression, high mortality, and poor prognosis. Excessive immune system activation results in cytokine hypersecretion, which is an important reason for the aggravation of symptoms, and can spread throughout the body leading to systemic multiple organ dysfunction, namely, cytokine release syndrome (CRS). Although many diseases related to CRS have been identified, the mechanism of CRS is rarely mentioned clearly. This review is intended to clarify the pathogenetic mechanism of CRS in the deterioration of related diseases, describe the important signaling pathways and clinical pathophysiological characteristics of CRS, and provide ideas for further research and development of specific drugs for corresponding targets to treat CRS. [ABSTRACT FROM AUTHOR]

Many studies have been conducted over the last few decades to understand better the functions of IRF3 and IRF7 in antiviral immune responses. However, the precise underlying molecular mechanism of IRF1-mediated immune response remains largely unknown. Recent studies indicate that IRF1 exerts strong antiviral activities against several viral infections through diverse mechanisms, both in IFN-dependent and IFN-independent manners. Nevertheless, the efficacy and kinetics of inducing IFNs and ISGs remain unknown. Here we summarize the recent advances in IRF1 research and highlight its potential roles in initiating IFN immune responses and subsequent IRF1-triggering antiviral responses. Challenges regarding the IFN positive feedback mediated by IRF7 during infection will be discussed; this classical loop may also be mediated in part by IRF1. Therefore, we propose a revised model that may help decipher the functional roles of IRF1 in antiviral immunity. [Display omitted] • IRF1 induces both IFN production and basal level of ISGs. • IRF1 involves an interferon induction in an IRF3 and IRF7 independent manner. • IRF1 is involved in the modification of JAK1, STAT1. • IRF1 is involved in the epigenetic regulation of ISGs. • Viruses evolve to antagonize the IRF1 mediated signaling pathway. [ABSTRACT FROM AUTHOR]

When DDR factors are defective or cytosolic DNA degradation enzymes are functionally mutated, aberrant DNAs will accumulate in the nucleus or the cytosol and be recognized by DNA sensors to trigger immune signaling activation. The DDR components RAD51 and RPA could bind to short nuclear ssDNA fragments, thereby preventing ssDNA's cytosolic leakage from inducing cGAS-dependent IFN-I activation [[29]]. Different DNA sensors recognize DNA depending on the structural features of the DNA ligands (circular or linear), the localization (in the nucleus or the cytoplasm), the source (damaged DNA or virus DNA), and the length of the DNA fragment. DNA damage accumulates gradually during genotoxic stress of replication, ionizing radiation, chemical regent, and virus infection, leading to the persistent activation of DNA damage sensors and the DNA damage responses (DDR). [Extracted from the article]

DExD/H-box helicases play critical roles in multiple cellular processes, including transcription, cellular RNA metabolism, translation, and infections. Several seminal studies over the past decades have delineated the distinct functions of DExD/H-box helicases in regulating antiviral innate immune signaling pathways, including Toll-like receptors, retinoic acid-inducible gene I-like receptors, cyclic GMP-AMP synthase-the stimulator of interferon gene, and NOD-like receptors signaling pathways. Besides the prominent regulatory roles, there is increasing attention on their functions as nucleic acid sensors involved in antiviral innate immunity. Here we summarize the complex regulatory roles of DExD/H-box helicases in antiviral innate immunity. A better understanding of the underlying molecular mechanisms of DExD/H-box helicases' regulatory roles is vital for developing new therapeutics targeting DExD/H-box helicases and their mediated signaling transduction in viral infectious diseases. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations in the PKD1 (~85%) or PKD2 (~15%) gene which, respectively, encode polycystin-1 (PC1) and polycystin-2 (PC2). How PC1 regulates cell proliferation and apoptosis has been studied for decades but the underlying mechanisms remain controversial. Protein kinase RNA-activated (PKR) is activated by interferons or double-stranded RNAs, inhibits protein translation, and induces cell apoptosis. In a previous study, we found that PC1 reduces apoptosis through suppressing the PKR/eIF2α signaling. Whether and how PKR is involved in PC1-inhibited proliferation and protein synthesis remains unknown. Here we found that knockdown of PKR abolishes PC1-inhibited proliferation and translation. Because suppressed PKR-eIF2α signaling/activity by PC1 would stimulate, rather than inhibit, the proliferation and translation, we examined the effect of dominant negative PKR mutant K296R that has no kinase activity and found that it enhances the inhibition of proliferation and translation by PC1. Thus, our study showed that inhibition of cell proliferation and protein synthesis by PC1 is mediated by the total expression but not the kinase activity of PKR, possibly through physical association. [ABSTRACT FROM AUTHOR]

Rhodiola crenulata is clinically used to combat hypobaric hypoxia brain injury at high altitude with the function of invigorating Qi and promoting blood circulation in Tibetan medicine. Salidroside (Sal), an active compound identified from Rhodiola species, has been shown to exert neuroprotective effects against hypoxic brain injury. However, its mitochondrial protective mechanisms remain largely unknown. The present study aimed to explore the mitochondrial protection of Sal and the involved mechanisms related to mitochondrial dynamics homeostasis on hypoxia-induced injury of HT22 cells. Hypoxic condition was performed as cells cultured in a tri-gas incubator with 1% O 2 , 5% CO 2 and 94% N 2. We firstly investigated the effects of different concentrations of Sal on the viability of normal or hypoxic HT22 cells. Whereafter, the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), adenosine triphosphate (ATP) and Na+-K+-ATPase were tested by commercial kits. Meanwhile, mitochondrial superoxide, intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were determined by specific labeled probes. Mitochondrial morphology was detected by mito-tracker green with confocal microscopy. Additionally, the potential interactions of Sal with Sirt1/p53/Drp1 signaling pathway-related proteins were predicted and tested by molecular docking and localized surface plasmon resonance (LSPR) techniques, respectively. Furthermore, the protein levels of Sirt1, p53, ac-p53, Drp1, p-Drp1(s616), Fis1 and Mfn2 were estimated by western blot analysis. Sal alleviated hypoxia-induced oxidative stress in HT22 cells as evidenced by increased cell viability and SOD activity, while decreased LDH release and MDA content. The protected mitochondrial function by Sal treatment was indicated by the increases of ATP level, Na+-K+-ATPase activity and MMP. Miraculously, Sal reduced hypoxia-induced mitochondrial fission, while increased mitochondrial tubular or linear morphology. The results of molecular docking and LSPR confirmed the potential binding of Sal to proteins Sirt1, p53, Fis1 and Mfn2 with affinity values 1.38 × 10−2, 5.26 × 10−3, 6.46 × 10−3 and 7.26 × 10−3 KD, respectively. And western blot analysis further demonstrated that Sal memorably raised the levels of Sirt1 and Mfn2, while decreased the levels of ac-p53, Drp1, p-Drp1 (s616) and Fis1. Collectively, our data confirm that Sal can maintain mitochondrial dynamics homeostasis by activating the Sirt1/p53/Drp1 signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

The purpose of this study is to determine whether IL-27 regulates macrophage ABCA1 expression, foam cell formation, and also explore the underlying mechanisms. Here, we revealed that IL-27 decreased lipid accumulation in THP-1 derived macrophages through markedly enhancing cholesterol efflux and increasing ABCA1 expression at both protein and mRNA levels. Our study further demonstrated that IL-27 increased ABCA1 level via activation of signal transducer and activator of transcription 3 (STAT3). Inhibition of Janus kinase 2, (JAK2)/STAT3 suppressed the stimulatory effects of IL-27 on ABCA1 expression. The present study concluded that IL-27 reduces lipid accumulation of foam cell by upregulating ABCA1 expression via JAK2/STAT3. Therefore, targeting IL-27 may offer a promising strategy to treat atherosclerotic vascular disease. [ABSTRACT FROM AUTHOR]

Summary: Hydrogen peroxide (H2O2) can serve as a beneficial signaling agent or toxin depending on its concentration and location within a cell or organism. Methods to measure the localized accumulation of H2O2 in living specimens remain limited. Motivated to meet this need, we have developed a nuclear-localized fluorescent probe for H2O2, Nuclear Peroxy Emerald 1 (NucPE1), to selectively interrogate ROS fluxes within this sensitive organelle. NucPE1 selectively accumulates in the nuclei of a variety of mammalian cell lines as well as in whole model organisms like Caenorhabditis elegans, where it can respond to subcellular changes in H2O2 fluxes. Moreover, in vivo NucPE1 imaging reveals a reduction in nuclear H2O2 levels in worms overexpressing sir-2.1 compared with wild-type congeners, supporting a link between this longevity-promoting sirtuin protein and enhanced regulation of nuclear ROS pools. [ABSTRACT FROM AUTHOR]

Microcystin-LR (MC-LR) contamination is a worldwide environmental problem that poses a grave threat to the water ecosystem and public health. Exposure to MC-LR has been associated with the development of intestinal injury, but there are no effective treatments for MC-LR-induced intestinal disease. Probiotics are "live microorganisms that are beneficial to the health of the host when administered in sufficient quantities". It has been demonstrated that probiotics can prevent or treat a variety of human diseases; however, their ability to mitigate MC-LR-induced intestinal harm has not yet been investigated. The objective of this study was to determine whether probiotics can mitigate MC-LR-induced intestinal toxicity and its underlying mechanisms. We first evaluated the pathological changes in colorectal tissues using an animal model with sub-chronic exposure to low-dose MC-LR, HE staining to assess colorectal histopathologic changes, qPCR to detect the expression levels of inflammatory factors in colorectal tissues, and WB to detect the alterations on CSF1R signaling pathway proteins in colorectal tissues. Microbial sequencing analysis and screening of fecal microorganisms differential to MC-LR treatment in mice. To investigate the role of microorganisms in MC-LR-induced colorectal injury, an in vitro model of MC-LR co-treatment with microorganisms was developed. Our findings demonstrated that MC-LR treatment induced an inflammatory response in mouse colorectal tissues, promoted the expression of inflammatory factors, activated the CSF1R signaling pathway, and significantly decreased the abundance of Lactobacillus. In a model of co-treatment with MC-LR and Lactobacillus fermentum (L. fermentum), it was discovered that L. fermentum substantially reduced the incidence of the colorectal inflammatory response induced by MC-LR and inhibited the protein expression of the CSF1R signaling pathway. This is the first study to suggest that L. fermentum inhibits the CSF1R signaling pathway to reduce the incidence of MC-LR-induced colorectal inflammation. This research may provide an excellent experimental foundation for the development of strategies for the prevention and treatment of intestinal diseases in MC-LR. [ABSTRACT FROM AUTHOR]

Previous studies have primarily concentrated on the hepatotoxicity of MC-LR, whereas its gastric toxicity effects and mechanisms of long-term exposure under low dosage remain unknown. Herein, the gastric tissue from C57BL/6 mice fed with drinking water contaminated by low-dose MC-LR (including 1, 60, and 120 μg/L) was investigated. The results obtained showed that exposure to different concentrations of MC-LR resulted in significant shedding and necrosis of gastric epithelial cells in mice, and a down-regulation of tight junction markers, including ZO-1, Claudin1, and Occludin in the stomach, which might lead to increased permeability of the gastric mucosa. Moreover, the protein expression levels of p-RAF/RAF, p-ERK1/2/ERK1/2, Pink1, Parkin, and LC3-II/LC-3-I were increased in the gastric tissue of mice exposed to 120 μg/L of MC-LR, while the protein expression level of P62 was significantly decreased. Furthermore, we found that pro-inflammatory factors, including IL-6 and TNF-ɑ, were dramatically increased, while the anti-inflammatory factor IL-10 was significantly decreased in the gastric tissue of MC-LR-exposed mice. The activation of the MAPK signaling pathway and mitophagy might contribute to the development of gastric damage by promoting inflammation. We first reported that long-term exposure to MC-LR induced gastric toxicity by activating the MAPK signaling pathway, providing a new insight into the gastric toxic mechanisms caused by MC-LR. [ABSTRACT FROM AUTHOR]

Cell migration and invasion were measured by wound-healing (e) and Transwell assays (f) in the presence or absence of LY294002. g Western blotting analysis of the expression of p-AKT, p-PI3K, total AKT and total PI3K. 6AGK stimulates the PI3K/AKT signalling pathway. a KEGG analysis was conducted to identify the pathways activated by AGK overexpression in RCC. b MTT assay, c colony formation assay and d flow cytometric analysis of the proliferation of the indicated RCC cells in the presence or absence of the PI3K inhibitor LY294002. Correction: Acylglycerol kinase promotes tumour growth and metastasis via activating the PI3K/AKT/GSK3 signalling pathway in renal cell carcinoma. [Extracted from the article]

For patients exhibiting non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a first-line treatment. However, most patients who initially responded to EGFR-TKIs eventually developed acquired resistance, limiting the effectiveness of therapy. It has long been known that epithelial–mesenchymal transition (EMT) leads to acquired resistance to EGFR-TKIs in NSCLC. However, the mechanisms underlying the resistance dependent on EMT are unknown. This research aimed to reveal the effects of LMNA in the regulation of acquired resistance to erlotinib by EMT in NSCLC. The acquired erlotinib-resistant cells (HCC827/ER) were induced by gradual increase of concentrations of erlotinib in erlotinib-sensitive HCC827 cells. RNA sequencing and bioinformatics analysis were performed to uncover the involvement of LMNA in the EMT process that induced acquired resistance to erlotinib. The effect of LMNA on cell proliferation and migration was measured by clone-formation, wound-healing, and transwell assays, respectively. The EMT-related protein, nuclear shape and volume, and cytoskeleton changes were examined by immunofluorescence. Western blot was used to identify the underlying molecular mechanism of LMNA regulation of EMT. HCC827/ER cells with acquired resistance to erlotinib underwent EMT and exhibited lower LMNA expression compared to parental sensitive cells. LMNA negatively regulated the expression of EMT markers; HCC827/ER cells showed a significant up-regulation of mesenchymal markers, such as CDH2, SNAI2, VIM, ZEB1, and TWIST1. The overexpression of LMNA in HCC827/ER cells significantly inhibited EMT and cell proliferation, and this inhibitory effect of LMNA was enhanced in the presence of 2.5 μM erlotinib. Furthermore, a decrease in LMNA expression resulted in a higher nuclear deformability and cytoskeletal changes. In HCC827/ER cells, AKT, FGFR, ERK1/2, and c-fos phosphorylation levels were higher than those in HCC827 cells; Furthermore, overexpression of LMNA in HCC827/ER cells reduced the phosphorylation of AKT, ERK1/2, c-fos, and FGFR. In conclusion, our findings first demonstrated that downregulation of LMNA promotes acquired EGFR-TKI resistance in NSCLC with EGFR mutations by EMT. LMNA inhibits cell proliferation and migration of erlotinib-resistant cells via inhibition of the FGFR/MAPK/c-fos signaling pathway. These findings indicated LMNA as a driver of acquired resistance to erlotinib and provided important information about the development of resistance to erlotinib treatment in NSCLC patients with EGFR mutations. [ABSTRACT FROM AUTHOR]

Background: The source of SAN is debated among researchers. Many studies have shown that RA and Wnt signaling are involved in heart development. In this study, we investigated the role of retinoic acid (RA) and Wnt signaling in the induction of sinus node-like cells. Methods: The experimental samples were divided into four groups: control group (CHIR = 0), CHIR = 3, RA + CHIR = 0 andRA + CHIR = 3. After 20 days of differentiation, Western blot, RT-qPCR, immunofluorescence and flow cytometry were performed to identify sinus node-like cells. Finally, whole-cell patch clamp technique was used to record pacing funny current and action potential (AP) in four groups. Results: The best intervention method used in our experiment was RA = 0.25 µmol/L D5-D9 + CHIR = 3 µmol/L D5-D7. Results showed that CHIR can increase the expression of ISL-1 and TBX3, while RA mainly elevated Shox2. Immunofluorescence assay and flow cytometry further illustrated that combining RA with CHIR can induce sinus node-like cells (CTNT+Shox2+Nkx2.5−). Moreover, CHIR might reduce the frequency of cell beats, but in conjunction with RA could partly compensate for this side effect. Whole cell patch clamps were able to record funny current and the typical sinus node AP in the experimental group, which did not appear in the control group. Conclusions: Combining RA with Wnt signaling within a specific period can induce sinus node-like cells. [ABSTRACT FROM AUTHOR]

Background: The source of SAN is debated among researchers. Many studies have shown that RA and Wnt signaling are involved in heart development. In this study, we investigated the role of retinoic acid (RA) and Wnt signaling in the induction of sinus node-like cells. Methods: The experimental samples were divided into four groups: control group (CHIR = 0), CHIR = 3, RA + CHIR = 0 andRA + CHIR = 3. After 20 days of differentiation, Western blot, RT-qPCR, immunofluorescence and flow cytometry were performed to identify sinus node-like cells. Finally, whole-cell patch clamp technique was used to record pacing funny current and action potential (AP) in four groups. Results: The best intervention method used in our experiment was RA = 0.25 µmol/L D5-D9 + CHIR = 3 µmol/L D5-D7. Results showed that CHIR can increase the expression of ISL-1 and TBX3, while RA mainly elevated Shox2. Immunofluorescence assay and flow cytometry further illustrated that combining RA with CHIR can induce sinus node-like cells (CTNT+Shox2+Nkx2.5−). Moreover, CHIR might reduce the frequency of cell beats, but in conjunction with RA could partly compensate for this side effect. Whole cell patch clamps were able to record funny current and the typical sinus node AP in the experimental group, which did not appear in the control group. Conclusions: Combining RA with Wnt signaling within a specific period can induce sinus node-like cells. [ABSTRACT FROM AUTHOR]

Promoting the recovery of cerebral blood circulation after cerebral infarction (CI) is an important intervention. Buyang Huanwu decoction (BHD) is a classic prescription for treating CI that promotes angiogenesis. Cytoplasmic glycolysis ischaemic-region cells after CI may be highly activated to maintain metabolic activity under hypoxia. From the perspective of long-term maintenance of glycolytic metabolism in the ischaemic area after CI, it may be beneficial to promote angiogenesis and maintain glial cell activation and neuronal survival. In this context, the regulatory relationship of lncRNAs and miRNAs with mRNAs is worthy of attention. Mining the competitive binding relationships among RNAs will aid in the screening of key gene targets post-CI. In this study, network pharmacology and bioinformatics were used to construct a ceRNA network, screen key targets, and explore the effect of glycolysis on angiogenesis during BHD-mediated CI regulation. This study aimed to explore the effect of BHD on angiogenesis after glycolysis regulation in CI. According to the 21 active BHD ingredients we identified by our research team, we conducted network pharmacology. BHD targets that can regulate glycolysis and angiogenesis after CI were screened from the GeneCards, CTD and OMIM databases. We retrieved CI-related datasets from the GEO database and screened for differentially expressed lncRNAs and miRNAs. LncRNA‒miRNA–mRNA/TF targeting relationships were screened and organized with the miRcode, miRDB, TargetScan, miRWalk, and TransmiR v2.0 databases. Cytoscape was used to construct an lncRNA‒miRNA–mRNA/TF ceRNA network. Through BioGPS, key mRNAs/TFs in the network were screened for enrichment analysis. Animal experiments were then conducted to validate some key mRNAs/TFs and enriched signalling pathways. PFKFB3 and other genes may help regulate glycolysis and angiogenesis through AMPK and other signalling pathways. The anti-CI effect of BHD may involve maintaining activation of genes such as AMPK and PFKFB3 in the ischaemic cortex, maintaining moderate glycolysis levels in brain tissue, and promoting angiogenesis. BHD can regulate glycolysis and promote angiogenesis after CI through multiple pathways and targets, in which AMPK signalling pathway activation may be important. [Display omitted] • Glycolysis is the main energy source of angiogenesis after cerebral infarction. • BHD regulates glycolysis and promotes angiogenesis after cerebral infarction. • BHD promotes angiogenesis may be related to the maintenance of AMPK activation. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a prevalent cancer that plagues people worldwide. Identifying prognostic markers would be useful in treating human OS. In this study, we aimed to explore the functions of Ras-related protein Rab-31 (RAB31) in OS-cell proliferation, migration, and invasion as well as its roles in the Hedgehog signaling pathway for better understanding of the mechanism. To assess the detailed regulatory mechanism of RAB31 silencing on OS, both RT-qPCR and Western blot analysis were employed to evaluate the expressions of RAB31 as well as the Hedgehog signaling pathway-related genes. Besides, we also investigated the effects of silenced RAB31 both in vitro and in vivo. First, we found that in OS tissues, both mRNA and protein expressions of RAB31 and PCNA had a significant increase. Second, the Hedgehog signaling pathway was detected to play an integral role in OS progression. Finally, after transfection of RAB31-siRNA to reduce the expression of RAB31, the Hedgehog signaling pathway was suppressed, along with cell proliferation, invasion, and migration. Therefore, we conclude that RAB31 plays an important role in OS development and its silencing delays the OS progression via suppression of the Hedgehog signaling pathway. [ABSTRACT FROM AUTHOR]

The authors have retracted this article. After publication the authors discovered that they were unable to repeat their results. In this article the authors concluded that silencing the rab31 gene inhibits hedgehog pathway activation, but in the repeated experiments the authors found that the Hedgehog pathway was not activated when the rab31 gene was over-expressed. [ABSTRACT FROM AUTHOR]

Our previous study demonstrated that the melastatin-related transient receptor potential channel 7 (TRPM7) was highly expressed in ovarian carcinomas and its overexpression was significantly associated with poor prognosis in ovarian cancer patients. However, the function of TRPM7 in ovarian cancer is mostly unknown. In this study, we examined the roles of TRPM7 in ovarian cancer cell proliferation, migration and invasion. We found that short hairpin RNA interference-mediated silence of TRPM7 significantly inhibited cell proliferation, colony formation, migration and invasion in multiple ovarian cancer cell lines. Mechanistic investigation revealed that silence of TRPM7 decreased phosphorylation levels of Akt, Src and p38 and increased filamentous actin and focal adhesion number in ovarian cancer cells. Thus, our results suggest that TRPM7 is required for proliferation, migration and invasion of ovarian cancer cells through regulating multiple signaling transduction pathways and the formation of focal adhesions. [ABSTRACT FROM AUTHOR]

Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-β protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(−), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer. [ABSTRACT FROM AUTHOR]

The rapid increase in cancer morbidity and mortality worldwide is a major challenge for public health providers. Therefore, there is an urgent need to explore the molecular mechanism of tumorigenesis and identify potential diagnostic biomarkers and therapeutic methods. Circular RNA (circRNA) is characterized by a stable structure and tissue-specific expression; these features are useful in medical research and clinical applications. In recent years, with the development of high-throughput sequencing technology, the potential use of circRNA in cancer prognosis and treatment has been extensively explored. Abnormal circRNA expression interferes with specific signaling pathways such as the MAPK pathway; this phenomenon may provide potential diagnostic biomarkers and new therapeutic targets. The present article discusses the research progress on the regulatory roles of MAPK/ERK pathway-related circRNA molecules in the development and progression of different types of tumors. This review may provide insight into the development of circRNA-based cancer management strategies. [ABSTRACT FROM AUTHOR]

Abstract: Mesenchymal stem cells (MSCs) are pluripotent progenitors that can differentiate into a variety of cell types. Vascular endothelial growth factor (VEGF) is one of the major factors of initiating and regulating angiogenesis. It has been reported that VEGF can induce MSCs differentiated into endothelial cells (ECs). However, the mechanism that VEGF-induced MSC differentiation is not completely understood. Here, we showed that VEGF induced human and rat bone marrow-derived MSCs differentiation to ECs. Rho family plays an important role in VEGF-induced endothelial cell migration and angiogenesis. Our results indicated that in MSCs, VEGF activated Rho/ROCK signaling pathway and promoted nuclear translocation of myocardin-related transcription factor-A (MRTF-A), which is controlled by Rho/ROCK signaling. In addition, Rho inhibitor C3 transferase, ROCK inhibitor Y27632 or depletion of endogenous MRTF-A abolished the VEGF-induced differentiation of MSCs into ECs. Furthermore, VEGF also enhanced the expression levels of CYR61/CCN1, as a regulator of vascular development and angiogenesis, and knockdown of endogenous MRTF-A reduced VEGF-induced the upregulation of CYR61/CCN1. Report assays with site-direct mutation analysis of CYR61/CCN1 promoter demonstrated that MRTF-A transactivated CYR61/CCN1 promoter mainly depending on CArG box. In this study, we identify the Rho/MRTF-A signaling pathway as a main actor in controlling VEGF-induced differentiation of human and rat bone marrow-derived MSCs into endothelial cells. [Copyright &y& Elsevier]

BACKGROUND AND PURPOSE One key mechanism for endothelial dysfunction is endothelial NOS (eNOS) uncoupling, whereby eNOS generates superoxide (O2•−) rather than NO. We explored the effect of pyridoxine on eNOS uncoupling induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells (HUVECs) and the potential molecular mechanism. EXPERIMENTAL APPROACH HUVECs were incubated with ox-LDL with/without pyridoxine, NG-nitro-L-arginine methylester (L-NAME), chelerythrine chloride (CHCI) or apocynin. Endothelial O2•− was measured using lucigenin chemiluminescence, and O2•−-sensitive fluorescent dye dihydroethidium (DHE). NO levels were measured by chemiluminescence, PepTag Assay for non-radioactive detection of PKC activity, depletion of PKCα and p47phox by siRNA silencing and the states of phospho-eNOS Thr495, total-eNOS, phospho-PKCα/βII, total PKC, phospho-PKCα, total PKCα and p47phox were measured by Western blot. KEY RESULTS Ox-LDL significantly increased O2•− production and reduced NO levels released from HUVECs; an effect reversed by eNOS inhibitor, L-NAME. Pyridoxine pretreatment significantly inhibited ox-LDL-induced O2•− generation and preserved NO levels. Pyridoxine also prevented the ox-LDL-induced reduction in phospho-eNOS Thr495 and PKC activity. These protective effects of pyridoxine were abolished by the PKC inhibitor, CHCI, or siRNA silencing of PKCα. However, depletion of p47phox or treatment with the NADPH oxidase inhibitor, apocynin, had no influence on these effects. Also, cytosol p47phox expression was unchanged by the different treatments. CONCLUSIONS AND IMPLICATIONS Pyridoxine mitigated eNOS uncoupling induced by ox-LDL. This protectant effect was related to phosphorylation of eNOS Thr495 stimulated by PKCα, not via NADPH oxidase. These results provide support for the use of pyridoxine in ox-LDL-related vascular endothelial dysfunction. [ABSTRACT FROM AUTHOR]