Simulated Microgravity Inhibits Rodent Dermal Fibroblastic Differentiation of Mesenchymal Stem Cells by Suppressing ERK/β-Catenin Signaling Pathway

Studies have shown that bone marrow-derived mesenchymal stem cells (BMSCs) can differentiate into dermal fibroblasts to participate in skin-repairing. However, at present, little is known about how microgravity affects dermal fibroblastic differentiation of BMSCs in space. The aim of this study was to investigate the effect of simulated microgravity (SMG) on the differentiation of BMSCs into dermal fibroblasts and the related molecular mechanism. Here, using a 2D-clinostat device to simulate microgravity, we found that SMG inhibited the differentiation and suppressed the Wnt/β-catenin signaling and phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2). After upregulating the Wnt/β-catenin signaling with lithium chloride (LiCl) treatment, we found that the effect of the differentiation was restored. Moreover, the Wnt/β-catenin signaling was upregulated when phosphorylation of ERK1/2 was activated with tert-Butylhydroquinone (tBHQ) treatment. Taken together, our findings suggest that SMG inhibits dermal fibroblastic differentiation of BMSCs by suppressing ERK/β-catenin signaling pathway, inferring that ERK/β-catenin signaling pathway may act as a potential intervention target for repairing skin injury under microgravity conditions.

Syndecan-2, negatively regulated by miR-20b-5p, contributes to 5-fluorouracil resistance of colorectal cancer cells via the JNK/ERK signaling pathway

5-Fluorouracil (5-FU) resistance has been long considered as an obstacle to the efficacy of chemotherapy in colorectal cancer (CRC). In this study, we demonstrated the role of miR-20b-5p-regulated syndecan-2 (SDC2) in 5-FU resistance of CRC cells. 5-FU-resistant SW480 CRC cells were established by treatment of SW480 cells with stepwise increase of 5-FU concentration. The results showed that SDC2 was expressed significantly higher in SW480/5-FU cells than in SW480/WT cells as revealed by quantitative real-time polymerase chain reaction and western blot analysis. MTT assay and BrdU assay showed that SDC2 overexpression led to increased cell survival rate, while SDC2 knockdown reversed the drug resistance of SW480/5-FU cells. Wound healing and transwell invasion assays revealed that knockdown of SDC2 inhibited the migratory and invasive ability of SW480/5-FU cells. Moreover, animal experiments indicated that si-SDC2 plays a suppressive role in tumor growth in vivo. We also confirmed that miR-20b-5p interacted with SDC2, which reversed the effect of SDC2 in SW480/5-FU cells via the c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinases (ERK) signaling pathway. These findings showed that JNK/ERK signaling pathway is involved in miR-20b-5p/SDC2 axis-mediated 5-FU resistance in SW480/5-FU cells, indicating that the miR-20b-5p/SDC2 axis is a potential target for reversing 5-FU resistance in CRC.

The neuroprotection effects of exosome in central nervous system injuries: A new target for therapeutic intervention

Central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI) and subarachnoid hemorrhage (SAH), are the most common cause of death and disability around the world. As a key subset of extracellular vesicles (EVs), exosomes have recently attracted great attentions due to their functions in remodeling extracellular matrix, and transmitting signals and molecules. A large number of studies have suggested that exosomes played an important role in brain development and involved in many neurological disorders, particularly in CNS injuries. It has been proposed that exosomes could improve cognition function, inhibit apoptosis, suppress inflammation, regulate autophagy and protect blood brain barrier (BBB) in CNS injuries via different molecules and pathways including microRNA (miRNA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ph1osphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), Notch1 and extracellular regulated protein kinases (ERK). Therefore, exosomes showed great promise as potential targets in CNS injuries. In this article, we present a review highlighting the applications of exosomes in CNS injuries. Hence, on the basis of these properties and effects, exosomes may be developed as therapeutic agents for CNS injury patients.

P2X7 Receptor Deficiency Ameliorates STZ-induced Cardiac Damage and Remodeling Through PKCβ and ERK

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus which result in cardiac remodeling and subsequent heart failure. However, the role of P2X7 receptor (P2X7R) in DCM has yet to be elucidated. The principal objective of this study was to investigate whether P2X7R participates in the pathogenesis of DCM. In this study, the C57BL/6 diabetic mouse model was treated with a P2X7R inhibitor (A438079). Cardiac dysfunction and remodeling were attenuated by the intraperitoneal injection of A438079 or P2X7R deficiency. In vitro, A438079 reduced high glucose (HG) induced cell damage in H9c2 cells and primary rat cardiomyocytes. Furthermore, HG/streptozotocin (STZ)-induced P2X7R activation mediated downstream protein kinase C-β (PKCβ) and extracellular regulated protein kinases (ERK) activation. This study provided evidence that P2X7R plays an important role in the pathogenesis of STZ-induced diabetic cardiac damage and remodeling through the PKCβ/ERK axis and suggested that P2X7R might be a potential target in the treatment of diabetic cardiomyopathy.

The S1PR1 Agonist SEW2871 promotes the Survival of Skin Flap

Skin flap transfer is an important method to repair and reconstruct various tissue defects. However, avascular necrosis largely affects the success of flap transfer. The sphingosine-1-phosphate receptor 1 (S1PR1) agonist SEW2871 has been proven to ameliorate ischemic injury. However, its effect on flap survival has not been reported. In this study, an experimental skin flap model was established in rats to investigate the roles of SEW2871. The results indicated that SEW2871 greatly increased the survival of the skin flap, alleviated pathological injury, promoted the angiogenesis, and inhibited cells apoptosis in skin flap tissues. SEW2871 activated S1PR1 downstream signaling pathways, including heat shock protein 27 (HSP27), extracellular regulated protein kinases (ERK) and Akt. In addition, SEW2871 promoted the expression of S1PR1. These findings may provide novel insights for skin flap transfer.

Chemerin Promotes Mitogen-activated Protein Kinase / Extracellular Regulated Protein Kinases Activation to Induce Inflammatory Factor Production in Rat Synoviocytes

AimChemerin is a chemokine from adipose tissue that specifically binds to the G protein-coupled receptor ChemR23 and has a chemotactic effect on macrophages and dendritic cells. A correlation between chemerin levels in synovial fluid and disease severity has been demonstrated in patients with osteoarthritis. However, the specific mechanism by which chemerin exerts its effects on osteoarthritis remains unclear. In this study, we investigated the mechanism of chemerin-associated synoviocyte inflammation.MethodsCell Counting Kit-8 (CCK-8) assays were used to identify concentrations of chemerin that had an effect on normal rat synoviocytes. The expression changes of mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinases (ERK) pathway marker genes, including MEK, ERK, matrix metalloproteinase (MMP)-3 and MMP-13, were detected by fluorescence quantitative polymerase chain reaction (PCR). The phosphorylation of MEK, ERK1/2 and p38 mitogen-activated protein kinases (p38MAPK) by chemerin was analyzed by Western blotting, and the production of inflammatory factors after chemerin treatment was determined by enzyme-linked immunosorbent assay (ELISA). For in vivo assessment of chemerin function, rats were subjected to knee operation to provide a model for arthritis. The knees were then injected with normal saline or recombinant chemerin, and three weeks later, the synovium and knee joint tissue were harvested for HE staining observation and the synovial tissue was harvested for ELISA.ResultsChemerin was demonstrated to enhance the proliferation of synoviocytes in a dose-dependent manner. The stimulatory effect of chemerin on synoviocytes was shown to involve the activation of MEK, ERK1/2 and p38, which was associated with the production of MMP-13, MMP-3, interleukin (IL)-6 and IL-1β by synoviocytes. Inhibition of the ERK1/2 signaling pathway significantly inhibited chemerin-induced MMP-13, MMP-3, IL-6 and IL-1β production. HE staining showed that the degree of synovial hyperplasia and articular cartilage abrasion was more severe in chemerin-treated rats after knee operation. The articular cartilage surface was damaged, and the synovial tissue showed inflammatory cell infiltration. In rats that underwent operation without chemerin treatment, there was a slight inflammatory infiltration and higher levels of inflammatory factors as compared to unoperated rats; however, secretion of the downstream inflammatory factors IL-6, matrix metalloproteinases (MMP-3 and MMP-13) and IL-1β was significantly greater in the drug-treated group (P<0.05).ConclusionChemerin enhances the production of inflammatory factors in synoviocytes by activating the MEK/ERK signaling pathway.

Toxic Effects of Docosahexaenoic Acid Treatment in the Rat Liver BRL-3A Cell

The cytotoxicity of docosahexaenoic acid (DHA) on normal cells is still unclear. This study investigated the effects of DHA on the cytotoxicity and possible mechanism in the BRL-3A cell. The cultured rat liver BRL-3A cell line was treated with 50, 100 and 200 μM DHA for 24 h. The cell viability was increased in the 50 and 100 μM DHA treatments, but decreased in the 200 μM DHA treatment. The 50, 100 and 200 μM DHA treatments increased the proportion of the apoptotic cells, the levels of lactate dehydrogenase (LDH), alkaline phosphatase (AKP) and IL-6 in the supernatant, and the ratio of the phosphonated p38MAPK to the p38MAPK (p-p38/p38) protein in the cells. The expression of TGF beta-activated kinase 1 (TAK1), nuclear transcription factor-κB p65 (NF-κB p65) and the inhibitor of NF-κB alpha (IκBα) mRNA, and the ratio of the phosphonated IκBα (p-IκBα) to IκBα protein were increased in the 200 μM DHA treatment, while the ratio of phosphonated extracellular regulated protein kinases (p-ERK) to ERK protein was decreased in the 200 μM DHA treatment. These results indicate that DHA-treated (50, 100 and 200 μM) BRL-3A cells for 24 h promotes cell apoptosis and inflammatory response, and the p38 MAPK, ERK and NF-κB signal pathways were involved in mediating the apoptosis and inflammatory response.

Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy

Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.

Latilactobacillus curvatus: A Candidate Probiotic with Excellent Fermentation Properties and Health Benefits

Latilactobacillus curvatus is a candidate probiotic that has been included in the list of recommended biological agents for certification by the European Food Safety Authority. According to the published genomic information, L. curvatus has several genes that encode metabolic pathways of carbohydrate utilization. In addition, there are some differences in cell surface complex related genes of L. curvatus from different sources. L. curvatus also has several genes that encode bacteriocin production, which can produce Curvacin A and Sakacin P. Due to its ability to produce bacteriocin, it is often used as a bioprotective agent in fermented meat products, to inhibit the growth of a variety of pathogenic and spoilage bacteria. L. curvatus exerts some probiotic effects, such as mediating the production of IL-10 by dendritic cells through NF-κB and extracellular regulated protein kinases (ERK) signals to relieve colitis in mice. This review is the first summary of the genomic and biological characteristics of L. curvatus. Our knowledge on its role in the food industry and human health is also discussed, with the aim of providing a theoretical basis for the development of applications of L. curvatus.