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Additionally, we found that over time hBEX3 transits from liquid condensates to aggregates that are reversible upon temperature increment and dissolved by 1,6-hexanediol. hBEX3 assemblies display different morphology in the presence of the tRFs that seems to protect from amyloid formation. Collectively, our findings support a role for tRFs in hBEX3 disorder-to-order transition and modulation of phase transitions. Moreover, hBEX3 aggregation-prone features and the specificity in interaction with tRNA fragments advocate paramount importance toward understanding BEX family involvement in neurodevelopment and cell death. In the beginning stage of heart disease, the blockage of blood flow frequently occurs due to the persistent damage and even death of myocardium. Cicatricial tissue developed after the death of myocardium can affect heart function, which ultimately leads to heart failure. In recent years, several studies carried out about the use of stem cells such as embryonic, pluripotent, cardiac and bone marrow-derived stem cells as well as myoblasts to repair injured myocardium. Current studies focus more on finding appropriate measures to enhance cell homing and survival in order to increase paracrine function. Until now, there is no universal delivery route for mesenchymal stem cells (MSCs) for different diseases. In this review, we summarize the advantages and challenges of the systemic and local pathways of MSC delivery. In addition, we also describe some advanced measures of cell delivery to improve the efficiency of transplantation. The combination of cells and therapeutic substances could be the most reliable method, which allows donor cells to deliver sufficient amounts of paracrine factors and provide long-lasting effects. The cardiac support devices or tissue engineering techniques have the potential to facilitate the controlled release of stem cells on local tissue for a sustained period. A novel promising epicardial drug delivery system is highlighted here, which not only provides MSCs with a favorable environment to promote retention but also increases the contact area and a number of cells recruited in the heart muscle. Identification of the roles of epigenetic alterations in cancers has suggested that different molecules involved in this process are potentially therapeutic targets. Given the role of histone deacetylases (HDACs) enzymes in leukemogenesis, we designed a study to investigate the anti-leukemic property of panobinostat, a HDAC inhibitor, in acute lymphoblastic leukemia (ALL) cells. Our results showed that panobinostat decreased cell viability of pre-B ALL-derived cells. The favorable anti-leukemic effects of the inhibitor was further confirmed by cell cycle analysis, where we found that panobinostat prolonged the transition of the cells from G1 phase probably through c-Myc-mediated up-regulation of cyclin-dependent kinase inhibitors. Unlike the apoptotic effect of panobinostat on Nalm-6 cells, the expression of anti-apoptotic nuclear factor-kappa B (NF-κB) target genes remained unchanged. Accordingly, we found that the inhibition of NF-κB pathway using bortezomib boosted the effect of panobinostat, indicating that panobinostat-induced apoptosis could be attenuated through the activation of the NF-κB pathway. The results of the present study reflected another aspect of autophagy in leukemic cells, as we showed that although Nalm-6 cells could exploit autophagy to override the anti-survival effect of HDAC inhibition, the presence of an autophagy inhibitor could alter the compensatory circumstance to induce cell death. Beyond panobinostat cytotoxicity as a single agent, synergistic experiments outlined that pharmaceutical targeting of HDACs could amplify the cytotoxicity of vincristine in ALL cells, delineating that panobinostat, either as a single agent or in a combined modality, possesses novel promising potentials for the treatment of ALL. Initiation of necroptosis has been considered as a promising strategy for anticancer therapies, especially for eradicating apoptosis-resistant malignant cells. Jujubisode B is a natural saponins extracted from the seeds of Zizyphi Spinosi Semen, and possesses multiple pharmacological activities, including antianxiety, anti-inflammation, antiplatelet aggregation and induction of apoptosis. This study aims to explore the effect of jujuboside B on acute leukemic cells and the underlying mechanisms. Our results showed that jujuboside B inhibited leukemia cell growth in a dose-dependent manner and attenuated the clonogenic ability of U937 cells, concomitant with activation of RIPK1/RIPK3/MLKL pathway; these phenomena were evidently blocked by necroptosis inhibitor (Nec-1). check details With the help of Molecular Operating Environment (MOE) program, we identified that RIPK1, RIPK3 and MLKL are potential targets of jujuboside B. To the best of our knowledge, this is the first study to provide evidence that jujuboside B possesses antileukemic activity via a mechanism involving activation of RIPK1/RIPK3/MLKL pathway. link2 Chronic inflammation is the hallmark of cardiovascular pathologies with a major role in both disease progression and occurrence of long-term complications. The massive release of ATP during the inflammatory process activates various purinergic receptors, including P2Y11. This receptor is less studied but ubiquitously expressed in all cells relevant for cardiovascular pathology cardiomyocytes, fibroblasts, endothelial and immune cells. While several studies suggested a potential pro-inflammatory role for P2Y11 receptors, recent literature data are supportive of an anti-inflammatory profile characterized by the immunosuppression of dendritic cells, inhibition of fibroblast proliferation and of cytokines and ATP secretion. Moreover, modulation of its activity appears to mediate the positive inotropic effect of ATP and mitigate endothelial dysfunction, thus rendering this receptor a promising therapeutic target in the cardiovascular disease armamentarium. The aim of the present review is to summarize the current available knowledge on P2Y11-related purinergic signaling in the setting of inflammation and cardio-metabolic diseases. V.AIMS To investigate the role and mechanism of insulin-like growth factor 1(IGF-1)-mediated EMT on multiple myeloma (MM) growth and metastasis. MATERIALS AND METHODS The expression data from GEO datasets were utilized to explore the expression levels of IGF-1 and epithelial-mesenchymal transition (EMT) markers in MM. Western blotting and flow cytometry analysis were performed to detect the protein levels of EMT markers as well as key components of the PI3K/Akt pathway. Cell proliferation ability was assessed using colony formation assay and EdU incorporation assays. Transwell migration and invasion assays were performed to assess cell metastasis properties. Vimentin was knocked down by using electro-transfection with small interfering RNA (siRNA) to detect the effect of IGF-1-mediated EMT on MM cell growth and metastasis. KEY FINDINGS First of all, the analysis of GEO database revealed that IGF-1 was excessively expressed and closely correlated with the expression of the EMT markers in MM patients. Furthermore, we demonstrated that IGF-1 enhanced the acquisition of mesenchymal features in a time-dependent manner. Additionally, in vitro studies revealed that IGF-1-mediated mesenchymal phenotype promoted MM migration, invasion and colony formation. Finally, the mechanism study showed PI3K/Akt signaling pathway was involved in the IGF-1-induced EMT in MM cells. SIGNIFICANCE IGF-1-induced mesenchymal phenotype contributed to MM progression via the PI3K/Akt pathway regulation. AIMS Aldehyde reductase (AKR1A) is involved in the synthesis of ascorbic acid (AsA) as well as the detoxification of aldehydes. AKR1A-/- (KO) mice produce about 10% of the normal amounts of AsA compared to AKR1A+/+ (WT) mice. link3 We investigated physiologic roles of AKR1A in running using the KO mice. MAIN METHODS The KO mice were subjected to a treadmill test under either restricted AsA production or a sufficiency by supplementation and compared the results with those of WT mice. Contents of glucose, aspartate aminotransferase, AsA and free fatty acids in blood were measured. Glycogen contents were measured in the liver and skeletal muscle, and hepatic proteins were examined by immunoblot analyses. KEY FINDINGS Running performance was higher in the KO mice than the WT mice irrespective of the AsA status. After the exercise period, blood glucose levels were decreased in the WT mice but were preserved in the KO mice. Liver glycogen levels were also consistently preserved in the KO mice after exercise. Free fatty acid levels tended to be originally high in blood plasma compared to those of the WT mice and were increased to similar extent in them. A key regulator of energy metabolism, PGC-1α, and the products of downstream target genes that encode for glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphatase, were constitutively at high levels in the KO mice. SIGNIFICANCE The genetic ablation of AKR1A activates the PGC-1α pathway and spare glucose, which would consequently confer exercise endurance. AIMS Doxorubicin (DOX) is an effective anthracycline anticancer drug. However, the clinical usage of it is limited due to its severe cardiotoxicity side effects. Metformin (Met) is a kind of first-line antihyperglycemic drug which has a potential protective effect on the heart，it is often used for oral treatment of type 2 diabetes. In this study, we explored whether Met could attenuate cardiotoxicity induced by DOX. MATERIALS AND METHODS For the sake of exploring the Met protective effect and mechanism, we established the DOX-induced cardiotoxicity models both in H9C2 cells incubated with 5 μM DOX in vitro and Sprague-Dawley rats treated with 20 mg/kg cumulative dose of DOX. KEY FINDINGS Met is able to inhibit growth inhibition and apoptosis of H9C2 cells induced by DOX. The heart indexes of rats were examined to evaluate the Met cardiotoxicity protection. Met improved the abnormal indexes, serum markers of cardiac heart injury, echocardiography, electrocardiogram, cardiac pathology, cardiomyocyte apoptosis, and oxidative stress markers induced by DOX. Furthermore, in vivo and in vitro studies demonstrated that Met protected against DOX-induced increasing cleaved caspase-3 and Bax. Met also prevented the downregulation of Bcl-2, activated the AMPK pathway, and inhibited the MAPK pathway. SIGNIFICANCE Met showed protective effects on DOX-induced cardiotoxicity by reducing oxidative stress and apoptosis, as well as regulating AMPK and MAPK signaling pathways. AIMS Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response against infection that triggers systemic inflammatory response syndrome. l-theanine (LT), a glutamate derivative, is a non-protein amino acid derived from tea (Camellia sinensis), and a valuable nutraceutical product used as an additive in the food industry. This study we aimed to investigate whether LT would exert any therapeutic effect on liver and kidney tissues in Sprague Dawley rats with sepsis induced with cecal ligation and puncture (CLP). MAIN METHODS Rats were divided into four groups; sham, CLP, CLP+LT1 (2x250 mg/kg) and CLP+LT2 (2 × 750 mg/kg). Liver and kidney tissues were subjected to histopathological examination. Apoptotic index percentages (AI%) were examined using the TUNEL method. The oxidized glutathione to total glutathione (GSSG/TGSH) ratio (as a marker of oxidative stress, levels of caspase-3 (a marker of apoptosis), glutathione peroxidase (GPx) and glutathione S-transferase (GST) (as antioxidant enzymes), inducible nitric oxide synthase (iNOS) and the tumor necrosis factor-α to Interleukin-10 ratio (TNF-α/IL-10) (as markers of inflammation) were investigated using commercial kits.
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