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This study aimed to investigate the role of interleukin-6 (IL-6) in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (NHIE). Sprague-Dawley (SD) rats were used for the establishment of hypoxic-ischemic (HI) model. The Zea-Longa scoring was used to evaluate the extent of the neurological deficits. Triphenyl tetrazolium chloride (TTC) staining was used to measure the volume of infarction in the brain following HI protocol. The expression of IL-6 in the cortex and/or hippocampus at multiple time points after HI was examined by immunohistochemistry, western blotting and immunofluorescence. Moreover, small interfering RNAs (siRNA) were used to inhibit the expression of IL-6 in-vitro and in-vivo, and the concomitant expression of the Bcl-2 associated X protein (BAX) and caspase 3 was also measured. HI induced a significant brain damage, and these pathological changes were accompanied by IL-6 upregulation which was found localized in cortical neurons. The inhibition of IL-6 expression fostered neuronal and axonal growth, and a reduction in cellular apoptosis in cortical neuronal cultures, and cortex and hippocampus of neonatal rats. The expression of apoptotic markers such as BAX and caspase 3 was closely associated with IL-6. Downregulation of IL-6 could ameliorate HI-induced deficiencies by mediating the expression of caspase 3 and BAX.
Myocardial ischemia-reperfusion injury (IRI) is one of the most leading concerns for public health globally. Diazepam, a local anesthetic, has been reported for its cardioprotective potential. The present investigation aimed to evaluate the possible mechanism of action of diazepam against left anterior descending ligation-induced myocardial IRI in experimental rats. IRI was induced in healthy male rats by ligating coronary artery for 30 min and then reperfused for 60 min. The animals were pre-treated with either vehicle or diltiazem (10 mg/kg) or diazepam (1, 2.5, and 5 mg/kg) for 14 days. Compared to the IRI group, diazepam (2.5 and 5 mg/kg) markedly (P<0.05) attenuated IRI-induced alterations in cardiac function and oxido-nitrosative stress. In addition, diazepam prominently (P<0.05) improved cardiac Na+K+ATPase, Ca2+ATPase levels and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA expression. It also significantly (P<0.05) down-regulated cardiac mRNA expressions of cardiac troponin I (cTn-I), C-C chemokine receptor type 2 (CCR2), tumor necrosis factor-alpha (TNF-α), interleukins (IL)-1β, and IL-6. In western blot analysis, IRI-induced myocardial apoptosis was reduced by diazepam treatment reflected by a marked (P<0.05) decreased in Bcl-2-associated X protein (Bax) and Caspase-3 protein expression. Diazepam also efficiently (P<0.05) improved IRI-induced histological aberration in cardiac tissue. In conclusion, diazepam exerts cardioprotective effect by inhibiting inflammatory release (CCR2, TNF-α, and ILs), oxido-nitrosative stress, and apoptosis (Bax and Caspase-3) pathway during myocardial IRI in experimental rats.
Background: Bcl-2 associated athanogene2 (BAG2) is reported to act as an oncogene or a tumor-suppressor in tumors in a context-dependent way; however, its function in hepatocellular carcinoma (HCC) remains unclear. Methods: Immunohistochemistry (IHC) staining, cell counting kit-8 (CCK-8) assay, apoptotic assay, cell invasion assay and a set of bioinformatics tools were integrated to analyze the role of BAG2 in hepatocellular carcinoma. Results: BAG2 was significantly up-regulated in HCC. Prognostic analysis indicated that HCC patients with high expression of BAG2 had significantly shorter overall survival, progression free survival and disease specific survival. Besides, silencing BAG2 in HCC cells impaired cell proliferation, facilitated apoptosis and repressed invasion of the cells. Bioinformatics analysis showed that BAG2 might regulate ribosome biogenesis in HCC. Conclusion: This study revealed that the up-regulated BAG2 in HCC was associated with a worse prognosis and might favor the progression of the disease.
As pathogenic Parkin mutations result in the defective clearance of damaged mitochondria, Parkin-dependent mitophagy is thought to be protective against the dopaminergic neurodegeneration observed in Parkinson's disease. Recent studies, however, have demonstrated that Parkin can promote cell death in the context of severe mitochondrial damage by degrading the pro-survival Bcl-2 family member, Mcl-1. Therefore, Parkin may act as a 'switch' that can shift the balance between protective or pro-death pathways depending on the degree of mitochondrial damage. Here, we report that the Parkin interacting protein, Bcl-2-associated athanogene 5 (BAG5), impairs mitophagy by suppressing Parkin recruitment to damaged mitochondria and reducing the movement of damaged mitochondria into the lysosomes. BAG5 also enhanced Parkin-mediated Mcl-1 degradation and cell death following severe mitochondrial insult. These results suggest that BAG5 may regulate the bi-modal activity of Parkin, promoting cell death by suppressing Parkin-dependent mitophagy and enhancing Parkin-mediated Mcl-1 degradation.
BAG6 is an essential protein that functions in two distinct biological pathways, ubiquitin-mediated protein degradation of defective polypeptides and tail-anchored (TA) transmembrane protein biogenesis in mammals, although its structural and functional properties remain unknown. We solved a crystal structure of the C-terminal heterodimerization domains of BAG6 and Ubl4a and characterized their interaction biochemically. Unexpectedly, the specificity and structure of the C terminus of BAG6, which was previously classified as a BAG domain, were completely distinct from those of the canonical BAG domain. Furthermore, the tight association of BAG6 and Ubl4a resulted in modulation of Ubl4a protein stability in cells. Therefore, we propose to designate the Ubl4a-binding region of BAG6 as the novel BAG-similar (BAGS) domain. The structure of Ubl4a, which interacts with BAG6, is similar to the yeast homologue Get5, which forms a homodimer. These observations indicate that the BAGS domain of BAG6 promotes the TA protein biogenesis pathway in mammals by the interaction with Ubl4a.
Programmed mammalian cell death (apoptosis) is an essential mechanism in life that tightly regulates embryogenesis and removal of dysfunctional cells. In its intrinsic (mitochondrial) pathway, opposing members of the Bcl-2 (B cell lymphoma 2) protein family meet at the mitochondrial outer membrane (MOM) to control its integrity. Any imbalance can cause disorders, with upregulation of the cell-guarding antiapoptotic Bcl-2 protein itself being common in many, often incurable, cancers. Normally, the Bcl-2 protein itself is embedded in the MOM where it sequesters cell-killing apoptotic proteins such as Bax (Bcl-2-associated X protein) that would otherwise perforate the MOM and subsequently cause cell death. However, the molecular basis of Bcl-2's ability to recognize those apoptotic proteins via their common BH3 death motifs remains elusive due to the lack of structural insight. By employing nuclear magnetic resonance on fully functional human Bcl-2 protein in membrane-mimicking micelles, we identified glycine residues across all functional domains of the Bcl-2 protein and could monitor their residue-specific individual response upon the presence of a Bax-derived 36aa long BH3 domain. The observed chemical shift perturbations allowed us to determine the response and individual affinity of each glycine residue and provide an overall picture of the individual roles by which Bcl-2's functional domains engage in recognizing and inhibiting apoptotic proteins via their prominent BH3 motifs. This way, we provide a unique residue- and domain-specific insight into the molecular functioning of Bcl-2 at the membrane level, an insight also opening up for interfering with this cell-protecting mechanism in cancer therapy.
Bcl-2-associated athanogene (BAG), a group of proteins evolutionarily conserved and functioned as co-chaperones in plants and animals, is involved in various cell activities and diverse physiological processes. However, the biological functions of this gene family in rice are largely unknown. In this study, we identified a total of six BAG members in rice. These genes were classified into two groups, OsBAG1, -2, -3, and -4 are in group I with a conserved ubiquitin-like structure and OsBAG5 and -6 are in group Ⅱ with a calmodulin-binding domain, in addition to a common BAG domain. The BAG genes exhibited diverse expression patterns, with OsBAG4 showing the highest expression level, followed by OsBAG1 and OsBAG3, and OsBAG6 preferentially expressed in the panicle, endosperm, and calli. The co-expression analysis and the hierarchical cluster analysis indicated that the OsBAG1 and OsBAG3 were co-expressed with primary cell wall-biosynthesizing genes, OsBAG4 was co-expressed with phytohormone and transcriptional factors, and OsBAG6 was co-expressed with disease and shock-associated genes. β-glucuronidase (GUS) staining further indicated that OsBAG3 is mainly involved in primary young tissues under both primary and secondary growth. In addition, the expression of the BAG genes under brown planthopper (BPH) feeding, N, P, and K deficiency, heat, drought and plant hormones treatments was investigated. Our results clearly showed that OsBAGs are multifunctional molecules as inferred by their protein structures, subcellular localizations, and expression profiles. BAGs in group I are mainly involved in plant development, whereas BAGs in group II are reactive in gene regulations and stress responses. Our results provide a solid basis for the further elucidation of the biological functions of plant BAG genes.
B-cell lymphoma2 (Bcl-2)-associated athanogene (BAG) family proteins are evolutionary conserved across all eukaryotes. These proteins interact with HSP70/HSC70 and function as co-chaperones during stress response and developmental pathways. Compared to the animal counterpart, the BAG proteins in plants are much less studied and primarily Arabidopsis BAG proteins have been identified and characterized for their role in programmed cell death, homeostasis, growth and development, abiotic and biotic stress response. Here, we have identified BAG protein family (SlBAGs) in tomato, an economically important and a model fruit crop using genome-wide scanning. We have performed phylogenetic analysis, genes architecture assessment, chromosomal location and in silico promoter analysis. Our data suggest that SlBAGs show differential tissue specific expression pattern during plant development particularly fruit development and ripening. Furthermore, we reported that expression of SlBAGs is modulated during abiotic stresses and is regulated by stress hormones ABA and ethylene. In planta subcellular localization reveals their diverse subcellular localization, and many members are localized in nucleus and cytoplasm. Like previous reports, our protein-protein interaction network and yeast two-hybrid analysis uncover that SlBAGs interact with HSP70. The current study provides insights into role of SlBAGs in plant development particualry fruit ripening and abiotic stress response.
The anti-apoptotic B-cell CLL/lymphoma-2 (Bcl-2) protein and its counterpart, the pro-apoptotic Bcl-2-associated X protein (Bax), are key players in the regulation of the mitochondrial pathway of apoptosis. However, how they interact at the mitochondrial outer membrane (MOM) and there determine whether the cell will live or be sentenced to death remains unknown. Competing models have been presented that describe how Bcl-2 inhibits the cell-killing activity of Bax, which is common in treatment-resistant tumors where Bcl-2 is overexpressed. Some studies suggest that Bcl-2 binds directly to and sequesters Bax, while others suggest an indirect process whereby Bcl-2 blocks BH3-only proteins and prevents them from activating Bax. Here we present the results of a biophysical study in which we investigated the putative interaction of solubilized full-length human Bcl-2 with Bax and the scope for incorporating the former into a native-like lipid environment. Far-UV circular dichroism (CD) spectroscopy was used to detect direct Bcl-2-Bax-interactions in the presence of polyoxyethylene-(23)-lauryl-ether (Brij-35) detergent at a level below its critical micelle concentration (CMC). Additional surface plasmon resonance (SPR) measurements confirmed this observation and revealed a high affinity between the Bax and Bcl-2 proteins. Upon formation of this protein-protein complex, Bax also prevented the binding of antimycin A2 (a known inhibitory ligand of Bcl-2) to the Bcl-2 protein, as fluorescence spectroscopy experiments showed. In addition, Bcl-2 was able to form mixed micelles with Triton X-100 solubilized neutral phospholipids in the presence of high concentrations of Brij-35 (above its CMC). Following detergent removal, the integral membrane protein was found to have been fully reconstituted into a native-like membrane environment, as confirmed by ultracentrifugation and subsequent SDS-PAGE experiments.
This study examined the α-glucosidase inhibitory, and apoptosis- and anti-muscular-related factors of goat meat extracts from forelegs, hind legs, loin, and ribs. The goat meat extracts were evaluated for their α-glucosidase inhibitory activity. The gene and protein expression levels of Bcl-2-associated X (bax), p53, and p21 were examined by reverse transcription polymerase chain reaction (RT-PCR) and immunoblotting in AGS and HT-29 cells. The expression levels of Atrogin-1 and MHC1b were examined by RT-PCR in C2C12 myoblasts, and the expression levels of Atrogin-1, muscle atrophy F-box (MAFbx), muscle RING-finger protein-1 (MuRF-1), and myosin heavy chain-7 were investigated by immunoblotting. α-Glucosidase inhibitory activity was higher in ethanol extract than in hydrous and hot water extracts. BAX and p53 expression levels were higher (p<0.05) in AGS cells treated with goat meat extract than those of cells treated with no goat meat extract. In HT-29 cells, the protein expression levels of BAX, p53, and p21 were higher (p<0.05) in the cells treated with goat meat extract than those of cells not treated with goat meat extract. In dexamethasone-treated C2C12 cells, goat meat extract treatment lower (p<0.05) the expression of Atrogin-1 and lower (p<0.05) the expression of MAFbx and MuRF-1. The results of the present study indicate that goat meat extracts have α-glucosidase inhibitory activity in vitro. In addition, apoptosis was induced in AGS cells and HT-29 cells treated with goat meat extract, and anti-muscular atrophy activity was also observed in C2C12 cells treated with goat meat extract.
An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown. We identified B-cell lymphoma 2 (BCL-2) as a BEX1-interacting protein using a yeast two-hybrid screen. The interaction between BEX1 and BCL-2 was subsequently confirmed by co-immunoprecipitation assays. Like BCL-2, BEX1 was localized to the mitochondria. The region between 33K and 64Q on BEX1 is important for its localization to the mitochondria and its ability to interact with BCL-2. Additionally, we found that this region is essential for BEX1-regulated imatinib-induced apoptosis. Furthermore, we demonstrated that the interaction between BCL-2 and BEX1 promotes imatinib-induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2-associated X protein (BAX) heterodimers. Our results revealed an interaction between BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated by the BEX1/BCL-2 pathway.
Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.
Cardiomyocyte apoptosis is an important process occurred during cardiac ischaemia-reperfusion injury. Long non-coding RNAs (lncRNA) participate in the regulation of various cardiac diseases including ischaemic reperfusion (I/R) injury. In this study, we explored the potential role of lncRNA ACART (anti-cardiomyocyte apoptosis-related transcript) in cardiomyocyte injury and the underlying mechanism for the first time. We found that ACART was significantly down-regulated in cardiac tissue of mice subjected to I/R injury or cultured cardiomyocytes treated with hydrogen peroxide (H2 O2 ). Knockdown of ACART led to significant cardiomyocyte injury as indicated by reduced cell viability and increased apoptosis. In contrast, overexpression of ACART enhanced cell viability and reduced apoptosis of cardiomyocytes treated with H2 O2 . Meanwhile, ACART increased the expression of the B cell lymphoma 2 (Bcl-2) and suppressed the expression of Bcl-2-associated X (Bax) and cytochrome-C (Cyt-C). In addition, PPAR-γ was up-regulated by ACART and inhibition of PPAR-γ abolished the regulatory effects of ACART on cell apoptosis and the expression of Bcl-2, Bax and Cyt-C under H2 O2 treatment. However, the activation of PPAR-γ reversed the effects of ACART inhibition. The results demonstrate that ACART protects cardiomyocyte injury through modulating the expression of Bcl-2, Bax and Cyt-C, which is mediated by PPAR-γ activation. These findings provide a new understanding of the role of lncRNA ACART in regulation of cardiac I/R injury.
Helicobacter pylori-associated gastritis is a major threat to public health and Polygonum capitatum (PC) may have beneficial effects on the disease. However, the molecular mechanism remains unknown. Quercetin was isolated from PC and found to be a main bioactive compound. The effects of quercetin on human gastric cancer cells GES-1 were determined by xCELLigence. H. pylori-infected mouse models were established. All mice were divided into three groups: control (CG, healthy mice), model (MG, H. pylori infection) and quercetin (QG, mouse model treated by quercetin) groups. IL-8 (interleukin-8) levels were detected via enzyme-linked immunosorbent assay (ELISA). Cell cycle and apoptosis were measured by flow cytometry (FCM). Quantitative reverse transcription PCR (qRT-PCR) and Western Blot were used to detect the levels of p38MAPK (38-kD tyrosine phosphorylated protein kinase), apoptosis regulator BCL-2-associated protein X (BAX) and B cell lymphoma gene 2 (BCL-2). The levels of IL-8 were increased by 8.1-fold in a MG group and 4.3-fold in a QG group when compared with a CG group. In a MG group, G0-G1(phases of the cell cycle)% ratio was higher than a CG group while S phase fraction was lower in a model group than in a control group (p < 0.01). After quercetin treatment, G0-G1% ratio was lower in a QG group than a MG group while S phase fraction was higher than a MG group (p < 0.01). Quercetin treatment reduced the levels of p38MAPK and BAX, and increased the levels of BCL-2 when compared with a MG group (p < 0.05). Quercetin regulates the balance of gastric cell proliferation and apoptosis to protect against gastritis. Quercetin protects against gastric inflammation and apoptosis associated with H. pylori infection by affecting the levels of p38MAPK, BCL-2 and BAX.
The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.
Myocardial injury is a frequently occurring complication of sepsis. This study aims to investigate the molecular mechanism of long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1)-mediated DNA methyltransferase 1/B-cell lymphoma-2 (DNMT1/Bcl-2) axis in sepsis-induced myocardial injury. Mice and HL-1 cells were treated with lipopolysaccharide (LPS) to establish animal and cellular models simulating sepsis and inflammation. LncRNA SNHG1 was screened out as a differentially expressed lncRNA in sepsis samples through microarray profiling, and the upregulated expression of lncRNA SNHG1 was confirmed in myocardial tissues of LPS-induced septic mice and HL-1 cells. Further experiments suggested that silencing of lncRNA SNHG1 reduced the inflammation and apoptotic rate of LPS-induced HL-1 cells. LncRNA SNHG1 inhibited Bcl-2 expression by recruiting DNMT1 to Bcl-2 promoter region to cause methylation. Inhibition of Bcl-2 promoter methylation reduced the inflammation and apoptotic rate of LPS-induced HL-1 cells. In vivo experiments substantiated that lncRNA SNHG1 silencing alleviated sepsis-induced myocardial injury in mice. Taken together, lncRNA SNHG1 promotes LPS-induced myocardial injury in septic mice by downregulating Bcl-2 through DNMT1-mediated Bcl-2 methylation.
Remodeling and spacing factor 1 (Rsf‑1) has been reported as overexpressed in numerous cancers; however, its expression, biological functions and mechanisms in malignant melanoma remain unknown. In the present study, the expression of Rsf‑1 was investigated in 50 cases of malignant melanoma samples using immunohistochemistry. The results revealed that Rsf‑1 expression was elevated in 38% of specimens. MTT, colony formation, Transwell and flow cytometry assays were performed to investigate the functions of Rsf‑1. Knockdown of Rsf‑1 in the MV3 and A375 melanoma cell lines decreased the viability, invasion and cell cycle transition of cells. Conversely, overexpression of Rsf‑1 in M14 cells with low endogenous Rsf‑1 expression induced opposing effects. Further analysis revealed that Rsf‑1 knockdown decreased matrix metalloproteinase‑2, cyclin E and phosphorylated‑IκB expression. Additionally, Rsf‑1 depletion reduced cisplatin resistance and significantly increased the cisplatin‑associated apoptotic rate, whereas Rsf‑1 overexpression exhibited opposing effects. Rsf‑1 also maintained the mitochondrial membrane potential following cisplatin treatment. Analysis of apoptosis‑associated proteins revealed that Rsf‑1 positively regulated B‑cell lymphoma 2 (Bcl‑2), cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2, and downregulated Bcl‑2‑associated X protein expression. Nuclear factor κ‑light‑chain‑enhancer of activated B‑cells (NF‑κB) inhibition reversed the effects of Rsf‑1 on Bcl‑2. In conclusion, Rsf‑1 was overexpressed in malignant melanoma and may contribute to the malignant behaviors of melanoma cells, possibly via the regulation of NF‑κB signaling. Therefore, Rsf‑1 may be a potential therapeutic target in the treatment of malignant melanoma.
p27(BBP)/eIF6 (beta4-binding protein/eukaryotic initiation factor 6) regulates the joining of 40S and 60S ribosomal subunits, on receptor for activated C kinase 1 binding and protein kinase C phosphorylation in serine 235. In Xenopus, p27(BBP)/eIF6 is abundantly expressed in the majority of the embryonic anlagen. Although p27(BBP)/eIF6 abundance may be required for a general regulation of protein synthesis, our data suggest that p27(BBP)/eIF6 may target the translation of specific mRNAs. We injected Xp27(BBP)/eIF6 mRNA in one blastomere of two-cell-stage embryos and obtained a bent phenotype, the curvature being lateral with respect to the embryo antero-posterior axis. The injected side had fewer apoptotic cells than the uninjected side, whereas cell proliferation appeared unaffected. Accordingly, in Xp27(BBP)/eIF6 morphants, endogenous apoptosis increased. Injection of Xp27(BBP)/eIF6 point mutants indicated that the anti-apoptotic action of Xp27(BBP)/eIF6 requires the conserved S235. The bent phenotype was also obtained with B-cell lymphoma gene-2 (Bcl-2) overexpression and was rescued by Bcl-2-associated X protein (Bax)/Xp27(BBP)/eIF6 co-injection. In addition, embryos overexpressing Xp27(BBP)/eIF6 had a higher amount of Bcl-2 and an unchanged amount of Bax with respect to controls. In Xp27(BBP)/eIF6 morphants, Bcl-2 levels were unaffected and Bax levels were higher than in the controls. Thus, we propose that Xp27(BBP)/eIF6 is part of a mechanism acting on the specific translation of messengers regulating cell survival. In particular, we suggest that Xp27(BBP)/eIF6 may regulate the translation of factors upstream of Bcl-2/Bax.
The present study aimed to investigate the molecular mechanisms of cyclic stretch-induced apoptosis in human intervertebral disc cartilage endplate-derived stem cells (CESCs). CESCs were stretched by the Flexercell-4000™ Tension Plus system, the effect on cell viability was measured by a Cell Counting Kit-8 assay, while cell apoptosis was detected by flow cytometry. Western blot analysis was used to evaluate the expression of B-cell lymphoma 2 (Bcl-2)/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), Bcl-2, Bcl-2 homologous antagonist killer (Bak), Bcl-2-associated X protein (Bax), Bcl extra large (Bcl-xl) and the activity of caspase-3, while Z-VAD-FMK was used to inhibit caspase-3. Compared with the control group, the cell viability decreased in a time-dependent manner after stretching. Furthermore, cell apoptosis and the activity of caspase-3 were increased in a time-dependent manner. The ratio of pro-death factor BNIP3 to anti-apoptotic protein Bcl-2 was significantly increased. When cells were stretched for 36 h, the apoptosis-associated proteins Bak and Bax were increased, while Bcl-xl was decreased. The viability and apoptotic ratio of stretched cells were significantly restored after caspase-3 was repressed. In conclusion, cyclic tensile stretch induced apoptosis of CESCs, which was probably due to upregulation of the expression of BNIP3.
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