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Background: MicroRNAs (miRNAs) are involved in various pathological processes, such as proliferation, growth, and apoptosis, of intervertebral disc (IVD) cells and play an important role in the development of intervertebral disc degeneration (IDD). Although some studies have reported the role of miRNAs in IDD, scientific econometric analysis in this field is not available. Objectives: We designed this study to describe the current research trends and potential mechanisms associated with the role of miRNAs in IDD and to provide new ideas for future research in this field. Methods: We conducted a bibliometric analysis of the publications on the role of miRNAs in IDD included in the Web of Science core collection database to elucidate the current research trends in this field. The potential mechanisms were constructed using the Arrowsmith project. Results: We found that the number of miRNAs and IDD-related publications increased over the years. China was the most important contributor to research in this field. The top three institutions in terms of number of articles published were Huazhong University of Science and Technology, Shanghai Jiao Tong University, and Xi'an Jiao Tong University. Shanghai Jiao Tong University had the highest number of citations. Experimental and thermal medicine had the maximum number of documents, and Cell promotion had the most citations. The journal with the most mean times cited per study was Annals of the Rheumatic Diseases. The author Wang K had the highest number of publications, and Wang HQ had the highest number of citations. These two authors made important contributions to the research in this field. The keyword analysis showed that recent studies have focused on miRNAs regulating nucleus pulposus cell apoptosis and proliferation. Moreover, we revealed the potential mechanisms of miRNAs associated with IDD, including miRNAs regulating the extracellular matrix (ECM) degradation, mediating cartilage endplate (CEP) degeneration, and participating in inflammatory responses. Conclusion: We demonstrated the knowledge map of miRNAs and IDD-related research through bibliometric analysis and elucidated the current research status and hotspots in this field. The mechanisms by which miRNAs regulate the apoptosis and proliferation of degenerated IVDs, promote ECM degradation, mediate CEP degeneration, and participate in inflammatory responses should be explored in further studies. [ABSTRACT FROM AUTHOR]

Globally, cancer is a serious health problem. It is unfortunate that current anti-cancer strategies are insufficiently specific and damage the normal tissues. There's urgent need for development of new anti-cancer strategies. More recently, increasing attention has been paid to the new application of ferroptosis and nano materials in cancer research. Ferroptosis, a condition characterized by excessive reactive oxygen species-induced lipid peroxidation, as a new programmed cell death mode, exists in the process of a number of diseases, including cancers, neurodegenerative disease, cerebral hemorrhage, liver disease, and renal failure. There is growing evidence that inducing ferroptosis has proven to be an effective strategy against a variety of chemo-resistant cancer cells. Nano-drug delivery system based on nanotechnology provides a highly promising platform with the benefits of precise control of drug release and reduced toxicity and side effects. This paper reviews the latest advances of combination therapy strategies based on biomedical nanotechnology induced ferroptosis for cancer therapeutics. Given the new chances and challenges in this emerging area, we need more attention to the combination of nanotechnology and ferroptosis in the treatment of cancer in the future. [Display omitted] • Current anti-cancer strategies are lack of specificity and damage normal tissues. • Ferroptosis is an effective strategy against chemo-resistant cancer cells. • Nanotechnology provides of precise control of drug release and reduced toxicity. • Combination therapy based on ferroptosis-induced nano-DDS brings enhanced antitumor effect and has satisfactory safety. [ABSTRACT FROM AUTHOR]

Thrombocytopenia is a critical complication after radiation therapy and exposure. Dysfunction of megakaryocyte development and platelet production are key pathophysiological stages in ionizing radiation (IR)-induced thrombocytopenia. Protein kinase C (PKC) plays an important role in regulating megakaryocyte development and platelet production. However, it remains unclear how PKC regulates IR-induced megakaryocyte apoptosis. In this study, we found that pretreatment of PKC pan-inhibitor Go6983 delayed IR-induced megakaryocyte apoptosis, and inhibited IR-induced mitochondrial membrane potential and ROS production in CMK cells. Moreover, suppressing PKC activation inhibited cleaved caspase3 expression and reduced p38 phosphorylation levels, and IR-induced PKC activation might be regulated by p53. In vivo experiments confirmed that Go6983 promoted platelet count recovery after 21 days of 3 Gy total body irradiation. Furthermore, Go6983 reduced megakaryocyte apoptosis, increased the number of megakaryocyte and polyploid formation in bone marrow, and improved the survival rate of 6 Gy total body irradiation. In conclusion, our results provided a potential therapeutic target for IR-induced thrombocytopenia. [ABSTRACT FROM AUTHOR]

Coxsackievirus group B (CVB) is considered as one of the most common pathogens of human viral myocarditis. CVB-induced myocarditis is mainly characterized by the persistence of the virus infection and immune-mediated inflammatory injury. Costimulatory signals are crucial for the activation of adaptive immunity. Our data reveal that the CVB type 3 (CVB3) infection altered the expression profile of costimulatory molecules in host cells. CVB3 infection caused the decrease of PD-1 ligand expression, partially due to the cleavage of AU-rich element binding protein AUF1 by the viral protease 3Cpro, leading to the exacerbated inflammatory injury of the myocardium. Moreover, systemic PD-L1 treatment, which augmented the apoptosis of proliferating lymphocytes, alleviated myocardial inflammatory injury. Our findings suggest that PD1-pathway can be a potential immunologic therapeutic target for CVB-induced myocarditis. • Coxsackievirus B3 infection causes costimulatory molecules profile changes. • Coxsackievirus B3 induces decrease of programmed cell death 1 ligands. • Treatment with programmed cell death ligand recombinant Ig could relieve myocardial inflammatory injury. [ABSTRACT FROM AUTHOR]

Melatonin reversed arginine vasopressin-induced apoptosis on H9c2 cardiomyoblasts by increasing Mst1-Nrf2 activity, yielding anti-oxidative enzyme up-regulation and lowered apoptosis; thus, it could serve as a potential heart failure treatment. [Display omitted] Heart failure patients have elevated arginine vasopressin (AVP) levels, which are involved in inducing peripheral vasoconstriction and cardiac hypertrophy. This hypertrophy, along with cardiomyocyte apoptosis, results from oxidative stress. Therefore, the antioxidant drug, melatonin (Mel), is commonly used to treat cardiac hypertrophy and apoptosis; however, whether it could alleviate AVP-induced myocardial injury remains to be addressed. In this study, high AVP doses were found to induce H9c2 cardiomyoblast apoptosis, demonstrated by increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, pro-apoptotic B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) up-regulation, and anti-apoptotic Bcl-2 downregulation. This AVP-induced apoptotic increase, along with lowered cell viability, was also associated with higher reactive oxygen species (ROS) levels and lowered mitochondrial membrane potentials (MMP), which were all reversed upon Mel administration. Further investigations found that apoptosis, ROS, and MMP outcomes under high AVP were associated with Mst1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway suppression, yielding mitochondrial dysfunction, and Mel reversed them via promoting Mst1 phosphorylation, which then activated Nrf2 to increase anti-oxidative enzyme production. These findings were supported by siRNA gene suppression, where knocking down either Nrf2 or Mst1 abrogated the anti-apoptotic effects of Mel in cardiomyoblasts. Therefore, Mel could reduce cardiomyoblast apoptosis under high AVP levels, via Mst1-Nrf2 pathway re-activation, to enhance anti-oxidative responses. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate the apoptotic effect of a proteasome inhibitor MG-132 on Tca-8113, a cell line of human tongue squamous cell carcinoma. Tca-8113 cells were treated with 10, 20, and 30μM of MG-132, or 5μM thapsigargin. Apoptosis rate was determined with annexin V/propidium iodide double staining. Expression of E3ubiquitin-protein ligase was determined by ELISA, and Grp78 and caspase-12 mRNA, and Grp78 and caspase-12 protein was assessed by RT-PCR and Western blot, respectively. Apoptosis was observed 18h after MG-132 treatment. The apoptotic rate in the 10, 20, and 30μM MG-132 group was 13.5, 19.6 and 34.7%, respectively, which was higher than in the thapsigargin (8.5%, P <0.01) or control group (0.5%, P <0.01). The expression of E3 ubiquitin-protein ligase in the 10, 20, and 30μM MG-132 group was 28.75±2.28, 18.16±0.65, 8.85±0.72, respectively, which was lower than in the thapsigargin (38.96±0.33, P <0.05 or 0.01) or control (40.88±4.52, P <0.05 or 0.01) group. The levels of Grp78 and capase-12 mRNA, Grp78 and caspase-12 protein in the MG-132 groups were higher than in the control group (P <0.01). In conclusion, MG-132 induces apoptosis in Tca-8113 cells in a concentration-dependent manner. The MG-132-induced apoptosis may involve downregulation of E3 ubiquitin ligase, and upregulation of Grp78 and caspase-12. [Copyright &y& Elsevier]

Temperature is a crucial environmental factor that affects embryonic development, particularly for marine organisms with long embryonic development periods. However, the sensitive period of embryonic development and the role of autophagy/apoptosis in temperature regulation in cephalopods remain unclear. In this study, we cultured embryos of Sepiella japonica, a typical species in the local area of the East China Sea, at different incubation temperatures (18 °C, 23 °C, and 28 °C) to investigate various developmental aspects, including morphological and histological characteristics, mortality rates, the duration of embryonic development, and expression patterns of autophagy-related genes (LC3, BECN1, Inx4) and apoptosis marker genes (Cas3, p53) at 25 developmental stages. Our findings indicate that embryos in the high-temperature (28 °C) group had significantly higher mortality and embryonic malformation rates than those in the low-temperature (18 °C) group. Furthermore, high temperature (28 °C) shortened the duration of embryonic development by 7 days compared to the optimal temperature (23 °C), while low temperature (18 °C) caused a delay of 9 days. Therefore, embryos of S. japonica were more intolerant to high temperatures (28 °C), emphasizing the critical importance of maintaining an appropriate incubation temperature (approximately 23 °C). Additionally, our study observed, for the first time, that the Early blastula, Blastopore closure, and Optic vesicle to Caudal end stages were the most sensitive stages. During these periods, abnormalities in the expression of autophagy-related and apoptosis-related genes were associated with higher rates of mortality and malformations, highlighting the strong correlation and potential interaction between autophagy and apoptosis in embryonic development under varying temperature conditions. [ABSTRACT FROM AUTHOR]

The reversible oxidation-reduction homeostasis mechanism functions as a specific signal transduction system, eliciting related physiological responses. Disruptions to redox homeostasis can have negative consequences, including the potential for cancer development and progression, which are closely linked to a series of redox processes, such as adjustment of reactive oxygen species (ROS) levels and species, changes in antioxidant capacity, and differential effects of ROS on downstream cell fate and immune capacity. The tumor microenvironment (TME) exhibits a complex interplay between immunity and regulatory cell death, especially autophagy and apoptosis, which is crucially regulated by ROS. The present study aims to investigate the mechanism by which multi-source ROS affects apoptosis, autophagy, and the anti-tumor immune response in the TME and the mutual crosstalk between these three processes. Given the intricate role of ROS in controlling cell fate and immunity, we will further examine the relationship between traditional cancer therapy and ROS. It is worth noting that we will discuss some potential ROS-related treatment options for further future studies. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON), a frequent food and feed contaminant, poses a severe threat to human and livestock health. Some studies have demonstrated that DON could induce liver damage and cell death. However, novel cell death styles and detailed mechanisms to explain DON-induced liver inflammatory injury are still lacking. Here, we found both chronic and subacute oral administration of DON (3 mg/kg for 4 weeks and 4 mg/kg for 8 days) induced mouse liver inflammatory injury and activated caspase-3, PARP and gasdermin E (GSDME), which were inhibited by caspase-3 inhibitor Z-DEVD and Ac-DEVD. In vitro, HepaRG cells showed typical pyroptotic characteristics after 32 and 64 μM DON exposure for 24 h, including balloon-like bubbling emerging, release of lactate dehydrogenase (LDH), secretion of IL-1β and IL-6 and activation of caspase-3 and GSDME. Furthermore, knocking down GSDME and inhibiting caspases activity by Z-VAD and Z-DEVD dramatically blocked DON-induced pyroptotic characteristics, while over-expressed GSDME prompted that. These data demonstrate that caspase-3/GSDME pathway plays a key factor in DON-induced pyroptosis and inflammation in liver. Interestingly, knocking down GSDME could inhibit DON-induced pyroptosis but prompt DON-induced apoptosis, while opposite results were obtained when over-expressed GSDME, indicating the critical role of GSDME in DON-induced crosstalk between apoptosis and pyroptosis. Taken together, our data determine DON-induced caspase-3/GSDME-dependent pyroptosis in liver and its role in DON-induced liver inflammatory injury, which provide a novel mechanistic view into DON-induced hepatotoxicity and may offer a new target to reduce latent harm of DON to both humans and animals. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD) constitutes a crucial pathological foundation for spinal degenerative diseases (SDD) and stands as a primary contributor to both low back pain (LBP) and disability. The progression of IVDD is linked to structural and functional alterations in tissues, where an imbalance in the inflammatory microenvironment can induce extracellular matrix (ECM) degradation, senescence, and apoptosis. This imbalance is a key pathomechanism in the disease's development, gaining considerable attention in recent years. This study aims to conduct a bibliometric analysis of publications pertaining to the inflammatory mechanisms of IVDD to quantitatively assess current research hotspots and directions. In this study, we queried the Web of Science Core Collection (WOSCC) database covering the period from January 1, 2001, to November 7, 2023. Content in this area was analyzed and visualized using software such as Citespace, Vosviewer, and the bibliometrix package. Findings indicate a consistent annual increase in the number of publications, highlighting the widespread attention garnered by research on the inflammatory mechanisms of IVDD. In terms of journal research, Spine emerged with the highest number of publications, along with significantly elevated total citations and average citations compared to other journals. Regarding country analysis, China led in the number of publications, while the USA claimed the highest number of citations and total link strength. Institutional analysis revealed Sun Yat-sen University as having the highest number of publications and total link strength, with Thomas Jefferson University securing the highest total citations. Author analysis identified Ohtori, S. with the highest number of publications, Risbud, M.V. with the highest number of citations, and Inoue, G. with the highest total link strength, all of whom have made significant contributions to the field's development. Citation and co-citation analyses indicated that highly cited documents primarily focused on classical studies exploring inflammatory mechanisms in IVDD pathogenesis. Keyword analysis showcased the ongoing research hotspot as the further investigation of mechanisms and treatment studies. Recent years have seen a shift towards exploring pyroptosis, necrotic apoptosis, autophagy, ferroptosis, oxidative stress, and bacterial infection, among other mechanisms. In terms of treatment, alongside traditional monomer, drug, and compound therapies for IVDD, research is increasingly concentrating on stem cell therapy, exosomes, hydrogels, and scaffolds. This bibliometric analysis of research on inflammatory mechanisms in IVDD provides insights into the current status, hotspots, and potential future trends. These findings can serve as a valuable reference and guide for researchers in the field. • This study is the first to explore the hotspots and future trends in the study of inflammatory mechanisms in IVDD through bibliometric methods. • The ongoing research hotspot as the further investigation of mechanisms and treatment studies. [ABSTRACT FROM AUTHOR]

Abstract: This study was designed to investigate the function of 17β-estradiol (17β-E2) against oxidative stress on the cell death of mice bone marrow mesenchymal stem cells (BMSCs) induced by hydrogen peroxide (H2O2). BMSCs were treated with 17β-E2 for 24h and then treated with 100μM H2O2 for 1h. Cell viability, apoptosis, caspase-9 mRNA, JNKs (Jun N-terminal kinases) and c-Jun protein expression in BMSCs were evaluated. Cell apoptosis of BMSCs were increased in a dose-dependent manner after treated with H2O2 compared to control group. But pretreatment with 17β-E2 can inhibit apoptosis of BMSCs, preserve the mitochondrial transmembrane potential, decrease caspase-9 mRNA, JNK1/2 and c-Jun protein expression. In conclusion, 17β-E2 exerts antiapoptotic effects in BMSCs which related to the mitochondria death pathway and JNKs pathway. The study revealed that 17β-E2 can reduce the donor stem cells damage. [Copyright &y& Elsevier]

Glioma is a brain tumor that originates from brain or spine glial cells. Despite alternative treatments, the overall survival rate remains low. Oridonin (ORI) is purified from the Chinese herb Rabdosia rubescens, which has exhibited positive effects on tumors. This study aimed to investigate the effect of ORI on U87MG glioblastoma cells and whether the Hippo/YAP-related signaling pathway was involved. Malignant glioblastoma U87MG cells and male athymic nude mice (BALB/cnu/nu) were used as the experimental models. The YAP inhibitor Verteporfin (VP) and the overexpression of YAP were used to investigate its potential relation with glioma. Here, we found that ORI inhibited cell proliferation and promoted cell apoptosis in a dose-dependent manner in U87MG cells. Moreover, ORI inhibited Bcl-2, YAP, and c-Myc protein expression but increased Bax, caspase-3, and p-YAP protein expression. Furthermore, the effect of ORI was also confirmed in a mouse model bearing glioma. ORI reversed the effect of overexpression of YAP. Collectively, oridonin suppressed glioblastoma oncogenesis via the Hippo/YAP signaling pathway and could be a potential therapeutic target in the treatment of glioblastoma. [Display omitted] • Oridonin suppressed glioblastoma oncogenesis in U87MG glioblastoma cells. • Oridonin suppressed glioblastoma oncogenesis growth in mouse model bearing glioma. • Oridonin suppressed glioblastoma oncogenesis via the Hippo/YAP signaling pathway. [ABSTRACT FROM AUTHOR]

The insidious clinical symptoms of pancreatic cancer (PACA), extensive tolerance to radiotherapy and chemotherapy, and insensitivity to immunotherapy result in an inferior prognosis. Redox dyshomeostasis could trigger programmed cell death and contribute to functional changes in immune cells, which is strongly associated with tumorigenesis and tumor development. Therefore, it is warranted to decipher the crosstalk between regulated cell death and immunity in the context of redox dyshomeostasis for PACA. Herein, four redox-related subtypes of PACA were identified: C1 and C2 displayed malignant phenotypes with dismal clinical outcomes, conspicuous enrichment in cell death pathways, high redox score, low immune activation, and "immune-desert" tumor immune microenvironment (TIME); C3, an immune-rejection/excluded subtype, with abundant immune cells, high co-stimulatory, co-inhibitory, and MHC molecules, and potential response to immunotherapy; C4, with the best prognosis, low redox pattern, high level of autophagy, low enrichment of most cell death-related pathways, and "immune-hot" TIME. Overall, this study found an attractive platform from the perspective of redox-related pathways, which would propose insights into the intricate and elaborate molecular mechanisms of PACA and offer more effective and tailored intervention protocols. • The higher basal oxidative state in PACA was related to higher programmed cell death signals, conducting an "immune-cold" TIME. • Relatively low levels of redox state portended favorable clinical outcomes in PACA patients. • ROS manipulation treatment may be a novel potential therapeutic approach for C1 and C2 patients. [ABSTRACT FROM AUTHOR]

Keloids are benign fibrous overgrowths that occur as a result of abnormal wound healing following cutaneous injury. MicroRNAs (miRNAs/miRs) are short non-coding RNAs that serve critical roles in numerous important biological processes, such as cell proliferation, differentiation and apoptosis. However, their role in keloid development remains largely unknown. In the present study, the role of miR-30a-5p, a miRNA regulated by Trichostatin A (TSA), in apoptosis within cultured keloid fibroblasts was investigated. An MTT assay was used to detect the proliferation of cultured keloid fibroblasts treated with TSA. Cell apoptosis and cell cycle phases were analyzed using flow cytometry. In addition, an miRNA microarray was performed to compare expression profiles between cultured keloid fibroblasts treated with or without 1,000 nM TSA. Reverse transcription-quantitative polymerase chain reaction analysis was conducted to estimate miRNA expression levels. The direct target of miR-30a-5p was identified using a dual-luciferase reporter assay. Western blotting was employed to assess protein expression levels in keloid fibroblasts. The results demonstrated that TSA inhibited the proliferation of keloid fibroblasts in a time- and dose-dependent manner. The miRNA microarray revealed alterations in the expression of numerous miRNA sequences in response to TSA when compared with controls. Notably, the expression of miR-30a-5p was downregulated in keloid tissues. In addition, overexpression of miR-30a-5p induced apoptosis by targeting B-cell lymphoma 2, which was similar to that observed in response to TSA. These results provide important information regarding a novel miR-30a-5p-mediated signaling pathway induced by TSA treatment, and suggest a potential use for TSA and miR-30a-5p as effective therapeutic strategies for keloids. [ABSTRACT FROM AUTHOR]

Macrophages are the master regulator of the dynamic fibrogenesis-fibrosis resolution paradigm. TNF-like ligand 1 aberrance (TL1A) was found to be able to induce intestinal inflammation and fibrosis. Furthermore, significantly increased TL1A had been detected in liver tissues and mononuclear cells of patients with primary biliary cirrhosis (PBC). This study was to investigate the effect of myeloid cells with constitutive TL1A expression on liver fibrogenesis. We found that TL1A expressions in liver tissues and macrophages were significantly increased in mice with liver fibrosis induced by injection of carbon tetrachloride (CCl4). TL1A overexpression in myeloid cells induced liver function injury, accelerated the necrosis and apoptosis of hepatocytes, recruited macrophages, and promoted activation of hepatic stellate cells (HSCs) and fibrosis. In vitro results of our study showed that TL1A overexpression in macrophages promoted secretion of platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Culturing macrophages with TL1A overexpression could accelerate the activation and proliferation of primary HSCs. These results indicated that constitutive TL1A expression in myeloid cells exacerbated liver fibrosis, probably through macrophage recruitment and secretion of proinflammatory and profibrotic cytokines. [ABSTRACT FROM AUTHOR]

Background: G protein-coupled receptors (GPR) are involved in a wide range of physiological processes, some of which, however, can be hijacked by tumor cells. Over-expression of G protein-coupled receptors 137 (GPR137) are associated with the growth of tumor cells, but under-expression of GPR137 has shown to inhibit cell proliferation in several different types of cancers. Currently, the role of GPR137 in leukemia is still unclear. In this study, the effect of under-expression of GPR137 on inhibiting the proliferation of leukemia cells is explored, to identify a novel target for leukemia treatment. Materials and methods: In this study, lentivirus-mediated RNA interference (RNAi) was employed to investigate the role of GPR137 in two leukemia cell lines K562 and HL60. The gene expression of GPR137 was analyzed by RT-PCR and its protein expression was determined by Western blot. Flow cytometry and Annexin V/7-AAD Apoptosis Detection Kit was used respectively in cell cycle and apoptosis analysis. The protein expression of CyclinD1, CDK4, BCL-2 and caspase-3 were also determined. Results: There was high level of constitutive expression of GPR137 in leukemia cancer cell lines K562 and HL60. Lentivirus-mediated RNAi could significantly down-regulate gene and protein expression of GPR137 in both cell lines. Down regulation of GPR137 was associated with the reduction in proliferation rate and colony forming capacity. In addition, down regulation of GPR137 arrested cells in the G0/G1 phase of cell cycle and induced apoptosis in both leukemia cell lines K562 and HL60. Conclusions: The expression of GPR137 is associated with the proliferation of leukemia cell lines. Down regulation of GPR137 could inhibit proliferation and promote apoptosis in leukemia cells, which makes it a promising bio-marker and therapeutic target to treat patients with leukemia. [ABSTRACT FROM AUTHOR]

Previous evidences suggested that atorvastatin not only reduced blood lipids but also reduced myocardial hypertrophy and remodeling. And it was reported that C/EBPβ (CCAAT/enhancer-binding protein β) played a pivotal role both in the physiologic and pathological cardiac hypertrophy. However, it has not been reported before whether this signaling pathway of C/EBPβ participates in protective effect of atorvastatin for hypertrophy cardiomyocytes. In present study, We found that overexpression of C/EBPβ significantly abrogated the effect of atorvastatin on increasing Bcl-2/Bax and PGC-1α while the early and late apoptosis rate increased and mitochondrial membrane potential (MMP) was reduced. In conclusion, we further identified the protective effect of atorvastatin on hypertrophic cardiomyocytes induced by Angiotensin II by rescuing the MMP and inhibiting apoptosis, which might be at least partly attributed to down-regulation of C/EBPβ. And C/EBPβ might be a new target to rescue mitochondrion function and apoptosis in pathological cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Exposure of Tca-8113 cells to proteasome inhibitor carbobenzoxy-Leu-Leu-leucinal (MG-132) causing apoptosis is associated with endoplasmic reticulum (ER) stress. X-box-binding protein-1 (XBP1) is an important regulator of a subset of genes active during ER stress, which is related to cell survival and is required for tumor growth. The present study is to evaluate the effect of MG-132 on ROS production, XBP1 gene expression, tumor necrosis factor receptor-associated factor 2 (TRAF2), ASK1 and c -jun protein expression in tongue squamous cell carcinoma cell line Tca-8113 cells. ROS production was measured by reactive oxygen species assay. X-box binding protein-1 (XBP1) mRNA was analyzed by real-time–PCR, TRAF2, ASK1 and c -jun protein were investigated by western blot and immunocytochemistry respectively. The result indicated that ROS production, TRAF2, ASK1 and c -jun were elevated in MG-132 treated cells. Giving ROS scavenger N -acetyl- L -cysteine (NAC) largely prevented the effects of MG-132. Furthermore, treating with MG-132 lead to decreased XBP1 mRNA expression but could not completely block the expression of XBP1. Taken together, these findings provide the evidence that MG-132 induced ER stress lead to Tca-8113 cells apoptosis through ROS generation and TRAF2-ASK1-JNK signal pathway activation. [ABSTRACT FROM AUTHOR]

The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM. [ABSTRACT FROM AUTHOR]

Summary: We report that in the presence of signal 1 (NF-κB), the NLRP3 inflammasome was activated by mitochondrial apoptotic signaling that licensed production of interleukin-1β (IL-1β). NLRP3 secondary signal activators such as ATP induced mitochondrial dysfunction and apoptosis, resulting in release of oxidized mitochondrial DNA (mtDNA) into the cytosol, where it bound to and activated the NLRP3 inflammasome. The antiapoptotic protein Bcl-2 inversely regulated mitochondrial dysfunction and NLRP3 inflammasome activation. Mitochondrial DNA directly induced NLRP3 inflammasome activation, because macrophages lacking mtDNA had severely attenuated IL-1β production, yet still underwent apoptosis. Both binding of oxidized mtDNA to the NLRP3 inflammasome and IL-1β secretion could be competitively inhibited by the oxidized nucleoside 8-OH-dG. Thus, our data reveal that oxidized mtDNA released during programmed cell death causes activation of the NLRP3 inflammasome. These results provide a missing link between apoptosis and inflammasome activation, via binding of cytosolic oxidized mtDNA to the NLRP3 inflammasome. [Copyright &y& Elsevier]

Chemoresistance is one of the main obstacles in the therapy of human cancers, including colorectal cancer (CRC). Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (lncRNA HAND2-AS1) has been demonstrated to be associated with CRC. However, the function of HAND2-AS1 in 5-Fluorouracil (5-FU) resistance of CRC remains unclear. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of HAND2-AS1, miR-20a and programmed cell death factor 4 (PDCD4) mRNA. 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was conducted to evaluate IC50 of 5-FU and cell proliferation. Flow cytometry analysis was used to determine cell apoptosis. Transwell assay was carried out to measure cell migration and invasion. Western blot assay was conducted to examine the protein levels of B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), matrix metalloprotein 2 (MMP2), MMP9 and PDCD4. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay were utilized to verify the combination between miR-20a and HAND2-AS1. Dual-luciferase reporter assay was used to analyze the association between miR-20a and PDCD4. Murine xenograft assay was used to confirm the function of HAND2-AS1 in vivo. HAND2-AS1 and PDCD4 were downregulated and miR-20a was upregulated in 5-FU-resistant CRC tissues and cells. HAND2-AS1 suppressed 5-FU resistance, cell proliferation, migration and invasion and promoted cell apoptosis in 5-FU-resistant CRC cells. HAND2-AS1 acted as a sponge of miR-20a to regulate PDCD4 expression. Moreover, HAND2-AS1 suppressed cell progression and 5-FU resistance by upregulating PDCD4 via sponging miR-20a in 5-FU-resistant CRC cells. Besides, HAND2-AS1 inhibited tumor growth in vivo. HAND2-AS1/miR-20a/PDCD4 axis inhibited cell progression and 5-FU resistance in 5-FU-resistant CRC cells. • HAND2-AS1, miR-20a and PDCD4 are dysregulated in 5-FU-resistant colorectal cancer tissues and cells. • HAND2-AS1 inhibits 5-FU resistance in 5-FU-resistant colorectal cancer cells. • HAND2-AS1 is a sponge of miR-20a and PDCD4 is a target of miR-20a in 5-FU-resistant colorectal cancer cells. • HAND2-AS1 suppresses 5-FU resistance by regulating miR-20a/PDCD4 axis in colorectal cancer cells. • HAND2-AS1 represses tumor growth in vivo. [ABSTRACT FROM AUTHOR]