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Background and Aim: The tumor-suppressing role of Ras-association domain family 1A (RASSF1A) has been described in several systems. In this study, we tested its tumor-suppressing ability and the potential molecular mechanisms in hepatocellular carcinoma (HCC) from Qidong County. Methods: Reverse transcription polymerase chain reaction and Northern blotting were employed to detect the expression of RASSF1A in HCC. After establishing stable RASSF1A (wild type or mutant) expressing ‘qi dong gan ai yan jiu suo’ ([Qidong Institute of Liver Cancer] QGY)-7703 cell lines, we tested the effects of RASSF1A expression on cell growth by cell proliferation rate, cell colony formation, and cell cycle progression. We also tested the effects of RASSF1A expression on tumorigenesis in nude mice and on cellular sensitivity to mitomycin treatment. Results: The RASSF1A transcript was not found in 75% (three of four) of HCC cell lines and 67% (32/48) of HCC primary biopsies. The stepwise regression analyses indicated that the loss of RASSF1A expression was more frequent in patients who were hepatitis B virus surface antigen positive (HBsAg+) compared to those who were HBsAg(−), both in tumor and corresponding non-cancerous tissues. The wild-type (wt)-RASSF1A expression in the QGY-7703 cell line resulted in fewer and smaller clones, decreased xenograft tumor volume and weight, and G1/S arrest in vitro and in vivo. The wt-RASSF1A expression also decreased the cyclin D1 protein expression, which appeared to be at the level of post-transcriptional control. In addition, the wt-RASSF1A expression increased cell growth inhibition and the percentage of cells with sub-G1 DNA content when the cells were treated with mitomycin. Conclusion: RASSF1A is a tumor suppressor in HCC. The loss of RASSF1A expression may be related to HBsAg+ in hepatocarcinogenesis. Its inactivation may play an important role in the development of HCC. [ABSTRACT FROM AUTHOR]

The article presents a research which investigates the possible suppressive effect of Ginsenoside Rh2 to the MSB-1 cells by using flow cytometry.

Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1β and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-κB signaling pathway via increasing reactive oxygen species (ROS) levels in A549 and H1299 cells, and N-acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-κB and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-κB/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future. [ABSTRACT FROM AUTHOR]

Zearalenone (ZEA) is a prevalent mycotoxin with high toxicity in animals. In order to study its effect on juvenile grass carp (Ctenopharyngodon idella), six diets supplemented with different levels of ZEA (0, 535, 1041, 1548, 2002, and 2507 μg/kg diet) for 10 weeks were studied to assess its toxicity on intestinal structural integrity and potential mechanisms of action. Our report firstly proved that ZEA led to growth retardation and body deformity, and impaired the intestinal structural integrity of juvenile grass carp, as revealed by the following findings: (1) ZEA accumulated in the intestine and caused histopathological lesions; (2) ZEA resulted in oxidative injury, apoptosis, and breached tight junctions in the fish intestine, which were probably associated with Nuclear factor-erythroid 2-related factor 2 (Nrf2), p38 mitogen activated protein kinases (p38MAPK), and myosin light chain kinase (MLCK) signaling pathways, respectively. ZEA had no influence on the antioxidant gene levels of Kelch-like ECH associating protein 1 (Keap1)b (rather than Keap1a), glutathione-S-transferase (GST)P1, GSTP2 (not in the distal intestine (DI)), tight junctions occludin, claudin-c (not in the proximal intestine (PI)), or claudin-3c (not in the mid intestine (MI) or DI). [ABSTRACT FROM AUTHOR]

Background: Ischemia/reperfusion (I/R) caused by ischemic stroke treatments leads to brain injury, and autophagy plays a role in the pathology. Astragaloside IV is a potential neuroprotectant, but its underlying mechanism on cerebral I/R injury needs to be explored. The objective of this study is to investigate the neuroprotective mechanism of Astragaloside IV against cerebral I/R injury. Methods: Middle cerebral artery occlusion method (MCAO) and oxygen and glucose deprivation/reoxygenation (OGD/R) method were used to simulate cerebral I/R injury in Sprague-Dawley (SD) rats and HT22 cells, respectively. The neurological score, 2,3,5-Triphe-nyltetrazolium chloride (TTC) staining, and transmission electron microscope were used to detect cerebral damage in SD rats. Cell viability and cytotoxicity assay were tested in vitro. Fluorescent staining and flow cytometry were applied to detect the level of apoptosis. Western blotting was conducted to examine the expression of proteins associated with autophagy. Results: This study found that Astragaloside IV could decrease the neurological score, reduce the infarct volume in the brain, and alleviate cerebral I/R injury in MCAO rats. Astragaloside IV promoted cell viability and balanced Bcl-2 and Bax expression in vitro, reduced the rate of apoptosis, decreased the expression of P62, and increased the expression of LC3II/LC3I in HT22 cells after OGD/R. Conclusions: These data suggested that Astragaloside IV plays a neuroprotective role by down-regulating apoptosis by promoting the degree of autophagy. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have been confirmed to play a crucial part in oncogenesis. Several studies suggested that MiR-3174 act as a tumor promoter in various Malignant neoplasm. However, the biological function of miR-3174 in hepatocellular carcinoma (HCC) still highly unexplored. We screened differentially over-expressed miRNAs by The Cancer Genome Atlas (TCGA) and the GEO databases. The expression of miR-3174 in HCC cells and tissues was detected by qRT-PCR. The cellular behaviors of transfected cells were respectively examined by colony formation assays, EdU Assays and flow cytometry. Forkhead box O1 transcription factor (FOXO1) was predicted and confirmed as a direct target of miR-3174 by bioinformatics analysis and dual-luciferase reporter gene assay. MiR-3174 was up-regulated in HCC tissues and cells, and the expression level of it was highly associated with tumor size and Edmondson grade. Our study pioneering validates that upregulated miR-3174 promote cell proliferation and inhibit cell apoptosis in vitro and in vivo. Meanwhile, our study verified that miR-3174 regulate Bim, P21, cyclin D1 and c-MYC expression by directly targeting FOXO1. The upregulated miR-3174 promote cell proliferation and inhibit cell apoptosis by downregulating FOXO1 expression in HCC. MiR-3174 may be a novel candidate for targeted delivery of miRNA therapeutics for HCC patients. • Combination of TCGA and GEO database sorts out novel miRNA candidates for HCC therapy. • MiR-3174 expression is significantly up-regulated in HCC tissues and cells. • Upregulation of miR-3174 plays a vital role in promoting proliferation in HCC cells. • FOXO1 is validated to be a tissue-specific target of miR-3174 in HCC. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the effects of dietary pyridoxine (PN) deficiency on intestinal antioxidant capacity, cell apoptosis and intercellular tight junction in young grass carp ( Ctenopharyngodon idella ). A total of 540 young grass carp (231.85 ± 0.63 g) were fed six diets containing graded levels of PN (0.12–7.48 mg/kg diet) for 10 weeks. At the end of the feeding trial, the fish were challenged with Aeromonas hydrophila for 2 weeks. The results showed that compared with the optimal PN level, PN deficiency (1) increased the contents of reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (PC), decreased the activities and mRNA levels of antioxidant enzymes such as copper, zinc superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione- S -transferase (GST) and glutathione reductase (GR) ( P  < .05); (2) up-regulated the mRNA levels of cysteinyl aspartic acid-protease-3 (caspase-3), caspase-7, caspase-8, caspase-9, Bcl-2 associated X protein (Bax), apoptotic protease activating factor-1 (Apaf-1) and Fas ligand (FasL), and down-regulated the mRNA levels of inhibitor of apoptosis proteins (IAP), B-cell lymphoma protein-2 (Bcl-2) and myeloid cell leukaemia-1 (Mcl-1) ( P  < .05); (3) down-regulated the mRNA levels of ZO-1, occludin [only in middle intestine (MI)], claudin-b, claudin-c, claudin-f, claudin-3c, claudin-7a, claudin-7b and claudin-11, and up-regulated the mRNA levels of claudin-12 and claudin-15a ( P  < .05), which might be partly linked to Kelch-like-ECH-associated protein 1a (Keap1a)/NF-E2-related factor 2 (Nrf2), p38 mitogen-activated protein kinase (p38MAPK) and myosin light chain kinase (MLCK) signalling in the intestines of fish. However, the activities and mRNA levels of MnSOD, the mRNA levels of Keap1b, c-Jun N-terminal protein kinase (JNK) and claudin-15b in three intestinal segments, and the mRNA levels of occludin in the proximal intestine (PI) and distal intestine (DI) were not affected by graded levels of PN. These data indicate that PN deficiency could disturb the intestinal physical barrier function of fish. Additionally, based on the quadratic regression analysis for MDA content and GST activity, the dietary PN requirements for young grass carp were estimated as 4.85 and 5.02 mg/kg diet, respectively. [ABSTRACT FROM AUTHOR]

Purpose: Apoptosis is an important physiological process, making a great difference to development and tissue homeostasis. Osteoarthritis (OA) is a chronic joint disease characterized by degeneration and destruction of articular cartilage and bone hyperplasia. This purpose of this study is to provide an updated review of the role of apoptosis in the pathogenesis of osteoarthritis. Methods: A comprehensive review of the literature on osteoarthritis and apoptosis was performed, which mainly focused on the regulatory factors and signaling pathways associated with chondrocyte apoptosis in osteoarthritis and other pathogenic mechanisms involved in chondrocyte apoptosis. Results: Inflammatory mediators such as reactive oxygen species (ROS), nitric oxide (NO), IL-1β, tumor necrosis factor-α (TNF-α), and Fas are closely related to chondrocyte apoptosis. NF-κB signaling pathway, Wnt signaling pathway, and Notch signaling pathway activate proteins and gene targets that promote or inhibit the progression of osteoarthritis disease, including chondrocyte apoptosis and ECM degradation. Long non-coding RNAs (LncRNAs) and microRNAs (microRNAs) have gradually replaced single and localized research methods and become the main research approaches. In addition, the relationship between cellular senescence, autophagy, and apoptosis was also briefly explained. Conclusion: This review offers a better molecular delineation of apoptotic processes that may help in designing new therapeutic options for OA treatment. [ABSTRACT FROM AUTHOR]

Programmed cell death protein 1/Programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors are the most promising treatments for malignant tumors currently, but the low response rate limits their further clinical utilization. To address this problem, our group constructed an engineered strain of VNP20009-Abvec-Igκ-mPD-1 [V-A-mPD-1 (mPD-1, murine PD-1)] to combine oncolytic bacterial therapy with immunotherapy. Further, we evaluated its growth performance and mPD-1 expression ability in vitro while establishing the melanoma mice model to explore its potential anti-cancer effects in tumor therapy. Our results indicated that the V-A-mPD-1 strain has superior growth performance and can invade B16F10 melanoma cells and express PD-1. In addition, in the melanoma mice model, we observed a marked reduction in tumor volume and the formation of a larger necrotic area. V-A-mPD-1 administration resulted in a high expression of mPD-1 at the tumor site, inhibiting tumor cell proliferation via the down-regulation of the expression of rat sarcoma (Ras), phosphorylated mitogen-activated protein kinase (p-MEK)/MEK, and phosphorylated extracellular signal-regulated kinase (p-ERK)/ERK expression significantly inhibited tumor cell proliferation. Tumor cell apoptosis was promoted by down-regulating phosphoinositide 3 kinase (PI3K) and protein kinase B (AKT) signaling pathways, as evidenced by an increased Bcl-2-associated X protein/B cell lymphoma-2 (Bax/Bcl-2) expression ratio. Meanwhile, the expression levels of systemic inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), were substantially reduced. In conclusion, our research demonstrated that V-A-mPD-1 has an excellent anti-tumor effect, prompting that the combined application of microbial therapy and immunotherapy is a feasible cancer treatment strategy. [ABSTRACT FROM AUTHOR]

Autophagy modulation has been considered as a potential therapeutic strategy for lung diseases. The PI3K-Akt-mTOR pathway may be one of the main targets for regulation of autophagy. We previously reported that a PI3 K/mTOR dual inhibitor PF-04691502 suppressed hepatoma cells growth in vitro . However, it is still unclear whether PF-04691502 induces autophagy and its roles in DNA damage and cell death in human lung cancer cells. In this study, we investigate the effects of PF-04691502 on the autophagy and its correlation with cell apoptosis and DNA damage in non-small-cell lung cancer (NSCLC) cell lines. PF-04691502 efficiently inhibited the phosphorylation of Akt and showed dose-dependent cytotoxicity in A549 and H1299 cells. PF-04691502 also triggered apoptosis and the cleavage of caspase-3 and PARP. Phosphorylated histone H2AX (γ-H2AX), a hallmark of DNA damage response, was dramatically induced by PF-04691502 treatment. By exposure to PF-04691502, A549 cells acquired a senescent-like phenotype with an increase in the level of β-galactosidase. Furthermore, PF-04691502 enhanced the expression of LC3-II in a concentration-dependent manner. More interestingly, effects of PF-04691502 on toxicity and DNA damage were remarkably increased by co-treatment with an autophagy inhibitor, chloroquine (CQ), in human lung cancer cells. These data suggest that a strategy of blocking autophagy to enhance the activity of PI3 K/mTOR inhibitors warrants further attention in treatment of NSCLC cells. [ABSTRACT FROM AUTHOR]

Increasing evidence shows the potential threat of gill rot in freshwater fish culture. F. columnare is wide-spread in aquatic environments, which can cause fish gill rot and result in high mortality and losses of fish. This study investigated the effects of myo -inositol (MI) on the proliferation, structural integrity, and different death modes of grass carp (Ctenopharyngodon idella) gill epithelial cells, as well as its possible mechanism. 30 mg/L MI up-regulated CCK8 OD value and the protein level of solute carrier family 5A 3 (SLC5A3), and down-regulated the reactive oxygen species (ROS) content in gill cells and lactate dehydrogenase (LDH) release in the culture medium (P < 0.05). MI up-regulated the protein level of Beclin1, the protein level and fluorescence expression of microtubule-associated protein light chain 3B (LC3B) and down-regulated the protein level of sequestosome-1 (SQSTM1, also called p62) (P < 0.05). MI down-regulated the protein levels of Cysteine aspartate protease-1 (caspase-1), Gasdermin E (GSDME) and Cleaved interleukin 1 beta (IL-1β) (P < 0.05). MI up-regulated the protein level of caspase-8 (P < 0.05), but had no effect on apoptosis (P > 0.05). MI down-regulated the mRNA expressions and protein levels of tumor necrosis factor α (tnfα), TNF receptor 1 (tnfr1), receptor interacting protein 1 (ripk1), receptor interacting protein 3 (ripk3) and mixed lineage kinase domain-like protein (mlkl), and reduce the ratio of p-MLKL/MLKL (P < 0.05). The addition of MI or necrosulfonamide (NSA) alone, or the addition of MI after induction of necroptosis, significantly up-regulated the cell activity and the protein level of SLC5A3 in gill cells, and significantly reduced the LDH release in the culture medium and the intracellular ROS content, the number of necroptosis cells, the protein expression of TNFα, TNFR1 and RIPK1, and the ratio of p-RIPK3/RIPK3 and p-MLKL/MLKL (P < 0.05). It indicated MI induce autophagy may relate to Beclin1/LC3/p62 signaling pathway, inhibits pyroptosis may attribute to Caspase-1/GSDMD/IL-1β signaling pathway, and inhibits necroptosis via MLKL signaling pathway. However, MI had no effect on apoptosis. • The primary gill epithelial cells of grass carp were isolated for the first time. • MI induce autophagy may relate to Beclin1/LC3/p62 signaling pathway. • MI inhibits pyroptosis may attribute to Caspase-1/GSDMD/IL-1β signaling pathway. • MI inhibited necroptosis of gill epithelial cells through MLKL signaling pathway. • MI had no effect on apoptosis, probably by up-regulating caspase-8 to normal levels. [ABSTRACT FROM AUTHOR]

Da-Chai-Hu-Tang (DCHT), a Chinese traditional herbal compound, has been utilized for the treatment of Hepatic diseases in China for over 1800 years. The DCHT formula contains eight herbals: Bupleurum chinense DC. (chaihu), Scutellaria baicalensis Georgi (huangqin), Paeonia lactiflora Pall. (baishao), Pinellia ternata (Thunb.) Makino (banxia), Rheum officinale Baill. (dahuang), Citrus × aurantium L. (zhishi), Zingiber officinale Roscoe (shengjiang), Ziziphus jujuba Mill. (dazao). Clinical studies have demonstrated the effectiveness of DCHT in hepatocellular carcinoma (HCC) and its ability to enhance the immunity of patients with hepatocellular carcinoma. A total of 20 Chinese articles have been published on the use of DCHT in treating HCC. The study aimed to validate the effect of DCHT in HCC cells and to identify related targets (TP53, AKT1, BCL2, STAT3) in treating HCC by DCHT in vitro experiments. Cell proliferation and migration were investigated in vitro. Flow cytometry analysis was used to evaluate the cell cycle and apoptosis. Apoptotic bodies in HepG2 cells were observed using a confocal microscope. Biochemical detection was employed to analyze LDH release, MDA levels, and SOD levels. Bioinformatics analysis was used to predict core targets between DCHT and HCC, as well as potential signaling pathways. The protein levels of metastasis-associated, apoptosis, and PI3K, AKT, p-AKT, and STAT3 were further determined through Western blotting. Following treatment with DCHT, the inhibition of viability, migration, and G2/M arrest was observed in HepG2 cells. Flow cytometry analysis and Morphological apoptosis studies provided evidence that DCHT could induce apoptosis in HepG2 cells. Biochemical detection revealed that DCHT could increase LDH release and the level of MDA, and inhibit the viability of the SOD. Bioinformatics analysis identified key targets such as TP53, AKT1, BCL2, STAT3. The PI3K/AKT/STAT3 signaling pathway emerged as a critical pathway in the KEGG enrichment analysis. Western blotting results indicated that DCHT could enhance the expression of E-cadherin, p53, and Bax, while reducing the content of N-cadherin, Bcl-2, PI3K, p-AKT, AKT1, and STAT3. The results proved that DCHT could inhibit the progression and metastasis of HCC by regulating the expression of E-cadherin, N-cadherin, p53, Bax, Bcl-2, PI3K, p-AKT, AKT, and STAT3 through the PI3K/AKT/STAT3 signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

Leucine is an essential amino acid for fish. The ability of leucine to resist stress in fish has not been reported. Nitrite is a common pollutant in the aquatic environment. Therefore, we investigated the effects of dietary leucine on growth performance and nitrite-induced liver damage, mitochondrial dysfunction, autophagy, and apoptosis for sub-adult grass carp. A total of 450 grass carp (615.91 ± 1.15 g) were selected and randomly placed into 18 net cages. The leucine contents of the six diets were 2.91, 5.90, 8.92, 11.91, 14.93, and 17.92 g/kg, respectively. After a 9-week feeding trial, the nitrite exposure experiment was set up for 96 h. These results indicated that dietary leucine significantly promoted FW, WG, PWG, and SGR of sub-adult grass carp (P < 0.05). Appropriate levels of dietary leucine (11.91–17.92 g/kg) decreased the activities of serum parameters (glucose, cortisol, and methemoglobin contents, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase), the contents of reactive oxygen species (ROS), nitric oxide (NO) and peroxynitrite (ONOO−). In addition, appropriate levels of dietary leucine (11.91–17.92 g/kg) increased the mRNA levels of mitochondrial biogenesis genes (PGC-1α, Nrf1/2, TFAM), fusion-related genes (Opa1, Mfn1/2) (P < 0.05), and decreased the mRNA levels of caspase 3, caspase 8, caspase 9, fission-related gene (Drp1), mitophagy-related genes (Pink1, Parkin) and autophagy-related genes (Beclin1, Ulk1, Atg5, Atg7, Atg12) (P < 0.05). Appropriate levels of dietary leucine (8.92–17.92 g/kg) also increased the protein levels of AMP-activated protein kinase (AMPK), prostacyclin (p62) and decreased the protein levels of protein light chain 3 (LC3), E3 ubiquitin ligase (Parkin), and Cytochrome c (Cytc). Appropriate levels of leucine (8.92–17.92 g/kg) could promote growth performance and alleviate nitrite-induced mitochondrial dysfunction, autophagy, apoptosis for sub-adult grass carp. Based on quadratic regression analysis of PWG and serum GPT activity, dietary leucine requirements of sub-adult grass carp were recommended to be 12.47 g/kg diet and 12.55 g/kg diet, respectively. [Display omitted] • Leucine could alleviate nitrite-induced liver damage of grass carp. • Leucine alleviated liver damage probably via reducing nitrite-induced autophagy, apoptosis, and mitochondrial dysfunction. • Based on PWG and serum GPT, leucine requirement was determined to be 12.47 g/kg and 12.55 g/kg diet for sub-adult grass carp. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we aimed at examining the immunosuppressive activity of saikosaponin a, a triterpene saponin derived from Bupleurum falcatum L. (Umbelliferae), and the underlying mechanisms. Saikosaponin a significantly inhibited the proliferation and activation of T cells activated by concanavalin A (Con A) in a concentration-dependent manner. Additionally, it potently suppressed Con A-stimulated IL-2, IFN-γ and TNF-α production in mouse T cells. Saikosaponin a also caused G0/G1 arrest of activated T cells through down-regulating the protein levels of CDK6 and Cyclin D3 and up-regulating the protein level of p27kip. Furthermore, the compound dose-dependently induced apoptosis of Con A-activated T cells rather than those non-activated, as determined by Annexin V/PI staining. Besides, it induced a remarkable collapse of mitochondrial membrane potential and caused significant release of cytochrome c from mitochondria to cytosol. In summary, these results suggest that the G0/G1 arrest as well as the induction of apoptosis via mitochondrial pathway are involved in the immunosuppressive activity of saikosaponin a against activated T cells. This may herald a novel approach for further studies of saikosaponin a as a candidate for the treatment of inflammatory and autoimmune diseases. [Copyright &y& Elsevier]

Purpose: There is increasing evidence that non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), produce a critical regulatory effect on osteosarcoma (OS). LINC01278, as a newly discovered lncRNA, is found to be highly expressed in OS, but its related mechanism remains unclear. This research, therefore, is designed to study the mechanism of LINC01278 in OS and to find potential targets for clinical use. Methods: qRT-PCR was applied to determine the relative expression of LINC01278 and analyze its diagnostic value in OS. CCK-8, Transwell and flow cytometry were utilized for the determination of cell proliferation, migration/invasion, and apoptosis. RIP and RNA pull-down experiments were used to verify the targeted binding effect of miR-134-5p and LINC01278. The relationship between miR-134-5p and LINC01278 or KRAS was analyzed using dual luciferase reporter gene. The effects of LINC01278 on tumor growth in nude mice was analyzed by in vivo experiment. Results: qRT-PCR showed that LINC01278 increased in OS tissues and serum, indicating poor prognosis. In addition, LINC01278 was also of high value for OS diagnosis. Functional experiments showed that LINC01278 inhibited KRAS-mediated OS cell proliferation and metastasis through miR-134-5p. Finally, the results of an in vivo animal model indicated that LINC01278 promoted OS growth. Conclusion: LINC01278 is expressed highly in OS, and patients with high LINC01278 expression have poor prognosis. Moreover, LINC01278 can suppress the proliferation and apoptosis of OS cells through mediating miR-134-5p/KRAS axis, which is expected to become a potential therapeutic target for OS. [ABSTRACT FROM AUTHOR]

The effects of dietary pyridoxine (PN) on the gill immunity, apoptosis, antioxidant and tight junction of grass cap (Ctenopharyngodon idella) were investigated in this study. Fish were fed semi-purified diets containing graded levels of PN for 10 weeks, and then challenged with Flavobacterium columnare by bath immersion exposure for 3 days. The results indicated that compared with the optimal PN level, PN deficiency resulted in a decline in the antimicrobial compound production of gill. In addition, PN deficiency up-regulated the pro-inflammatory cytokines and down-regulated the anti-inflammatory cytokines gene expression, which might be associated with the enhanced nuclear factor κB p65 and the inhibited target of rapamycin signalling pathways, respectively, suggesting that PN deficiency could impair gill immune barrier function. Furthermore, PN deficiency (1) induced cell apoptosis, which may be partly associated with the (apoptotic protease activating factor-1, Bcl-2 associated X protein)/caspase-9 and c-Rel/tumor necrosis factor α (rather than FasL)/caspase-8 mediated apoptosis pathway. (2) Inhibited Kelch-like ECH-associating protein 1a/NF-E2-related factor 2 mRNA expression, decreased the mRNA expression and activities of antioxidant enzymes, increased the levels of reactive oxygen species, protein carbonyl and malondialdehyde. (3) Increased the mRNA expression level of myosin light chain kinase, which may be result in the down-regulation of tight junction complexes such as zonula occludens 1, occludin and claudins (expect claudin-12 and claudin-15). These results suggest that PN deficiency could impair gill physical barrier function. In summary, dietary PN deficiency could cause the impairment of gill barrier function associated with immunity, apoptosis, antioxidant and tight junction, which may result in the increased the susceptibility of fish to pathogenic bacteria. Moreover, based on the gill rot morbidity, LZ activity and MDA content, the dietary PN requirements for grass cap were estimated to be 4.85, 4.78 and 4.77 mg kg−1 diet, respectively. • Dietary pyridoxine deficiency impaired immune function of fish gill. • Dietary pyridoxine deficiency impaired apoptosis, antioxidant system and intercellular tight junction of fish gill. • Dietary pyridoxine regulated the signalling of NF-κB, TOR, p38MAPK, Nrf2 and MLCK in fish. [ABSTRACT FROM AUTHOR]

As a part of our ongoing search for neuroprotective compounds from natural products, two new iridoid glycosides, vibsansuspenside A-B (1-2), along with five known terpenoids (3-7), were isolated from the dry leaves of Viburnum odoratissimum. Their chemical structures were well determined by means of NMR spectroscopic data as well as HRESIMS analysis. All compounds were detected for their neuroprotective effects against H2O2-induced damage in human dopaminergic neuroblastoma cells (SH-SY5Y). Among them, compound 3 displayed the most potent neuroprotective ability, and further investigation by Annexin V/PI and Western blot analysis demonstrated that compound 3 could protect SH-SY5Y cells from oxidative damage through inhibiting cell apoptosis. [ABSTRACT FROM AUTHOR]

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To investigate effects of vitamin A (VA) on fish immune function and structural integrity in the head kidney and spleen of fish, total of 540 on-growing grass carp (Ctenopharyngodon idella) were divided into six groups, feeding graded levels of VA (0, 600, 1200, 1800, 2800 and 3800 IU/kg diet) for 70 days. Results showed that dietary VA deficiency depressed antibacterial ability and aggravated inflammatory response partially linked to nuclear factor κB p65 (NF-κB p65) and target of rapamycin (TOR) signaling pathways in the head kidney and spleen of fish. Meanwhile, VA deficiency caused oxidative damage, apoptosis and disruption of tight junctions (TJs), which were partially attributed to the down-regulation of NF-E2-related factor 2 (Nrf2) signaling mediated antioxidant ability, the up-regulation of p38 mitogen-activated protein kinase (p38MAPK) signaling mediated apoptosis and myosin light chain kinase (MLCK) signaling mediated disruption of tight junctions (TJs). Taken together, current study firstly demonstrated that VA deficiency decreased the immune function and damaged the structural integrity of the head kidney and spleen in fish. • Vitamin A deficiency impaired immunity in the head kidney and spleen of fish. • Vitamin A deficiency disrupted the structural integrity of systemic immune organs in fish. • Vitamin A regulated p38MAPK, NF-κB, TOR, Nrf2 and MLCK signaling pathways. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON) is a common mycotoxin existed in animal feed, and lead to significant economic loss due to its negative impacts on animal growth performance and animal health. The gill is a primary mucosal immune organ in teleosts, and the structural integrity of the gill is closely relevant with fish healthy growth. Hence, this study assessed the influences of DON on the gill structural integrity of juvenile grass carp, Ctenopharyngodan idella (initial average weight 12.17 ± 0.01 g), when offered with six different diets which contained various content of DON (27, 318, 636, 922, 1243 and 1515 μg/kg diet) for 60 days. Our research firstly systematically elaborated that DON caused histopathological lesions, oxidative injury, reduction of antioxidant ability, apoptosis as well as damages of tight junctions in fish gills. Comparing these data to the control, we found that DON at dose of more than 318 μg/kg diet led to oxidative injury, apoptosis and disruption of tight junctions in fish gill, which were likely to be relevant with Nrf2, JNK and MLCK signalling pathways, respectively. It was worth noting that DON was not found to affect the gene expressions of Keap1b (rather than Keap1a), claudin-b, claudin-3c and claudin-15b (not claudin-15a) in fish gills. Furthermore, based on MDA and T-AOC activities in the gill, the maximum permissible levels of DON were evaluated to be 375.60 as well as 412.91 μg/kg diet in grass carp, respectively. • Deoxynivalenol (DON) caused oxidative damage and declining antioxidant capacity in the fish gill. • DON aggravated apoptosis in the fish gill. • DON disrupted tight junctions in the fish gill. • DON regulated Nrf2, JNK and MLCK signalling. • DON did not affect Keap1b, claudin-b, claudin-3c and claudin-15b in fish gill. [ABSTRACT FROM AUTHOR]

Research has revealed that microRNA (miR)-4500 is downregulated in non-small cell lung cancer (NSCLC), and miR-4500 suppresses tumor growth by targeting lin-28 homolog B and NRAS proto-oncogene, GTPase. In the present study, it was reported that signal transducer and activator of transcription 3 (STAT3) may function as a novel target gene for miR-4500 in NSCLC. The experiments conducted in the present study confirmed that the miR-4500 expression was decreased in NSCLC tissues and cells compared with adjacent normal tissues and a normal lung cell line. miR-4500 suppressed the cell proliferation, migration, invasion and promoted apoptosis of the human NSCLC cell lines A549 and H1975. Expression of STAT3 was negatively correlated with miR-4500 expression in vivo. A luciferase reporter assay suggested that miR-4500 directly targeted the 3′ untranslated region of STAT3. The tumor inhibition effect of small interfering RNA STAT3 in A549 and H1975 lines may be partially impaired by a miR-4500 inhibitor. The results of the present study suggests that miR-4500 may be a tumor suppressor and a potential therapeutic target in NSCLC. [ABSTRACT FROM AUTHOR]

Ischemic stroke poses a serious risk to public health and quality of life. Jie-Du-Huo-Xue decoction (JDHXD) is a classical and well-known Chinese formula for stroke treatment, but the pharmacological mechanism is still unclear. This study aims to investigate the mechanism underlying microglial pyroptosis and polarization, as well as the potential efficacy of JDHXD against cerebral ischemia-reperfusion injury (CIRI). Models of CIRI were established by the middle cerebral artery occlusion/reperfusion (MCAO/R) method in rats. In the first stage, 36 SD rats were randomly divided into sham group, I/R group, JDHXD-L group (5.36 g/kg/day), JDHXD-M group (10.71 g/kg/day), JDHXD-H group (21.42 g/kg/day), and positive drug edaravone group. The effectiveness of JDHXD on CIRI was confirmed by neurological function testing and cerebral infarct measuring. The best dose (JDXHD-M) was subsequently chosen to perform the tests that followed. In the second stage, 36 SD rats were randomly divided into the sham group, the I/R group, and the JDHXD-M group. Detection of nerve damage using Nissl staining, proteins of pyroptosis, Iba-1, and NeuN expressions were detected by western blotting, and proteins of microglial pyroptosis and M1/M2 phenotypic polarization were detected by immunofluorescence. In rats after CIRI, JDHXD significantly reduced neurological impairment and cerebral infarction. In addition, JDHXD facilitated the M1-to-M2 transition of microglia in order to minimize neuroinflammation and improve anti-inflammatory repair. In addition, JDXHD inhibited microglial pyroptosis by blocking the cleavage of caspase-1 P10 and gasdermin D, hence reducing neuronal damage and enhancing neuronal survival following reperfusion. Interestingly, JDHXD also demonstrated a protective effect on the glial-vascular unit (GVU). Our investigation demonstrated that JDHXD exerted a GVU-protective effect on CIRI rats by decreasing neuroinflammation-associated microglial pyroptosis, suppressing microglial M1 activation, and promoting microglial M2 activation. [Display omitted] • Jie-Du-Huo-Xue decoction reduced neuronal damage in stroke. • Jie-Du-Huo-Xue decoction promoted the M1-to-M2 transition of microglia. • Jie-Du-Huo-Xue decoction blocked canonical pathway pyroptosis of microglia in the glial-vascular unit after reperfusion. [ABSTRACT FROM AUTHOR]

Aspirin, as a first-line drug for the treatment of cardiovascular diseases, currently has high clinical usage. However, reports of aspirin-induced gastric mucosal injury are increasing. Xiaojianzhong decoction (XJZD), a classic traditional Chinese medicine formula, has been shown to alleviate gastric mucosal injury, although its potential mechanism of action requires further study. This study aimed to explore the effect and mechanism of XJZD in preventing aspirin-induced gastric mucosal injury. Aspirin was used to induce damage in the morning, while XJZD was applied as an intervention in the afternoon. The compounds in the XJZD were analyzed by means of both high-performance liquid chromatography and ultra-performance liquid chromatography–tandem mass spectrometry. The overall condition of the aspirin-related gastric mucosal injury was evaluated. The expressions of inflammatory factors and tight-junction-related proteins and apoptosis were observed via immunohistochemistry and immunofluorescence. The expression levels of the apoptosis-related proteins were detected using Western blot. Transcriptomics was used to perform the integrative analysis of gastric tissues, which was then validated. Molecular dynamics was used to explore the interaction of key compounds within the XJZD with relevant targets. Finally, non-targeted metabolomics was used to observe any metabolic changes and construct a network between the differentially expressed genes and the differential metabolites to elucidate their potential relationship. XJZD can alleviate inflammation response, maintain the gastric mucosal barrier's integrity, reduce apoptosis and necroptosis levels, and promote the proliferation and repair of gastric mucosal tissues. Its mechanism of action may be related to the regulation of TNF-α signaling. Furthermore, molecular docking showed that the cinnamaldehyde within XJZD played an important role in its effects. In addition, XJZD can correct metabolic disorders, mainly regulating amino acid metabolism pathways. Moreover, six differential genes (Cyp1a2, Cyp1a1, Pla2g4c, etc.) were determined to alleviate both gastric mucosal injury and inflammation by regulating arachidonic acid metabolism, Tryptophan metabolism, etc. This study is the first to report that XJZD can inhibit necroptosis and gastric mucosal injury induced by aspirin, thereby revealing the complex mechanism of XJZD in relation to alleviating gastric mucosal injury from multiple levels and perspectives. [Display omitted] • XJZD can improves gastric mucosal injury aspirin-induced gastric mucosal injury, inhibit inflammation, maintain barrier integrity and reduce apoptosis of gastric mucosal epithelial cells. • XJZD can inhibit necroptosis promote the proliferation and repair of gastric tissue and down-regulate the level of necroptosis. • XJZD can correct the imbalance of differential metabolites during gastric mucosal injury. [ABSTRACT FROM AUTHOR]

Objective: To discover the expression pattern and potential underlying mechanism of the caspase recruitment domain‐containing protein 9 (CARD9) in oral squamous cell carcinoma (OSCC). Methods: Caspase recruitment domain‐containing protein 9 expression was detected by qRT‐PCR and Western blot in OSCC tissues and cells, and OSCC (CGHNC9 and OECM‐1) cell lines were divided into control, NC siRNA, and CARD9 siRNA groups. Then, MTT, flow cytometry, wound‐healing, and Transwell assays were carried out to determine the changes in cellular biological characteristics. Immunoblot assay was performed for the expressions of NF‐κB pathway. Finally, we constructed the xenograft models in nude mice to validate the in vivo effect of CARD9 siRNA on OSCC cell growth. Results: Caspase recruitment domain‐containing protein 9 was upregulated in both OSCC tissues and cells, exhibiting a close relation with major clinicopathological features of OSCC patients. Transfection of CARD9 siRNA inhibited the proliferation, migration, and invasion of OSCC cells with the enhanced cell apoptosis, and meanwhile, CARD9, p‐p65/p65, p‐IKKα/IKKα, and p‐IkBα/IkBα were downregulated. The tumor formation assay on nude mice also suggested that CARD9 siRNA might block the in vivo growth of OSCC cells. Conclusion: Caspase recruitment domain‐containing protein 9 suppression results in the upregulation of NF‐κB pathway with suppressed proliferation, migration, and invasion of OSCC cells and facilitates the apoptosis. [ABSTRACT FROM AUTHOR]

In the present study, the expression of microRNA (miR)-671-3p in non-small-cell lung cancer (NSCLC) was detected via reverse transcription-quantitative polymerase chain reaction analysis, and its role in cell proliferation, apoptosis, migration and invasion was investigated via Cell Counting Kit-8, colony formation, flow cytometry, Transwell and scratch assays, respectively. It was observed that the expression of miR-671-3p was upregulated in NSCLC tissues and cell lines (A549 and H1975). Treatment with miR-671-3p inhibitors suppressed cell proliferation, migration and invasion, and increased apoptosis in vitro, suggesting that miR-671-3p functions as an oncogene in NSCLC. In addition, forkhead box P2 (FOXP2) has been reported to be a tumor suppressor that is downregulated in several types of cancer, and its low expression was confirmed in NSCLC tissues and cell lines in the current study via western blotting. The results of the luciferase reporter assay also demonstrated that miR-671-3p targeted directly the 3′-untranslated region of FOXP2. Furthermore, overexpression of FOXP2 in A549 and H1975 cell lines suppressed the growth, migration and invasion, and promoted apoptosis, whereas these effects were reversed by transfection with miR-671-3p mimics, suggesting that miR-671-3p promoted tumor progression via regulating FOXP2. Taken together, the results reported in the present study implied that miR-671-3p may be a potential therapeutic target in NSCLC. [ABSTRACT FROM AUTHOR]

One new triterpenoid saponin (1), as well as six known ones (2–7), were isolated from the ethanol extract of the thorns of Gleditsia sinensis. Their structures were elucidated by extensive spectroscopic analysis in conjunction with chemical evidence. Cytotoxic activity of compounds 1–6 was evaluated against human breast cancer MCF 7 cells in vitro by the MTT method. Our results revealed moderate activities for compounds 1–6 with IC50 values of 18.43, 30.47, 18.46, 10.02, 30.76, and 17.32 μM, respectively. Furthermore, compounds 1, 3, 4, and 6 induced apoptosis in MCF 7 cell, with 1 and 6 causing late apoptosis of MCF 7 cells, while 3 and 4 acting oppositely. [ABSTRACT FROM AUTHOR]

Selenium (Se) deficiency induces typical clinical and pathological changes and causes various pathological responses at the molecular level in several different chicken organs; the kidney is one of the target organs of Se deficiency. To explore the mechanisms that underlie the effects of microRNA‐33‐3p (miR‐33‐3p) on Se deficiency‐induced kidney apoptosis, 60 chickens were randomly divided into two groups (30 chickens per group). We found that Se deficiency increased the expression of miR‐33‐3p in the chicken kidney. A disintegrin and metalloprotease domain 10 (ADAM10) was verified to be a target of miR‐33‐3p in the chicken kidney. The overexpression of miR‐33‐3p decreased the expression levels of β‐catenin, cyclinD1, T‐cell factor (TCF), c‐myc, survivin, and Bcl‐2; it increased the expression levels of E‐cadherin, Bak, Bax, and caspase‐3; and it increased the number of chicken kidney cells in the G0/G1 phase. In addition, Se deficiency caused the ultrastructure of the kidney to develop apoptotic characteristics. The results of flow cytometry analysis and AO/EB staining showed that the number of apoptotic chicken kidney cells increased in the miR‐33‐3p mimic group. All these results suggest that Se deficiency‐induced cell cycle arrest and apoptosis in vivo and in vitro in the chicken kidney via the regulation of miR‐33‐3p, which targets ADAM10. [ABSTRACT FROM AUTHOR]

Objective: Bufalin has been reported to kill various types of cancer including human colorectal cancer. Our previous study demonstrated that bufalin induced cell death via autophagy in HT-29 and Caco-2 colon cancer cells, but the action of bufalin remains unclear. This study was conducted to investigate the role of bufalin in other colon cancer HCT-116 and SW620 cells as well as its potential mechanism. Methods: The effect of bufalin in HCT-116 and SW620 colon cancer cells was detected by assessing cell viability and cell death. Apoptotic cells were analyzed by Western blot and trypan blue dye exclusion assay. Mitochondrial ROS production was analyzed by flow cytometry after DCFDA and DHR-123 staining. The potential mechanism was investigated via pharmacological inhibitors. Results: Bufalin had high potency against HCT-116 and SW620 cells with IC50 values of 12.823 ± 1.792 nM and 26.303 ± 2.498 nM in HCT-116 and SW620 cells, respectively. Bufalin decreased cell viability, increased cell death as well as caspase-3 downstream target (cleaved PARP) accumulation, and these actions were significantly blocked by pan-caspase inhibitor zVAD-FMK. Mechanistically, ROS production, but neither the NAD(P)H oxidase, AMPK, ERK nor p38, is responsible for bufalin-induced apoptotic cell death. Moreover, bufalin-induced ROS generation is derived from mitochondria. Conclusion: Bufalin significantly induces apoptosis in HCT-116 and SW620 colon cancer cells via mitochondrial ROS-mediated caspase-3 activation. We believe that our novel findings will greatly alter our current understanding on the anti-cancer mechanism of bufalin in colon cancer cells and will pave the way for further exploiting the clinical application. [ABSTRACT FROM AUTHOR]

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The aim of this study was to determine the function of the NEAT1/miR‐23a‐3p/SMC1A axis in cell proliferation and apoptosis in acute myeloid leukemia (AML). Microarray analysis was used to screen differentially expressed lncRNAs/miRNAs/mRNAs in primary AML cells. The expression of nuclear paraspeckle assembly transcript 1 (NEAT1), miR‐23a‐3p, and structural maintenance of chromosome 1 alpha (SMC1A) in primary AML cells and THP‐1 cells were measured by quantitative real‐time polymerase chain reaction (qRT‐PCR). A Cell Counting Kit‐8 (CCK‐8) assay was used to analyze proliferation. Cell cycle progression and apoptosis were examined by flow cytometry. RNA immunoprecipitation (RIP) and dual‐luciferase assays were performed to determine the correlation between miR‐23a‐3p and NEAT1 or SMC1A. The qRT‐PCR illustrated that NEAT1 and SMC1A expression was decreased but that miR‐23a‐3p expression was increased in primary AML cells and THP‐1 cells compared with that in normal cells. The RIP assay and dual‐luciferase assay revealed the targeting relationship between miR‐23a‐3p and NEAT1 or SMC1A. The CCK‐8 assay showed that the overexpression of NEAT1 and SMC1A or repression of miR‐23a‐3p inhibited cell proliferation. Flow cytometry showed that the upregulation of NEAT1 and SMC1A or repression of miR‐23a‐3p promoted apoptosis and affected the cell cycle. NEAT1 repressed the expression of miR‐23a‐3p, and therefore promoted SMC1A, which in turn suppressed myeloid leukemia cell proliferation and enhanced apoptosis. 1.This study illustrates the molecular interaction between nuclear paraspeckle assembly transcript 1 (NEAT1), miR‐23a, and structural maintenance of chromosome 1 alpha (SMC1A) in acute myeloid leukemia (AML). 2.Reduced expression of NEAT1 induced the tumorigenesis and progression of AML through the miR‐23a‐3p/SMC1A axis. 3.These results suggest that this axis can be used as a promising therapeutic target to mitigate the progression of AML. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC. In addition, the NAMPT inhibitor FK866 or lentivirus‐mediated silencing induced CRC cell growth inhibition. Mechanistically, NAMPT regulated Sirt1 and P53 expression and induced G0/G1 cell cycle arrest, along with the upregulation of downstream p21 and downregulation of cyclin D1, cyclin E1, and cyclin E2 expression. FK866 administration or knockdown of NAMPT induced CRC cell apoptosis via upregulation of caspase‐3. In conclusion, NAMPT regulated Sirt1/P53 signaling during CRC cell growth and warrants further investigation for clinical administration in CRC. 1.Overexpression of nicotinamide phosphoribosyl transferase (NAMPT) was detected in colorectal cancer (CRC) tissue compared to normal colorectal samples. 2.NAMPT inhibitor FK866 or lentivirus‐mediated silencing induced CRC cell growth inhibition. 3.NAMPT regulated Sirt1/P53 signaling during CRC cell growth. [ABSTRACT FROM AUTHOR]

Abstract A 60 days feeding trial was conducted to investigate the effects of dietary nucleotides levels on growth performance, proximate composition, physicochemical properties, amino acids constituents, fatty acids composition, apoptosis and antioxidant status related mechanism of grass carp (Ctenopharyngodon idella) (initial weight: 200.00 ± 1.00 g). Six graded levels of dietary nucleotides were designed as 0, 200.0, 400.0, 600.0, 800.0 and 1000.0 mg/kg, respectively. The results showed that, compared with control group, dietary nucleotides supplementation increased the growth of grass carp with higher final body weight, percentage weight gain and specific growth rate, decreased moisture but increased protein and lipid in muscle. However, dietary nucleotides had no effect on ash, calcium and phosphorus in fish fillets (P >.05). Dietary nucleotides supplementation increased the content of umami and sweetness-associated amino acids, flavor nucleotide (inosine mono-phosphate), healthcare n-3 PUFAs (EPA and DHA) and the ratio of n-3/n6 in fish muscle. Meanwhile, dietary nucleotides increased water holding capacity, tenderness and pH to enhance flesh quality, which were partly related to inhibited apoptosis with regulation of apoptosis-related gene expression, decreased hydroxyproline with increase of cathepsins activities and decreased lactate in muscle, respectively. In addition, dietary nucleotides enhanced flesh quality of grass carp fillets concerning increasing antioxidant enzymes activities and its gene expression, which were modulated by signaling molecules (TOR and Nrf2) gene and protein expression in grass carp muscle. In summary, dietary nucleotides supplementation increased growth performance, flavor characteristics, healthy fatty acid contents, physicochemical properties (water holding capacity, tenderness and pH), anti-apoptotic ability and antioxidant capacity in fish. This study demonstrated that nucleotides was a promising feed additives to enhance flesh quality in fish. Highlights • Nucleotides enhance muscle flavor quality and health benefits in fish. • Nucleotides are effective in enhancing flesh quality related parameters. • Nucleotides-enhanced WHC, tenderness and pH is related to decreasing apoptosis, collagen and lactate content in muscle. • Inhibition of oxidation is due to increases of antioxidant capacity regulated by Nrf2 and TOR signaling. • The nucleotides supplementation for fish growth and flesh quality were evaluated. [ABSTRACT FROM AUTHOR]

Fluorine or fluoride can have toxic effects on bone tissue and soft tissue at high concentrations. These negative effects include but not limited to cytotoxicity, immunotoxicity, blood toxicity, and oxidative damage. Apoptosis plays an important role in fluoride-induced toxicity of kidney, liver, spleen, thymus, bursa of Fabricius, cecal tonsil, and cultured cells. Here, apoptosis activated by high level of fluoride has been systematically reviewed, focusing on three pathways: mitochondrion-mediated, endoplasmic reticulum (ER) stress-mediated, and death receptor-mediated pathways. However, very limited reports are focused on the death receptor-mediated apoptosis pathways in the fluoride-induced apoptosis. Therefore, understanding and discovery of more pathways and molecular mechanisms of fluoride-induced apoptosis may contribute to designing measures for preventing fluoride toxicity. [ABSTRACT FROM AUTHOR]

Blood retinal barrier (BRB) damage is an important pathogenesis of diabetic retinopathy, and alleviating BRB damage has become a key target for DR treatment. We previously found that Lycopene seed polyphenols (LSP) maintained BRB integrity by inhibiting NLRP3 inflammasome-mediated inflammation. However, it is still unknown whether LSP inhibits retinal neovascularization with abnormal capillaries and its mechanism of action. Here, we employed db/db mice and hRECs to find that LSP increases the level of glycolipid metabolism, maintains the morphology of retinal endothelial cells and inhibits acellular capillary neogenesis. Mechanistic studies revealed that LSP inhibits the NLRP3 inflammasome, reduces cell apoptosis in retinal tissue, increases tight junction protein (TJ) expression, and reduces vascular endothelial growth factor (VEGF) and Ve-Cadherin in vivo and in vitro. Collectively, this study finds that LSP inhibits inflammation and angiogenesis to improve BRB function to ameliorate DR. [Display omitted] ● Inflammasomes, apoptosis, and angiogenesis coexist in the pathogenesis of DR, and multitargeted intervention is required to achieve good therapeutic effects. ● LSP could exert anti-inflammatory, anti-apoptotic and TJ protective effects in a high glucose environment. ● BRB dysfunction secondary to inflammasomes and apoptosis is a typical pathologic change in DR. ● LSP improved BRB function by inhibiting inflammation, apoptosis and neovascularization to effectively treat DR. [ABSTRACT FROM AUTHOR]

Abstract This study focused on the effects of dietary selenium deficiency on structural integrity of the head kidney, spleen and skin in young grass carp (Ctenopharyngodon idella). A total of 540 healthy grass carp (mean weight 226.48 ± 0.68 g) were randomly divided into six groups and fed six separate diets with graded dietary levels of selenium (0.025–1.049 mg/kg diet) for 80 days. Results showed that selenium deficiency (1) caused oxidative damage in part by reducing the activities of antioxidant enzymes (such as SOD, CAT, GPx, GST and GR) and glutathione (GSH) content, down-regulating the transcript abundances of antioxidant enzymes (except GSTp1) partly related to Kelch-like-ECH-associated protein 1a (Keap1a)/NF-E2-related factor 2 (Nrf2) signalling; (2) aggravated apoptosis in part by up-regulating the mRNA levels of caspase-2 , -3 , -7 , -8 and - 9 , which were partially related to p38MAPK/FasL/caspase-8 signalling and JNK/(BAX, Bcl-2, Mcl-1b, IAP)/(Apaf1, caspase-9) signalling; (3) damaged the tight junctions in part by down-regulating the mRNA levels of ZO-1 (except spleen), ZO-2 (except spleen), claudin-c , -f , -7 , -11 and claudin-15 , and up-regulating the mRNA levels of claudin-12 , which were partially related to myosin light chain kinase (MLCK) signalling. Interesting, selenium deficiency failed to affect the expression of GSTp1 , Keap1a , occludin, claudin-b , claudin-3c , ZO-1 (spleen only) and ZO-2 (spleen only) in the head kidney, spleen and skin of grass carp. Finally, based on the activities of glutathione peroxidase (GPx) and reactive oxygen species (ROS) content in the head kidney, spleen and skin, the dietary selenium requirements for young grass carp were estimated to be 0.558–0.588 mg/kg diet. [ABSTRACT FROM AUTHOR]

Abstract Dexamethasone (Dex) can induce injury to human osteoblasts. Long non-coding RNA ( LncRNA ) EPIC1 ( Lnc-EPIC1 ) is a novel Myc-interacting LncRNA. Its effect on Dex-treated human osteoblasts is studied here. In OB-6 osteoblastic cells and primary human osteoblasts, treatment with Dex increased expression of Lnc-EPIC1. Its expression is also elevated in the necrotic femoral head tissues of Dex-taking patients. Ectopic overexpression of Lnc-EPIC1 inhibited Dex-induced apoptosis and programmed necrosis in OB-6 cells and primary human osteoblasts. Reversely, Lnc-EPIC1 silencing by targeted siRNA potentiated Dex-induced cytotoxicity. Myc is the target of Lnc-EPIC1 in osteoblasts. Exogenous overexpression of Myc protected OB-6 cells from Dex. Conversely, Myc knockout by CRISPR-Cas-9 method abolished Lnc-EPIC1 -induced OB-6 cytoprotection against Dex. Together, Lnc-EPIC1 expression protects human osteoblasts from Dex possible via regulation of Myc. Highlights • Dexamethasone (Dex) increases Lnc-EPIC1 expression in human osteoblasts. • Lnc-EPIC1 expression is elevated in necrotic femoral head tissues of Dex-taking patients. • Ectopic Lnc-EPIC1 overexpression protects human osteoblasts from Dex. • Lnc-EPIC1 siRNA potentiates Dex-induced cytotoxicity in human osteoblasts. • Myc is the primary target of Lnc-EPIC1 in human osteoblasts. [ABSTRACT FROM AUTHOR]

Craniofacial malformations are common congenital birth defects and usually caused by abnormal development of the cranial neural crest cells. Some nucleolar ribosome biogenesis factors are implicated in neural crest disorders also known as neurocristopathies. However, the underlying mechanisms linking ribosome biogenesis and neural crest cell (NCC) development remain to be elucidated. Here we report a novel zebrafish model with a CRISPR/Cas9‐generated esf1 mutation, which exhibits severe NCC‐derived pharyngeal cartilage loss and defects in the eyes, brain, and heart. The expression of several typical NCC markers, including sox10, dlx2a, nrp2b, crestin, vgll2a, and sox9a, was reduced in the head of the esf1 mutants, which indicates that esf1 plays a role in the development of zebrafish NCCs. We demonstrate that, similar to the yeast, loss of esf1 in zebrafish leads to defects in 18S rRNA biogenesis and ribosome biogenesis. We also show strong upregulation of p53 signaling as well as apoptosis, and poor proliferation in mutants. Inactivation of p53 rescues the early tissue defects and pharyngeal cartilage loss observed in esf1 mutants, indicating that increased cell death and pharyngeal cartilage defects observed in esf1 mutants are mediated via upregulated p53 signaling pathways. Based on transplantation analysis, we found esf1 functions in NCC in a cell autonomous fashion. Together, our results suggest that esf1 is required for NCC development and pharyngeal cartilage formation. These studies provide a potential model for investigating the relationship between ribosome biogenesis defects and craniofacial neurocristopathies. [ABSTRACT FROM AUTHOR]

The present study determines the role of the Gab1 in hydrogen peroxide (H 2 O 2 )-induced death of human osteoblasts. We show that Gab1 is required for H 2 O 2 -induced Akt activation to promote osteoblast survival. In OB-6 human osteoblasts, Gab1 silencing (by targeted-shRNA) or complete knockout (by CRISPR-Cas9 KO plasmid) largely attenuated Akt activation by H 2 O 2 . Gab1-depleted OB-6 cells were more vulnerable to H 2 O 2 . Conversely, forced over-expression of Gab1 by an adenovirus vector increased Akt activation to protect OB-6 cells from H 2 O 2 . Significantly, the anti-sense of microRNA-29a (“antagomiR-29a”) induced Gab1 expression to facilitate H 2 O 2 -induced Akt activation, which protected OB-6 cells from apoptosis. AntagomiR-29a was however ineffective in Gab1-deficient and Akt-inhibited OB-6 cells. Forced over-expression of miR-29a induced Gab1 downregulation to inhibit H 2 O 2 -induced Akt activation, causing enhanced OB-6 cell death. miR-29a-induced actions were abolished by an adenovirus constitutively-active Akt1 (Ad-caAkt1) in OB-6 cells. Together, microRNA-29a inhibition induces Gab1 upregulation and Akt activation to protect OB-6 osteoblasts from H 2 O 2 . [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON) is one of the most common mycotoxin contaminants of animal feed worldwide and brings significant threats to the animal production. However, studies concerning the effect of DON on fish intestine are scarce. This study explored the effects of DON on intestinal physical barrier in juvenile grass carp ( Ctenopharyngodon idella ). A total of 1440 juvenile grass carp (12.17 ± 0.01 g) were fed six diets containing graded levels of DON (27, 318, 636, 922, 1243 and 1515 μg/kg diet) for 60 days. This study for the first time documented that DON caused body malformation in fish, and histopathological lesions, oxidative damage, declining antioxidant capacity, cell apoptosis and destruction of tight junctions in the intestine of fish. The results indicated that compared with control group (27 μg/kg diet), DON: (1) increased the reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (PC) content, and up-regulated the mRNA levels of Kelch-like-ECH-associated protein 1 (Keap1: Keap1a but not Keap1b), whereas decreased glutathione (GSH) content and antioxidant enzymes activities, and down-regulated the mRNA levels of antioxidant enzymes (except GSTR in MI) and NF-E2-related factor 2 (Nrf2), as well as the protein levels of Nrf2 in fish intestine. (2) up-regulated cysteinyl aspartic acid-protease (caspase) -3, -7, -8, -9, apoptotic protease activating factor-1 (Apaf-1), Bcl2-associated X protein (Bax), Fas ligand (FasL) and c-Jun N-terminal protein kinase (JNK) mRNA levels, whereas down-regulated B-cell lymphoma-2 (bcl-2) and myeloid cell leukemia-1 (Mcl-1) mRNA levels in fish intestine. (3) down-regulated the mRNA levels of ZO-1, ZO-2b, occludin, claudin-c, -f, -7a, -7b, -11 (except claudin-b and claudin-3c), whereas up-regulated the mRNA levels of claudin-12, -15a (not -15b) and myosin light chain kinase (MLCK) in fish intestine. All above data indicated that DON caused the oxidative damage, apoptosis and the destruction of tight junctions via Nrf2, JNK and MLCK signaling in the intestine of fish, respectively. Finally, based on PWG, FE, PC and MDA, the safe dose of DON for grass carp were all estimated to be 318 μg/kg diet. [ABSTRACT FROM AUTHOR]

IL-8 over-expression could enhance cancer metastasis. In present study, berberine hydrochloride (BER) triggered proliferative inhibition and G2/M arrest in AGS cells, down-regulated protein expression of cyclin B1, Bcl-2, up-regulated expression of p21, p53 and cleaved caspase 3, but showed no effect on protein expression of CHOP, Bip, and caspase 4. BER could down-regulate the enhanced IL-8 expression through down-regulating ERK1/2 and p38 MAPK over-activation induced by SN 38. The increased IL-8 mediated adhesive ability of AGS cells to HUVECs induced by SN 38, could be reduced by BER. Thus, BER could reduce the side-effect of SN 38 in clinic. [ABSTRACT FROM AUTHOR]

Background: Targeted therapy has always been the focus in developing therapeutic approaches in cancer, especially in the treatment of acute myeloid leukemia (AML). A new small molecular inhibitor, JQ1, targeting BRD4, which recognizes the acetylated lysine residues, has been shown to induce cell cycle arrest in different cancers by inhibiting MYC oncogene. However, the downstream signaling of MYC inhibition induced by BET inhibitor is not well understood.Methods: In this study, we explored the more mechanisms of JQ1-induced cell death in acute myeloid lukemia and downstream signaling of JQ1.Results: We found that JQ1 is able to reactivate the tumor suppressor gene, TXNIP, and induces apoptosis through the ASK1-MAPK pathway. Further studies confirmed that MYC could repress the expression of TXNIP through the miR-17-92 cluster.Conclusions: These findings provide novel insight on how BET inhibitor can induce apoptosis in AML, and further support the development of BET inhibitors as a promising therapeutic strategy against AML. [ABSTRACT FROM AUTHOR]

T helper 17 (Th17) cells are crucial for the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in animals. High frequency of Th17 cells and low sensitivity to activation-induced cell death (AICD) are detected in MS patients. However, the mechanisms underlying apoptosis resistance of T cells remain unclear. Perp is an apoptosis-associated target of p53 and implicated in the development of cancers. Here, we show that loss of Perp in T cells does not affect Th1, Th17, or Treg cell differentiation, but does significantly increase the resistance of Perp-/- Th17 cells to AICD and anti-Fas in Lck-Cre × Perpfl/fl mice by inhibiting the caspase-dependent apoptotic pathway. Moreover, Lck-Cre × Perpfl/fl mice exhibited earlier onset of EAE and severe spinal cord inflammation and demyelination, accompanied by increased levels of pro-inflammatory cytokines and enlarged population of Th17 cells. Therefore, Perp deletion promoted Th17 responses and exacerbated the development and severity of EAE. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of graded levels of vitamin E (0–225 mg/kg) on gill immune response and physical barriers, and relative mRNA levels of signalling molecules in the gill of grass carp ( Ctenopharyngodon idella ) under infection of Flavobacterium columnare. The results indicated that compared with optimal vitamin E supplementation, vitamin E deficiency (1) increased the rate of gill rot morbidity and aggravated gill histopathological injuries following F. columnare infection ( P < 0.05); (2) decreased LA and ACP activities, complement component 3, complement component 4 and IgM contents and down-regulated antimicrobial peptides (liver-expressed antimicrobial peptide-2A, -2B, hepcidin, β-defensin) and IgT mRNA levels ( P < 0.05); (3) down-regulated the mRNA levels of anti-inflammatory cytokines and the signalling molecules inhibitory protein κBα, the target of rapamycin and ribosome protein S6 kinase 1 ( P < 0.05) and up-regulated the mRNA levels of pro-inflammatory cytokines and the signalling molecules NF-κB p65, IκB kinase α (IKKα), IKKβ and eIF4E-binding protein 1 ( P < 0.05); (4) decreased activities of anti-superoxide anion, Cu/ZnSOD, MnSOD, GPx, GST and GR, and down-regulated mRNA levels of those antioxidant enzymes and signalling molecule NF-E2-related factor 2 in the gills of fish ( P < 0.05); (5) down-regulated the relative mRNA levels of B cell lymphoma-2 protein, and up-regulated the relative mRNA levels of caspase-2, -3, -7, -9, Bcl-2 associated X protein and apoptotic protease activating facter-1 ( P < 0.05); (6) down-regulated the relative mRNA levels of tight junction proteins (occludin, zonula occludens-1, ZO-2, claudin-3, -b, -c and -11a) and up-regulated signalling molecule myosin light chain kinase mRNA levels ( P < 0.05). In conclusion, vitamin E deficiency disrupted gill immune barriers and physical barrier function via impairing gill immunity and antioxidant capacity, inducing apoptosis and changing tight junction protein transcription abundances and the related signalling molecules in the gills of fish. The optimal vitamin E requirements for against gill rot morbidity of grass carp (266–1026 g) were estimated to be 139.56 mg/kg diet. Meanwhile, based on immune indicator (ACP activity) and antioxidant indicator (MDA content), the optimal vitamin E requirements for young grass carp were estimated to be 130.67 and128.53 mg/kg diet, respectively. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF) α can induce cell apoptosis and activate nuclear transcription (NF)-κB in different cell types. Activated NF-κB further promotes or suppresses cellular apoptosis in different cases. The present study explored the effect of activated NF-κB on adipocyte apoptosis induced by TNFα and which microRNAs (miRNAs) were involved in the process. Our findings demonstrated that treatment of differentiated 3T3-L1 adipocytes with TNFα (20 ng/mL) rapidly activated NF-κB and induced moderate apoptosis. Pyrrolidinedithiocarbamic acid (PDTC, 60 µM), a specific NF-κB inhibitor, abated NF-κB activation that rendered the adipocytes vulnerable to TNFα-induced apoptosis. Dozens of miRNAs exhibited significant expression changes following TNFα treatment and the addition of PDTC. In which, miRNA-224-5p (miR-224) was up-regulated by TNFα exposure but down-regulated by PDTC addition. Furthermore, over-expression of miR-224 promoted NF-κB activation and prevented the adipocyte apoptosis induced by TNFα, while miR-224 deficiency showed the opposite effects. The TRAF-associated NF-κBactivator (TANK) gene was identified as a direct target of miR-224 by computational and luciferase reporter assays. Additionally, silencing the TANK gene by the small interfering RNA similarly promoted NF-κB activation and attenuated the cellular apoptosis. In conclusion, these findings demonstrate that miR-224 plays an essential role in adipocyte apoptosis caused by TNFα through control of NF-κB activation via targeting the TANK gene. [ABSTRACT FROM AUTHOR]

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The present study explored the possible preventive effects of dietary glutamate (Glu) on LPS-induced oxidative damage, mRNA expression changes of tight junction (TJ) and defensin proteins, inflammatory and apoptosis response signaling molecules in fish intestine. Young Jian carp were fed five diets supplemental graded levels of Glu (0, 4, 8, 16 and 32 g kg −1 diet) for 63 days. The results indicated that Glu supplementation depressed LPS induced the production of reactive oxygen species (ROS) and severe oxidative damage (lipid peroxidation and protein oxidation) in fish intestine, which was partially due to the increased glutathione (GSH) content and antioxidant enzyme activities including superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione- S -transferase (GST), and glutathione reductase (GR) ( P < 0.05). Further investigations indicated that Glu supplementation caused elevation of those antioxidant enzyme activities are related to the up-regulation of corresponding antioxidant enzymes and the related signaling factor Nrf2 mRNA levels ( P < 0.05). Meanwhile, Glu pre-treatment significantly suppressed LPS-induced COX-2 and inflammatory cytokines mRNA expression and down-regulated NF-κB p65 and MAPK p38 transcription. Furthermore, pre-treatment with Glu prevented LPS induced apoptosis-related gene expression (caspase 3 and 9, P < 0.05). Lastly, Glu supplementation also attenuated LPS induced intestinal barrier function-related gene TJ proteins (ZO-1, occludin1, claudin2, 3, and 7), β-defensin1 and 3 mRNA expressions decreasing ( P < 0.05). Taken together, the present results showed Glu could attenuate LPS induced the oxidative damage by Nrf2 signal pathway and depress LPS induced inflammation response (cytokines, COX-2, NF-κB p65, and MAPK p38), apoptosis (caspase3 and 9), and barrier function (ZO-1, occludin1, claudin2, 3 and 7, and β-defensin 1 and 3) - related gene expression changes of fish intestine. [ABSTRACT FROM AUTHOR]

This study is for the first time to explore the possible effects of dietary manganese (Mn) on structural integrity and the related signaling in the gills of fish. Grass carp ( Ctenopharyngodon idella ) were fed with six diets containing graded levels of Mn [3.65–27.86 mg Mn/kg diet] for 8 weeks. The results firstly demonstrated that Mn deficiency aggravated inflammation indicated by up-regulation of pro-inflammatory cytokines (tumour necrosis factor α, interleukin 8, and interleukin 1β mRNA levels) and down-regulation of anti-inflammatory cytokines (interleukin 10, transforming growth factor-β1) mRNA levels, which might be partially related to the up-regulation of nuclear factor kappa B (NF-κB p65) and down-regulation of nuclear inhibitor factor κBα (iκBα) mRNA levels in the gills of fish. Meanwhile, Mn deficiency caused DNA fragmentation, which might be partially associated with the up-regulation of the apoptosis signaling (caspase-3, caspase-8 and caspase-9) in the gills of fish. Furthermore, Mn deficiency-caused apoptosis might be partly related to the increases of oxidative damage that indicated by increases of lipid peroxidation and protein oxidation, and decreases of antioxidant enzyme activities [included Mn superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione- S -transferase (GST)]. However, Mn deficiency only down-regulated MnSOD and GST mRNA levels, which might be partially related to the up-regulation of NF-E2-related factor-2 (Nrf2) inhibitor (Keap1), and only down-regulated the gene expression of claudin-b and claudin-15 to disrupt the TJ in the gills of fish. Excessive Mn led to negative effects on partial parameters studied in the gills of fish. The optimal levels of Mn based on protecting against ROS, MDA and PC in the gills of grass carp were 17.04, 16.86 and 21.20 mg/kg diet, respectively. Collectively, Mn deficiency or excess could cause inflammation, apoptosis, antioxidant system disruption and change tight junction protein (claudin-b and claudin-15) transcription abundances, which might be partially related to the NF-κB p65, caspase-(3,8,9) and Nrf2 signaling, in the gills of fish. [ABSTRACT FROM AUTHOR]

Background: As an active component from traditional Chinese medicine, trigonelline has a protective effect on diabetes. This study evaluated the protective effects of trigonelline on diabetic mice during pregnancy. Methods: Diabetes was induced in female mice by intraperitoneal injection for continuous 5-day of 40 mg/kg/day streptozotocin. Female mice were divided into 4 groups after they were allowed to mate with normal male mice: nondiabetic, nondiabetic treated with trigonelline (70 mg/kg) for 18 days, diabetic, and diabetic treated with trigonelline (70 mg/kg). Results: Diabetic pregnant mice had significantly higher levels of blood glucose, serum total cholesterol, triglyceride, insulin, and leptin but lower serum omentin-1 level and insulin sensitivity index than the nondiabetic ones. Trigonelline improved the hyperglycemia, dyslipidemia, insulin resistance, and adipocytokine of diabetic pregnant mice. Diabetic pregnant mice had significantly reduced fetus numbers, fetal weight, and fetal/placental ratio, which were reversed by trigonelline. Trigonelline prevented the increase in proinflammatory cytokines and reduced interleukin-10 level in placenta of diabetic pregnant mice. Trigonelline increased β-cell replication and the decreased β-cell mass, and decreased the β-cell apoptosis of diabetic pregnant mice. Conclusion: These findings suggest that trigonelline protects diabetic pregnancy partly by suppressing inflammation, regulating the secretion of adipocytokines, increasing β-cell mass, replication, and decreasing β-cell apoptosis. [ABSTRACT FROM AUTHOR]