Search

The anti-apoptotic mechanism of breast cancer stem cells (BCSCs) makes it an obstacle to traditional apoptosis as the primary way of death. Ferroptosis is a recently reported mode of programmed cell death caused by the accumulation of iron-dependent lipid peroxidation (LPO) in cells. High dependence on iron makes BCSCs more sensitive to ferroptosis. However, the high level of the Prominin2 protein and high concentration of GSH in BCSCs make BCSCs able to efflux excess iron ions and clear LPO, which limits the therapeutic efficacy of ferroptosis in BCSCs. To overcome this obstacle, we designed a hyaluronic acid (HA)-coated siProminin2-loaded FeOOH nanoparticle (FeOOH/siPROM2@HA) to amplify ferroptosis. The FeOOH/siPROM2@HA is stable under physiologically neutral conditions but generates Fe3+ in an acidic microenvironment; meanwhile, the released siProminin2 inhibits its efflux, and then Fe3+ undergoes a redox reaction with endogenous GSH to produce Fe2+, which initiates the Fenton reaction-based ferroptosis by LPO elevation. Both in vitro and in vivo studies showed that these pH-sensitive NPs significantly inhibited tumor growth by downregulating glutathione peroxidase 4 (GPX4). Overall, this work demonstrates a "three-pronged" strategy for amplified ferroptotic therapy by simultaneously promoting intracellular iron, inhibiting iron efflux, and depleting GSH, which presents a potential strategy for CSC-targeted cancer therapy. As the root of recurrence and metastasis, breast cancer stem cells (BCSCs) are resistant to traditional apoptotic death, so it is urgent to explore a new death mode for BCSCs. It has been reported that BCSCs are highly iron-dependent and, therefore, more sensitive to ferroptosis; however, the therapeutic efficacy is greatly limited by the overexpression of Prominin2 in BCSCs, which is correlated with resistance to ferroptosis by exocytosis of iron ions. In this work, we designed a hyaluronic acid-coated siProminin2-loaded FeOOH nano-drug (FeOOH/siPROM2@HA) to accelerate ferroptosis of BCSCs by simultaneously increasing iron ion content, inhibiting iron efflux, and scavenging GSH. This "three-pronged" strategy has significant implications for BCSC-targeted cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening organ dysfunction caused by an exaggerated response to infection. In the lungs, one of the most susceptible organs, this can manifest as acute respiratory distress syndrome (ARDS). Shenfu (SF) injection is a prominent traditional Chinese medicine used to treat sepsis. However, the exact mechanism of its action has rarely been reported in the literature. In the present study, we detected the protective effect of SF injection on sepsis-induced ARDS and explored its underlying mechanism. We investigated the potential targets and regulatory mechanisms of SF injections using a combination of network pharmacology and RNA sequencing. This study was conducted both in vivo and in vitro using a mouse model of ARDS and lipopolysaccharide (LPS)-stimulated MLE-12 cells, respectively. The results showed that SF injection could effectively inhibit inflammation, oxidative stress, and apoptosis to alleviate LPS-induced ARDS. SF inhibited the PI3K-AKT pathway, which controls autophagy and apoptosis. Subsequently, MLE-12 cells were treated with 3-methyladenine to assess its effects on autophagy and apoptosis. Additional experiments were conducted by adding rapamycin, an mTOR antagonist, or SC79, an AKT agonist, to investigate the effects of SF injection on autophagy, apoptosis, and the PI3K-AKT pathway. Overall, we found that SF administration could enhance autophagic activity, reduce apoptosis, suppress inflammatory responses and oxidative stress, and inhibit the PI3K-AKT pathway, thus ameliorating sepsis-induced ARDS. SF injection can activate autophagy, alleviate the inflammatory response, relieve oxidative stress, and reduce apoptosis by suppressing the PI3K/AKT pathway, making it a promising candidate for treating sepsis-induced ARDS. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Glioblastoma (GBM) is the most common malignant glioma among brain tumors with low survival rate and high recurrence rate. Columbianadin (CBN) has pharmacological properties such as anti-inflammatory, analgesic, thrombogenesis-inhibiting and anti-tumor effects. However, it remains unknown that the effect of CBN on GBM cells and its underlying molecular mechanisms. In the present study, we found that CBN inhibited the growth and proliferation of GBM cells in a dose-dependent manner. Subsequently, we found that CBN arrested the cell cycle in G0/G1 phase and induced the apoptosis of GBM cells. In addition, CBN also inhibited the migration and invasion of GBM cells. Mechanistically, we chose network pharmacology approach by screening intersecting genes through targets of CBN in anti-GBM, performing PPI network construction followed by GO analysis and KEGG analysis to screen potential candidate signaling pathway, and found that phosphatidylinositol 3-kinase/Protein Kinase-B (PI3K/Akt) signaling pathway was a potential target signaling pathway of CBN in anti-GBM. As expected, CBN treatment indeed inhibited the PI3K/Akt signaling pathway in GBM cells. Furthermore, YS-49, an agonist of PI3K/Akt signaling, partially restored the anti-GBM effect of CBN. Finally, we found that CBN inhibited GBM growth in an orthotopic mouse model of GBM through inhibiting PI3K/Akt signaling pathway. Together, these results suggest that CBN has an anti-GBM effect by suppressing PI3K/Akt signaling pathway, and is a promising drug for treating GBM effectively. [ABSTRACT FROM AUTHOR]

To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells. Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1). High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients. The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor. [ABSTRACT FROM AUTHOR]

• miR-18a-5p was suppressed in TNF-α induced inflammatory condition. • Overexpressing of miR-18a or deregulating of HIF1-α and NLRP3 could reverse the effect of TNF-α. • TNF-α negatively regulates osteoblasts via the 18a/HIF1-α/NLRP3 pathway. • miR-18a could attenuate inflammation and PANoptosis, then promote the healing of infected bone defects in vivo. Tumor necrosis factor-α (TNF-α) is involved in inflammatory responses and promotes cell death and the inhibition of osteogenic differentiation. MicroRNA (miRNA) plays a crucial role in the infected bone diseases, however, the biological role of miRNAs in inflammation-induced impaired osteogenic differentiation remains unclear. This study aimed to explore the role of miRNA-18a-5p (miR-18a) in regulating PANoptosis and osteogenic differentiation in an inflammatory environment via hypoxia-inducible factor-1α (HIF1-α). The expression of miR-18a in MC3T3-E1 cells was analyzed using quantitative reverse transcription-polymerase chain reaction in an inflammatory environment induced by TNF-α. The expression of HIF1-α and NLRP3 in LV-miR-18a or sh-miR-18a cells was analyzed using western blotting. Fluorescence imaging for cell death, flow cytometry, and alkaline phosphatase activity analysis were used to analyze the role of miR-18a in TNF-α-induced PANoptosis and the inhibition of osteogenic differentiation. An animal model of infectious bone defect was established to validate the regulatory role of miR-18a in an inflammatory environment. The expression of miRNA-18a in the MC3T3-E1 cell line was significantly lower under TNF-α stimulation than in the normal environment. miR-18a significantly inhibited the expression of HIF1-α and NLRP3, and inhibition of HIF1-α expression further inhibited NLRP3 expression. Furthermore, inhibition of miR-18a expression promoted the TNF-α-induced PANoptosis and inhibition of osteogenic differentiation, whereas miR-18a overexpression and the inhibition of both HIF1-α and NLRP3 reduced the effects of TNF-α. These findings are consistent with those of the animal experiments. miRNA-18a negatively affects HIF1-α/NLRP3 expression, inhibits inflammation-induced PANoptosis, and impairs osteogenic differentiation. Thus, it is a potential therapeutic candidate for developing anti-inflammatory strategies for infected bone diseases. [ABSTRACT FROM AUTHOR]

The bromodomain and extra-terminal domain protein BRD4 has been recognized as a key oncogenic driver and a druggable target against cancer. However, these BRD4 inhibitors as monotherapy were moderate in efficacy in preclinical models. Here we utilized a small-scale drug synergy screen that combined the BRD4 inhibitor (JQ1) with 8 epigenetic or transcriptional targeted chemicals and identified THZ1 (a CDK7 inhibitor) acting synergistically with JQ1 against head neck squamous cell carcinoma (HNSCC). Combinational JQ1 and THZ1 treatment impaired cell proliferation, induced apoptosis and senescence, which were largely recapitulated by dual BRD4 and CDK7 knockdown. Combinational treatment inhibited tumor growth and progression in 4NQO-induced HNSCC and xenograft animal models. RNA-sequencing analyses identified hundreds of differentially expressed genes modulated by JQ1 and THZ1, which were significantly enriched in categories including cell cycle and apoptosis. Mechanistically, combinational treatment reduced H3K27ac enrichment in the super-enhancer region of YAP1, which inactivated its transcription and in turn induced anti-proliferative and pro-apoptotic effects. Combined BRD4 and CDK7 upregulation associated with worst prognosis in HNSCC patients. Collectively, our findings reveal a novel therapeutic strategy of pharmacological inhibitions of BRD4 and CDK7 against HNSCC. [ABSTRACT FROM AUTHOR]

Lead (Pb), as a heavy metal that is easily exposed in daily life, can cause damage to various systems of body. Apoptosis is an autonomous cell death process regulated by genes in order to maintain the stability of internal environment, which plays an important role in the development of nervous system. RB binding protein 4 (RBBP4) is one of the core histone binding subunits and is closely related to the apoptosis process of nervous system cells. However, it is not known whether RBBP4 can regulate neuronal apoptosis in lead-exposed environments. We exposed PC12 cells to 0 μM (control group), 1 μM, and 100 μM PbAc for 24 h to obtain cell samples. The female rats ingested drinking water containing 0, 0.5 g/L, and 2.0 g/L PbAc from the first day of pregnancy to three weeks after delivery to obtain hippocampal tissue samples from mammary rats. The results of TUNEL showed that lead exposure promoted the onset of apoptosis in cells and hippocampus. The mRNA and protein levels of the apoptosis-related protein Survivin were significantly reduced in the lead-exposed group compared to the control group. In addition, we found that lead exposure reduces the mRNA and protein levels of RBBP4 in PC12 cells and hippocampus, and increases the mRNA and protein levels of NFκB p65. Moreover, inhibiting NFκB p65 can reverse the decrease in RBBP4 expression in the lead exposure model. Overexpression of RBBP4 increased Survivin expression and reduced apoptosis induced by lead exposure. This suggests that lead exposure induces apoptosis through the NFκB p65/RBBP4/Survivin signaling pathway. • RBBP4 function have been explored in a lead exposure model. • The NFκB p65/RBBP4/Survivin signaling pathway is a novel mechanism of lead neurotoxicity [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a malignant digestive tumor mostly prevalent among adolescents and has great proliferation potential. Baicalin is a flavonoid derived from the dried root of Scutellaria baicalensis , it has tumor-suppressing effects on various kinds of tumors. Although baicalin has been shown to regulate genes associated with CRC, its role in cancer proliferation remains poorly illustrated. In this work, we evaluated the effect of baicalin on the proliferative ability of three CRC cell lines using a cell counting kit-8 assay. Furthermore, we screened for differentially expressed genes in HCT-116 cells using baicalin-treated samples and control samples on a gene expression profile microarray. We identified 19 genes were identified significantly downregulated by baicalin, which may potentially play an indispensable role in the proliferation of HCT-116 cells. High-content screening evaluated whether silencing the 19 genes affected HCT-116 cell growth. The results showed that knocking down ARRDC4 exhibited the most potent inhibition of cell proliferation. ARRDC4 expression was knocked down by transfecting CRC cells with lentiviral shRNA. MTT assay, Caspase-Glo 3/7 assay and immunohistochemistry analysis were performed to explore the effects of baicalin on proliferation and apoptosis of CRC cells. Besides, RT-PCR showed that the expression levels of ARRDC4 mRNA decreased significantly in HCT-116 cells after baicalin treatment. In conclusion, these findings indicated that baicalin may attenuated the expression of ARRDC4 via regulating the levels of LCN2, Claudin-2 and GSTA4 to inhibit HCT-116 cell proliferation. The theoretical underpinnings for the investigation of the pharmacological effects of baicalin in the treatment of human CRC were also established in this study. [ABSTRACT FROM AUTHOR]

LRWXG has previously been reported to have a protective effect on chondrocytes, preventing apoptosis induced by oxidative stress. In this study, we were aimed at determining whether LRWXG exerts its anti-apoptotic activity through the MAPK signaling pathways in chondrocytes. Our results show that, at the cellular level, apoptosis of chondrocytes in the groups treated by LRWXG decreases compared with groups treated by inhibitors alone and model group under conditions of oxidative stress in a dose-dependent manner. Mechanistically at the molecular level, LRWXG regulates the MAPK pathway induced by oxidative stress: The levels of phosphorylation of JNK and p38 proteins in the groups treated by LRWXG are lower than model group, while compared with corresponding groups of inhibitors, there are no significant difference; For other related proteins, LRWXG reduces the levels of the apoptosis-related proteins BAX and cleaved caspase-3, and increases the level of anti-apoptotic protein BCL2. In addition, LRWXG can significantly reduce the levels of inflammatory-related factors such as COX2, PEG2, TNF α and IL1 β , and inhibits the expression of MMPs, increasing the content of type II collagen. The results of this research strongly suggest that LRWXG exerts its anti-apoptotic activity via regulating the MAPK signaling pathways in vitro. [ABSTRACT FROM AUTHOR]

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common disease following long-term use or large doses of glucocorticoids. The pathogenesis of GIONFH remains controversial, and abnormal bone metabolism caused by glucocorticoids(GCs) may be one of the important factors. Due to its positive effect on bone remodeling, naringin shows potential therapeutic effects in bone metabolism-related diseases. In this study, we hypothesized that naringin regulated bone metabolism in rat GIONFH via the Akt/Bad signal cascades. In vitro, a dexamethasone (Dex)- or naringin-treated cell model was used to evaluate the function of naringin. In vivo, methylprednisolone (MPS)-treated rat model was used to evaluate the function of naringin in GIONFH. In vitro, Cell Counting Kit-8 (CCK-8) and Edu staining was used to evaluate the proliferation of osteocytes, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, Annexin V-FITC-PI, and western blotting were used to evaluate the apoptosis of osteocytes. We also verified the effects of naringin on osteogenesis and osteoclastogenesis. In vivo, we used micro-CT (computed tomography), histological, and immunohistochemical analysis to evaluate the effect of naringin. Moreover, the mechanism of naringin regulating the bone metabolism through the Akt/Bad pathway was also investigated using bioinformatics analysis and western blotting. The results of in vitro study showed that Akt activated by naringin promoted osteogenesis and osteocyte proliferation; in addition, osteocyte apoptosis and osteoclastogenesis was inhibited by Akt activation and Bad suppression. According to the in vivo study, naringin prevented GIONFH in a rat model as shown by micro-CT scanning and histological and immunohistochemical analysis. Therefore, we concluded that naringin is an effective compound for promoting bone repair and preventing bone loss in rats with GIONFH through Akt/Bad signal cascades. • Akt activated by naringin promoted osteogenesis and osteocyte proliferation. • Naringin inhibite osteocyte apoptosis and osteoclastogenesis. • Naringin prevented GIONFH in a rat model. [ABSTRACT FROM AUTHOR]

Abstract Chronic exposure to high levels of arsenic is closely associated with nervous system disorders that harm learning, memory, and intelligence. Studies have shown that the primary characteristic of brain damage is neuronal apoptosis. Arsenic induces apoptosis in a variety of nerve cells. Therefore, substance that inhibit apoptosis promise to mitigate arsenic toxicity. Pigment epithelium-derived factor (PEDF) is widely distributed in brain tissues and has various effects on neurons, including induction of apoptosis. Our previous study suggested that PEDF might augment arsenic-induced apoptosis in rat brains. In this study of 151 adults with normal, mild, moderate, and high exposure to arsenic, the measured serum PEDF levels were 15.46 ± 5.87 ng/mL, 17.33 ± 8.22 ng/mL, 19.43 ± 9.51 ng/mL and 21.65 ± 14.46 ng/mL, respectively. Multiple linear regression analysis revealed an independent positive correlation between serum PEDF levels and arsenic exposure in drinking water. To study the underlying mechanism of arsenic-induced apoptosis, we exposed PEDF-transfected PC12 cells to NaAsO 2. We discovered that NaAsO 2- -induced mitochondrial apoptosis was enhanced in cells that over expressed PEDF. Moreover, p53 up regulated modulator of apoptosis (PUMA) gene and B-cell lymphoma 2 (Bcl-2) protein were primary factors in the progression of arsenic-induced apoptosis. Taken together, our results suggest that PEDF inhibition might mitigate arsenic toxicity to nerve cells. Graphical abstract Image Highlights • PEDF level in serum is positively correlated with arsenic exposure in drinking water. • PEDF promoted the mitochondrial apoptosis of nerve cells. • PEDF promoted the mitochondrial apoptosis induced by arsenic. [ABSTRACT FROM AUTHOR]

Abstract Spinal cord injury (SCI) is a major reason of paralysis, disability and even death in severe cases. Mulberrin (Mul) is a major compound of ramulus mori and turned out that it has potent ability on tyrosinase inhibition. Ramulus mori has been reported to possess anti-inflammation, anti-oxidative stress and anti-apoptosis effects. However, the effects of Mul on SCI progression and the underlying molecular mechanism have never been elucidated before. Here, we established a SCI rat model, which subsequently received Mul treatment. The findings showed that Mul treatment improved the functional recovery of SCI rats, along with reduced spinal cord water contents and myeloperoxidase (MPO) activity. SCI-induced apoptosis was attenuated by Mul, as evidenced by the reduced TUNEL-positive cells, and the decreased pro-apoptotic signals expressions, while increased anti-apoptotic molecule. Further, Mul inhibited inflammatory response in the spinal cord tissues of SCI rats through inactivating nuclear factor-kappa B (NF-κB) pathway. Oxidative stress was also decreased by Mul treatment in SCI mice, associated with the up-regulation of heme oxygenase-1 (HO-1)/nuclear factor E2-related factor 2 (HO-1/Nrf-2) pathway. Significantly, SCI rats showed high expression of miR-337 in spinal cord tissue samples. Astrocytes (AST) stimulated by LPS also had higher expression of miR-337. Nrf-2 was found to be a direct target for miR-337. Over-expressing miR-337 markedly reduced Nrf-2 expression in AST, whereas inhibiting miR-337, Nrf-2 expressions were significantly increased. In vitro, AST transfected with miR-337 inhibitor showed attenuated inflammation, apoptosis and oxidative stress in LPS-treated AST, which was, intriguingly, abolished by Nrf-2 knockdown. Together, the findings above indicated that Mul could attenuate SCI by reducing miR-337 expressions to reduce apoptosis, inflammation and oxidative stress via regulating Nrf-2. [ABSTRACT FROM AUTHOR]

Highlights • TGF-β1 and TRPM7 expressed higher than those from control mice by time-dependent in asthmatic mice model with airway remodeling. • TGF-β1 increases TRPM7 expression in ASMCs through TGFβR/Smad3 pathway. • Knocking down TRPM7 decreases Ca2+ influx, ASMCs proliferation and induces apoptosis. Abstract Background TRPM7 in mast cells plays a key role in asthma. However, the effect of TRPM7 on TGF-β1-induced airway smooth muscle cell (ASMC) proliferation remains unclear. Therefore, we designed this study to explore whether TRPM7 is involved in TGF-β1-induced ASMC proliferation. Methods An asthmatic mouse model was established, and the expressions of TGF-β1 and TRPM7 in mice lungs were detected using enzyme-linked immunosorbent assay (ELISA) and western blotting. In addition, murine ASMCs were cultured and stimulated with TGF-β1. Possible TGF-β1 and TRPM7 interactions were examined using RT-PCR and western blotting analyses with ASMCs. The effect of TRPM7 knockdown on ASMC calcium influx was assessed by the fluorescent indicator indo-1. MTT and flow cytometry were applied to evaluate the effects of TRPM7 knockdown on ASMC proliferation and apoptosis. Results TGF-β1 elevated the expression of TRPM7 via TGFβR/SMAD3. Knocking down TRPM7 decreased the intracellular Ca2+ concentration and cellular proliferation of ASMCs, although apoptosis remained unaffected. Conclusions Our initial findings suggest that TRPM7 inhibition may prevent asthma-induced airway remodeling. [ABSTRACT FROM AUTHOR]

JNK1/2 and NF-κB signal are essential signaling pathways that mediate a variety of cellular processes, including cell survival, apoptosis, inflammation and angiogenesis. JNK1/2 activation and NF-κBp65 nuclear translocation have been found in ischemia/reperfusion (I/R)-induced injury. However, the regulation of JNK1/2-NF-κBp65 signaling pathway remains unclear. To examine the function and possible mechanism of HMGB2 in I/R-induced cell injury, human AC16 cardiomyocytes transfected with pLVX-Puro-HMGB2 were treated with SP600125 (JNK1/2 inhibitor) or PDTC (NF-κB inhibitor) and that following I/R injury were transfected with HMGB2-shRNA. The cell proliferation and apoptosis were measured by CCK-8, flow cytometry and TUNEL, respectively. The expression of HMGB2, Cleaved PARP and Caspase-3, Bax and Bcl-2 and activity of MAPKs and NF-κBp65 were measured by Western blot. Here, we found that I/R time-dependently induced the increase in the expression of HMGB2 in AC16 cardiomyocytes. HMGB2 silencing significantly inhibited I/R-induced the cell proliferation reduction, cell apoptosis, activation of ERK1/2, JNK1/2 and NF-κBp65, increased Bax, Cleaved PARP and Caspase-3 and decreased Bcl-2 expression. HMBG2 overexpression mimicked the effect of I/R-induced injury in AC16 cardiomyocytes, which was reversed by treatment with SP600125 or PDTC. Moreover, PDTC treatment in rats following I/R injury also showed decreases in the cell apoptosis, HMGB2, Cleaved PARP and Caspase-3 and Bax expression, and JNK1/2 activation. Taken together, our findings suggest that HMBG2 overexpression promotes I/R-induced cell apoptosis through activating the JNK1/2-NF-κBp65 signaling in AC16 cardiomyocytes. [ABSTRACT FROM AUTHOR]

• Liensinine can alleviate renal dysfunction in LPS-induced AKI. • Liensinine alleviates LPS-induced AKI by inhibiting inflammation and subsequent events caused by inflammatory responses. • Liensinine protects against renal injury in sepsis by regulating the JNK/p38-ATF 2 axis. Liensinine is mainly derived from alkaloids extracted and isolated from lotus seeds (Nelumbo nucifera Gaertn). It possesses anti-inflammatory, and antioxidant, according to contemporary pharmacological investigations. However, the effects and therapeutic mechanisms of liensinine on acute kidney injury (AKI) models of sepsis are unclear. To gain insight into these mechanisms, we established a sepsis kidney injury model by LPS injection of mice treated with liensinine, and stimulation of HK-2 with LPS in vitro and treated with liensinine and inhibitors of p38 MAPK, JNK MAPK. We first found that liensinine significantly reduced kidney injury in sepsis mice, while suppressing excessive inflammatory responses, restoring renal oxidative stress-related biomarkers, reducing increased apoptosis in TUNEL-positive cells and excessive autophagy, and that this process was accompanied by an increase in JNK/ p38-ATF 2 axis. In vitro experiments further demonstrated that lensinine reduced the expression of KIM-1, NGAL, inhibited pro- and anti-inflammatory secretion disorders, regulated the activation of the JNK/p38-ATF 2 axis, and reduced the accumulation of ROS, as well as the reduction of apoptotic cells detected by flow cytometry, and that this process played the same role as that of p38 MAPK, JNK MAPK inhibitors. We speculate that liensinine and p38 MAPK, JNK MAPK inhibitors may act on the same targets and could be involved in the mechanism of alleviating sepsis kidney injury in part through modulation of the JNK/p38-ATF 2 axis. Our study demonstrates that lensinine is a potential drug and thus provides a potential avenue for the treatment of AKI. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON), zearalenone (ZEN) and fumonisin B 1 (FB 1 ) are among the most toxicologically important Fusarium toxins commonly found in nature that lead to nephrotoxicity in animals. The present study investigated that the individual and combined effects of subcytotoxic DON (0.25 μM), ZEN (20 μM) and FB 1 (10 μM) on oxidative stress and apoptosis in porcine kidney cells (PK15). In addition, the protective effect of N -acetylcysteine (NAC) against the toxicity of Fusarium toxins was also evaluated. Our results showed that the activities of glutathione reductase (GR) and total superoxide dismutase (SOD) were affected by DON, ZEN and FB 1 , and this change in activity induced reactive oxygen species (ROS) and malondialdehyde (MDA) production, increased apoptosis and regulated the mRNA expression of Bax, Bcl-2, caspase-3, caspase-9, cytochrome c (cyto c) and P53. This study demonstrated the complexity of combined mycotoxin infection since the combination of toxins exhibited more profound defects in the oxidative stress responses and apoptosis. Moreover, NAC reduced the oxidative damage and inhibited the apoptosis induced by Fusarium toxins. It was concluded that oxidative damage and apoptosis through the mitochondria-dependent channel were the mechanisms of Fusarium toxin mediated toxicity, and NAC reversed these damages to some extent. [ABSTRACT FROM AUTHOR]

The different mechanisms of nerve growth factor (NGF) and erythropoietin (EPO) in promoting repair of peripheral nerve injuries suggest a potential therapeutic application through the synergism of the two. Yet NGF has also been reported to induce early nerve apoptosis after injury. To utilize the potential synergism of NGF and EPO while minimize the possible defect, in this study, we first confirmed the time dependency of NGF caused nerve apoptosis, and then established a sequential and sustained delivery system for NGF and EPO with poly(lactide- co -glycolide) (PLGA), which has been approved by the US FDA for human use because of its injectable, biocompatible, and biodegradable properties. EPO was encapsulated in PLGA-microspheres (MS) for sustained releasing, while NGF was encapsulated in BSA-incorporated PLGA (B-PLGA) MS to postpone its release. In rat model of sciatic nerve injury, co-delivery of EPO/PLGA-MS and NGF/B-PLGA-MS resulted in significant nerve recovery. Hopefully, this sequential delivery system could provide a new therapeutic strategy for peripheral never injury. [ABSTRACT FROM AUTHOR]

Melatonin confers cardioprotective effects on multiple cardiovascular diseases, including doxorubicin-induced cardiomyopathy. The effectiveness of melatonin in mitigating myocardial injuries caused by Doxorubicin through enhancement of mitochondrial function is already established, however, the role of melatonin in regulating the Sirtuin-1 (Sirt1)/Nuclear factor E2-associated factor 2 (Nrf2) pathway in lessening the onset of Doxorubicin-induced cardiomyopathy is yet to be elucidated. To address this, H9C2 cardiomyocytes and C57BL/6 mice were employed to construct in vitro and in vivo models of Dox-induced myocardial impairments, respectively. Results showed that Dox markedly evoked oxidative stress, pyroptosis and apoptosis both in vitro and in vivo, which were significantly alleviated by melatonin administration. Mechanistically, melatonin attenuated Dox-induced downregulation of Sirt1 and Nrf2, and both inhibition of Sirt1 and Nrf2 significantly reversed the cardioprotective effects of melatonin. In conclusion, our studies suggest that the activation of the Sirt1/Nrf2 pathway is the underlying mechanism behind melatonin's ability to curtail oxidative stress, pyroptosis, and apoptosis in Dox-induced cardiomyopathy. These promising results demonstrated the potential application of melatonin as a treatment for doxorubicin-induced cardiac injury. [Display omitted] • Melatonin alleviates doxorubicin-induced cardiac injury by inhibiting oxidative stress. • Melatonin ameliorates doxorubicin-evoked cardiac damage via suppressing pyroptosis. • Melatonin mitigates doxorubicin-triggered cardiac impairment through restraining apoptosis. • Melatonin protects against doxorubicin-provoked cardiotoxicity via regulating Sirt1/Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Nano-carriers, especially lipid nanoparticles have been used widely in “a good manner”, for instance in the treatment of cancer, by enhancing the targetability and reducing required dose. Here in the contrary, we presented a new possibility: nanoDEN, a nanoparticle-packed “bad guy”, which is more effective and efficient in generating liver tumor in mice. We have shown that nanoDEN, same as diethylnitrosamine (DEN), induced overexpression of multiple pivotal factors (including COX-2, β-catenin and PCNA) during oncogenesis. Moreover, nanoDEN increased the apoptosis of liver cells compared with DEN alone. This apoptotic effect of nanoDEN is more efficient on normal cells than on cancer cells. Taken into consideration the fact that there are endogenous nanoparticles naturally formed inside our body, our research enlarged our views of all the aspects of oncogenic chemicals, while also established a better method of producing animal model of liver cancer, which has future investigational and therapeutical potential. [ABSTRACT FROM AUTHOR]

Oxidative stress and mitochondrial dysfunction play crucial role in the dopaminergic neurons death, which is the pathological feature of Parkinson's disease (PD). Resveratrol (Res), a polyphenol derived from grapes and blueberries, has been reported to reduce oxidative stress injury and to restore mitochondrial function. In this study, we aimed to explore the underlying molecular mechanism of the beneficial effects of Res against MPP+- induced mitochondrial dysfunction and cell apoptosis in SN4741 cells. The data showed that Res significantly alleviated MPP+- induce cytotoxicity and restored MPP+- induced mitochondrial dysfunction in SN4741 cells. Moreover, Res rescued MPP+- induced a decline on the level of p-AKT, p-GSK-3βand the ratio of Bcl-2/Bax, and an elevation on the expression of Bax and caspase-3, 9. However, inhibition GSK-3β activity clearly abolished the protective effects of Res. Taken together, these results suggest that Res attenuates MPP+- induced mitochondrial dysfunction and cell apoptosis, and these protections may be achieved through AKT/GSK-3β pathway. These also indicate that Res could be a promising therapeutic agent for PD. [ABSTRACT FROM AUTHOR]

• The biodegradable therapeutic FePi-PEG@DOX nanosheets were constructed. • These nanosheets can be degraded under the stimulation of tumor microenvironment. • The autophagy capacity of tumor cells was inhibited to cause damage accumulation. • Tumor elimination was achieved through enhanced apoptosis/ferroptosis pathway. Killing tumor cells through apoptosis and/or ferroptosis pathways has been extensively explored for tumor therapy. However, the therapeutic efficacy is always impaired by the autophagy-mediated self-repairing capacity of tumor cells. Herein, a novel autophagy inhibition-enhanced apoptosis/ferroptosis strategy was developed for synergistic tumor elimination, which was realized through the doxorubicin (DOX)-loaded ferric phosphate nanosheets. When located in tumor regions, these nanosheets can be specifically degraded under the stimulation of tumor microenvironment. The released DOX can not only damage DNA to induce cell apoptosis directly but also up-regulate intracellular hydrogen peroxide level. Free Fe2+ can be generated from Fe3+ through intracellular over-expressed glutathione-participated redox reaction, which can further react with hydrogen peroxide through the Fenton reaction to produce highly oxidative hydroxyl radicals. This redox process simultaneously breaks the antioxidant capacity of tumor cells through the depletion of glutathione and the inactivation of intracellular antioxidase glutathione peroxidase 4, promoting the generation and accumulation of lipid peroxidation to cause tumor ferroptosis. Especially, PO 4 3− disrupts the pH balance in lysosomes by forming conjugated acid anions to disable the self-repairing capacity of tumor cells, enhancing the antitumor therapeutic effect. This work offers a promising method with desirable biocompatibility for specific tumor elimination through autophagy inhibition-enhanced apoptosis/ferroptosis strategy. [ABSTRACT FROM AUTHOR]

Marsdeniae tenacissimae extract (MTE), commonly known as Xiao-Ai-Ping in China, is a traditional Chinese herb medicine capable of inhibiting proliferation and metastasis and boosting apoptosis in various cancer cells. However, little is known about the contribution of MTE towards tumor angiogenesis and the underlying mechanism. The present study aimed to evaluate the effects of MTE on the proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) and the molecular mechanism. 3−(4,5-dimethylthiazol-2-yl)−5(3-carboxymethoxyphenyl)−2−(4-sulfopheny)−2H-tetrazolium, inner salt (MTS) and PI-stained flow cytometry assays revealed that MTE dose-dependently reduced the proliferation of HUVECs by arresting cell cycle at S phase ( P < 0.05). Annexin V-FITC/PI-stained flow cytometry confirmed that MTE (160 μL·L −1 ) enhanced the apoptosis of HUVECs significantly ( P < 0.001). Real-time quantitative RT-PCR and Western blot analyses showed an increase in Bax expression and a sharply decline in Bcl-2 expression; caspase-3 was activated simultaneously in a dose-dependent manner ( P < 0.05). Further study observed the dose-dependent down-regulation of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2), P2Y6 receptor (P2Y6R), and chemokine (C-C motif) ligand 2 (CCL-2), along with the activation of PKC Δ and up-regulation of p53 in a dose-dependent manner in MTE-treated selected cells ( P < 0.05). Collectively, the results from the present study suggested that MTE suppressed the proliferation by attenuating CCL-2-mediated VEGF/VEGFR2 interactions and promoted the apoptosis through PKCΔ-induced p53-dependent mitochondrial pathway in HUVECs, supporting that MTE may be developed as a potent anti-cancer medicine. [ABSTRACT FROM AUTHOR]

A series of 9-benzylamino acridine derivatives were synthesized as an extension of our discovery of acridine antitumor agents. Most of these acridine compounds displayed good antiproliferative activity with IC 50 values in low micromole range and structure-activity relationships were studied. Topo I- and II- mediated relaxation studies suggested that all of our compounds displayed strong Topo II inhibitory activity at 100 μM, while only four exhibited moderate Topo I inhibitory activity. The typical compound 8p could penetrate A549 cancer cells efficiently. Compound 8p could intercalate within the double-stranded DNA structure and induce DNA damage. Moreover, compound 8p could induce A549 cells apoptosis through caspase-dependent intrinsic pathway and arrest A549 cells at the G2/M phase. [ABSTRACT FROM AUTHOR]

microRNA-21 (miR-21) contributes to anti-apoptosis, proliferation and migration in many cells, but its role in inhibiting apoptosis in bone marrow mesenchymal stem cells (BMSC) remains unclear. The aim of this study was to determine the role of miR-21 in H 2 O 2 -induced BMSC apoptosis. We used quantitative real time-polymerase chain reaction (RT-PCR) to demonstrate the level of miR-21 after treatment of BMSC with H 2 O 2 . BMSC apoptosis was induced by different concentrations of H 2 O 2 and was decreased in miR-21-upregulated cells. The expression of PTEN, a functional target gene of miR-21 in BMSC, was regulated by miR-21. The RT-PCR results indicated that miR-21 was significantly up-regulated, and western blot analysis indicated that Bcl-2 was up-regulated, whereas the apoptosis-related genes caspase 3/9 and Bax were down-regulated in miR-21-up-regulated cells. The miR-21-up-regulated cells had significantly enhanced Akt phosphorylation, as measured by western blot analysis. LY294002, an inhibitor of Akt activation, abolished the protective effects of miR-21-up-regulated cells. These results suggest that miR-21 contributes to inhibition of apoptosis in BMSC by down-regulating PTEN, potentially via the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

The biflavonoid isochamaejasmin is mainly distributed in the root of Stellera chamaejasme L. (Thymelaeaceae) that is used in traditional Chinese medicine (TCM) to treat tumors, tuberculosis, and psoriasis. Herein, isochamaejasmin was found to show similar bioactivity against Bcl-2 family proteins to the reference Bcl-2 ligand (−)-gossypol through 3D similarity search. It selectively bound to Bcl- x l and Mcl-1 with K i values being 1.93 ± 0.13 μmol·L −1 and 9.98 ± 0.21 μmol·L −1 , respectively. In addition, isochamaejasmin showed slight growth inhibitory activity against HL-60 with IC 50 value being 50.40 ± 1.21 μmol·L −1 and moderate growth inhibitory activity against K562 cells with IC 50 value being 24.51 ± 1.62 μmol·L −1 . Furthermore, isochamaejasmin induced apoptosis of K562 cells by increasing the intracellular expression levels of proteins of the cleavage of caspase-9, caspase-3, and PARP which involved in the Bcl-2-induced apoptosis pathway. These results indicated that isochamaejasmin induces apoptosis in leukemia cells by inhibiting the activity of Bcl-2 family proteins, providing evidence for further studying the underlying anti-cancer mechanism of S. chamaejasme L. [ABSTRACT FROM AUTHOR]

Postoperative cognitive dysfunction (POCD) is a frequent complication following major surgery in the elderly. However, the exact pathogenic mechanisms are still unknown. Dexmedetomidine, a selective alpha 2 adrenal receptor agonist, was revealed anesthesia and brain protective role. The present study aimed to examine whether dexmedetomdine protects against POCD induced by major surgical trauma under general anesthesia in aged mice. In the present study, cognitive function was assessed by Y-maze. Proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α), apoptosis-related factor caspase-3 and Bax were detected by real-time PCR, Western blot or immunohistochemistry. The results showed that anesthesia alone caused weak cognitive dysfunction on the first day after general anesthesia. Cognitive function in mice with splenectomy under general anesthesia was significantly exacerbated at the first and third days after surgery, and was significantly improved by dexmedetomidine administration. Splenectomy increased the expression of IL-1β, TNF-α, Bax and caspase-3 in hippocampus. These changes were significantly inversed by dexmedetomidine. These results suggest that hippocampal inflammatory response and neuronal apoptosis may contribute to POCD, and selective alpha 2 adrenal receptor excitation play a protective role. [ABSTRACT FROM AUTHOR]

Highlights: [•] S-Allylmercaptocysteines (CySSR) act synergistically with sodium selenite to mediate apoptosis in breast cancer cells. [•] The major CySSRs derived from onion and garlic are similarly potent, but act preferentially on different cellular targets. [•] The proposed mechanism is that cells import and reduce CySSR, then export thiols to reduce selenite to the cytotoxic H2Se. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) are a group of endogenous, small, noncoding RNAs that function as key post-transcriptional regulators. miRNAs are involved in many biological processes including apoptosis. In this study, mouse miR-702 (mmu-miR-702), a mirtron derived from the 13th intron of the Plod3 gene, was identified as a regulator of anti-apoptosis. mmu-miR-702 was down-regulated after treatment with the apoptosis-inducer isoproterenol both in vivo and in vitro. According to over-expression experiments, mmu-miR-702 inhibited apoptosis as well as the expression levels of a subset of apoptosis-related genes including activating transcription factor 6 (ATF6). An interaction between mmu-miR-702 and the ATF6 3′-UTR binding site was confirmed using luciferase reporter and western blot assays. This is the first report of ATF6 interaction with miRNA. Although the possible existence of miR-702 in the human genome is low, our results indicate that mirtrons also participate in the process of apoptosis and may provide a novel study strategy for apoptosis. [Copyright &y& Elsevier]

Abstract: Despite surgical discectomy is one of the most effective treatments for intervertebral disc degeneration and lumbar disc herniation, a number of patients still complain of reserved low back pain, sciatica and numbness post-operatively with decreased life quality. Sciatica in patients with disc herniation is not only due to mechanical compression from herniated nucleus pulposus, but chemical and immunity agents. The intervertebral disc is composed of annulus fibrosus in the wedge and gelatinous nucleus pulposus in the centre with cartilage endplate sandwiched. Similar to other immune privilege organs, human intervertebral disc is one of the biggest avascular structures with FasL expression. Moreover, FasL–Fas and TRAIL death pathways might play roles in the machinery of immune privilege of the disc. We found that down-regulated miR-155 promotes Fas-mediated apoptosis in disc degeneration. Furthermore, once exposed to human immune system, nucleus pulposus can activate multiple specific and non-specific immune responses with cellular and fluid immune cells and molecules involved. Taken together, we hypothesize that a combined molecular immunotherapy with local and systemic immunity regulators might shed a novel light on the treatment strategies for disc degeneration and herniation. [Copyright &y& Elsevier]

Abstract: Stroke is a leading cause of permanent disability and death. A complex series of biochemical and molecular mechanisms (e.g. the release of ROS/NOS, proapoptotic proteins and proinflammatory cytokine; neuronal depolarization, Ca2+ accumulation and so on) impair the neurologic functions of cerebral ischemia and stroke. We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. The principal mammalian estrogen (17β estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However the incidence of stroke in women is lower than in men until decades past menopause, suggesting that factors beyond sex hormone contribute to these epidemiological sex differences. So a new concept is emerging: both sex steroids and biologic sex are important factors in clinical and experimental strokes. In this review, we will address sex steroids and gender differences in influencing the mechanisms and outcomes of brain ischemia stroke. These sex differences need to be identified which could help future translation to human neuroprotection. [Copyright &y& Elsevier]

Abstract: In this Letter, the anticancer activity of novel rosin-derivatives introducing indicated side chains at position C18 of dehydroabietic acid (DHAA) was reported. Gratifyingly, all of these derivatives showed significantly cytotoxicity toward diverse human carcinoma cell lines. We found the compound 4 could induce cell membrane damage at high concentration as well as cell apoptosis at low concentration. However, compound 5, attachment of quinidine to dehydroabietic acid via thiourea bond, only induced apoptotic cell death. In addition, all these active compounds induced apoptosis mainly through mitochondrial-dependent pathway. Interestingly, compound 5 exhibited the highest anticancer activity and little toxicity to normal cells compared with the other derivatives. Therefore, 5 merits further investigation as a potential agent for future anticancer treatment. [Copyright &y& Elsevier]

Abstract: Insulin-like peptide 3 (INSL3) is a peptide hormone belonging to the insulin/relaxin superfamily, which mediates testes descent in the male fetus, and suppresses male germ cell apoptosis and promotes oocyte maturation in adults by activating the leucine-rich repeat-containing G-protein coupled receptor RXFP2. In a previous work, we prepared mature two-chain INSL3 by recombinant expression of a designed single-chain precursor in Escherichia coli and subsequent in vitro maturation. To establish a convenient high throughput receptor-binding assay for screening novel RXFP2 agonists or antagonists, in the present study we designed and recombinantly prepared a fully active easily-labeled INSL3 analog. Due to presence of a single primary amine moiety, the easily-labeled analog was conveniently mono-labeled by a DTPA/Eu3+-moiety at the A-chain N-terminus through reacting with excess modification reagent in a simple one-step procedure. The DTPA/Eu3+-labeled INSL3 analog bound receptor RXFP2 with high affinity and low non-specific binding. Using this non-radioactive tracer, we established a high throughput cell-based receptor-binding assay for screening of novel RXFP2 agonists or antagonists in future studies. [Copyright &y& Elsevier]

Abstract: Hyperglycemia clearly plays a key role in the development and progression of diabetic neuropathy. Hyperglycemia induces oxidative stress to generate reactive oxygen species in diabetic neurons resulting in neuronal damage and dysfunction. Apoptosis has been proposed as a possible mechanism for high glucose-induced neural dysfunction and neuronal cell injury. High glucose per se enhances lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) expression via activation of NADPH oxidase/reactive oxygen species pathway in endothelial cells. Selaginellin, a component extracted from Saussurea pulvinata (Hook. et Grev.) Maxim, was assessed for its ability to protect rat pheochromocytoma (PC12) cells against oxidative toxicity induced by high glucose. The differentiated PC12 cells were pretreated with various concentrations (10−7, 3×10−7 or 10−6 M) of selaginellin for 1h and then co-treated with selaginellin and d-glucose (75mM) for 72h. Selaginellin was shown to protect differentiated PC12 cells against high glucose toxicity, as determined by characteristic morphological features, cell viability, and apoptosis as evaluated by Hoechst 33,258 staining assay, annexin V-propidium iodide double staining assay and caspase-3 activity. In addition, the increase in NADPH oxidase activity, mRNA expression of NADPH oxidase subunits (NOX-1 and NOX-2) and LOX-1, and reactive oxygen species production induced by high glucose were significantly inhibited by selaginellin or by anti-LOX-1 antibody. The present study demonstrated that inhibitory effect of selaginellin on high glucose-induced cell injury and apoptosis in differentiated PC12 cells is related to inhibition of LOX-1/NADPH oxidase–reactive oxygen species/caspase-3 signaling pathway. [Copyright &y& Elsevier]

Abstract: Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE) is a marine bromophenol compound derived from marine algae. Previous reports have shown that BDDE possesses cytotoxic activity. However, the mechanisms of its apoptotic activity as well as its potential cellular targets remain unclear. The present study demonstrated that BDDE displays broad-spectrum in vitro anticancer capabilities and exhibits potent apoptotic activity in K562 cells via mitochondrial pathway. Further study revealed that BDDE inhibits the activity of topoisomerase I but does not stimulate the formation of topoisomerase I–DNA complex nor intercalate into DNA. Ethidium bromide displacement fluorescence assay and molecular modeling results showed that BDDE mainly targets DNA and binds to DNA minor groove, and thereafter inhibits the activity of topoisomerase I. The results of this study indicated that BDDE, which has unique chemical structure different from current topoisomerase I inhibitors, could serve as a lead template for rational drug design and for future anticancer agents development. [Copyright &y& Elsevier]

Abstract: Fibroblast-like synoviocytes (FLSs) contribute significantly to the pathogenesis of Rheumatoid arthritis (RA). Through introducing apoptosis inducer FasL to suppress the proliferation of arthritic FLSs may provide an efficient approach for treatment of RA. CTLA4-FasL, a fusion product integrating two inhibitory elements of CTLA4 (which can induce T cell anergy through blocking costimulatory signal) and FasL (which may upregulate Fas-mediated apoptosis in inflammatory synoviocytes) into one molecule, might be a desirable engineered derivative of soluble FasL which exerts severe side effects and poor activities. In present study, we investigated the possible effect of CTLA4-FasL protein on suppressing the proliferation of inflammatory FLSs and inflammation in experimental model of RA. The purified CTLA4-FasL protein exerted a significant proliferation-inhibition activity to activated arthritic FLSs through both unbounded free and membrane-anchorage manners. CTLA4-FasL gene delivery by recombinant adeno-associated virus (rAAV) vector in joint, provided more powerfully preventive effects than mature FasL on rat adjuvant-induced arthritis (AIA) as reflected in clinical signs and typically histological characters. Treatment with rAAV.CTLA4-FasL also significantly decreased the levels of key proinflammatory cytokines in AIA joints. Our observations indicate that CTLA4-FasL protein represents a significantly suppressive effect on inflammatory FLSs’ proliferation and CTLA4-FasL gene transfer profoundly suppresses AIA, implicating potential application for treatment of RA by local joint delivery of CTLA4-FasL. [Copyright &y& Elsevier]

Abstract: Pecan oil is an edible pressed oil extracted from the pecan nut; it contains approximately 90% unsaturated fat. Previous study showed that unsaturated faty had potent antioxidant activity. Oxidative stress is a pathological change which is higher in postmenopausal women. In the present study, we reported the apoptosis inhibition of hippocampal cells by pecan oil in ovariectomized rats. And the results showed that the pecan oil has protective effect on hippocampal cell apoptosis induced by ovariectomized operation. The mechanism of action could be related to enhancement of the antioxidant activity and adjustment of Caspase-3 expression. [Copyright &y& Elsevier]

Background and Aims: Patients with diabetes show enhanced susceptibility to myocardial ischemia/reperfusion (MI/R) injury. Epidemiological studies indicated that consumption of α-linolenic acid (ALA) significantly reduces the risk of cardiac events in post-acute myocardial infarction patients. The present study attempted to investigate the effects of ALA intake on MI/R injury in normal and diabetic rats and its mechanisms. Methods: The high-fat diet-fed streptozotocin (HFD-STZ) rat model was developed. Age-matched normal and HFD-STZ rats were randomly assigned to receive normal diet or ALA (oral gavage, 500 μg/kg per day). After 4 weeks of feeding, animals were subjected to 30 min of myocardial ischemia and 4 or 6 h of reperfusion. Results: Compared with the normal control, HFD-STZ rats showed more severe myocardial functional impairment and injury. Although ALA intake for 4 weeks did not change myocardial function and injury in normal rats, it significantly improved the instantaneous first derivation of left ventricle pressure, reduced infarct size, plasma creatine kinase and lactate dehydrogenase activities, and apotosis at the end of reperfusion in HFD-STZ diabetic rats. Moreover, ALA intake not only significantly reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) concentrations but reduced the increase in superoxide production and malonaldialdehyde formation and simultaneously enhanced the antioxidant capacity in the diabetic hearts. Myocardial PI3K expression and Akt phosphorylation were increased by ALA intake in diabetic but not normal rats. Conclusions: Chronic ALA intake confers cardioprotection in MI/R by exerting anti-inflammatory and anti-oxidative stress effects in diabetic but not normal rats, which is possibly through PI3K-Akt-dependent mechanism. [ABSTRACT FROM AUTHOR]

Abstract: Epidemiological and experimental studies have indicated selenium could reduce the risk of some cancers. In our present study, growth inhibition and apoptosis were detected upon methylseleninic acid (MSA) treatment in human esophageal squamous cell carcinoma cell lines EC9706 and KYSE150. MSA reduced β-catenin protein levels, while there was no significant change observed on transcriptional levels. Moreover, we found MSA accelerated the degradation of β-catenin and activated glycogen synthase kinase 3β (GSK-3β). Some targets of β-catenin/TCF pathway and apoptosis-related genes altered after MSA treatment. Notably, utilizing the inducible 293-TR/β-catenin cell line, we found the apoptotic phenotypes induced by MSA were partially reversed by the overexpression of β-catenin. Overall, our data indicate the effects induced by MSA in ESCC cells may act on the inhibition of β-catenin/TCF pathway. [Copyright &y& Elsevier]

Objective: Interferon-α (IFNα) therapy leads to hematological remissions and a reduction of the JAK2V617F allele burden in patients with polycythemia vera (PV). In this study, the cellular target by which IFNα affects hematopoiesis in PV patients was evaluated. Materials and Methods: CD34+ cells were isolated from normal bone marrow and the peripheral blood of patients with PV and were treated in vitro with each of the three commercially available forms of IFNα: IFNα 2b, pegylated IFNα 2a (Peg-IFNα 2a), and pegylated IFNα 2b (Peg-IFNα 2b). Results: Each form of IFNα was equally potent in suppressing hematopoietic colony formation by normal CD34+ cells, but Peg-IFNα 2a and IFNα 2b were more effective than Peg-IFNα 2b in inhibiting burst-forming unit erythroid−derived colony formation by PV CD34+ cells. In addition, exposure of PV CD34+ cells to equal doses of Peg-IFNα 2a and IFNα 2b resulted in a 38% to 40% reduction in the proportion of JAK2V617F-positive hematopoietic progenitor cells (HPC), while equivalent doses of Peg-IFNα 2b did not reduce the number of malignant HPC. Further studies explored the mechanism by which IFNα induced PV HPC growth inhibition. Treatment of Peg-IFNα 2a increased the rate of apoptosis of PV CD34+ cells and the phosphorylation/activation of p38 mitogen-activated protein kinase in PV CD34+ cells, while the p38-specific inhibitor SB203580 reversed the growth inhibition and apoptosis induced by Peg-IFNα 2a. Conclusion: These data suggest that low doses of IFNα selectively and directly suppress PV JAK2V617F HPC and that these agents act through the p38 mitogen-activated protein kinase pathway. [Copyright &y& Elsevier]

Abstract: Skin-derived precursors (SKPs) are derived from mesoblast and can differentiate into smooth muscle cells, adipocytes, and less neuronal phenotypes. This study demonstrates that retinoic acid (RA) improves SKPs exit from self-proliferation to neural differentiation through up-regulating of NeuroD and cell-cycle regulatory protein p21, meanwhile RA also induces p75 neurotrophin receptor (p75NTR) up-regulation and apoptosis of SKPs. When treated sequentially with neurotrophin-3 (NT-3) after RA induction, the survival and neural differentiation of SKPs were enhanced significantly, and cell apoptosis induced by RA was decreased. These effects could be reversed by p75NTR inhibitor Pep5 instead of Trk receptor inhibitor K252a. The results indicate that NT-3 improves the neural differentiation of SKPs induced by RA through a p75NTR-dependent signaling pathway. [Copyright &y& Elsevier]

Abstract: The aim of this study is to investigate the effects of the clinostat-simulated microgravity on MCF-7 cells (a breast cancer cell line) biological characteristics. MCF-7 cells were incubated for 24h in an incubator and then rotated in a clinostat as a model of simulated microgravity for 24, 48 and 72h, respectively. The effects of the clinostat-simulated microgravity on MCF-7 cells proliferation, invasion, migration, gelatinase production, adhesion, cell cycle, apoptosis and vinculin expression were detected. The results showed that the clinostat-simulated microgravity affected breast cancer cell invasion, migration, adhesion, cell cycle, cell apoptosis and vinculin expression. These results may explore a new field of vision to study tumor metastasis in future. [Copyright &y& Elsevier]

Abstract: Cerebral amyloid-beta protein (Aβ) deposition and associated neuroinflammation and apoptosis are increasingly recognized as an important component leading to cognitive impairment in Alzheimer’s disease (AD). Humanin (HN) and its derivative, S14G-HN (HNG), are best known for their ability to suppress neuronal death induced by AD-related insults in vitro. Furthermore, limited in vivo studies show that HNG can ameliorate memory impairment induced by intracerebroventricular injection of anti-cholinergic drugs or Aβ25-35. However, the mechanism underlying the in vivo effect remains unclear. In this study, we sought to determine the effects of HNG on neuroinflammatory responses and apoptosis associated with behavioral deficits induced by Aβ25-35 in vivo. Our results indicate that intracerebroventricular injection of aggregated Aβ25-35 induced impairment of learning and memory, markedly elevated numbers of reactive astrocytes, activated microglia, and apoptotic cells, as well as remarkable increased levels of IL-6 and TNFα. Moreover, intraperitoneal HNG treatment ameliorated behavioral deficits, and reduced neuroinflammatory responses and apoptotic cells in the brain. Cumulatively, these finding demonstrate for the first time that HNG may have the potential for attenuating Aβ-induced cognitive deficits by reducing inflammatory responses and apoptosis in vivo, which may add to the novel evidence for anti-inflammatory and antiapoptosis properties of HNG in AD treatment. [Copyright &y& Elsevier]

Abstract: Leptin plays a critical role in regulating body weight, lipid metabolism, apoptosis and microvasculature of adipose tissue. To explore multiple signaling pathways of leptin action on adipose tissue, real-time PCR utilizing TaqMan® low-density arrays was performed to compare mRNA expression in adipose tissue of ob/ob mice treated with vehicle or leptin (2.5 μg/d or 10 μg/d) for 14 days via subcutaneous osmotic minipumps. Of the 24 target genes selected for characterization, many were differentially expressed between control ob/ob mice and leptin-treated ob/ob mice. Increases in mRNA expression were found for hormone sensitive lipase (HSL), uncoupling protein 2 (UCP2), adrenergic receptor 3 (ADR3), mitofusin 2 (Mfn2), sirtuin 3 (Sirt3), transcription factor sterol regulatory element binding factor 1 (SREBF1), Bcl-2, Bax, Caspase 3, tumor necrosis factor α (TNFα), adiponectin and angiopoietin 2 (Ang-2). Decreases in expression were found for stearoyl-coenzyme A desaturase 1 (SCD1), fatty acid synthase (FAS), and retinol binding protein 4 (RBP4). There were no changes in expression of transcription factors involved in adipocyte differentiation (C/EBPα, PPARα, and PPARγ). These results confirm that alterations in the expression of specific adipose tissue genes including those associated with the promotion of lipid mobilization, energy dissipation, and apoptosis may mediate leptin-induced fat loss in ob/ob mice. [Copyright &y& Elsevier]

Abstract: Objective: High glucose-induced apoptosis in vascular endothelial cells contributes to the acceleration of atherosclerosis associated with diabetes. We hypothesized that α-linolenic acid (ALA) might attenuate high glucose-induced apoptosis in cultured human umbilical vein endothelial cells (HUVECs). Methods: HUVECs were cultured at 5.5 and 33 mmol/L for 72 h. ALA with different concentrations was added with defatted bovine serum albumin as a carrier for 18 h before incubation with high glucose. Results: Exposure of HUVECs to high glucose media for 72 h significantly increased the number of apoptotic cells compared with normal glucose control, as evaluated by flow cytometry and terminal deoxyuridine triphosphate nick end labeling assay. Pretreatment with low concentrations of ALA (10, 50, and 100 μmol/L) significantly attenuated high glucose-induced apoptosis of HUVECs, but increasing ALA to 200 μmol/L exerted the opposite effect. Furthermore, high glucose reduced phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) with subsequent nitric oxide production, whereas ALA treatment attenuated the reduction caused by high glucose. Pretreatment with phosphatidylinositol 3’ -kinase kinase inhibitor LY294002 and eNOS inhibitor NG -nitro-arginine methyl esyer eliminated ALA’ antiapoptotic effect. Conclusion: ALA exerts an antiapoptotic effect by the phosphatidylinositol 3’-kinase/Akt/eNOS pathway in HUVECs exposed to high glucose and thus may represent a candidate therapeutic agent for diabetic cardiovascular complications. [Copyright &y& Elsevier]

Protein kinase C (PKC), a kinase family involved in cell signal transduction, is overexpressed in most pituitary adenoma cells. We studied the effect of tamoxifen, an estrogen receptor antagonist and also a protein kinase inhibitor, on pituitary tumor cell proliferation and the induction of apoptosis; and we compared its effects with those of another PKC inhibitor, staurosporine. Tamoxifen induced growth arrest and apoptosis in a mouse pituitary adenoma cell line, AtT20, and in low-passage human primary pituitary tumor cell cultures. Staurosporine also inhibited pituitary tumor cell growth. PKC activity in AtT20 cells was inhibited by staurosporine and by prolonged treatment with phorbol myristate acetate, which down-regulates PKC activity, but not by tamoxifen, at the dosages used to induce apoptosis. Our findings suggest that tamoxifen induces apoptosis in AtT20 cells independent of a classical PKC isozyme pathway. [Copyright &y& Elsevier]

To date, Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disease associated with clinical complications. Dietary fatty acids have been suggested to be involved in preventing or reversing the accumulation of hepatic fat. However, contradicting roles of monounsaturated fatty acids to the liver have been implicated in various human and murine models, mainly due to the insolubility nature of fatty acids. High pressure homogenization methods were used to fabricate oleic acid embedded lipid nanoparticles (OALNs). The in vitro and in vivo models were used to validate the physiological effect of this OALNs via various cellular and molecular approaches including cell viability essay, fluorescent staining, electron microscope, RNAseq, qPCR, Western blots, and IHC staining. We successfully fabricated OALNs with enhanced stability and solubility. More importantly, lipid accumulation was successfully induced in hepatocytes via the application of OALNs in a dose-dependent manner. Overload of OALNs resulted in ROS accumulation and apoptosis of hepatocytes dose-dependently. With the help of transcriptome sequencing and traditional experimental approaches, we demonstrated that the lipotoxic effect induced by OALNs was exerted via the DDIT3/BCL2/BAX/Caspases signaling. Moreover, we also verified that OALNs induced steatosis and subsequent apoptosis in the liver of mice via the activation of DDIT3 in vivo. In all, our results established a potential pathogenic model of NAFLD for further studies and indicated the possible involvement of DDIT3 signaling in abnormal steatosis process of the liver. 1. Oleic acid was encapsulated in to lipid nanoparticles with a diameter of around 200 nm and a zeta potential of around −40 mV, which could be stably stored in 4 °C for at least 3 months.2. Oleic acid lipid nanoparticle (OALN) induced lipid and ROS accumulation in hepatocytes, which subsequently induced apoptosis via the mitochondrial-dependent pathways.3. OALNs' treatment increased the expression and nuclear localization of DDIT3, suggesting the possible involvement of DDIT3/BCL2/BAX/Caspases signaling in abnormal steatosis process of the liver. [Display omitted] • Oleic acid could be stably encapsulated into LNPs as OALNs, at a diameter of ∼200 nm and a zeta potential of -40 mV. • Both in vitro and in vivo study showed that OALNs could induce aberrant lipid and ROS accumulation in hepatocytes, and subsequently apotosis via the mitochondrial-dependent pathways. • OALNs' treatment also implies that DDIT3/BCL2/BAX/Caspases signaling could be involved in abnormal steatosis process of the liver. [ABSTRACT FROM AUTHOR]

Previous studies mainly focused on the inflammatory responses caused by Mycoplasma gallisepticum (MG) in the chicken respiratory mucosa, setting the stage for chronic infection and disease manifestation. However, the underlying mechanism is still unknown. Spleen and thymus are important immune organs, which play a critical role in eliciting protective immune responses to ensure healing process and elimination of harmful stimuli. In the present study, the effects of MG infection on chicken spleen and thymus were investigated. The results showed that MG infection reduced antioxidant activities and induced oxidative stress in the spleen and thymus tissues. Histological examination showed normal morphology of chicken spleen and thymus in control group compared to MG infection group. In contrast, increased number of necrotic and nuclear debris, lymphocytolysis, prominent reticuloepithelial cells and loose arrangement of cells in the spleen and thymus were seen in MG-infected chickens. Ultrastructural analysis indicated nuclear and mitochondrial damage including mitochondrial swelling, deformation of nuclear membrane and congestion of chromatin material in MG infection group. The mRNA and protein expression of apoptosis-related genes were significantly upregulated in the spleen and thymus of MG-infected chickens compared to control group. Moreover, Terminal deoxynucleotidyl transferase–mediated dUTP nick endlabeling (TUNEL) assay results suggested that MG infection increased the number of positive-stained nuclei in the spleen and thymus. Meanwhile, the mRNA expression of mitochondrial dynamics in the spleen and thymus were altered by MG infection. In summary, these results showed that MG induced oxidative stress and apoptosis, which could be the possible causes associated with the immune damage, structural impairment and disease pathogenesis of MG infection. • The effect of MG-infection on spleen and thymus were investigated in the present study. • Mycoplasma gallisepticum -induced pathological changes in both spleen and thymus. • The level of oxidative stress and apoptosis significantly increased in both organs. • The study provides insights into the mechanisms of infection-mediated damage in chicken. [ABSTRACT FROM AUTHOR]

• Nano-Al 2 O 3 is transported via olfactory nerve pathways into brain tissue. • Nano-Al 2 O 3 is deposited in olfactory bulb, hippocampus, and striatum. • Toxic damage can be brought by Nano-Al 2 O 3 to crucial functional sub-brain regions. • Nano-Al 2 O 3 activates the p53 pathway by oxidative stress of dopaminergic neuron. • Nano-Al 2 O 3 can cause mitochondrial function damage, cell cycle arrest and apoptosis. The central nervous system is a potential target for Al 2 O 3 nanoparticles (Nano-Al 2 O 3). Here, we investigated the effects of intranasal instillation of Nano-Al 2 O 3 on the distribution and damage in crucial functional sub-brain regions of rats. In vivo results show that Nano-Al 2 O 3 was translocated into the brain via the olfactory nerve pathway. Nano-Al 2 O 3 accumulated in the hippocampus, olfactory bulb, cerebral cortex, and striatum, causing ultrastructural changes, oxidative damage, inflammatory responses, and histopathological damage in sub-brain regions. As indicated by in vitro studies, cell viability decreased with the addition of Nano-Al 2 O 3, which increased the levels of lactate dehydrogenase and oxidative stress. Nano-Al 2 O 3 also impaired mitochondrial function, disturbed the cell cycle and induced apoptosis. In addition, Nano-Al 2 O 3 decreased the expression of cyclin D1, bcl-2, Mdm2, and phospho-Rb and increased the expression of p53, p21, Bax, and Rb. Therefore, oxidative stress, mitochondrial dysfunction, and p53-related pathways might be important in the process of dopaminergic neurotoxicity induced by Nano-Al 2 O 3. The current study establishes a striatum damage model and identifies molecular biomarkers of dopaminergic neuron damage induced by Nano-Al 2 O 3. In brief, our study demonstrates that Nano-Al 2 O 3 exposure can be a risk factor for neurodegenerative diseases and may negatively impact the hippocampus, striatum, and dopaminergic neurons. [ABSTRACT FROM AUTHOR]

• CySSR + Se show synergistic anticancer effects. • CySSR + Se upregulated GSK3 and activated JNK pathway to induce apoptosis. • CySSR reductive metabolites activated Se as H 2 Se to contribute on apoptosis induction. • CySSPe is similarly potent as the well-studied CySSA in signaling apoptosis. S -Allylmercaptocysteine (CySSA) from garlic and its onion analog S -1-propenylmercaptocysteine (CySSPe) show potential anti-cancer abilities. In this study, apoptosis induction by these two S -alk(en)lymercaptocysteine (CySSR) analogs in combination with Na 2 SeO 3 (Se) was investigated in MDA-MD-231 breast cancer cells. CySSA and CySSPe alone did not affect cell viability, whereas CySSPe + Se and CySSA + Se showed dose-dependent reduction in cell viability. Synergistic effect was confirmed by isobologram analysis. Annexin-V staining and flow cytometric analysis revealed induction of apoptosis. Mechanistically, CySSR + Se upregulated GSK-3α/β and activated p53 to trigger apoptosis. Both CySSR + Se activated JNK pathway at an early stage, but only CySSPe + Se exhibited sustained JNK activation. Inhibition of the cystine/glutamate (x C -) antiporter by sulfasalazine attenuated the antiproliferative effects of CySSR + Se suggesting the involvement of x C - in CySSR + Se− induced apoptosis. This study indicates that the onion analogue CySSPe was similarly as effective as the major studied garlic analogue CySSA in apoptosis induction in ER− breast cancer cells. [ABSTRACT FROM AUTHOR]