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At least 1,495 records · Page 83

Perturbations of carotenoid and tetrapyrrole biosynthetic pathways result in differential alterations in chloroplast function and plastid signaling

In this study, we used the biosynthetic inhibitors of carotenoid and tetrapyrrole biosynthetic pathways, norflurazon (NF) and oxyfluorfen (OF), as tools to gain insight into mechanisms of photooxidation in rice plants. NF resulted in bleaching symptom on leaves of the treated plants, whereas OF treatment developed a fast symptom of an apparent necrotic phenotype. Both plants exhibited decreases in photosynthetic efficiency, as indicated by F{sub v}/F{sub m}. NF caused severe disruption in thylakoid membranes, whereas OF-treated plants exhibited disruption of chloroplast envelope and plasma membrane. Levels of Lhca and Lhcb proteins in photosystem I (PSI) and PSII were reduced by photooxidative stress in NF- and OF-treated plants, with a greater decrease in NF plants. The down-regulation of nuclear-encoded photosynthesis genes Lhcb and rbcS was also found in both NF- and OF-treated plants, whereas plastid-encoded photosynthetic genes including RbcL, PsaC, and PsbD accumulated normally in NF plants but decreased drastically in OF plants. This proposes that the plastids in NF plants retain their potential to develop thylakoid membranes and that photobleaching is mainly controlled by nuclear genes. Distinct photooxidation patterns between NF- and OF-treated plants developed differential signaling, which might enable the plant to coordinate the expression of photosynthetic genes from the nuclear and plastidic genomes. - Highlights: • Two modes of photooxidation by carotenoid and tetrapyrrole biosynthetic inhibitors. • We examine differential alterations in chloroplast function and plastid signaling. • NF and OF cause differential alterations in chloroplast ultrastructure and function. • Photooxidation coordinates photosynthetic gene expression from nucleus and plastid.

60 APPLIED LIFE SCIENCES↗

Par3L enhances colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway

Partitioning defective 3-like protein (Par3L) is a recently identified cell polarity protein that plays an important role in mammary stem cell maintenance. Previously, we showed that high expression of Par3L is associated with poor survival in malignant colorectal cancer (CRC), but the underlying mechanism remained unknown. To this end, we established a Par3L knockout colorectal cancer cell line using the CRISPR/Cas system. Interestingly, reduced proliferation, enhanced cell death and caspase-3 activation were observed in Par3L knockout (KO) cells as compared with wildtype (WT) cells. Consistent with previous studies, we showed that Par3L interacts with a tumor suppressor protein liver kinase B1 (Lkb1). Moreover, Par3L depletion resulted in abnormal activation of Lkb1/AMPK signaling cascade. Knockdown of Lkb1 in these cells could significantly reduce AMPK activity and partially rescue cell death caused by Par3L knockdown. Furthermore, we showed that Par3L KO cells were more sensitive to chemotherapies and irradiation. Together, these results suggest that Par3L is essential for colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway, and is a putative therapeutic target for CRC. - Highlights: • Par3L knockout using the CRISPR/Cas system induces apoptosis in colorectal cancer cells. • Par3L interacts with Lkb1 and regulates the activity of AMPK signaling cascade. • Par3L knockout cells are more sensitive to treatment of different chemotherapy drugs and irradiation.

60 APPLIED LIFE SCIENCES↗

Nuclear import of Nkx2-2 is mediated by multiple pathways

Nkx2-2 homeoprotein is essential for the development of the central nervous system and pancreas. Although the nuclear localization signals of Nkx2-2 have been identified, the responsible transport receptor is still unknown. Here, we demonstrate that imp α1 not only interacts with Nkx2-2 but also transports it into the nucleus in vitro by acting together with imp β1. However, the nuclear import of Nkx2-2 in cells was not inhibited in response to knockdown expression of endogenous imp β1 or over-expression of Bimax2. Furthermore, imp β1 and imp 13, but not imp 4, directly interact with Nkx2-2 and are capable of transporting Nkx2-2 in an in vitro import assay. By GST pull-down assay, we demonstrate that mutation of NLS1 or NLS2 has no effect on interaction with imp α1 or imp 13, but significantly reduced binding to imp β1. Thus, the nuclear import of Nkx2-2 is mediated not only by the classical import pathway but also directly by imp β1 or imp 13.

60 APPLIED LIFE SCIENCES↗

PRRT2 inhibits the proliferation of glioma cells by modulating unfolded protein response pathway

Accumulating studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for several paroxysmal neurological disorders, including paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). However, the impact of PRRT2 in tumorigenesis is not known. Based on a large-scale data analysis, we found that PRRT2 was down-regulated in glioma tumor tissues compared with normal brain tissue. Dysregulation of PRRT2 was not induced by mutation, copy number variation and epigenetic modification, but modulated by microRNA-30a-5p. Overexpression of PRRT2 strongly impaired the cell viability and promoted cell apoptosis and these anti-tumor effects could be largely reversed by microRNA-30a-5p. Mechanistically, PRRT2 expression was closely correlated genes involved in unfolded protein response (UPR) pathway and introduction of PRRT2 inhibited gene expression in the three branches of UPR, including PERK axis, IRE1 axis and ATF6 axis. Taken together, our findings identify PRRT2 as a tumor suppressor in glioma and provide a promising target for potential therapeutic intervention. - Highlights: • PRRT2 is decreased in glioma and is targeted by miR-30a-5p. • PRRT2 exhibits tumor-suppressive effects on glioma cells. • PRRT2 correlates genes involved in unfolded protein response. • Over-expressed PRRT2 induces unfolded protein response in glioma in vitro.

60 APPLIED LIFE SCIENCES↗

Resveratrol rescues cadmium-induced mitochondrial injury by enhancing transcriptional regulation of PGC-1α and SOD2 via the Sirt3/FoxO3a pathway in TCMK-1 cells

Resveratrol has been reported to ameliorate Cd-induced nephrotoxicity. However, the beneficial effects of resveratrol on Cd-induced nephrotoxicity and the underlying mechanisms of this protection remain unclear. Here, we showed that mouse renal tubular epithelial (TCMK-1) cells exposed to Cd experienced significantly increased mitochondrial reactive oxygen species (mROS) production, as well as decreased mitochondrial biogenesis and function. Cd exposure dramatically decreased Sirt3 protein expression and activity and promoted the acetylation of forkhead box O3 (FoxO3a). Moreover, Cd exposure led to a decreased binding affinity of FoxO3a to the promoters of both peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α and superoxide dismutase 2 (SOD2), powerful and broad regulators of mitochondrial biogenesis and mROS metabolism. Meanwhile, resveratrol remarkably reduced mROS generation by promoting Sirt3 enrichment within the mitochondria and subsequent upregulation of FoxO3a-mediated mitochondria gene expression of PGC-1α and SOD2. Importantly, mechanistic study revealed that ERK1/2 activation was associated with increased apoptosis induced by Cd, resveratrol suppressed Cd-induced apoptosis in mice kidney. Taken together, our data suggest a novel mechanism of action for resveratrol-attenuated Cd-induced cellular damage, which, in part, was mediated through the activation of the Sirt3/FoxO3a signaling pathway. - Highlights: • Resveratrol alleviates Cd-induced mitochondrial damage and improves mitochondrial biogenesis. • Mitochondrial-protective effect of resveratrol on Cd-induced nephrotoxicity is through a Sirt3-FoxO3a-dependent mechanism. • Resveratrol suppresses Cd-induced apoptosis through ERK1/2 in vivo.

60 APPLIED LIFE SCIENCES↗

Activation of Wnt3α/β-catenin signal pathway attenuates apoptosis of the cerebral microvascular endothelial cells induced by oxygen-glucose deprivation

Brain microvascular endothelial cells (BMECs) play vital roles in cerebral ischemia, during which many signal pathways mediate BMECs apoptosis. In this study, we explored the potential role of Wnt3α/β-catenin signal in BMECs apoptosis induced by ischemia. Here, we found that oxygen-glucose deprivation (OGD) could induce apoptosis of BMECs with Wnt3a mRNA expression decrease. Meanwhile, activation Wnt3a/β-catenin signal with exogenous Wnt3α protein (100 ng/ml) or Lithium Chloride (LiCl, 4 mM) decreased significantly apoptosis of BMECs induced by OGD with increasing expression of Bcl-2 in the whole cell and β-catenin in the nucleus. But, inhibition Wnt3a/β-catenin signal with DKK1 (100 ng/ml) or 2.4-diamino quinazoline (DQ, 0.2 μM) increased apoptosis of BMECs with decreasing expression of Bcl-2. These results suggest that activation Wnt3α/β-catenin signal attenuate apoptosis of BMECs induced by ischemia. - Highlights: • OGD induced BMECs apoptosis with Wnt3a mRNA expression decrease. • Activation Wnt signal reduced BMECs apoptosis with increasing Bcl-2 and β-catenin. • Inhibition Wnt signal increased BMECs apoptosis with decreasing Bcl-2. • Wnt3α/β-catenin signal attenuates apoptosis of BMECs induced by ischemia.

60 APPLIED LIFE SCIENCES↗

Molecular interaction between K-Ras and H-REV107 in the Ras signaling pathway

Ras proteins are small GTPases that serve as master moderators of a large number of signaling pathways involved in various cellular processes. Activating mutations in Ras are found in about one-third of cancers. H-REV107, a K-Ras binding protein, plays an important role in determining K-Ras function. H-REV107 is a member of the HREV107 family of class II tumor suppressor genes and a growth inhibitory Ras target gene that suppresses cellular growth, differentiation, and apoptosis. Expression of H-REV107 was strongly reduced in about 50% of human carcinoma cell lines. However, the specific molecular mechanism by which H-REV107 inhibits Ras is still unknown. In the present study, we suggest that H-REV107 forms a strong complex with activating oncogenic mutation Q61H K-Ras from various biochemical binding assays and modeled structures. In addition, the interaction sites between K-Ras and H-REV107 were predicted based on homology modeling. Here, we found that some structure-based mutants of the K-Ras disrupted the complex formation with H-REV107. Finally, a novel molecular mechanism describing K-Ras and H-REV107 binding is suggested and insights into new K-Ras effector target drugs are provided. - Highlights: • H-REV107 interacts strongly with active GNP-bound K-Ras mutation. • H-REV107 rotated dramatically to interact with K-Ras Q61H (GNP) from the binding position with K-Ras WT (GDP). • In the K-Ras and H-REV107 interaction, E31 of K-Ras is an important binding residue. • H-REV107 can be a stable drug target for oncogenic K-Ras mutation.

60 APPLIED LIFE SCIENCES↗

RACK1 promotes radiation resistance in esophageal cancer via regulating AKT pathway and Bcl-2 expression

RACK1 is a seven Trp-Asp 40 repeat protein, which interacts with a wide range of kinases and proteins. RACK1 plays an important role in the proliferation and progression of various cancers. The aim of this study is to detect the role of RACK1 in the radioresistance in esophageal cancer. The results indicated that downregulation of RACK1 reduced the colony formation ability, proliferation ability and resistance of cells to radiation effection through regulating the radiation-related proteins including pAKT, Bcl-2 and Bim; whereas upregulation of RACK1 promoted the ability and radioresistance of ESCC cells. Our findings suggest that RACK1 promotes proliferation and radioresistance in ESCC cells by activating the AKT pathway, upregulating Bcl-2 expression and downregulating protein levels of Bim. Our study fills in gaps in the field of RACK1 and radiation resistance and may provide new possibilities for improving strategies of radiotherapy in esophageal cancer. - Highlights: • RACK1 is proposed to influence the proliferation ability of cells after irradiation. • Present the relationship between RACK1 and radiation resistance of esophageal cancer. • Analyze the mechanism by which RACK1 plays a role in radiation resistance.

60 APPLIED LIFE SCIENCES↗

C6 glioma-conditioned medium induces malignant transformation of mesenchymal stem cells: Possible role of S100B/RAGE pathway

Highlights: • C6 glioma-conditioned medium induces MSCs malignant transformation. • The transformed cells are tumorigenesis and phenotypically distinct from MSCs. • GCM increases MSCs RAGE, Akt1 and STAT3 expression. • S100B increases MSCs RAGE, Akt1, STAT3 and proliferation, migration and invasion. • RAGE inhibitor abolish S100B induced Akt1, STAT3 activation and cellular functions. Mesenchymal stem cells (MSCs) have been widely studied as an attractive therapeutic agent for the treatment of tumors. However, the adverse effects of the tumor paracrine factors who affect MSCs are still unclear. In this study, we report for the first time that C6 glioma-conditioned medium (GCM) induces malignant transformation of MSCs. In contrast to MSCs, the transformed mesenchymal stem cells (TMCs) exhibited tumor cell characterizations in vitro and highly tumorigenic in vivo. Furthermore, GCM and recombinant S100B increased receptor for advanced glycation end products (RAGE) and its downstream Akt1, STAT3 genes expression as well as phosphorylation and transcriptional activation. Finally, blockage of S100B-RAGE interaction by RAGE inhibitor FPS-ZM1 attenuated GCM and S100B-induced Akt1, STAT3 activation, abolished its cell proliferation, migration and invasion actions. Together, these results suggest that the RAGE pathway may play a possible role in malignant transformation procedure of MSCs, and that this process may be mediated through S100B.

60 APPLIED LIFE SCIENCES↗

Effect of dexmedetomidine on rats with convulsive status epilepticus and association with activation of cholinergic anti-inflammatory pathway

Convulsive status epilepticus (CSE) is a neurological disease with contraction and extension of limbs, leading to damage of hippocampus and cognition. This study aimed to explore the effects of dexmedetomidine (DEX) on the cognitive function and neuroinflammation in CSE rats. All rats were divided into control group, CSE group and DEX group. Morris water maze test was used to measure cognitive function. Acute hippocampal slices were made to detect long-term potentiation (LTP). Immunohistochemistry was used to determine the expression of α7-nicotinic acetylcholine receptor (α7-nAChR) and interleukin-1β (IL-1β). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum levels of IL-1β, tumor necrosis factor-α (TNF-α), S-100β and brain-derived neurotrophic factor (BDNF). Our results showed that DEX improved the memory damage caused by CSE. DEX reduced seizure severity and increased the amplitudes and sustainable time of LTP, and also inhibited the hippocampal expression of α7-nAChR and IL-1β in CSE rats. DEX treatment decreased serum IL-1β, TNF-α and S-100β levels and increased BDNF levels. The effects of DEX on seizure severity and LTP could be simulated by nicotine or attenuated by concurrent α-bungarotoxin (α-BGT) treatment. In conclusions, DEX significantly improved spatial cognitive dysfunction, reduced seizure severity and increased LTP in CSE rats. Improvements by DEX were closely related to enhancement of cholinergic anti-inflammatory pathway.

60 APPLIED LIFE SCIENCES↗

A catalytically inactive gelatinase B/MMP-9 mutant impairs homing of chronic lymphocytic leukemia cells by altering migration regulatory pathways

Highlights: • MMP-9MutE (non-catalytic) impairs migration and in vivo homing of CLL cells. • MMP-9MutE-impaired migration does not involve RhoAGTPase activity. • MMP-9MutE downregulates p-ERK and increases PTEN expression. • MMP-9MutE affects signaling pathways regulating CLL cell migration. • MMP-9 contributes to CLL progression by catalytic and non-catalytic activities. We previously showed that MMP-9 overexpression impairs migration of primary CLL cells and MEC-1 cells transfected with MMP-9. To determine the contribution of non-proteolytic activities to this effect we generated MEC-1 transfectants stably expressing catalytically inactive MMP-9MutE (MMP-9MutE-cells). In xenograft models in mice, MMP-9MutE-cells showed impaired homing to spleen and bone marrow, compared to cells transfected with empty vector (Mock-cells). In vitro transendothelial and random migration of MMP-9MutE-cells were also reduced. Biochemical analyses indicated that RhoAGTPase and p-Akt were not downregulated by MMP-9MutE, at difference with MMP-9. However, MMP-9MutE-cells or primary cells incubated with MMP-9MutE had significantly reduced p-ERK and increased PTEN, accounting for the impaired migration. Our results emphasize the role of non-proteolytic MMP-9 functions contributing to CLL progression.

60 APPLIED LIFE SCIENCES↗

WDR74 participates in an early cleavage of the pre-rRNA processing pathway in cooperation with the nucleolar AAA-ATPase NVL2

Highlights: • WDR74, along with NVL2, participates in the cleavage of pre-rRNA ITS1 at site 2. • NVL2 strips WDR74 away from the MTR4-exosome to relocate it in the nucleolus. • MTR4-bound WDR74 accumulates in the nucleoplasm of NVL2-deficient cells. • WDR74-MTR4 interaction is regulated by NVL2 during ribosome biogenesis. WD repeat-containing protein 74 (WDR74), a nucleolar-localized protein, is the mammalian ortholog of Nsa1, a 60S ribosome assembly factor in yeast. We previously showed that WDR74 associates with MTR4, the nuclear exosome-assisting RNA helicase, whose dissociation is prohibited by an ATPase-deficient mutant of the AAA-type chaperone NVL2. However, the functions and regulation of WDR74 during ribosome biogenesis in cooperation with NVL2 remains unknown. Here, we demonstrated that knockdown of WDR74 leads to significant defects in the pre-rRNA cleavage within the internal transcribed spacer 1 (ITS1), occurring in an early stage of the processing pathway. Interestingly, when the dissociation of WDR74 from the MTR4-containing exonuclease complex was impaired upon expression of the mutant NVL2, the same processing defect, with partial migration of WDR74 from the nucleolus towards the nucleoplasm, was observed. In the nucleoplasm, an increased interaction between WDR74 and MTR4 was detected by in situ proximity ligation assay. Therefore, the dissociation of WDR74 from MTR4 in a late stage of rRNA synthesis is thought to be required for appropriate maturation of the pre-60S particles. These results suggest that the spatiotemporal regulation of ribosome biogenesis in the nucleolus is mediated by the ATPase activity of NVL2.

60 APPLIED LIFE SCIENCES↗

Up-regulated lnc-SNHG1 contributes to osteosarcoma progression through sequestration of miR-577 and activation of WNT2B/Wnt/β-catenin pathway

Highlights: • Up-regulated Lnc-SNHG1 is positively correlatedwith tumor size, TNM stage and lymph node metastasis. • Lnc-SNHG1 overexpression promoted malignantphenotype in vitro and in vivo. • MiR-577 could act as a ceRNA of lnc-SNHG1 andtarget WNT2B in OS cells. • The lnc-SNHG1/miR-577/WNT2B/Wnt/β-catenin axisregulatory network might provide a potential new therapeutic strategy for OStreatment. Long noncoding RNA small nucleolar RNA host gene 1 (lnc-SNHG1) was reported to play an oncogenic role in the progression of cancers. However, the roles of SNHG1 and its molecular mechanism in osteosarcoma (OS) cells are largely unknown. In present study, we found that the expression of SNHG1 was up-regulated in OS tissues and cell lines. OS patients with the high SNHG1 expression were positively correlated with tumor size, TNM stage and lymph node metastasis. In addition, SNHG1 overexpression promoted cell proliferation, cell migration and EMT process in U2OS and MG63 cells and tumor growth in vivo. Furthermore, we also found that miR-577 could act as a ceRNAof SNHG1 in OS cells and the promotion of OS progression induced by lnc-SNHG1 overexpression required the inactivity of miR-577. Besides, we identified that WNT2B acted as a target of miR-577, and WNT2B played the oncogenic role in OS cells by activating Wnt/β-catenin pathway. In short, our study suggested that lnc-SNHG1 could promote OS progression via miR-577 and WNT2B. The lnc-SNHG1/miR-577/WNT2B/Wnt/β-catenin axis regulatory network might provide a potential new therapeutic strategy for OS treatment.

60 APPLIED LIFE SCIENCES↗

Fucoxanthin attenuates fatty acid-induced lipid accumulation in FL83B hepatocytes through regulated Sirt1/AMPK signaling pathway

Highlights: • Fucoxanthin decreases expression oftranscription factors associated withlipogenesis. • Fucoxanthin is effective for increasinglipolysis. • Fucoxanthin increases phosphorylation of AMPK,leading to decrease activity of ACC for fatty acid synthesis. The fucoxanthin, isolated from brown algae, was reported to have multiple biological functions to anti-inflammation, anti-tumor, and ameliorated obesity in mice. In this study we investigated whether fucoxanthin could inhibit lipids accumulation in FL83B hepatocytes. FL83B cells were induced as fatty liver cell model by 0.5 mM oleic acid for 48 h, and treated with various concentration of fucoxanthin for 24 h. The results demonstrated that fucoxanthin significantly suppressed lipid accumulation and decreased lipid peroxidation in hepatocytes. Fucoxanthin could decrease lipogenesis-related transcription factor expression, including sterol regulatory element-binding proteins 1c and peroxisome proliferator-activated receptor γ. It also reduced fatty acid synthase expression and increased adipose triglyceride lipase and the phosphorylation of hormone-sensitive lipase production for lipolysis. Furthermore, fucoxanthin significantly increased phosphorylation of AMP-activated protein kinase (AMPK), and decreased activity of acetyl-CoA carboxylase for regulating fatty acid synthesis. The results suggest that fucoxanthin is an effective marine nature compound for increasing lipolysis and inhibiting lipogenesis in oleic acid induced fatty liver cells through promoted Sirt1/AMPK pathway.

60 APPLIED LIFE SCIENCES↗

Downregulation of Nedd4L predicts poor prognosis, promotes tumor growth and inhibits MAPK/ERK signal pathway in hepatocellular carcinoma

Highlights: • Nedd4L is down-regulated in HCC tissues. • Downregulation of Nedd4L predicts poor prognosis of HCC. • Nedd4L inhibits the proliferation of HCC in vitro and in vivo. • Nedd4L phosphorylates ERK1/2 and regulates genes related with apoptosis. Accumulating evidence indicates that the neural precursor cell–expressed, developmentally downregulated 4–like (Nedd4L) related with some tumor progression pathways and was found abnormally expressed in several kinds of solid cancers. However, the role and mechanism of Nedd4L in HCC remain unknown. This study was to assess the role of Nedd4L in HCC tumorigenesis and prognosis. The real-time quantitative RT-PCR and immunohistochemistry results revealed that Nedd4L was downregulated in HCC tissues compared to corresponding peri-noncancerous tissue, and HCC patients with low expression of Nedd4L exhibited poor prognosis assessed by Kaplan-Meier and Cox regression analysis in 78 HCC patients. Furthermore, knockdown of Nedd4L could significantly promote proliferation of HCC cells by CCK-8 and colony formation assays in vitro; whereas ectopic expression of Nedd4L resulted in attenuating proliferation in vitro and tumor growth in vivc determined by nude mice xenografts model. Mechanically, Nedd4L could phosphorylate ERK1/2 and regulate genes related with apoptosis. Collectively, Nedd4L plays a tumor suppressive role in HCC, possibly through triggering MAPK/ERK-mediated apoptosis, and Nedd4L downregulation may be a potential prognostic biomarker as well as a therapeutic target for HCC.

60 APPLIED LIFE SCIENCES↗

Functional FRIGIDA allele enhances drought tolerance by regulating the P5CS1 pathway in Arabidopsis thaliana

Highlights: • ColFRI plants increase drought resistance. • FRI positively upregulates P5CS1 expression during drought tolerance. • The effect of FRI on drought resistance is dependent on FLC gene. Flowering at the right time is important for the reproductive success of plants and their response to environmental stress. In Arabidopsis, a major determinant of natural variation in flowering time is FRIGIDA (FRI). In the present study, we show that overexpression of the functional FRIGIDA gene in wild-type Col background (ColFRI) positively enhances the drought tolerance by activating P5CS1 expression and promoting proline accumulation during water stress. Furthermore, no significant changes in FRI gene and protein expression levels were observed with drought treatment, whereas P5CS1 protein expression significantly increased. In contrast, vernalization treatment efficiently reduced P5CS1 expression levels and resulted in a decrease in drought tolerance in the ColFRI plants. The flc mutants with a functional FRI background also relieved FRI-mediated activation of P5CS1 during drought tolerance. Taken together, our findings reveal the novel function of FRI in enhancing drought resistance through its downstream P5CS1 pathway during water-deficit stress, which is dependent on its target, the FLC gene.

60 APPLIED LIFE SCIENCES↗

Lycium barbarum polysaccharide protects against oxygen glucose deprivation/reoxygenation-induced apoptosis and autophagic cell death via the PI3K/Akt/mTOR signaling pathway in primary cultured hippocampal neurons

Lycium barbarum polysaccharide (LBP) is the main active ingredient of Lycium barbarum, which exhibits several beneficial effects, including neuroprotection, anti-aging and anti-oxidation. However, the mechanism by which LBP protects against cerebral ischemia/reperfusion-induced injury remains obscure. In this study, we found that LBP pretreatment greatly attenuated oxygen glucose deprivation/reperfusion (OGD/R) injury in primary cultured hippocampal neurons. LBP also suppressed OGD/R-induced lactate dehydrogenase (LDH) leakage, and ameliorated oxidative stress. In addition, LBP significantly reduced OGD/R-induced apoptosis and autophagic cell death. LBP caused the down-regulation of cleaved Caspase-3/Caspase-3, LC3II/LC3I and Beclin 1, as well as up-regulation of Bcl-2/Bax and p62. Furthermore, mechanistic studies indicated that LBP pretreatment increased p-Akt and p-mTOR levels after OGD/R. In summary, our results indicated that LBP protects against OGD/R-induced neuronal injury in primary hippocampal neurons by activating the PI3K/Akt/mTOR signaling pathway.

60 APPLIED LIFE SCIENCES↗

Cortistatin attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of the ERK1/2 signaling pathways

Highlights: • Treat with cortistatin results in decreased incidence of AAA. • Treat with cortistatin inhibit macrophage and inflammatory cytokine expression. • The mechanism relies on inhibition of the ERK1/2 signaling. Abdominal aortic aneurysm (AAA) is a fatal disease that is associated with chronic inflammation in the vessel wall. Cortistatin is implicated in inflammation, vascular smooth muscle cell migration and other cardiovascular pathologies. But, the hypothetical effect of cortistatin on AAA remains uncertain. We investigated the effect of cortistatin administration to angiotensin (Ang) II-induced AAA formation in apolipoprotein E deficient (Apoe{sup −/−}) mice. We showed that cortistatin administration significantly suppresses incidence and severity of AAA in Apoe{sup −/−} mice. A significant increase in macrophage infiltration, excretion of inflammatory cytokines, activities and expression levels of MMP2 and MMP9, reactive oxygen species levels and cell apoptosis in aneurysmal aortic wall of Apoe{sup −/−} mice infused with Ang-II, and these events were significantly alleviated by co-treatment with cortistatin. Mechanistic studies showed that the protective effects of cortistatin were related to the blocking of ERK1/2 signaling pathways, while does not was not actually affect JNK, P38 phosphorylation. In conclusion, cortistatin appears to play an essential role in the formation of AAA and indicate cortistatin may as novel therapeutic option for AAA.

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