Publications by authors named "Zong-Yang Li"

22 Publications

  • Page 1 of 1

Phragmunis a suppresses glioblastoma through the regulation of MCL1-FBXW7 by blocking ELK1-SRF complex-dependent transcription.

Neurochem Int 2021 Jul 9;147:105051. Epub 2021 May 9.

Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China. Electronic address:

Glioblastoma (GBM) is a highly aggressive brain tumor. During screening work, we found a new compound named phragmunis A (PGA), which is derived from the fruitbody of Trogia venenata, exhibits a potential cytotoxic effect on patient-derived recurrent GBM cells and temozolomide (TMZ)-resistant cell lines. The present study was designed to investigate the potential molecular mechanism of the anti-glioma effects of PGA in vitro and in vivo. Studies investigating the mechanism revealed that PGA diminished the binding efficiency of ETS family of transcription factor (ELK1) and Serum response factor (SRF), and suppressed ELK1-SRF complex-dependent transcription, which decreased the transcriptional levels of downstream genes Early growth response protein 1 (EGR1)-Polycomb ring finger (BMI1), thus inducing the imbalanced regulation between Myeloid cell leukaemia-1 (MCL1) and F-Box and WD repeat domain containing 7 (FBXW7). Finally, orthotopic xenograft models were established to confirm the anti-glioma effect of PGA on tumour growth. We showed, for the first time, that the cytotoxic effects of PGA occurred by inducing MCL1 inhibition and FBXW7 activation by blocking ELK1-SRF complex-dependent transcription. The blockage of ELK1-mediated transcription resulted in the suppression of EGR1-BMI1, which led to the upregulation of FBXW7 expression and downregulation of MCL1. These findings suggested that PGA could be a therapeutic drug candidate for the treatment of recurrent GBM by targeting the ELK1-SRF complex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuint.2021.105051DOI Listing
July 2021

Moschamindole induces glioma cell apoptosis by blocking Mia40-dependent mitochondrial intermembrane space assembly and oxidative respiration.

Phytother Res 2021 Apr 15. Epub 2021 Apr 15.

Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.

Glioblastoma multiforme (GBM) is the most frequent, lethal, and aggressive tumor of the central nervous system in adults. In this study, we found for the first time that moschamindole (MCD), a rare phenolic amide with 8/6/6/5/5 rings, is a major bioactive constituent derived from Phragmites communis Trin (Poaceae) that exhibits a potential cytotoxic effect on both TMZ-resistant GBM cell lines and xenograft models. MCD-induced intrinsic apoptosis signals and mitochondrial dysfunction were confirmed by cell cycle arrest, caspase-3/7 activation, and membrane potential depolarization. Furthermore, investigations exploring the mechanism showed that MCD specifically inhibits Mia40-mediated oxidative folding of mitochondrial intermembrane space (IMS) proteins via PCR assay and immunoblot analysis. MCD relies on its positive charge to associate with mitochondrial oxidative respiration, thus blocking energy metabolism and inducing apoptosis. Overexpression and upregulation of Mia40 were proven to reverse MCD-induced apoptosis and were correlated with the chemoresistance of GBM in vitro and in vivo, respectively. Taken together, our study demonstrates that Mia40 is a potential target of the chemoresistance of glioblastoma and suggests that MCD might be a potential agent for the individualized treatment of chemoresistant GBM based on mitochondrial metabolic characteristics and Mia40 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.7061DOI Listing
April 2021

Cassane diterpenoid derivative induces apoptosis in IDH1 mutant glioma cells through the inhibition of glutaminase in vitro and in vivo.

Phytomedicine 2021 Feb 11;82:153434. Epub 2020 Dec 11.

Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen 518035, China. Electronic address:

Background: Glioblastoma multiforme (GBM) is the most frequent, lethal and aggressive tumour of the central nervous system in adults. The discovery of novel anti-GBM agents based on the isocitrate dehydrogenase (IDH) mutant phenotypes and classifications have attracted comprehensive attention.

Purpose: Diterpenoids are a class of naturally occurring 20-carbon isoprenoid compounds, and have previously been shown to possess high cytotoxicity for a variety of human tumours in many scientific reports. In the present study, 31 cassane diterpenoids of four types, namely, butanolide lactone cassane diterpenoids (I) (1-10), tricyclic cassane diterpenoids (II) (11-15), polyoxybutanolide lactone cassane diterpenoids (III) (16-23), and fused furan ring cassane diterpenoids (IV) (24-31), were tested for their anti-glioblastoma activity and mechanism underlying based on IDH1 mutant phenotypes of primary GBM cell cultures and human oligodendroglioma (HOG) cell lines.

Results: We confirmed that tricyclic-type (II) and compound 13 (Caesalpin A, CSA) showed the best anti-neoplastic potencies in IDH1 mutant glioma cells compared with the other types and compounds. Furthermore, the structure-relationship analysis indicated that the carbonyl group at C-12 and an α, β-unsaturated ketone unit fundamentally contributed to enhancing the anti-glioma activity. Studies investigating the mechanism demonstrated that CSA induced oxidative stress via causing glutathione reduction and NOS activation by negatively regulating glutaminase (GLS), which proved to be highly dependent on IDH mutant type glioblastoma. Finally, GLS overexpression reversed the CSA-induced anti-glioma effects in vitro and in vivo, which indicated that the reduction of GLS contributed to the CSA-induced proliferation inhibition and apoptosis in HOG-IDH1-mu cells.

Conclusion: Therefore, the present results demonstrated that compared with other diterpenoids, tricyclic-type diterpenoids could be a targeted drug candidate for the treatment of secondary IDH1 mutant type glioblastoma through negatively regulating GLS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2020.153434DOI Listing
February 2021

Furanodienone overcomes temozolomide resistance in glioblastoma through the downregulation of CSPG4-Akt-ERK signalling by inhibiting EGR1-dependent transcription.

Phytother Res 2019 Jun 21;33(6):1736-1747. Epub 2019 Apr 21.

Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.

Glioblastoma multiforme (GBM) is a highly aggressive type of brain tumour. Patients with GBM respond poorly to chemotherapy and have poor survival outcomes. Neuron-glial antigen 2 (NG2), also known as chondroitin sulphate proteoglycan 4 (CSPG4), has been shown to contribute to critical processes, such as cell survival, proliferation, and chemotherapy resistance, during glioma progression. In this study, we found that furanodienone (FUR), a diene-type sesquiterpene isolated from the rhizomes of Rhizoma curcumae, exhibited a potential cytotoxic effect on temozolomide (TMZ)-resistant GBM cells in vitro by inhibiting CSPG4 and related signalling pathways. Studies investigating the mechanism demonstrated that FUR suppressed CSPG4-Akt-ERK signalling, inflammatory responses, and cytokine levels but activated caspase-dependent pathways and mitochondrial dysfunction. Furthermore, an immunofluorescence assay and a dual-luciferase reporter assay revealed that inhibition of EGR1-mediated transcription might have contributed to the FUR-dependent blockade of CSPG4 signalling and glioma cell survival. These results established a link between FUR-induced CSPG4 inhibition and the suppression of EGR1-dependent transcription. Attenuation of ERK1/2 and cytokine signalling might have generated the EGR1-dependent negative feedback loop of the CSPG4 pathway during FUR-induced apoptosis. These findings suggested that FUR could be a therapeutic candidate for the treatment of malignant glioma via targeting CSPG4 signalling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.6363DOI Listing
June 2019

Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR and .

Front Cell Neurosci 2019 4;13:61. Epub 2019 Mar 4.

Shenzhen Key Laboratory of Neurosurgery, Brain Center, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, China.

Aggregated amyloid-β protein (Aβ) and Aβ-induced neuronal apoptosis have been implicated as critical factors in the pathophysiology of Alzheimer's disease (AD). Certain preclinical results have indicated that the increased accumulation of protein aggregates in AD-affected neurons activates the unfolded protein response (UPR), a pathological phenomenon, which predominantly mediates the aberrant endoplasmic reticulum (ER) stress and apoptotic cascades in neuronal cells. In the present study, we confirmed that Santacruzamate A (STA, a natural product isolated from a Panamanian marine cyanobacterium) attenuates Aβ protein fragment 25-35 (Aβ)-induced toxicity in PC12 cells and rescues cognitive deficits in APPswe/PS1dE9 mice by enhancing ER stress tolerance. We first demonstrated the anti-apoptotic effects of STA by evaluating caspase-3 activity, annexin V/propidium iodide (PI) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Behavioral testing of STA-treated APPswe/PS1dE9 mice showed that the pronounced memory impairments were ameliorated and that the consolidated memories were stably maintained over a 2-week period. The mechanistic studies provided evidence that STA inhibited Aβ-induced UPR and ER stress by regulating the ER retention signal (KDEL) receptor, which reinforced the retention of resident chaperones in the ER lumen. Furthermore, STA regulated the expression of the mitochondrial intermembrane space assembly protein 40 (Mia40) and augmenter of liver regeneration (ALR), which ultimately attenuated the mitochondrial fission and apoptosis pathways. Together, our present findings suggest that the KDEL receptor and Mia40-ALR play a role in mitigating Aβ-induced neurotoxicity, which might in turn positively regulate learning and memory. These observations support that STA may be a promising agent for reversing the progression of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2019.00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409322PMC
March 2019

Mild hypothermia reduces endoplasmic reticulum stress-induced apoptosis and improves neuronal functions after severe traumatic brain injury.

Brain Behav 2019 04 4;9(4):e01248. Epub 2019 Mar 4.

Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

Background: Mild hypothermia is wildly used in clinical treatment of traumatic brain injury (TBI). However, the effect of mild hypothermia on endoplasmic reticulum (ER) stress-induced apoptosis after severe TBI is still unknown.

Methods: In the present study, we used BALB/c mice to investigate the efficacy of posttraumatic mild hypothermia in reducing ER stress. Severe TBI was induced by controlled cortical impact injury. Mild hypothermia treatment was performed immediately after surgery and maintained for 4 hr. The animals were euthanized at 1 and 7 days after severe TBI. The expression levels of ER stress marker proteins were evaluated using Western blot and immunofluorescence. Cell apoptosis rate was analyzed by TUNEL staining. Neuronal functions of the mice were assessed using rotarod test and Morris water maze.

Results: Our results revealed that mild hypothermia significantly attenuated ER stress marker proteins, including p-eIF2α/eIF2α, ATF4, CHOP and IRE-1α, and reduced apoptosis rate in the pericontusion region at 1 and 7 days after severe TBI. Interestingly, mild hypothermia also prevented the translocation of CHOP into nucleus. In addition, posttraumatic mild hypothermia significantly improved neuronal functions after severe TBI.

Conclusions: Our findings illustrated that mild hypothermia could reduce ER stress-induced apoptosis and improve neuronal functions after severe traumatic brain injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/brb3.1248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456779PMC
April 2019

Tanshinone IIA induces apoptosis via inhibition of Wnt/β‑catenin/MGMT signaling in AtT‑20 cells.

Mol Med Rep 2017 Nov 22;16(5):5908-5914. Epub 2017 Aug 22.

Brain Center, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, Guangdong 518035, P.R. China.

A strategy to suppress the expression of the DNA repair enzyme O6‑methylguanine‑DNA methyltransferase (MGMT) by inhibition of Wnt/β‑catenin signaling may be useful as a novel treatment for pituitary adenoma. Previous studies have reported that Tanshinone IIA (TSA), a major quinone compound isolated from Salvia miltiorrhiza, had antitumor effects. However, whether TSA has antitumor effects against pituitary adenoma and whether the mechanisms are associated with the Wnt/β‑catenin/MGMT pathway remains to be clarified. In the present study, TSA treatment caused apoptosis in AtT‑20 cells in a concentration‑dependent manner, as demonstrated by cell viability reduction, phophatidylserine externalization detected by Annexin V staining and mitochondrial membrane potential disruption detected by JC‑1 staining, which were associated with activation of caspase‑3 and DNA fragmentation detected by TUNEL in AtT‑20 cells. T‑cell factor (TCF)‑lymphoid‑enhancing factor (LEF) reporter activity was determined by dual luciferase reporter assay and the interaction between β‑catenin and TCF‑4 were detected using a co‑immunoprecipitation kit. The results indicated TSA treatment increased β‑catenin phosphorylation, inhibited β‑catenin nuclear translocation, reduced β‑catenin/TCF‑4 complex formation and TCF‑LEF luciferase reporter activity, and subsequently reduced the expression of cyclin D1 and MGMT. Notably, overexpression of MGMT in β‑catenin knock down AtT‑20 cells abrogated the TSA‑mediated effects in AtT‑20 cells. In conclusion, TSA induced apoptosis via inhibition of Wnt/β‑catenin‑dependent MGMT expression, which may provide novel insights into the understanding of the mechanism of the antitumor effects of Salvia miltiorrhiza.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/mmr.2017.7325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865768PMC
November 2017

Radicol, a Novel Trinorguaiane-Type Sesquiterpene, Induces Temozolomide-Resistant Glioma Cell Apoptosis via ER Stress and Akt/mTOR Pathway Blockade.

Phytother Res 2017 May 27;31(5):729-739. Epub 2017 Feb 27.

Department of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen, 518035, China.

Glioblastoma multiforme (GBM) is the most frequent, lethal and aggressive tumour of the central nervous system (CNS) in adults. Multidrug resistance (MDR) results in undesirable prognosis during GBM chemotherapy. In this study, we determined that Radicol (RAD), a novel trinorguaiane-type sesquiterpene originally isolated from the root of Dictamnus radicis Cortex, exhibited potently cytotoxic effect on temozolomide (TMZ)-resistant GBM cell lines in a dose-dependent manner. Radicol-induced apoptosis was confirmed with Hoechst 33342/propidium iodide and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labelling (TUNEL) staining. Studies investigating the mechanism revealed that RAD triggered an attenuation of protein disulphide isomerase (PDI) and induced the unmitigated unfolded protein response (UPR) and lethal endoplasmic reticulum (ER) stress. Simultaneously, we further demonstrated that RAD suppressed the activation of Akt/mTOR/p70S6K phosphorylation by up-regulating the induction of glycogen synthase kinase-3β (GSK-3β). These results established a link between RAD-induced ER stress and inhibition of the Akt/mTOR/p70S6K pathway, and the attenuation of PDI and activation of GSK-3β might be the synergistic target of antineoplastic effects during RAD-induced apoptosis. These findings suggested that RAD, possessing multiple cytotoxicity targets, low molecular weight and high lipid solubility, could be a promising agent for the treatment of malignant gliomas. Copyright © 2017 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.5793DOI Listing
May 2017

A novel HDAC6 inhibitor Tubastatin A: Controls HDAC6-p97/VCP-mediated ubiquitination-autophagy turnover and reverses Temozolomide-induced ER stress-tolerance in GBM cells.

Cancer Lett 2017 04 26;391:89-99. Epub 2017 Jan 26.

Shenzhen Key Laboratory of Neurosurgery, Department of Neurosurgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen 518035, China. Electronic address:

Temozolomide (TMZ) is the cornerstone of therapy for glioblastoma multiforme (GBM). However, its efficacy is limited due to the development of multidrug resistance (MDR). In this study, we first identified the occurrence of ER stress-tolerance (ERST) in glioma cells and confirmed that ERST was positively correlated with TMZ resistance. We further showed that the seesaw-effect of HDAC6-p97/VCP (increased HDAC6 and decreased p97/VCP) in glioma cells was crucial to ERST-associated TMZ resistance. Moreover, the combination treatment of Tubastatin A (TUB, a selective inhibitor of HDAC6) and TMZ synergistically overcame ERST, reduced cell viability and induced apoptosis in TMZ-resistant glioma cells. TUB and TMZ triggered pro-apoptotic signals of the unfolded protein response (UPR) and ER stress and reversed the ratio between HDAC6 and p97/VCP, which potentially attenuated the activation of heat shock proteins and mediated the reversal of ERST. The combination treatment also triggered the dissociation of Dynein-HDAC6 and attenuation of the Dynein-Dynactin motor complex. In addition, this treatment induced HDAC6-p97/VCP-mediated ubiquitination-autophagy turnover, which was involved in the degradation and clearance of ubiquitinated misfolded proteins. This effect could be partially reversed by HDAC6 KO and/or p97/VCP overexpression. Therefore, we proposed that glioma cells optimized the clearance of ubiquitinated misfolded proteins via the reinforcement of HDAC6-facilitated autophagy and attenuation of the p97/VCP-mediated ubiquitin-proteasome system (UPS). In conclusion, our findings showed that the balance of HDAC6-p97/VCP was crucial to ERST-associated TMZ resistance and that HDAC6 inhibition might be a synergistic target and strategy along with TMZ for the improvement of clinical glioma treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2017.01.025DOI Listing
April 2017

Over-expression of the long non-coding RNA HOTTIP inhibits glioma cell growth by BRE.

J Exp Clin Cancer Res 2016 10 12;35(1):162. Epub 2016 Oct 12.

The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.

Background: Gliomas are the most common type of primary brain tumour in the central nervous system of adults. The long non-coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) is transcribed from the 5' tip of the HOXA locus. HOTTIP has recently been shown to be dysregulated and play an important role in the progression of several cancers. However, little is known about whether and how HOTTIP regulates glioma development.

Methods: In this study, we assayed the expression of HOTTIP in glioma tissue samples and glioma cell lines using real-time polymerase chain reaction and defined the biological functions of HOTTIP using the CCK-8 assay, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL assay) and tumour formation assay in a nude mouse model. Finally, we discovered the underlying mechanism using the Apoptosis PCR 384HT Array, Western blot, RNA immunoprecipitation (RIP) and luciferase reporter assay.

Results: HOTTIP was aberrantly down-regulated in glioma tissues and glioma cell lines (U87-MG, U118-MG, U251 and A172), and over-expression of HOTTIP inhibited the growth of glioma cell lines in vitro and in vivo. Furthermore, HOTTIP could directly bind to the brain and reproductive expression (BRE) gene and down-regulate BRE gene expression. In addition, we further verified that over-expression of the BRE gene promoted the growth of glioma cell lines in vitro. Finally, over-expression of HOTTIP significantly suppressed the expression of the cyclin A and CDK2 proteins and increased the expression of the P53 protein. However, we found that the over-expression of BRE significantly increased the expression of the cyclin A and CDK2 proteins and suppressed the expression of the P53 protein. Taken together, these findings suggested that high levels of HOTTIP reduced glioma cell growth. Additionally, the mechanism of HOTTIP-mediated reduction of glioma cell growth may involve the suppression of cyclin A and CDK2 protein expression, which increases P53 protein expression via the down-regulation of BRE.

Conclusions: Our studies demonstrated that over-expression of HOTTIP promotes cell apoptosis and inhibits cell growth in U118-MG and U87-MG human glioma cell lines by down-regulating BRE expression to regulate the expression of P53, CDK2 and Cyclin A proteins. The data described in this study indicate that HOTTIP is an interesting candidate for further functional studies in glioma and demonstrate the potential application of HOTTIP in glioma therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-016-0431-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062847PMC
October 2016

Histone Deacetylase Inhibitor RGFP109 Overcomes Temozolomide Resistance by Blocking NF-κB-Dependent Transcription in Glioblastoma Cell Lines.

Neurochem Res 2016 Dec 8;41(12):3192-3205. Epub 2016 Sep 8.

Brain Center, Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, The Clinical College of Anhui Medical University, Shenzhen University 1st Affiliated Hospital, 3002# Sungang Road, Futian district, Shenzhen, 518035, China.

Glioblastoma (GBM) is the most frequent and aggressive tumour in the central nervous system. Many studies have demonstrated that upregulation of the NF-κB onco-pathway is accompanied by the acquisition of Temozolomide (TMZ) resistance in GBM cells. Here, we show that RGFP109, a selective histone deacetylase (HDAC1 and HDAC3) inhibitor, overcomes TMZ resistance and downregulates the expression of NF-κB-regulated pro-survival genes in a TMZ-resistant (TR) GBM cell line. RGFP109 did not alter the phosphorylation levels of NF-κB/p65 or inhibitory κBα (IκBα). Immunofluorescence microscopy showed that RGFP109 does not block the nuclear translocation of NF-κB/p65. However, co-immunoprecipitation assays revealed that RGFP109 induces the hyperacetylation of NF-κB/p65 and histones, and blocks interactions between NF-κB/p65 and its coactivators, p300 and p300/CBP-associated factor (PCAF). These results indicate that RGFP109-mediated post-translational nuclear acetylation may be involved in the regulation of NF-κB. Electrophoretic mobility shift assays revealed that RGFP109 reduces NF-κB/p65 binding to κB-DNA and decreased the transcriptional level of κB-mediated genes, suggesting that RGFP109-induced hyperacetylation leads to attenuated transcription of the κB gene. In addition, RGFP109 elevates the expression of inhibitor of growth 4 (ING4), which is typically downregulated in GBM cells. Importantly, we found that RGFP109 enhances ING4 recognition and binding to NF-κB/p65, which may be positively correlated with reduced interactions between NF-κB/p65 and p300/PCAF, thereby effecting transcription of the κB gene. Finally, we show that knockdown of ING4 with plasmids containing pcDNA3.1-ING4 shRNA abolished the effect of RGFP109. Therefore, ING4 may act as a corepressor and facilitate RGFP109-triggered suppression of the NF-κB pathway. Taken together, our data show that RGFP109, an HDAC inhibitor, in combination with TMZ may be a therapeutic candidate for patients with temozolomide-resistant GBM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-016-2043-5DOI Listing
December 2016

Cassane-type diterpenes from Caesalpinia minax induce apoptosis in pituitary adenoma: structure-activity relationship, ER stress and Wnt/β-catenin pathways.

J Asian Nat Prod Res 2017 May 2;19(5):423-435. Epub 2016 Sep 2.

a Zhongshan School of Medicine , Sun Yat-sen University , Guangzhou 510080 , China.

Plant-derived natural products have been the highly significant sources of novel antitumor agents. The cassane-type diterpenes of genus Caesalpinia have been reported to bear antiproliferative activities toward different types of cancer cells. In this study, we evaluated the antineoplasmic activities of 16 natural origin cassane-type diterpenes isolated from the CHCl extract of the seeds of C. minax in pituitary adenomas cells and identified caesalpin G (CAG) showed the strongest cytotoxicity. Moreover, we further investigated the structure-activity relationship and molecular mechanism of these derivatives systematically. The results confirmed the unsaturated lactone-type ring, hydroxyl at C-7, and alkenyl at C-11 or C-14 functionality as critical for anticancer activity in this family of natural products. In addition, the mechanism experiments also demonstrated unfolded protein response and ER stress and Wnt/β-catenin pathway were involved in the CAG-induced apoptosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10286020.2016.1217520DOI Listing
May 2017

HPOB, an HDAC6 inhibitor, attenuates corticosterone-induced injury in rat adrenal pheochromocytoma PC12 cells by inhibiting mitochondrial GR translocation and the intrinsic apoptosis pathway.

Neurochem Int 2016 10 12;99:239-251. Epub 2016 Aug 12.

Brain Center, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, 518035, China. Electronic address:

High levels of glucocorticoids (GCs) have been reported to damage normal hippocampal neurons, and such damage has been positively correlated with major depression (MD) and chronic stress. Our previous study showed that HDAC6 might be a potential target to regulate GC-induced glucocorticoid receptor (GR) translocation to the mitochondria and subsequent apoptosis. In the present study, we investigated the effect of HPOB, a selective HDAC6 inhibitor, on corticosterone (Cort)-induced apoptosis and explored the possible mechanism of action of HPOB in rat adrenal pheochromocytoma (PC12) cells, which possesses typical neuron features and expresses high levels of glucocorticoid receptors. We demonstrated that pre-treatment with HPOB remarkably reduced Cort-induced cytotoxicity and confirmed the anti-apoptotic effect of HPOB via the caspase-3 activity assay and H33342/PI and TUNEL double staining. Mechanistically, we demonstrated that HPOB reversed the Cort-induced elevation of GR levels in the mitochondria and blocked concomitant mitochondrial dysfunction and the intrinsic apoptosis pathway. Furthermore, HPOB was shown to attenuate expression of the multi-chaperone machinery (Hsp90-Hop-Hsp70) and cooperate with mitochondrial translocase of the outer/inner membrane (TOM/TIM) complex recruitment by triggering hyperacetylation of Hsps through HDAC6 inhibition. Considering all of these findings, the neuroprotective effect of HPOB demonstrated the crucial role of HDAC6 inhibition in reducing Cort-induced apoptosis in PC12 cells. The data further suggested that the anti-apoptotic activity of HDAC6 inhibition against the mitochondria-mediated impairment pathway might be mechanistically linked to the hyperacetylation of Hsps and consequent suppression of GR translocation to the mitochondria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuint.2016.08.004DOI Listing
October 2016

Early Biomarkers in 1H Nuclear Magnetic Resonance Spectroscopy of Striatal Pathological Mechanisms after Acute Carbon Monoxide Poisoning in Rats.

Biomed Environ Sci 2015 Oct;28(10):728-37

Research Center of Occupational Medicine, Peking University Third Hospital, Beijing 100191, China.

Objective: In vivo Proton Magnetic Resonance Spectroscopy (1H-MRS) can be used to evaluate the levels of specific neurochemical biomarkers of pathological mechanisms in the brain.

Methods: We conducted T2-Weighted Magnetic Resonance Imaging (MRI) and 1H-MRS with a 3.0-Tesla animal MRI system to investigate the early microstructural and metabolic profiles in vivo in the striatum of rats following carbon monoxide (CO) poisoning.

Results: Compared to baseline, we found significant cortical surface deformation, cerebral edema changes, which were indicated by the unclear gray/white matter border, and lateral ventricular volume changes in the brain. A significant reduction in the metabolite to total creatine (Cr) ratios of N-acetylaspartate (NAA) was observed as early as 1 h after the last CO administration, while the lactate (Lac) levels increased marginally. Both the Lac/Cr and NAA/Cr ratios leveled off at 6 h and showed no subsequent significant changes. In addition, compared to the control, the choline (Cho)/Cr ratio was slightly reduced in the early stages and significantly increased after 6 h. In addition, a pathological examination revealed mild cerebral edema on cessation of the insult and more severe cerebral injury after additional CO poisoning.

Conclusion: The present study demonstrated that 1H-MRS of the brain identified early metabolic changes after CO poisoning. Notably, the relationship between the increased Cho/Cr ratio in the striatum and delayed neuropsychologic sequelae requires further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3967/bes2015.103DOI Listing
October 2015

Upregulation of miR-107 Inhibits Glioma Angiogenesis and VEGF Expression.

Cell Mol Neurobiol 2016 Jan 18;36(1):113-20. Epub 2015 Jun 18.

Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

MicroRNAs can function as oncogenes or tumor suppressors in glioma. Previously, we showed that miR-107 inhibits glioma cell proliferation, migration, and invasion. Since tumor growth and invasion are closely related to angiogenesis, we further examined the role of miR-107 in glioma angiogenesis. In a co-culture of glioma cells and human brain microvascular endothelial cells (HBMVEC), overexpression of miR-107 in glioma cells led to the inhibition of HBMVEC proliferation, migration, and tube formation ability. ELISA, RT-PCR, and western blot assays revealed that upregulation of miR-107 in glioma cells inhibits VEGF expression. Our findings collectively support the critical involvement of miR-107 in glioma cell angiogenesis and highlight its potential as a therapeutic target for glioma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10571-015-0225-3DOI Listing
January 2016

Salvianolic acids attenuate rat hippocampal injury after acute CO poisoning by improving blood flow properties.

Biomed Res Int 2015 1;2015:526483. Epub 2015 Feb 1.

Research Center of Occupational Medicine, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China.

Carbon monoxide (CO) poisoning causes the major injury and death due to poisoning worldwide. The most severe damage via CO poisoning is brain injury and mortality. Delayed encephalopathy after acute CO poisoning (DEACMP) occurs in forty percent of the survivors of acute CO exposure. But the pathological cause for DEACMP is not well understood. And the corresponding therapy is not well developed. In order to investigate the effects of salvianolic acid (SA) on brain injury caused by CO exposure from the view point of hemorheology, we employed a rat model and studied the dynamic of blood changes in the hemorheological and coagulative properties over acute CO exposure. Compared with the groups of CO and 20% mannitol + CO treatments, the severe hippocampal injury caused by acute CO exposure was prevented by SA treatment. These protective effects were associated with the retaining level of hematocrit (Hct), plasma viscosity, fibrinogen, whole blood viscosities and malondialdehyde (MDA) levels in red blood cells (RBCs). These results indicated that SA treatment could significantly improve the deformation of erythrocytes and prevent the damage caused by CO poisoning. Meanwhile, hemorheological indexes are good indicators for monitoring the pathological dynamic after acute CO poisoning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/526483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331406PMC
November 2015

Tenuifolin, a secondary saponin from hydrolysates of polygalasaponins, counteracts the neurotoxicity induced by Aβ25-35 peptides in vitro and in vivo.

Pharmacol Biochem Behav 2015 Jan 14;128:14-22. Epub 2014 Nov 14.

Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China. Electronic address:

Alzheimer's disease (AD) is associated with damage to hippocampal neurons and declines in cognitive functions. The accumulation of amyloid peptides is regarded as a crucial event in the initiation of AD. The neurotoxicity induced by Aβ25-35 peptides was used to screen for cytoprotective factors in vitro, and the cognitive deficits induced by the injection of Aβ25-35 into the hippocampus were used to evaluate effect on learning and memory. Our previous study revealed that hydrolysate of polygalasaponins (HPS) clearly improve the cognitive deficits induced by the injection of Aβ25-35 in mice, but the potential active constituent of HPS remains unclear. The purposes of this study were to separate and purify the secondary saponins of HPS, screen for neuroprotective effects of the constituents in vitro, and to evaluate the effect of cognition in vivo. Various chromatographic methods were used to separate and purify the HPS. The neuroprotective effects were examined in Aβ25-35-damage-induced PC12 cells. The protective effect of tenuifolin on the cognitive impairments induced by Aβ25-35 injection was assessed using the Morris water maze and step-through passive avoidance tests. Tenuifolin and fallaxsaponin A were isolated from the HPS. Tenuifolin possessed neuroprotective effects against Aβ25-35-induced apoptosis in PC12 cells and significantly improved the cognitive deficits induced by the intrahippocampal injection of Aβ25-35 in mice. Thus, tenuifolin is one of the active constituents of HPS against the neurotoxicity induced by Aβ25-35 peptides in vitro and in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbb.2014.11.010DOI Listing
January 2015

Cajaninstilbene acid prevents corticosterone-induced apoptosis in PC12 cells by inhibiting the mitochondrial apoptotic pathway.

Cell Physiol Biochem 2014 1;34(3):1015-26. Epub 2014 Sep 1.

Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China.

Background/aims: Cajaninstilbene acid (3-hydroxy-4-prenyl-5-methoxystilben-2 -carboxylic acid, CSA), a natural stilbene isolated from the leaves of Cajanus cajan, has attracted considerable attention for its wide range of pharmacological activities. This study investigated whether CSA protects against corticosterone (CORT)-induced injury in PC12 cells and examined the potential mechanisms underlying this protective effect.

Methods: Cell viability and cytotoxicity were detected using a 3-(4,5-desethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and a lactate dehydrogenase (LDH) assay kit, respectively. PC12 cell apoptosis was measured using Hoechst 33342 staining and a DNA fragmentation assay kit, and intracellular Ca(2+) concentrations were assessed by fluorescent labelling. Next, the mitochondrial permeability transition pores (mPTPs) and mitochondrial membrane potentials (∆Ψm) were detected using a colorimetric mPTP detection kit and a 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) kit, respectively. Finally, cytochrome c, caspase-3 and inhibitor of caspase-activated deoxyribonuclease (ICAD) expression levels were monitored by western blot analysis.

Results: Treatment with 100 µmol/l CORT induced cytotoxicity in PC12 cells. However, CSA dose-dependently increased cell viability and decreased LDH release as well as CORT-induced apoptosis. Mechanistically, compared with the CORT-treated group, CSA strongly attenuated intracellular Ca(2+) overload and restored mitochondrial functions, including mPTPs and ∆Ψm. Furthermore, the down-regulation of cytochrome c and ICAD protein expression and the blockage of caspase-3 activity were observed upon CSA treatment.

Conclusions: In summary, our data are the first to show that the in vitro antidepressant-like effect of CSA may be attributed to the cytoprotection of neurons and that such neuroprotective mechanisms are correlated with intracellular Ca(2+) homeostasis and mitochondrial apoptotic pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000366317DOI Listing
June 2015

Saikosaponin D acts against corticosterone-induced apoptosis via regulation of mitochondrial GR translocation and a GR-dependent pathway.

Prog Neuropsychopharmacol Biol Psychiatry 2014 Aug 15;53:80-9. Epub 2014 Mar 15.

Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing 100193, China. Electronic address:

Saikosaponin D is an agonist of the glucocorticoid receptor (GR), and our preliminary study showed that it possesses neuroprotective effects in corticosterone-treated PC12 cells. However, further proof is required, and the molecular mechanisms of this neuroprotection remain unclear. This study sought to further examine the cytoprotective efficiency and potential mechanisms of action of Saikosaponin D in corticosterone-treated PC12 cells. The cells were treated with 250 μM corticosterone in the absence or presence of Saikosaponin D for 24 h; cell viability was then determined, and Hoechst 33342/propidium iodide (PI) and annexin/PI double staining, and TUNEL staining were performed. Next, mPTP, MMP, [Ca(2+)]i, translocation of the GR to the nucleus and Western blot analyses for caspase-3, caspase-9, cytochrome C, GR, GILZ, SGK-1, NF-Κb (P65), IκB-α, Bad, Akt, Hsp90 and HDAC-6 were investigated. The neuroprotective effects of Saikosaponin D were further confirmed by Hoechst 33342/PI, annexin/PI and TUNEL staining assays. These additional data suggested that Saikosaponin D partially reversed the physiological changes induced by corticosterone by inhibiting the translocation of the GR to the mitochondria, restoring mitochondrial function, down-regulating the expression of pro-apoptotic-related signalling events and up-regulating anti-apoptotic-related signalling events. These findings suggest that SSD exhibited its anti-apoptotic effects via differential regulation of mitochondrial and nuclear GR translocation, partial reversal of mitochondrial dysfunction, inhibition of the mitochondrial apoptotic pathway, and selective activation of the GR-dependent survival pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2014.02.010DOI Listing
August 2014

Neuroprotective effects of total saikosaponins of Bupleurum yinchowense on corticosterone-induced apoptosis in PC12 cells.

J Ethnopharmacol 2013 Jul 18;148(3):794-803. Epub 2013 May 18.

Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, No 151, North Road Malianwa, Haidian District, Beijing 100193, China.

Ethnopharmacological Relevance: The root of Bupleurum yinchowense Shan et Y. Li, a well-known medicinal plant in China, was originally documented in the "Shennong's Herbal", which is the oldest Chinese materia medica monographs. It has the action of soothing liver and relieving constraint for improving symptoms of emotional instability such as depression, anxiety and phobia. The in vivo experiment of our previous study has showed an efficacy of Total Saikosaponins (TSS) from Bupleurum yinchowense in acute stress and chronic unpredictable mild stress models. Nevertheless, there are no studies on the cytoprotection and potential mechanisms of TSS on corticosterone-induced apoptosis in PC12 cells. The present study focuses on cytoprotection against corticosterone-induced neurotoxicity in PC12 cells and its underlying molecule mechanisms of the antidepressant-like effect of TSS.

Materials And Methods: The PC12 cells were treated with 250 μM corticosterone in the absence or presence of different concentrations of TSS for 24 h, then the cell viability, lactate dehydrogenase (LDH) release, Hoechst 33342 and propidium iodide (PI) double staining and the DNA fragmentation of the apoptotic PC12 cells were determined. The mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (MMP), intracellular Ca(2+) ([Ca(2+)]i) concentration and western blot analysis of caspase-3, glucose-regulated protein 78 (GRP78), growth arrest and DNA damage inducible proteins 153 (GADD-153), X-box DNA-binding protein-1 (XBP-1), Bax, Bcl-2 were investigated.

Results: Pretreatment of PC12 cells with TSS (3.125, 6.25, 12.5, 25 μg/ml) partly reversed corticosterone-induced neurotoxicity in a dose dependent manner. TSS (25 =g/ml) reversed the increase of dead cells in the Hoechst 33342 stain, the accumulation in LDH leakage and the number of TUNEL positive cells induced by corticosterone to PC12 cells. Moreover, the cytoprotection of TSS was proved to be associated with the homeostasis of intracellular Ca(2+), the stabilization of ER stress via the down-regulation of GRP78, GADD-153, XBP-1, and the restoration of mitochondrial function, which included mPTP, MMP and caspase-3 activity. Furthermore, TSS (25 μg/ml) markedly ameliorated up-regulation of Bax and down-regulation of Bcl-2 in corticosterone-induced PC12 cells.

Conclusion: The result depicted that antidepressant-like effect of TSS in vivo may be associated with the cytoprotection of neuron, and the neuroprotective mechanisms were correlated with inhibiting the ER stress and the mitochondrial apoptotic pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2013.04.057DOI Listing
July 2013

Inhibitory effects of myricitrin on oxidative stress-induced endothelial damage and early atherosclerosis in ApoE-/- mice.

Toxicol Appl Pharmacol 2013 Aug 29;271(1):114-26. Epub 2013 Apr 29.

Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, 100193, Beijing, PR China.

Atherosclerosis (AS) is a state of heightened oxidative stress characterized by lipid and protein oxidation in vascular walls. Oxidative stress-induced vascular endothelial cell (VEC) injury is a major factor in the pathogenesis of AS. Myricitrin, a natural flavonoid isolated from the root bark of Myrica cerifera, was recently found to have a strong antioxidative effect. However, its use for treating cardiovascular diseases, especially AS is still unreported. Consequently, we evaluated the cytoprotective effect of myricitrin on AS by assessing oxidative stress-induced VEC damage. The in vivo study using an ApoE-/-mouse model of AS demonstrated that myricitrin treatment protects against VEC damage and inhibits early AS plaque formation. This effect is associated with the antioxidative effect of myricitrin, as observed in a hydrogen peroxide (H2O2)-induced rat model of artery endothelial injury and primary cultured human VECs. Myricitrin treatment also prevents and attenuates H2O2-induced endothelial injury. Further investigation of the cytoprotective effects of myricitrin demonstrated that myricitrin exerts its function by scavenging for reactive oxygen species, as well as reducing lipid peroxidation, blocking NO release, and maintaining mitochondrial transmembrane potential. Myricitrin treatment also significantly decreased H2O2-induced apoptosis in VECs, which was associated with significant inhibition of p53 gene expression, activation of caspase-3 and the MAPK signaling pathway, and alteration of the patterns of pro-apoptotic and anti-apoptotic gene expression. The resulting significantly increased bcl-2/bax ratio indicates that myricitrin may prevent the apoptosis induced by oxidative stress injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.taap.2013.04.015DOI Listing
August 2013

[Dynamic changes of hemorheology in rats after carbon monoxide poisoning].

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2010 Dec;28(12):885-90

Research Center of Occupational Medicine, The Third Hospital of Peking University, Beijing 100191, China.

Objective: To investigate the startup detail of circulation dysfunction and its role in the progress of delayed neuropsychologic sequelae (DNS) after carbon monoxide (CO) poisoning with comparison with the model of ischemia-reperfusion.

Methods: The ischemia-reperfusion rat model was established by Pulsinelli-Brierley method, and the CO poisoning rats model by i.p. injected with CO repeatedly respectively, and the rats were identified with DNS following the experiment of pathology and the ethnology.

Results: The whole blood viscosity, plasma viscosity, hematocrit and fibrinogen increased significantly immediately after reperfusion, and recovered gradually with the ischemia-reperfusion rat model. The whole blood viscosity decreased significantly immediately after CO treated i.p. Especially at low shear rate, the hematocrit also declined remarkably in the early stage after CO treatment. But 1day later, these parameters turned to the trend of the ischemia-reperfusion rats. There was a prominent elevation of both indexes until the 14th day following CO injection i.p.

Conclusion: There are significantly sustained hyper-coagulation and hyper-viscosity with circulation in rats after CO poisoning compared with ischemia-reperfusion model during the period of DNS, which might contribute to increase cerebral circulation resistance, blocked blood flow, and deteriorate hypoxemia in progression of DNS.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2010