Publications by authors named "Dongqing Guo"

31 Publications

The high expression of miR-31 in lung adenocarcinoma inhibits the malignancy of lung adenocarcinoma tumor stem cells.

Biochem Biophys Rep 2021 Dec 30;28:101122. Epub 2021 Aug 30.

School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Therapies for lung adenocarcinoma (LUAD) are mainly limited by drug resistance, metastasis or recurrence related to cancer stem cells (CSCs) with high proliferation and self-renewing. This research validated that miR-31 was over-expressed in LUAD by the analysis of generous clinical samples data. And the results of clinical data analysis showed that high expression of miR-31 was more common in patients with worse prognosis. The genes differentially expressed in LUAD tissues compared with normal tissues and A549CD133 cells (LUAD CSCs) compared with A549 cells were separately screened from Gene Expression Profiling Interactive Analysis and GEO datasets. The target genes that may play a role in the regulation of lung adenocarcinoma was screened by comparison between the differential genes and the target genes of miR-31. The functional enrichment analysis of GO Biological Processes showed that the expression of target genes related to cell proliferation was increased, while the expression of target genes related to cell invasion and metastasis was decreased in LUAD tissues and A549CD133 cells. The results suggested that miR-31 may have a significant inhibitory effect on the differentiation, invasion, metastasis and adhesion of LUAD CSCs, which was verified and experiments. Knock down of miR-31 accelerated xenograft tumor growth and liver metastasis . Likewise, the carcinogenicity, invasion and metastasis of A549CD133 CSCs were promoted after miR-31 knockdown. The study validated that miR-31 was up regulated in LUAD and its expression may affect the survival time of patients with lung adenocarcinoma, which indicated that miR-31 may have potential value for diagnosis and prognosis of LUAD. However, the inhibitory effect of miR-31 on tumorigenesis, invasion and metastasis of lung adenocarcinoma CSCs suggested its complexity in the regulation of lung adenocarcinoma, which may be related to its extensive regulation of various target genes.
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http://dx.doi.org/10.1016/j.bbrep.2021.101122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408630PMC
December 2021

The multi-faceted role of retinoid X receptor in cardiovascular diseases.

Biomed Pharmacother 2021 May 23;137:111264. Epub 2021 Feb 23.

School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China; College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Retinoid X receptors (RXRs) are members of ligand-dependent transcription factors whose effects on a diversity of cellular processes, including cellular proliferation, the immune response, and lipid and glucose metabolism. Knock out of RXRα causes a hypoplasia of the myocardium which is lethal during fetal life. In addition, the heart maintains a well-orchestrated balances in utilizing fatty acids (FAs) and other substrates to meet the high energy requirements. As the master transcriptional regulators of lipid metabolism, RXRs become particularly important for the energy needs of the heart. Accumulating evidence suggested that RXRs may exert direct beneficial effects in the heart both through heterodimerization with other nuclear receptors (NRs) and homodimerization, thus standing as suitable targets for treating in cardiovascular diseases. Although compounds that target RXRs are promising drugs, their use is limited by toxicity. A better understanding of the structural biology of RXRs in cardiovascular disease should enable the rational design of more selective nuclear receptor modulators to overcome these problems. Here, this review summarizes a brief overview of RXRs structure and versatility of RXR action in the control of cardiovascular diseases. And we also discussed the therapeutic potential of RXR ligand.
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http://dx.doi.org/10.1016/j.biopha.2021.111264DOI Listing
May 2021

Exploring the protective effects of PNS on acute myocardial ischaemia-induced heart failure by Transcriptome analysis.

J Ethnopharmacol 2021 May 17;271:113823. Epub 2021 Jan 17.

College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, PR China. Electronic address:

Ethnopharmacological Relevance: Panax notoginseng saponins (PNS) were extracted from Panax notoginseng (Burkill) F.H. Chen, a natural product often used as a therapeutic agent in China. PNS has showed obvious therapeutic effect in heart failure (HF) treatment. However, its targets and pharmacological mechanisms remain elusive.

Aim Of The Study: This research attempted to determine both the effects and mechanisms of PNS involved in AMI treatment, namely, acute myocardial infarction-induced HF.

Materials And Methods: An AMI-induced HF model was generated by left anterior descending (LAD) ligation in rats. Transcriptome analyses were performed to identify differentially expressed genes (DEGs) and pathway enrichment. Real-time quantitative PCR (RT-qPCR) verified the HF-related genes differentially expressed after PNS treatment. Finally, a model of H9C2 cells subjected to OGD/R, which is equivalent to oxygen-glucose deprivation/reperfusion, was established to identify the potential mechanism of PNS in the treatment of HF.

Results: PNS ameliorated cardiac function and protected against structural alterations of the myocardium in HF rats. Transcriptome analysis showed that PNS upregulated 1749 genes and downregulated 1069 genes in the heart. Functional enrichment analysis demonstrated that the metabolic process was enriched among the DEGs. KEGG pathway analysis revealed that the PPAR signalling pathway was particularly involved in the protective function of PNS. The effects of PNS on the PPAR pathway were validated in vivo; PNS treatment effectively increased the expression of PPARα, RXRα, and PGC1α in rats with AMI-induced HF. In addition, PNS was shown to regulate the expression of downstream energy metabolism-related proteins. Interestingly, the addition of the PPARα inhibitor GW6471 abolished the beneficial effects of PNS.

Conclusions: PNS exerts a cardioprotective function in a multicomponent and multitarget manner. The PPAR signalling pathway is one of the key pathways by which PNS protects against HF, and PPARα is a possible target for HF treatment.
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http://dx.doi.org/10.1016/j.jep.2021.113823DOI Listing
May 2021

Autophagy as a novel insight into mechanism of Danqi pill against post-acute myocardial infarction heart failure.

J Ethnopharmacol 2021 Feb 5;266:113404. Epub 2020 Oct 5.

College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China; School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Ethnopharmacological Relevance: Danqi Pill, composed of the root of Salvia miltiorrhiza Bunge and the root of Panax notoginseng, is effective in the clinical treatment of myocardial ischemia in coronary heart diseases. A number of studies have shown that autophagy plays an essential role in cardiac function and energy metabolism, and disordered autophagy is associated with the progression of heart failure. However, the effect and mechanism of Danqi pill on autophagy have not been reported yet.

Aim Of The Study: This study aims to elucidate whether Danqi pill restores autophagy to protect against HF and its potential mechanism.

Materials And Methods: Left anterior descending ligation was established to induce an HF rat model, HO-stimulated H9C2 cells model was conducted to clarify the effects and potential mechanism of Danqi pill. In vivo, Danqi pill (1.5 g/kg) were orally administered for four weeks and Fenofibrate (10 mg/kg) was selected as a positive group. In vitro, Danqi pill (10-200 μg/mL) was pre-cultured for 24 h and co-cultured with HO stimulation for 4 h. Importantly, transmission electron microscopy and fluorescence GPF-mRFP-LC3 reporter system were combined to monitor autophagy flux. Furtherly, we utilized Compound C, a specific AMPK inhibitor, to validate whether the autophagy was mediated by AMPK-TSC2-mTOR pathway.

Results: Danqi pill significantly improved cardiac function and myocardial injury in HF rats. Intriguingly, Danqi pill potently regulated autophagy mainly by promoting the formation of autophagosomes in vivo. Further results demonstrated that expressions of p-AMPK (P < 0.001) and p-TSC2 (P < 0.001) in cardiac tissue were upregulated by Danqi pill, accompanied with downregulation of p-mTOR (P < 0.01) and p-ULK1(P < 0.01). In parallel with the vivo experiment, in vitro study indicated that Danqi pill dramatically restored autophagy flux and regulated expressions of critical autophagy-related molecules. Finally, utilization of Compound C abrogated the effects of Danqi pill on autophagy flux and the expressions of p-TSC2 (P < 0.05), p-mTOR (P < 0.01) and p-ULK1 (P < 0.05).

Conclusion: Danqi pill could improve cardiac function and protect against cardiomyocytes injury by restoring autophagy via regulating the AMPK-TSC2-mTOR signaling pathway.
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http://dx.doi.org/10.1016/j.jep.2020.113404DOI Listing
February 2021

Danshen (Salvia miltiorrhiza) restricts MD2/TLR4-MyD88 complex formation and signalling in acute myocardial infarction-induced heart failure.

J Cell Mol Med 2020 09 5;24(18):10677-10692. Epub 2020 Aug 5.

School of Life Science, Beijing University of Chinese Medicine, Beijing, China.

Heart failure (HF) represents a major public health burden. Inflammation has been shown to be a critical factor in the progression of HF, regardless of the aetiology. Disappointingly, the majority of clinical trials targeting aspects of inflammation in patients with HF have been largely negative. Many clinical researches demonstrate that danshen has a good efficacy on HF, and however, whether danshen exerts anti-inflammatory effects against HF remains unclear. In our study, the employment of a water extracted and alcohol precipitated of danshen extract attenuated cardiac dysfunction and inflammation response in acute myocardial infarction-induced HF rats. Transcriptome technique and validation results revealed that TLR4 signalling pathway was involved in the anti-inflammation effects of danshen. In vitro, danshen reduced the release of inflammatory mediators in LPS-stimulated RAW264.7 macrophage cells. Besides, the LPS-stimulated macrophage conditioned media was applied to induce cardiac H9C2 cells injury, which could be attenuated by danshen. Furtherly, knock-down and overexpression of TLR4 were utilized to confirm that danshen ameliorated inflammatory injury via MyD88-dependent TLR4-TRAF6-NF-κB signalling pathway in cardiomyocytes. Furthermore, by utilizing co-immunoprecipitation, danshen was proved to suppress MD2/TLR4 complex formation and MyD88 recruitment. In conclusion, our results demonstrated that danshen ameliorates inflammatory injury by controlling MD2/TLR4-MyD88 complex formation and TLR4-TRAF6-NF-κB signalling pathway in acute myocardial infarction-induced HF.
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http://dx.doi.org/10.1111/jcmm.15688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521313PMC
September 2020

TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of Dihydrotanshinone I in doxorubicin-induced cardiotoxicity.

J Exp Clin Cancer Res 2020 May 24;39(1):93. Epub 2020 May 24.

School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China.

Background: Doxorubicin is effective in a variety of solid and hematological malignancies. Unfortunately, clinical application of doxorubicin is limited due to a cumulative dose-dependent cardiotoxicity. Dihydrotanshinone I (DHT) is a natural product from Salvia miltiorrhiza Bunge with multiple anti-tumor activity and anti-inflammation effects. However, its anti-doxorubicin-induced cardiotoxicity (DIC) effect, either in vivo or in vitro, has not been elucidated yet. This study aims to explore the anti-inflammation effects of DHT against DIC, and to elucidate the potential regulatory mechanism.

Methods: Effects of DHT on DIC were assessed in zebrafish, C57BL/6 mice and H9C2 cardiomyocytes. Echocardiography, histological examination, flow cytometry, immunochemistry and immunofluorescence were utilized to evaluate cardio-protective effects and anti-inflammation effects. mTOR agonist and lentivirus vector carrying GFP-TFEB were applied to explore the regulatory signaling pathway.

Results: DHT improved cardiac function via inhibiting the activation of M1 macrophages and the excessive release of pro-inflammatory cytokines both in vivo and in vitro. The activation and nuclear localization of NF-κB were suppressed by DHT, and the effect was abolished by mTOR agonist with concomitant reduced expression of nuclear TFEB. Furthermore, reduced expression of nuclear TFEB is accompanied by up-regulated phosphorylation of IKKα/β and NF-κB, while TFEB overexpression reversed these changes. Intriguingly, DHT could upregulate nuclear expression of TFEB and reduce expressions of p-IKKα/β and p-NF-κB.

Conclusions: Our results demonstrated that DHT can be applied as a novel cardioprotective compound in the anti-inflammation management of DIC via mTOR-TFEB-NF-κB signaling pathway. The current study implicates TFEB-IKK-NF-κB signaling axis as a previously undescribed, druggable pathway for DIC.
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http://dx.doi.org/10.1186/s13046-020-01595-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245789PMC
May 2020

Danqi Pill Protects Against Heart Failure Post-Acute Myocardial Infarction HIF-1α/PGC-1α Mediated Glucose Metabolism Pathway.

Front Pharmacol 2020 21;11:458. Epub 2020 Apr 21.

School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.

Aim: Heart failure (HF) post-acute myocardial infarction (AMI) leads to a large number of hospitalizations and deaths worldwide. Danqi pill (DQP) is included in the 2015 national pharmacopoeia and widely applied in the treatment of HF in clinics in China. We examined whether DQP acted on glucose metabolism to protect against HF post-AMI hypoxia inducible factor-1 alpha (HIF-1α)/peroxisome proliferator-activated receptor α co-activator (PGC-1α) pathway.

Methods And Results: In this study, left anterior descending (LAD) artery ligation induced HF post-AMI rats and oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 cell model were structured to explore the efficacy and mechanism of DQP. Here we showed that DQP protected the heart against ischemic damage as evidenced by improved cardiac functions and attenuated inflammatory infiltration. The expressions of critical proteins involved in glucose intake and transportation such as GLUT4 and PKM2 were up-regulated, while negative regulatory proteins involved in oxidative phosphorylation were attenuated in the treatment of DQP. Moreover, DQP up-regulated NRF1 and TFAM, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate (ATP) level. The protection effects of DQP were significantly compromised by HIF-1α siRNA, suggesting that HIF-1α signaling pathway was the potential target of DQP on HF post-AMI.

Conclusions: DQP exhibits the efficacy to improve myocardial glucose metabolism, mitochondrial oxidative phosphorylation and biogenesis by regulating HIF-1α/PGC-1α signaling pathway in HF post-AMI rats.
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http://dx.doi.org/10.3389/fphar.2020.00458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187888PMC
April 2020

Identification of the active compounds and drug targets of Chinese medicine in heart failure based on the PPARs-RXRα pathway.

J Ethnopharmacol 2020 Jul 12;257:112859. Epub 2020 Apr 12.

School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China; College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Ethnopharmacological Relevance: Danqi Pill (DQP), commonly known as a routinely prescribed traditional Chinese medicine (TCM), is composed of Salviae Miltiorrhizae Radix et Rhizoma and Notoginseng Radix et Rhizoma and effective in treating heart failure (HF) clinically due to their multicompound and multitarget properties. However, the exact active compounds and corresponding targets of DQP are still unknown.

Aim Of The Study: This study aimed to investigate active compounds and drug targets of DQP in heart failure based on the PPARs-RXRα pathway.

Materials And Methods: Network pharmacology was used to predict the compound-target interactions of DQP. Left anterior descending (LAD)-induced HF mouse model and oxygen-glucose deprivation/recovery (OGD/R)-induced H9C2 model were constructed to screen the active compounds of DQP.

Results: According to BATMAN-TCM (a bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine we previously developed), 24 compounds in DQP were significantly enriched in the peroxisome proliferator activated receptors-retinoid X receptor α (PPARs-RXRα) pathway. Among them, Ginsenoside Rb3 (G-Rb3) had the best pharmacodynamics against OGD/R-induced loss of cell viability, and it was selected to verify the compound-target interaction. In HF mice, G-Rb3 protected cardiac functions and activated the PPARs-RXRα pathway. In vitro, G-Rb3 protected against OGD/R-induced reactive oxygen species (ROS) production, promoted the expressions of RXRα and sirtuin 3 (SIRT3), thereafter improved the intracellular adenosine triphosphate (ATP) level. Immunofluorescent staining demonstrated that G-Rb3 could activate RXRα, and facilitate RXRα shifting to the nucleus. HX531, the specific inhibitor of RXRα, could abolish the protective effects of G-Rb3 on RXRα translocation. Consistently, the effect was also confirmed on RXRα siRNA cardiomyocytes model. Moreover, surface plasmon resonance (SPR) assays identified that G-Rb3 bound directly to RXRα with the affinity of KD = 10 × 10 M.

Conclusion: By integrating network pharmacology and experimental validation, we identified that as the major active compound of DQP, G-Rb3 could ameliorate ROS-induced energetic metabolism dysfunction, maintain mitochondrial function and facilitate energy metabolism via directly targeting on RXRα. This study provides a promising strategy to dissect the effective patterns for TCM and finally promote the modernization of TCM.
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http://dx.doi.org/10.1016/j.jep.2020.112859DOI Listing
July 2020

TMT-based proteomics analysis of the anti-hepatocellular carcinoma effect of combined dihydroartemisinin and sorafenib.

Biomed Pharmacother 2020 Jun 28;126:109862. Epub 2020 Feb 28.

School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Hepatocellular carcinoma (HCC), as the major primary liver cancer, is one of the most prevalent malignant diseases with a high mortality rate worldwide. Prior studies have demonstrated that dihydroartemisinin (DHA), the semisynthetic derivative of artemisinin, possesses anti-HCC activity. The multikinase inhibitor sorafenib has been approved for the treatment of HCC. However, the anti-HCC efficacy of DHA combined with sorafenib has not been reported. In this study, we confirmed the significantly enhanced anti-HCC efficacy of DHA in combination with sorafenib compared with that of each agent alone. Tandem Mass Tag (TMT) peptide labeling coupled with LC-MS/MS was used to quantify the proteins from the control, DHA, sorafenib, and DHA + sorafenib groups. In total, 532, 426, 628 differentially expressed proteins (fold change >1.20 or <0.83 and P-value <0.05) were determined by comparing DHA versus control, sorafenib versus control and DHA + sorafenib versus control groups, respectively. Moreover, optimized screening was performed, and 101 optimized differentially expressed proteins were identified. The results of functional analysis of the optimized differentially expressed proteins suggested that they were enriched in cell components such as membrane-bound vesicles, extracellular vesicles, and organelle lumens, and they were mainly involved in biological processes such as cellular component organization, response to stress, and response to chemicals; in addition, they were related to various molecular functions such as protein binding, chromatin binding and enzyme binding. KEGG pathway analysis showed that the optimized differentially expressed proteins were enriched in pyrimidine metabolism, RNA polymerase, base excision repair, and osteoclast differentiation. Protein-protein interaction (PPI) networks of some of the optimized upregulated proteins suggested that they might not only affect vitamin and fat digestion and absorption but may also be involved in tight junctions. In the PPI network, some of the optimized downregulated proteins were enriched in base excision repair, RNA polymerase, purine metabolism, pyrimidine metabolism and mucin type O-glycan biosynthesis. Overall, this research explored the anti-HCC efficacy of DHA combined with sorafenib by using the TMT-based quantitative proteomics technique and might facilitate the understanding of the related anti-HCC molecular mechanism.
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http://dx.doi.org/10.1016/j.biopha.2020.109862DOI Listing
June 2020

Qishen Granule alleviates endoplasmic reticulum stress-induced myocardial apoptosis through IRE-1-CRYAB pathway in myocardial ischemia.

J Ethnopharmacol 2020 Apr 13;252:112573. Epub 2020 Jan 13.

College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. Electronic address:

Ethnopharmacological Relevance: Qishen Granule (QSG) is a prevailing traditional Chinese medicine formula that displays impressive cardiovascular protection in clinical. However, underlying mechanisms by which QSG alleviates endoplasmic reticulum (ER) stress-induced apoptosis in myocardial ischemia still remain unknown.

Aim Of The Study: This study aims to elucidate whether QSG ameliorates ER stress-induced myocardial apoptosis to protect against myocardial ischemia via inositol requiring enzyme 1 (IRE-1)-αBcrystallin (CRYAB) signaling pathway.

Materials And Methods: Left anterior descending (LAD) ligation induced-ischemic heart model and oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 cells injury model were established to clarify the effects and potential mechanism of QSG. Ethanol extracts of QSG (2.352 g/kg) were orally administered for four weeks and Ginaton Tablets (100 mg/kg) was selected as a positive group in vivo. In vitro, QSG (800 μg/ml) or STF080310 (an inhibitor of IRE-1, 10 μM) was co-cultured under OGD/R in H9C2 cells. Inhibition of IRE-1 was conducted in H9C2 cells to further confirm the exact mechanism. Finally, to define the active components of anti-cardiomyocyte apoptosis in QSG which absorbed into the blood, we furtherly used the OGD/R-induced cardiomyocyte apoptosis model to evaluate the effects.

Results: QSG treatment improved cardiac function, ameliorated inflammatory cell infiltration and myocardial apoptosis. Similar effects were revalidated in OGD/R-induced H9C2 injury model. Western blots demonstrated QSG exerted anti-apoptotic effects by regulating apoptosis-related proteins, including increasing Bcl-2 and caspase 3/12, reducing the expressions of Bax and cleaved-caspase 3/12. Mechanistically, the IRE-1-CRYAB signaling pathway was significantly activated by QSG. Co-treatment with STF080310, the IRE-1 specific inhibitor significantly compromised the protective effects of QSG in vitro. Especially, the active components of QSG including Formononetin, Tanshinone IIA, Tanshinone I, Cryptotanshinon and Harpagoside showed significantly anti-apoptosis effects.

Conclusion: QSG protected against ER stress-induced myocardial apoptosis via the IRE-1-CRYAB pathway, which is proposed as a promising therapeutic target for myocardial ischemia.
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http://dx.doi.org/10.1016/j.jep.2020.112573DOI Listing
April 2020

Network pharmacology-based analysis of mechanisms of the anti-hepatocellular carcinoma effect by dihydroartemisinin.

Discov Med 2019 09;28(153):139-147

School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China.

As an important derivative of the herb medicine Artemisia annua L., dihydroartemisinin (DHA) exhibits anti-hepatocellular carcinoma (HCC) activities. However, the underlying molecular mechanism is still unclear. In the present study, the network pharmacology method was used to construct the ingredient-target network of DHA that was responsible for the anti-HCC effect and 11 targets including ALB, ATP5A1, CCT3, CLIC1, ENO1, HSPA8, HSPB1, NPM1, PPIA, PRDX1, and ZYX were selected. Functional category analysis showed that the anti-HCC effect of DHA might be related to the biological process of cell-cell adhesion. β1,6-branching of N-linked carbohydrate as one kind of glycosylation could participate in regulating cell-cell adhesion and has been reported to be overexpressed in HCC cells and tissues. Further lectin immunofluorescence and lectin blot analysis showed that DHA could down-regulate the expression of β1,6-branching of N-linked carbohydrate by suppressing the transcription of MGAT5. This study will provide a scientific basis for the elucidation of the mechanisms of DHA in anti-HCC from the angle of glycosylation.
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September 2019

Ginsenoside Rg3 regulates DNA damage in non-small cell lung cancer cells by activating VRK1/P53BP1 pathway.

Biomed Pharmacother 2019 Dec 16;120:109483. Epub 2019 Oct 16.

School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China. Electronic address:

Lung cancer is the leading cause of cancer-related deaths. Ginsenoside Rg3 is the main ingredient of Ginseng which is used to treat non-small cell lung cancer (NSCLC). It has been found to enhance the efficiency of chemotherapy thereby reducing its side effects. Previous studies found that ginsenoside Rg3 can reduce the occurrence of NSCLC by inducing DNA damage. Yet, its anti-DNA damaging effects and mechanisms in tumor cells are still not fully understood. This study explored the effect of ginsenoside Rg3 on DNA repair and VRK1/P53BP1 signaling pathway. Ginsenoside Rg3 treatment significantly decreased the incidence and invasionin a mouse model of lung cancer induced by urethane. The results of cell survival assay and single cell gel electrophoresis showed that ginsenoside Rg3 protected lung adenocarcinoma cells from DNA damage as well as inhibited the proliferation of tumor cells. Ginsenoside Rg3 increased the mRNA and protein expression of VRK1 in NSCLC cells as measured by RT-qPCR and western blot, respectively. These findings suggests that ginsenoside Rg3 regulates VRK1 signaling. Immunofluorescence assays showed that P53BP1 and VRK1 protein level increased, and the VRK1 protein translocated between the nuclei and cytoplasm. Finally, this conclusion was confirmed by the reverse validation in VRK1-knockdown cells. Taken together, these results show that ginsenoside Rg3 upregulate VRK1 expression and P53BP1 foci formation in response to DNA damage thereby inhibiting the tumorigenesis and viability of cancer cells. These findings reveal the role of Rg3 in lung cancer and provides therapeutic targets for developing new drugs in the prevention and treatment of lung cancer.
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http://dx.doi.org/10.1016/j.biopha.2019.109483DOI Listing
December 2019

Ginsenoside Rb3 regulates energy metabolism and apoptosis in cardiomyocytes via activating PPARα pathway.

Biomed Pharmacother 2019 Dec 29;120:109487. Epub 2019 Sep 29.

School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, China. Electronic address:

Heart failure (HF) leads to an increase in morbidity and mortality globally. Disorders of energy metabolism and apoptosis of cardiomyocytes are critically involved in the progression of HF. Ginsenoside Rb3 (G-Rb3) is a natural product derived from ginseng that has cardio-protective effect. The pharmacological mechanism of G-Rb3 in the treatment of HF remains to be clarified. In this study, we aimed to explore the regulative effects of G-Rb3 on fatty acids oxidation and apoptosis by in vivo and in vitro studies. Myocardial infarction (MI)-induced HF mice model and a cellular H9C2 injury model was induced by oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The results showed that G-Rb3 could protect heart functions in MI-induced HF model. G-Rb3 treatment up-regulated expressions of key enzymes involved in β-oxidation of fatty acids, including carnitine palmitoyltransterase-1α (CPT-1α), acyl-CoA dehydrogenase long chain (ACADL) and the major mitochondrial deacetylase enzyme sirtuin 3 (SIRT3). The upstream transcriptional regulator, peroxisome proliferator-activated receptor α (PPARα), was also up-regulated by G-Rb3 treatment. In vitro study demonstrated that G-Rb3 could protect mitochondrial membrane integrity and exert anti-apoptotic effects, in addition to regulating fatty acids oxidation. Impressively, after cells were co-treated with PPARα inhibitor, the regulative effects of G-Rb3 on energy metabolism and apoptosis were abrogated. Our study suggests that G-Rb3 is a promising agent and PPARα is potential target in the management of HF.
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http://dx.doi.org/10.1016/j.biopha.2019.109487DOI Listing
December 2019

Tanshinone IIA Restores Dynamic Balance of Autophagosome/Autolysosome in Doxorubicin-Induced Cardiotoxicity via Targeting Beclin1/LAMP1.

Cancers (Basel) 2019 Jun 28;11(7). Epub 2019 Jun 28.

School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, China.

Clinical use of the anti-cancer drug doxorubicin (DOX) is largely limited due to its severe cardiotoxicity. Dysregulation of autophagy is implicated in DOX-induced cardiotoxicity (DIC). Prior studies have indicated that Beclin1 and lysosomal-associated membrane proteins-1 (LAMP1) are critical mediators of autophagy. In this work, by assessing autophagic flux in a DOX-stimulated H9C2 model, we observed autolysosome accumulation caused by interruption of autolysosome degradation. Tanshinone IIA (TSA) is a well-known small molecule that exerts impressive cardioprotective effects on heart failure. Here, we investigated the regulation of TSA in DOX-treated zebrafish, mice, and H9C2 models. Results demonstrated that TSA remarkably improved heart function and reversed pathological changes in vivo, while TSA restored autophagic flux by promoting autolysosome degradation and autophagosome formation. Further experiments demonstrated that these effects were mediated through upregulation of Beclin1 and LAMP1. The mTOR agonist MHY1485 was shown to abrogate the effect of TSA via the UNC-51-like kinase 1 (ULK1)-Beclin1/TFEB-LAMP1 signaling pathway in vitro, demonstrating that TSA protects against DIC by promoting autophagy via the Beclin1/LAMP1 signaling pathway. We further employed a U87 model to assess whether TSA would compromise the antitumor activity of DOX. Intriguingly, the co-treatment of TSA was able to synergistically inhibit proliferative activity. Collectively, in this study we uncover the novel insight that TSA is able to reduce the cardiotoxicity of DOX without compromising antitumor activity.
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http://dx.doi.org/10.3390/cancers11070910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679133PMC
June 2019

Qishen granule attenuates cardiac fibrosis by regulating TGF-β /Smad3 and GSK-3β pathway.

Phytomedicine 2019 Sep 8;62:152949. Epub 2019 May 8.

School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing 100029, China. Electronic address:

Background: Cardiac fibrosis is a common pathological progress of cardiovascular disease resulting from the excessive accumulation of extracellular matrix (ECM). Transforming growth factor (TGF)-β/SMADs pathway is a canonical signaling pathway which directly induces expressions of ECM related genes. Qishen Granule (QSG), a traditional Chinese formula developed from Zhen-Wu Decoration for heart failure (HF), has been proven to have definite therapeutic effects on cardiac fibrosis. However, its underlying mechanisms remain unclear.

Purpose: To investigate the effects of QSG on TGF-β pathway and the downstream mediators including Smad3 and Glycogen synthase kinase (GSK)-3β.

Methods: HF model was induced by ligation of left coronary artery on male Sprague-Dawley (SD) rats. Rat were randomly divided into four groups including sham group, model group, QSG group and Fosinopril control group. Rats in each group were treated for 28 days, and 2D echocardiography was adopted to evaluate the heart function. The degree of cardiac fibrosis was assessed by Hematoxylin-Eosin (HE), Masson's trichrome and Picrosirius red (PSR) staining. Contents of collagen Ⅰ and Ⅲ were assessed by immunohistochemical method. Expressions of genes and proteins in TGF-β/SMADs and PI3K-GSK-3 signaling pathways were detected by Real-time Fluorescence Quantitative PCR (RT-qPCR) and Western blot respectively. TGF-β1-treated cardiac fibroblasts of neonatal SD rats were adopted for in vitro studies.

Results: 28 days after the surgery, cardiac ejection fraction (EF) and fractional shortening (FS) values in the model group showed a remarkable decrease, indicating the induction of HF model. QSG and Fosinopril elevated the EF and FS values, demonstrating cardio-protective effects. Pathological staining and immunohistochemistry showed that the contents of collagen I and III dramatically increased in the cardiac tissue of the model group compared with the sham group while QSG treatment reduced collagen contents. Furthermore, expressions of TGF-β1, p-Smad3 and p-GSK-3β were significantly decreased in the QSG treatment group compared with the model group, suggesting that the QSG may attenuate cardiac fibrosis through regulating TGF-β/Smad3 pathway. In vitro study further showed that the productions of type Ⅰ and Ⅲ collagen and α-smooth muscle actin (α-SMA) of cardiac fibroblasts were significantly increased by incubation with TGF-β1. QSG could markedly reduce the secretion of collagen Ⅰ and Ⅲ and α-SMA expression. Protein expressions of p-Smad3, PI3K, p-Akt and p-GSK-3β were significantly up-regulated by stimulation of TGF-β1. Treatment with QSG could suppress the activity of Smad3 and PI3K-GSK-3β signaling pathway in cardiac fibroblasts.

Conclusion: QSG improves cardiac function through inhibiting cardiac fibrosis. The anti-fibrotic effects are potentially mediated by the inhibition of the TGF-β/Smad3 pathway and the phosphorylation of GSK-3β.
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http://dx.doi.org/10.1016/j.phymed.2019.152949DOI Listing
September 2019

Tanshinone IIA protects against heart failure post-myocardial infarction via AMPKs/mTOR-dependent autophagy pathway.

Biomed Pharmacother 2019 Apr 21;112:108599. Epub 2019 Feb 21.

School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, China. Electronic address:

Heart failure (HF) leads to an increase in morbidity and mortality globally. Tanshinone IIA is an important traditional Chinese medicine monomer and has been shown to have remarkable protective effect against HF. Autophagy is critically involved in the progression of HF. The effect of Tanshinone IIA on autophagy has not been clarified yet. In this study, left anterior descending (LAD) ligation was used to induce HF model and a hydrogen peroxide-(HO-)-induced H9C2 cell injury model was established. in vivo, echocardiography results showed that Tanshinone IIA could significantly improve heart function. Western Blot result showed that Tanshinone IIA treatment enhanced autophagy and regulated expressions of key autophagy-related molecules, including protein 1 light chain 3 (LC3), p62 and Beclin1. Tanshinone IIA also inhibited apoptosis and regulated expressions of key apoptotic protein, including B cell lymphoma-2 (Bcl-2) and Bcl-2 Associated X Protein (Bax) and cleaved caspase-3 and -7. Further experiments demonstrated that the effects of Tanshinone IIA were mediated through upregulation of AMP-activated protein kinase (AMPK) and downregulation of mammalian target of rapamycin (mTOR) simultaneously. The mTOR agonist MHY1485 could abrogate the therapeutic effect of Tanshinone IIA in vitro. In conclusion, Tanshinone IIA protects cardiomyocytes and improves cardiac function by inhibiting apoptosis and inducing autophagy via activation of the AMPK-mTOR signaling pathway.
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http://dx.doi.org/10.1016/j.biopha.2019.108599DOI Listing
April 2019

Pro-angiogenic Role of Danqi Pill Through Activating Fatty Acids Oxidation Pathway Against Coronary Artery Disease.

Front Pharmacol 2018 4;9:1414. Epub 2018 Dec 4.

School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.

Coronary artery disease (CAD) is one of the leading causes of deaths worldwide. Energy metabolism disorders, including a reduction in fatty acids oxidation and upregulation of glycolysis pathway, are involved in the process of CAD. Therapeutic angiogenesis has become a promising treatment for CAD. Traditional Chinese medicines, such as Danqi Pill (DQP), have been proven to be effective in treating CAD in China for many years. However, the pro-angiogenic effects of DQP based on fatty acids oxidation are still unknown and the mechanism is worthy of investigation. In this study, left anterior descending (LAD) coronary artery was ligated to induce the CAD models , and cardiac functions were examined using echocardiography. Human umbilical vein endothelial cells (HUVEC) were subjected to HO-induced oxidative stress . The effects of DQP on CAD rat models and HUVEC were detected. Our results showed that DQP had cardio-protective effects in rat model. The intensity of capillaries in the marginal area of infarction of the rat heart was increased remarkably in DQP group, and the expression of PPARα and VEGF-2 were increased. The key enzymes involved in the transportation and intake of fatty acids, including CPT1A and CD36, both increased. In HO-induced endothelial cells injury models, DQP also showed protective roles and promoted capillary-like tube formation. DQP up-regulated key enzymes in fatty acids oxidation in HO-treated HUVEC. In addition, inhibition of CPT1A compromised the pro-angiogenic effects of DQP. In conclusion, fatty acids oxidation axis PPARα-CD36-CPT1A was involved in the pro-angiogenic roles of DQP against CAD. Cardiac CPT1A may serve as a target in therapeutic angiogenesis in clinics.
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http://dx.doi.org/10.3389/fphar.2018.01414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289089PMC
December 2018

The Effect of Chinese Medicine on Lipid and Glucose Metabolism in Acute Myocardial Infarction Through PPARγ Pathway.

Front Pharmacol 2018 24;9:1209. Epub 2018 Oct 24.

School of Life Science, Beijing University of Chinese Medicine, Beijing, China.

Danqi Pill (DQP), a Chinese medicine frequently prescribed in China, has been approved to improve cardiac function by regulating cardiac energy metabolism in heart failure (HF) after acute myocardial infarction (AMI) patients. The aim of this study was to explore whether the mechanism of DQP is associated to the lipid and glucose metabolism mediated PPARγ (peroxisome proliferator-activated receptor gamma) pathway both and . Model of HF after AMI was established with ligation of left anterior descending artery on Sprague-Dawley (SD) rats. Twenty-eight days after treatment, hematoxylin-eosin (HE) staining was applied to visualize cardiomyocyte morphological changes. High performance liquid chromatography (HPLC) was performed to assess the contents of adenosine phosphates in heart. Positron emission tomography and computed tomography (PET-CT) was conducted to evaluate the cardiac glucose metabolism. Expressions of key molecules such as PPARγ, sterol carrier protein 2 (SCP2) and long chain acyl CoA dehydrogenase (ACADL) were measured by Western blotting (WB) and immunohistochemistry (IHC). Oxygen-glucose deprivation-reperfusion (OGD/R)-induced H9C2 injury cardiomyocyte model was adopted for potential mechanism research . Treatment with DQP rescued hearts from structural and functional damages as well as inflammatory infiltration. Levels of adenosine triphosphate (ATP) and energy charge (EC) in DQP group were also up-regulated compared to model group. Further results demonstrated that critical enzymes both in lipid metabolism and glucose metabolism compromised in model group compared to sham group. Intriguingly, DQP could up-regulate critical enzymes including ACADL and SCP2 in lipid metabolism accompanying with promoting effect on molecules in glycolysis simultaneously. Results on upstreaming signaling pathway demonstrated that DQP could dramatically increase the expressions of PPARγ. study suggested the efficacy of DQP could be blocked by T0070907, a selective PPARγ inhibitor. DQP has cardioprotective effect in improving cardiac function and energy metabolism through regulating lipid and glucose metabolism. The effects may be mediated by PPARγ pathway.
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http://dx.doi.org/10.3389/fphar.2018.01209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207917PMC
October 2018

BYD Ameliorates Oxidative Stress-Induced Myocardial Apoptosis in Heart Failure Post-Acute Myocardial Infarction via the P38 MAPK-CRYAB Signaling Pathway.

Front Physiol 2018 8;9:505. Epub 2018 May 8.

Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.

Heart failure (HF) post-acute myocardial infarction (AMI) contributes to increasing mortality and morbidity worldwide. Baoyuan decoction (BYD) is a well-known traditional Chinese medicine formula that exhibits myocardial protection clinically. The aim of this study was to identify the effects of BYD on oxidative stress-induced apoptosis in HF post-AMI and characterize the underlying mechanism. In our study, we constructed left anterior descending (LAD)-induced AMI rat models and a macrophage-conditioned media (CM)-induced H9C2 injury model. , BYD could protect cardiac functions, decrease inflammatory cell infiltration and inhibit oxidative stress-induced apoptosis. , BYD inhibited cellular apoptosis and regulated the expressions of key apoptotic molecules, including reducing the expression of B cell lymphoma-2 (Bcl-2) associated X protein (Bax) and cleaved caspase-3 and -9. Interestingly, the P38 mitogen-activated protein kinase (MAPK)-αB-crystallin (CRYAB) signaling pathway was activated by BYD treatment, and the P38 MAPK inhibitor SB203580 could reverse the protective effects of BYD. This study identified that BYD protected against oxidative stress-induced myocardial apoptosis via the P38 MAPK-CRYAB pathway. CRYAB may become a novel therapeutic target for AMI.
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http://dx.doi.org/10.3389/fphys.2018.00505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999PMC
May 2018

Therapeutic Angiogenesis of Chinese Herbal Medicines in Ischemic Heart Disease: A Review.

Front Pharmacol 2018 26;9:428. Epub 2018 Apr 26.

School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, China.

Ischemic heart disease (IHD) is one of the primary causes of death around the world. Therapeutic angiogenesis is a promising innovative approach for treating IHD, improving cardiac function by promoting blood perfusion to the ischemic myocardium. This treatment is especially important for targeting patients that are unable to undergo angioplasty or bypass surgery. Chinese herbal medicines have been used for more than 2,500 years and they play an important role alongside contemporary medicines in China. Growing evidence in animal models show Chinese herbal medicines can provide therapeutic effect on IHD by targeting angiogenesis. Identifying the mechanism in which Chinese herbal medicines can promote angiogenesis in IHD is a major topic in the field of traditional Chinese medicine, and has the potential for advancing therapeutic treatment. This review summarizes the progression of research and highlights potential pro-angiogenic mechanisms of Chinese herbal medicines in IHD. In addition, an outline of the limitations of Chinese herbal medicines and challenges they face will be presented.
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http://dx.doi.org/10.3389/fphar.2018.00428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932161PMC
April 2018

CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory.

PLoS Genet 2018 01 25;14(1):e1007165. Epub 2018 Jan 25.

Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, China.

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBN mutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7 ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN-associated ID.
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http://dx.doi.org/10.1371/journal.pgen.1007165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800687PMC
January 2018

Vascular endothelial growth factor signaling requires glycine to promote angiogenesis.

Sci Rep 2017 11 7;7(1):14749. Epub 2017 Nov 7.

Molecular Pharmacology Laboratory, Institute of Molecular Medicine, Peking University, Beijing, 100871, China.

Peripheral vascular occlusive disease (PVOD) is a common manifestation of atherosclerosis, and it has a high rate of morbidity. Therapeutic angiogenesis would re-establish blood perfusion and rescue ischemic tissue. Vascular endothelial growth factor (VEGF) induces angiogenesis and can potentially be used to treat ischemic diseases, yet in clinical trials VEGF has not fulfilled its full potential with side effects. Whether amino acids promote angiogenesis and the molecular mechanisms are largely unknown. Here we showed that (1) Glycine significantly promoted angiogenesis both in vitro and in vivo and effectively protected mitochondrial function. (2) Activation of glycine transporter 1(GlyT1) induced by VEGF led to an increase in intracellular glycine. (3) Glycine directly bounded to voltage dependent anion channel 1 (VDAC1) on the mitochondrial outer membrane and inhibited its opening. These original results highlight glycine as a necessary mediator in VEGF signalling via the GlyT1-glycine-mTOR-VDAC1 axis pathway. Therefore, the findings in this study are of significance providing new mechanistic insights into angiogenesis and providing better understanding of glycine function in angiogenesis, which may provide valuable information for development of novel therapeutic targets for the treatment of angiogenic vascular disorders.
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http://dx.doi.org/10.1038/s41598-017-15246-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677092PMC
November 2017

VEGF stimulated the angiogenesis by promoting the mitochondrial functions.

Oncotarget 2017 Sep 18;8(44):77020-77027. Epub 2017 Aug 18.

School of Information and Control Engineering, China University of Mining and Technology, Xuzhou, 221116, China.

The vascular endothelial growth factor (VEGF) signaling pathway involved in angiogenesis which plays a pivotal role in normal development and also represents a major therapeutic target for tumors and intraocular neovascular disorders. The aims of the present study were to evaluate the effects of VEGF on endothelial cells and clarify the mechanism. Here, we showed that VEGF significantly stimulated the proliferation, migration and cell cycle of endothelial cells, and it also induced tube formation significantly. What's more, the mitochondrial functions were enhanced in response to VEGF, including mitochondrial oxidative respiration and intracellular ATP levels. The reactive oxygen species (ROS) production decreased, while the enzymes of ROS defence system, including catalase and glutathione peroxidase (GPX1), whose expression both increased in the VEGF stimulation. VEGF activated mammalian target of rapamycinm (mTOR) signaling pathway to promote the function of mitochondria. Rapamycin, the inhibitor of mTOR pathway could inhibit the proliferation and cell cycle induced by VEGF. In summary, our study identified that VEGF promoted the angiogenesis and provided evidence for mitochondria as new therapeutic target of VEGF signaling in the angiogenic vascular disorders.
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http://dx.doi.org/10.18632/oncotarget.20331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652760PMC
September 2017

Nifedipine stimulates proliferation and migration of different breast cancer cells by distinct pathways.

Mol Med Rep 2017 Aug 20;16(2):2259-2263. Epub 2017 Jun 20.

Changzhou Tumor Hospital Affiliated of Suzhou University, Changzhou, Jiangsu 213000, P.R. China.

Nifedipine is widely used to treat high blood pressure and angina. Were nifedipine able to promote the proliferation and migration of breast cancer, it would pose a significant threat for patients. Thus, it is important to determine the effects of nifedipine on breast cancer and the mechanism involved. The present study identified that nifedipine significantly promoted the proliferation and migration of breast cancer cells in vitro. The mechanism of nifedipine on different breast cancer cells was investigated and it was identified that the effects of nifedipine on MCF‑7 cells were via the protein kinase B‑endothelial constitutive nitric oxide synthase‑nitric oxide axis, and on MDA‑MB‑231 cells via activation of the extracellular signal‑regulated kinase pathway. These results identified the distinct pathways in the activation of cell proliferation and migration presented in different cell lines by nifedipine. The present study advises that nifedipine can promote breast cancer and should be avoided for women who suffer from breast cancer and hypertension.
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http://dx.doi.org/10.3892/mmr.2017.6818DOI Listing
August 2017

5-HTR3 and 5-HTR4 located on the mitochondrial membrane and functionally regulated mitochondrial functions.

Sci Rep 2016 11 22;6:37336. Epub 2016 Nov 22.

Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Beijing, China.

5-HT has been reported to possess significant effects on cardiac activities, but activation of 5-HTR on the cell membrane failed to illustrate the controversial cardiac reaction. Because 5-HT constantly comes across the cell membrane via 5-HT transporter (5-HTT) into the cytoplasm, whether 5-HTR is functional present on the cellular organelles is unknown. Here we show 5-HTR3 and 5-HTR4 were located in cardiac mitochondria, and regulated mitochondrial activities and cellular functions. Knock down 5-HTR3 and 5-HTR4 in neonatal cardiomyocytes resulted in significant increase of cell damage in response to hypoxia, and also led to alternation in heart beating. Activation of 5-HTR4 attenuated mitochondrial Ca uptake under the both normoxic and hypoxic conditions, whereas 5-HTR3 augmented Ca uptake only under hypoxia. 5-HTR3 and 5-HTR4 exerted the opposite effects on the mitochondrial respiration: 5-HTR3 increased RCR (respiration control ratio), but 5-HTR4 reduced RCR. Moreover, activation of 5-HTR3 and 5-HTR4 both significantly inhibited the opening of mPTP. Our results provided the first evidence that 5-HTR as a GPCR and an ion channel, functionally expressed in mitochondria and participated in the mitochondria function and regulation to maintain homeostasis of mitochondrial [Ca], ROS, and ATP generation efficiency in cardiomyocytes in response to stress and O tension.
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http://dx.doi.org/10.1038/srep37336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118798PMC
November 2016

Low-level expression of human ACAT2 gene in monocytic cells is regulated by the C/EBP transcription factors.

Acta Biochim Biophys Sin (Shanghai) 2016 Nov 29;48(11):980-989. Epub 2016 Sep 29.

Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Acyl-coenzyme A:cholesterol acyltransferases (ACATs) are the exclusive intracellular enzymes that catalyze the formation of cholesteryl/steryl esters (CE/SE). In our previous work, we found that the high-level expression of human ACAT2 gene with the CpG hypomethylation of its whole promoter was synergistically regulated by two transcription factors Cdx2 and HNF1α in the intestine and fetal liver. Here, we first observed that the specific CpG-hypomethylated promoter was correlated with the low expression of human ACAT2 gene in monocytic cell line THP-1. Then, two CCAAT/enhancer binding protein (C/EBP) elements within the activation domain in the specific CpG-hypomethylation promoter region were identified, and the expression of ACAT2 in THP-1 cells was evidently decreased when the C/EBP transcription factors were knock-downed using RNAi technology. Furthermore, ChIP assay confirmed that C/EBPs directly bind to their elements for low-level expression of human ACAT2 gene in THP-1 cells. Significantly, the increased expressions of ACAT2 and C/EBPs were also found in macrophages differentiated from both ATRA-treated THP-1 cells and cultured human blood monocytes. These results demonstrate that the low-level expression of human ACAT2 gene with specific CpG-hypomethylated promoter is regulated by the C/EBP transcription factors in monocytic cells, and imply that the lowly expressed ACAT2 catalyzes the synthesis of certain CE/SE that are assembled into lipoproteins for the secretion.
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http://dx.doi.org/10.1093/abbs/gmw091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091289PMC
November 2016

The ACAT2 expression of human leukocytes is responsible for the excretion of lipoproteins containing cholesteryl/steryl esters.

Acta Biochim Biophys Sin (Shanghai) 2016 Nov 29;48(11):990-997. Epub 2016 Sep 29.

Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Acyl-coenzymeA:cholesterol acyltransferase 2 (ACAT2) is abundantly expressed in intestine and fetal liver of healthy human. Our previous studies have shown that in monocytic cells the low-level expression of human ACAT2 gene with specific CpG-hypomethylated promoter is regulated by the CCAAT/enhancer binding protein (C/EBP) transcription factors. In this study, we further report that the ACAT2 gene expression is attributable to the C/EBPs in the human leukocytes and correlated with the excretion of fluorescent lipoproteins containing the ACAT2-catalyzed NBD22-steryl esters. Moreover, this lipoprotein excretion can be inhibited by the ACAT2 isoform-selective inhibitor pyripyropene A (PPPA) in a dose-dependent manner, and employed to determine the half maximum inhibitory concentration (IC) values of PPPA. Significantly, it is found that the differentiation-inducing factor all-trans retinoic acid, but not the proinflammatory cytokine tumor necrosis factor-α, enhances this ACAT2-dependent lipoprotein excretion. These data demonstrate that the ACAT2 expression of human leukocytes is responsible for the excretion of lipoproteins containing cholesteryl/steryl esters (CE/SE), and suggest that the excretion of lipoproteins containing the ACAT2-catalyzed CS/SE may avoid cytotoxicity through decreasing the excess intracellular cholesterols/sterols (especially various oxysterols), which is essential for the action of the human leukocytes.
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http://dx.doi.org/10.1093/abbs/gmw095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091290PMC
November 2016

Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to the development of pulmonary arterial hypertension.

J Mol Cell Cardiol 2016 Feb 13;91:179-87. Epub 2016 Jan 13.

Molecular Pharmacology Laboratory, Institute of Molecular Medicine, Peking University, Beijing 100871, China. Electronic address:

Aims: Pulmonary arterial hypertension [1] is a proliferative disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Reactive oxygen species (ROS) is implicated in the development of PAH and regulates the vascular tone and functions. However, which cellular signaling mechanisms are triggered by ROS in PAH is still unknown. Hence, here we wished to characterize the signaling mechanisms triggered by ROS.

Methods And Results: By Western blots, we showed that increased intracellular ROS caused inhibition of the glycolytic pyruvate kinase M2 (PKM2) activity through promoting the phosphorylation of PKM2. Monocrotaline (MCT)-induced rats developed severe PAH and right ventricular hypertrophy, with a significant increase in the P-PKM2 and decrease in pyruvate kinase activity which could be attenuated with the treatments of PKM2 activators, FBP and l-serine. The antioxidant NAC, apocynin and MnTBAP had the similar protective effects in the development of PAH. In vitro assays confirmed that inhibition of PKM2 activity could modulate the flux of glycolytic intermediates in support of cell proliferation through the increased pentose phosphate pathway (PPP). Increased ROS and decreased PKM2 activity also promoted the Cav1.2 expression and intracellular calcium.

Conclusion: Our data provide new evidence that PKM2 makes a critical regulatory contribution to the PAHs for the first time. Decreased pyruvate kinase M2 activity confers additional advantages to rat PASMCs by allowing them to sustain anti-oxidant responses and thereby support cell survival in PAH. It may become a novel treatment strategy in PAH by using of PKM2 activators.
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http://dx.doi.org/10.1016/j.yjmcc.2016.01.009DOI Listing
February 2016

Role of epithelial Na+ channels in endothelial function.

J Cell Sci 2016 Jan 30;129(2):290-7. Epub 2015 Nov 30.

Institute of Molecular Medicine, Peking University, Beijing, China, 100871

An increasing number of mechano-sensitive ion channels in endothelial cells have been identified in response to blood flow and hydrostatic pressure. However, how these channels respond to flow under different physiological and pathological conditions remains unknown. Our results show that epithelial Na(+) channels (ENaCs) colocalize with hemeoxygenase-1 (HO-1) and hemeoxygenase-2 (HO-2) within the caveolae on the apical membrane of endothelial cells and are sensitive to stretch pressure and shear stress. ENaCs exhibited low levels of activity until their physiological environment was changed; in this case, the upregulation of HO-1, which in turn facilitated heme degradation and hence increased the carbon monoxide (CO) generation. CO potently increased the bioactivity of ENaCs, releasing the channel from inhibition. Endothelial cells responded to shear stress by increasing the Na(+) influx rate. Elevation of intracellular Na(+) concentration hampered the transportation of l-arginine, resulting in impaired nitric oxide (NO) generation. Our data suggest that ENaCs that are endogenous to human endothelial cells are mechano-sensitive. Persistent activation of ENaCs could inevitably lead to endothelium dysfunction and even vascular diseases such as atherosclerosis.
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http://dx.doi.org/10.1242/jcs.168831DOI Listing
January 2016

ACAT1 regulates the dynamics of free cholesterols in plasma membrane which leads to the APP-α-processing alteration.

Acta Biochim Biophys Sin (Shanghai) 2015 Dec 15;47(12):951-9. Epub 2015 Oct 15.

Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a key enzyme exclusively using free cholesterols as the substrates in cell and is involved in the cellular cholesterol homeostasis. In this study, we used human neuroblastoma cell line SK-N-SH as a model and first observed that inhibiting ACAT1 can decrease the amyloid precursor protein (APP)-α-processing. Meanwhile, the transfection experiments using the small interfering RNA and expression plasmid of ACAT1 indicated that ACAT1 can dependently affect the APP-α-processing. Furthermore, inhibiting ACAT1 was found to increase the free cholesterols in plasma membrane (PM-FC), and the increased PM-FC caused by inhibiting ACAT1 can lead to the decrease of the APP-α-processing, indicating that ACAT1 regulates the dynamics of PM-FC, which leads to the alteration of the APP-α-processing. More importantly, further results showed that under the ACAT1 inhibition, the alterations of the PM-FC and the subsequent APP-α-processing are not dependent on the cellular total cholesterol level, confirming that ACAT1 regulates the dynamics of PM-FC. Finally, we revealed that even when the Niemann-Pick-Type C-dependent pathway is blocked, the ACAT1 inhibition still obviously results in the PM-FC increase, suggesting that the ACAT1-dependent pathway is responsible for the shuttling of PM-FC to the intracellular pool. Our data provide a novel insight that ACAT1 which enzymatically regulates the dynamics of PM-FC may play important roles in the human neuronal cells.
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http://dx.doi.org/10.1093/abbs/gmv101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659443PMC
December 2015
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