Publications by authors named "Shuangshuang Yin"

11 Publications

  • Page 1 of 1

HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt.

FASEB J 2020 09 24;34(9):12255-12268. Epub 2020 Jul 24.

Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Akt, a crucial protein involved in a variety of signaling pathways in cancer, acts as an important regulator of survival in hepatocellular carcinoma (HCC), and provides curative option for the related drugs development. We have found an active phenanthroindolizidine alkaloid, (13aR,14R)-9,11,12,13,13a,14-hexahydro-3,6,7-trimethoxydibenzo[f,h]pyrrolo[1,2-b]isoquinolin-14-ol (HTBPI), is a promising Akt inhibitor effective in the suppression of HCC cells proliferation through stimulating apoptotic and autophagic capability in vivo and in vitro. Treatment of HTBPI combined with a classical autophagy-lysosomal inhibitor (bafilomycin A1), could enhance stimulation effects of apoptosis on HCC cell lines. In addition, we confirmed HTBPI targeting Akt, occupied the kinase binding domain (Thr 308) of Akt to inactivate its function by CETSA and DARTS assay. In contrast, ectopic Akt-induced overexpression significantly abrogated inhibitory effects of HTBPI on cell viability and proliferation. Furthermore, high p-Akt (Thr 308) expression is collated with liver tumor formation and poor survival in HCC patients. In conclusions, HTBPI impeded HCC progress through regulation of apoptosis and autophagy machinery via interaction with p-Akt (Thr 308). This may provide potential molecular candidate by targeting Akt for the therapy of HCC patients.
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http://dx.doi.org/10.1096/fj.202000254RDOI Listing
September 2020

Anticancer activities of TCM and their active components against tumor metastasis.

Biomed Pharmacother 2021 Jan 11;133:111044. Epub 2020 Dec 11.

State Key Laboratory of Component-based Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. Electronic address:

Traditional Chinese Medicine (TCM) has the characteristics of multiple targets, slight side effects and good therapeutic effects. Good anti-tumor effects are shown by Traditional Chinese Medicine prescription, Chinese patent medicine, single Traditional Chinese Medicine and Traditional Chinese medicine monomer compound. Clinically, TCM prolonged the survival time of patients and improved the life quality of patients, due to less side effects. Cancer metastasis is a complex process involving numerous steps, multiple genes and their products. During the process of tumor metastasis, firstly, cancer cell increases its proliferative capacity by reducing autophagy and apoptosis, and then the cancer cell capacity is stimulated by increasing the ability of tumors to absorb nutrients from the outside through angiogenesis. Both of the two steps can increase tumor migration and invasion. Finally, the purpose of tumor metastasis is achieved. By inhibiting autophagy and apoptosis of tumor cells, angiogenesis and EMT outside the tumor can inhibit the invasion and migration of cancer, and consequently achieve the purpose of inhibiting tumor metastasis. This review explores the research achievements of Traditional Chinese Medicine on breast cancer, lung cancer, hepatic carcinoma, colorectal cancer, gastric cancer and other cancer metastasis in the past five years, summarizes the development direction of TCM on cancer metastasis research in the past five years and makes a prospect for the future.
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http://dx.doi.org/10.1016/j.biopha.2020.111044DOI Listing
January 2021

Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2.

Mol Cancer Res 2019 12 1;17(12):2469-2479. Epub 2019 Oct 1.

Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

is a traditional Chinese medicine commonly used to treat cancer in China. However, its active components and underlying mechanism remain ambiguous. In this study, we have screened the pharmacokinetic parameters of the main chemical constituents of by Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform and have found that Sophoridine is one of the best antitumor active ingredients. We have found that MAPKAPK2 is a potential target for Sophoridine by the PharmMapper and KEGG databXase analysis. Moreover, we have found that Sophoridine selectively inactivates phospho-MAPKAPK2 (Thr222) and directly binds into the ATP site of MAPKAPK2 by molecular docking. Furthermore, we have found out a direct binding between MAPKAPK2 and Sophoridine by cellular thermal shift assay and drug affinity responsive targets stability assay. The inhibition effects are further confirmed by Western blot: Sophoridine significantly decreases phospho-MAPKAPK2 (Thr222) in a time-dependent manner, but there is no obvious change in its total expression in colorectal cancer cells. Clinical studies have shown that a higher level of MAPKAPK2 is associated with a poorer percent survival rate (prognosis). Furthermore, a higher level of MAPKAPK2 is positively associated with the enrichment of downregulation of apoptosis and autophagy by gene set enrichment analysis, as well as upregulation of proliferation and cell-cycle arrest. Taken together, our results suggest that the MAPKAPK2 plays a key role in Sophoridine-inhibited growth and invasion in colorectal cancers. IMPLICATIONS: These studies show that Sophoridine may be a promising therapeutic strategy that blocks tumorigenesis in colorectal cancers.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0553DOI Listing
December 2019

7-Deoxynarciclasine shows promising antitumor efficacy by targeting Akt against hepatocellular carcinoma.

Int J Cancer 2019 12 23;145(12):3334-3346. Epub 2019 May 23.

Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Akt is a promising therapeutic target for cancer treatment. In our study, we have identified that 7-deoxynarciclasine (7-DONCS) is a potential inhibitor of Akt, which results in the repression of multiple oncogenic processes in hepatocellular carcinoma (HCC). We have found that 7-DONCS suppresses the growth of HCC by inducing the apoptotic and autophagic capacities, as well as by inhibiting epithelial-mesenchymal transition (EMT) in vitro and in vivo. Pretreatment of cells with specific autophagy inhibitor (Bafilomycin A1) or knockdown of endogenous LC‐3B by siRNA strongly enhences 7‐DONCS‐regulated apoptosis and EMT. Consequently, we have found that 7-DONCS selectively inhibits phospho-Akt (Ser473), and subsequent molecular docking reveals that 7-DONCS directly binds to the C-terminal domain of Akt. Overexpressing Akt significantly blocks these effects via 7-DONCS in HCC cells. Furthermore, 7-DONCS, by targeting Akt, exhibits a promising therapeutic effect in orthotopic hepatocellular tumors. Finally, higher p-Akt expression is associated with poor prognosis, and higher level of Akt was positively correlated with the enrichment of both apoptosis and autophagy downregulation, and EMT upregulation in HCC patients. These studies suggest that 7-DONCS serves as an attractive drug candidate by targeting Akt for future HCC therapy.
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http://dx.doi.org/10.1002/ijc.32395DOI Listing
December 2019

LncRNA MALAT1 promotes oxidized low-density lipoprotein-induced autophagy in HUVECs by inhibiting the PI3K/AKT pathway.

J Cell Biochem 2019 03 28;120(3):4092-4101. Epub 2018 Nov 28.

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.

Emerging evidence suggests that long noncoding RNAs (lncRNAs) are involved in many biological processes, such as cell growth, differentiation, apoptosis, and autophagy. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), highly expressed in endothelial cells, is well conserved and implicated in endothelial cell migration and proliferation. However, whether MALAT1 participates in oxidized low-density lipoprotein (ox-LDL)-induced autophagy regulation in human umbilical vein endothelial cells (HUVECs) remains unknown. In this study, we observed that autophagy was upregulated and MALAT1 expression was markedly increased in HUVECs treated with ox-LDL. The ox-LDL-induced autophagy of HUVECs is significantly associated with the PI3K/AKT pathway. Furthermore, we found that MALAT1 overexpression inhibited PI3K, Akt and p70S6K phosphorylation and downregulated RHEB expression, simultaneously increasing ox-LDL-induced autophagy. MALAT1 silencing caused higher phosphorylated PI3K, Akt and p70S6K levels, upregulated RHEB expression and markedly suppressed autophagy. These results indicated that lncRNA MALAT1 promotes ox-LDL-induced autophagy in HUVECs partly through the PI3K/AKT signaling pathway.
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http://dx.doi.org/10.1002/jcb.27694DOI Listing
March 2019

Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3.

Front Pharmacol 2018 8;9:881. Epub 2018 Aug 8.

Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Signal transducer and activator of transcription 3 (STAT3) is an attractive therapeutic target for cancer treatment. In this study, we identify lycorine is an effective inhibitor of STAT3, leading to repression of multiple oncogenic processes in colon carcinoma. Lycorine selectively inactivates phospho-STAT3 (Tyr-705), and subsequent molecular docking uncovers that lycorine directly binds to the SH2 domain of STAT3. Consequently, we find that lycorine exhibits anti-proliferative activity and induces cell apoptosis on human colorectal cancer (CRC) . Lycorine induces the activation of the caspase-dependent mitochondrial apoptotic pathway, as indicated by activation of caspase and increase of the ratio of Bax/Bcl-2 and mitochondrial depolarization. Overexpressing STAT3 greatly blocks these effects by lycorine in CRC cells. Finally, lycorine exhibits a potential therapeutic effect in xenograft colorectal tumors by targeting STAT3 without observed toxicity. Taken together, the present study indicates that lycorine acts as a promising inhibitor of STAT3, which blocks tumorigenesis in colon carcinoma.
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http://dx.doi.org/10.3389/fphar.2018.00881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092588PMC
August 2018

MicroRNA‑155 promotes ox‑LDL‑induced autophagy in human umbilical vein endothelial cells by targeting the PI3K/Akt/mTOR pathway.

Mol Med Rep 2018 Sep 29;18(3):2798-2806. Epub 2018 Jun 29.

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.

Endothelial cell autophagy has a protective role in inhibiting inflammation and preventing the development of atherosclerosis, which may be regulated by microRNA (miR)‑155. The present study aimed to investigate the mechanisms of autophagy in the development of atherosclerosis. Human umbilical vein endothelial cells model in vitro and using oxidized low‑density lipoprotein (ox‑LDL) stimulated cells to simulate the atherosclerosis. MiR‑155 mimics, miR‑155 inhibitors, and a negative control were respectively transfected in human umbilical vein endothelial cells to analyzed alterations in the expression of miR‑155. It was demonstrated that overexpression of miR‑155 promoted autophagic activity in oxidized low‑density lipoprotein‑stimulated human umbilical vein endothelial cells, whereas inhibition of the expression of miR‑155 reduced autophagic activity. Overexpression of miR‑155 revealed that it regulated autophagy via the phosphatidylinositol‑3 kinase (PI3K)/RAC‑α serine/threonine‑protein kinase (Akt)/mechanistic target of rapamycin pathway (mTOR) signaling pathway. A luciferase reporter assay demonstrated that miR‑155 directly bound to the PI3K catalytic subunit a and Ras homolog enriched in brain 3'‑untranslated region and inhibited its luciferase activity. Therefore, the results of the present study suggested that miR‑155 promoted autophagy in vascular endothelial cells and that this may have occurred via targeting of the PI3K/Akt/mTOR pathway. Thus, miR‑155 may be considered as a potential therapeutic target for the treatment of atherosclerosis.
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http://dx.doi.org/10.3892/mmr.2018.9236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102700PMC
September 2018

Magnolin promotes autophagy and cell cycle arrest via blocking LIF/Stat3/Mcl-1 axis in human colorectal cancers.

Cell Death Dis 2018 06 13;9(6):702. Epub 2018 Jun 13.

Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China.

Magnolin is a multi-bioactive natural compound that possesses underlying anti-cancer properties. However, the mechanisms underlying remain to be elucidated. Here, we report the role of magnolin in suppressing human colorectal cancer (CRC) cells via activating autophagy and cell cycle arrest in vitro and in vivo. Pre-treatment of cells with specific autophagy inhibitor (3-methyladenine) or knockdown of endogenous LC-3B by siRNA significantly abrogates magnolin-induced cell cycle arrest. Molecular validation mechanistically shows that magnolin-induced autophagy and cell cycle arrest in CRC cells is correlated with decreased transcriptional levels of leukemia inhibitory factor (LIF), and we further find that inhibition of LIF decreases phosphorylation level of Stat3 and represses transcriptional expression of Mcl-1. Furthermore, magnolin-induced autophagy and cell cycle arrest suppress the growth of xenograft colorectal tumors without apparent toxicity. Finally, we evaluate the clinical correlation of LIF/Stat3/Mcl-1 in CRC patient tissues. As expected, LIF, p-Stat3, and Mcl-1 levels are high in CRC tissue but are scarcely found in normal colon tissue. High positive expressions of LIF or Mcl-1 are associated with poor prognosis. Doubly positive cases have shown the worst outcome. Taken together, our results have clarified a novel molecular mechanism whereby magnolin induces autophagy and cell cycle arrest through LIF/Stat3/Mcl-1 pathway in CRCs. Our results also have revealed that magnolin has a promising therapeutic potential in CRCs.
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http://dx.doi.org/10.1038/s41419-018-0660-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999973PMC
June 2018

Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma.

Mol Cancer Ther 2017 Dec 28;16(12):2711-2723. Epub 2017 Sep 28.

Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells and Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance-associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorine-induced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0498DOI Listing
December 2017

Pharmacological evaluation of sedative-hypnotic activity and gastro-intestinal toxicity of Rhizoma Paridis saponins.

J Ethnopharmacol 2012 Oct 30;144(1):67-72. Epub 2012 Aug 30.

Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, Tianjin 300072, China.

Ethnopharmacological Relevance: Rhizoma Paridis saponins (RPS) have been well studied for antimicrobial, anti-hemorrhagic, and anticancer effects. However, scientific information on RPS regarding the toxic and neuropharmacological effects is limited. In this study, the acute oral toxicity, sedative-hypnotic activity and gastro-intestinal toxicity of RPS were investigated.

Materials And Methods: The acute toxicity was carried out by administering single doses (800-5000 mg/kg) of RPS to adult mice. Rotarod test and sodium pentobarbital-induced hypnosis activity were used to evaluate the neuropharmacological effects on mice. Gastric emptying and intestinal transit were used to investigate the gastric-intestinal system effects.

Results: A single oral administration of RPS dose-dependently caused adverse effects on the general behavior and mortality rate of mice. LD(50) value of oral acute toxicity was 2182.4 mg/kg, with 95% confidence limit of 1718.4-2807.8 mg/kg. In the test of sleeping mice, RPS acted in synergy with sodium pentobarbital at doses 250 and 500 mg/kg while motor coordination was not influenced within 120 min after treatment with RPS. Regarding the gastric-intestinal toxicity, RPS (100, 250, and 500 mg/kg) significantly inhibited gastric emptying but did not affect the intestinal transit.

Conclusions: RPS, which is a hypotoxic anticancer drug, possesses the sedative-hypnotic activity and gastric stimulus side effect.
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http://dx.doi.org/10.1016/j.jep.2012.08.027DOI Listing
October 2012

Comparative study on hemostatic, cytotoxic and hemolytic activities of different species of Paris L.

J Ethnopharmacol 2012 Aug 7;142(3):789-94. Epub 2012 Jun 7.

Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.

Ethnopharmacological Relevance: The rhizoma of Paris polyphylla var. yannanensis or P. polyphylla var. chinensis called Rhizoma Paridis as a traditional Chinese medicine has an effect of heat-clearing and detoxicating, detumescence and acesodyne in folk for a long time. The increasing application of Rhizoma Paridis resulted in the shortage of wildlife resources. Here, we compared the major activities of other species of genus Paris to find the replacement plants.

Materials And Methods: Six species (P. polyphylla var. yunnanensis, P. delavayi var. delavayi, P. fargesii var. Fargesii, P. bashanensis Wang et Tang, P. polyphyllar var. minora, and P. polyphylla var. pseudothibetical) were collected from three Provinces in China, and compared the hemostatic, cytotoxic and hemolytic activities by different assays.

Results: For the hemostatic activity, all the plants except Paris fargesii var. Fargesii could significantly shorten the tail bleeding time and blood clotting time (P<0.05). For further mechanism study, they reduced the prothrombin time (PT) and activated partial thromboplastin time (APTT), but they had no significant effect on thrombin time (TT). P. fargesii var. Fargesii showed the similar cytotoxicity to P. polyphylla var. yunnanensis (IC(50): 18.21 and 15.73 μg/mL, respectively). HD(50) was used as the index of hemolytic activity. P. delavayi var. delavayi and P. bashanensis Wang et Tang were the last to have this activity as the values were 3.027 and 1.222 mg/mL.

Conclusions: The different species of genus Paris have different activities. Paris delavayi var. delavayi and Paris bashanensis Wang et Tang could be used as the resources of hemostatic drugs and P. fargesii var. Fargesii as the antitumor medicine.
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http://dx.doi.org/10.1016/j.jep.2012.05.065DOI Listing
August 2012