Publications by authors named "Xinhai Zhu"

26 Publications

  • Page 1 of 1

Circadian misalignment leads to changes in cortisol rhythms, blood biochemical variables and serum miRNA profiles.

Biochem Biophys Res Commun 2021 Aug 12;567:9-16. Epub 2021 Jun 12.

State Key Laboratory of Biocontrol, Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address:

The circadian clock plays a critical role in synchronizing the inner molecular, metabolic and physiological processes to environmental cues that cycle with a period of 24 h. Non-24 h and shift schedules are commonly used in maritime operations, and both of which can disturb circadian rhythms. In this study, we first conducted an experiment in which the volunteers followed a 3-d rotary schedule with consecutive shift in sleep time (rotatory schedule), and analyzed the changes in salivary cortisol rhythms and blood variables. Next we conducted another experiment in which the volunteers followed an 8 h-on and 4-h off schedule (non-24-h schedule) to compare the changes in blood/serum variables. The rotatory schedule led to elevated levels of serum cortisol during the early stage, and the phase became delayed during the early and late stages. Interestingly, both of the schedules caused comprehensive changes in blood/serum biochemical variables and increased phosphate levels. Furthermore, transcriptomic analysis of the plasma miRNAs from the volunteers following the rotatory schedule identified a subset of serum miRNAs targeting genes involved in circadian rhythms, sleep homeostasis, phosphate transport and multiple important physiological processes. Overexpression of miRNAs targeting the phosphate transport associated genes, SLC20A1 and SLC20A2, showed altered expression due to rotary schedule resulted in attenuated cellular levels of phosphate, which might account for the changed levels in serum phosphate. These findings would further our understanding of the deleterious effects of shift schedules and help to optimize and enhance the performances and welfare of personnel working on similar schedules.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.015DOI Listing
August 2021

MicroRNA-133a-3p suppresses malignant behavior of non-small cell lung cancer cells by negatively regulating ERBB2.

Oncol Lett 2021 Jun 8;21(6):457. Epub 2021 Apr 8.

Department of Thoracic Surgery, Zhejiang Hospital, Hangzhou, Zhejiang 310030, P.R. China.

Non-small cell lung cancer (NSCLC) has high morbidity and mortality rates worldwide, and tumor metastasis is generally associated with poor prognosis. Chemotherapy resistance aggravates the challenges associated with treating NSCLC. Therefore, identifying effective targets and developing therapies based on these findings could bring novel perspectives for patients with metastatic NSCLC. The expression levels of receptor tyrosine-protein kinase erbB-2 (ERBB2) are associated with NSCLC progression. Differential microRNA (miR) expression profiles have been identified in tumors and can be used to identify multiple malignant phenotypes. miR-133a-3p expression is dysregulated in a variety of tumors. However, to the best of our knowledge, the association between miR-133a-3p and the NSCLC pathogenesis process has not been demonstrated yet. The present study revealed a decrease in miR-133a-3p expression in both tissues and cell lines, which was detected using reverse transcription-quantitative (RT-q)PCR, and western blotting and RT-qPCR demonstrated ERBB2 levels were increased at both protein and mRNA levels. Bioinformatics analysis and dual-luciferase reporter assays demonstrated that ERBB2 was a direct target of miR-133a-3p. Furthermore, MTT, wound healing and Transwell assays revealed that overexpression of miR-133a-3p suppressed proliferation, invasion and migration of NSCLC cells, respectively, effects that were inhibited following ERBB2 overexpression. In addition, immunofluorescence assays demonstrated that overexpression of ERBB2 upregulated N-cadherin expression, while E-cadherin expression was downregulated. In conclusion, the present data demonstrated that miR-133a-3p acted as a tumor suppressor by negatively regulating ERBB2 expression. The miR-133a-3p/ERBB2 axis may be a potential target for the diagnosis and treatment of NSCLC in the future.
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http://dx.doi.org/10.3892/ol.2021.12718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063298PMC
June 2021

Aeromonas hydrophila associated with red spot disease in Macrobrachium nipponense and host immune-related gene expression profiles.

J Invertebr Pathol 2021 Jun 31;182:107584. Epub 2021 Mar 31.

College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China. Electronic address:

In September 2018, a serious disease causing high mortality with red spot syndrome occurred in a Macrobrachium nipponense aquaculture farm in Jintan County, Jiangsu Province, China. In this study, a pathogenic isolate 5-S3 was isolated from diseased M. nipponense and was identified as Aeromonas hydrophila by phenotypically and molecularly. The pathogenicity of the isolate 5-S3 to M. nipponense was determined by challenge experiments. Results of artificial challenge showed A. hydrophila was pathogenic to M. nipponense, the LD was 9.58 × 10 CFU/mL, and histopathological analysis revealed that the hepatopancreas of infected M. nipponense exhibited obvious inflammatory responses to A. hydrophila infection. The isolate showed significant phenotypical activities such as the lecithinase, esterase, caseinase and hemolysin which are indicative of their virulence potential. Besides, virulence genes such as aerA, act, fla, ahpβ, alt, lip, eprCAI, hlyA, acg and gcaT were detected in the isolate 5-S3. Subsequently, the immune-related genes expression in M. nipponense were evaluated by quantitative real-time PCR (qRT-PCR), and the results showed that the expression levels of dorsal, relish, crustin1, crustin2, anti-lipopolysaccharide factors 1 (ALF1), anti-lipopolysaccharide factors 2 (ALF2), hemocyanin, i-lysozyme and prophenoloxidase were significantly up-regulated in hepatopancreas of M. nipponense after A. hydrophila infection, the stat, p38, crustin3, anti-lipopolysaccharide factors 3 (ALF3) genes had no significant change during the infection. The present results reveal that A. hydrophila was an etiological agent causing red spot syndrome and mass mortality of M. nipponense and the influence of A. hydrophila infection on host immune genes.
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http://dx.doi.org/10.1016/j.jip.2021.107584DOI Listing
June 2021

Multi-biomarker assessment in the giant freshwater prawn Macrobrachium rosenbergii after deltamethrin exposure.

Ecotoxicol Environ Saf 2021 May 25;214:112067. Epub 2021 Feb 25.

College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009 Jiangsu, China. Electronic address:

Deltamethrin (DM) is a synthetic pyrethroid used for agricultural purposes to control insects. However, its extensive use contaminates the aquatic environment and results in serious health problems in aquatic organisms. Knowledge about the toxic effect of DM in freshwater prawns is limited; therefore, this study aims to assess the toxicity of DM in Macrobrachium rosenbergii based on multiple biomarkers. Four-day acute toxicity tests showed that DM was highly toxic to M. rosenbergii with the 24 h, 48 h, 72 h and 96 h LC values to be 1.919, 0.603, 0.539, and 0.449 μg/L, respectively. According to 96 h LC, prawns were exposed to DM at three concentrations (0.02, 0.08, and 0.32 μg/L) for 4 days, and then moved into fresh water for decontamination to investigate the toxic effect of DM in M. rosenbergii. At low concentration (0.02 μg/L and 0.08 μg/L), DM did not cause obvious histopathological damage to hepatopancreas and gill tissue, while at high concentration (0.32 μg/L), the histopathological harm was serious and the damage did not recover to the initial level after 7-day decontamination. 0.02 μg/L DM exposure did not induce significant changes in most of the biomarkers except the increased lactate dehydrogenase (LDH) activity, lactic acid (LD) level, and the first increased then decreased mRNA expression of immune-related genes, indicating the stimulation of DM on energy production and immunity. 0.08 μg/L and 0.32 μg/L DM exposure resulted in varying degrees of damage on prawns, but overall, their toxic effects showed similar trends based on the biomarkers. Increase in malonaldehyde (MDA) and hydrogen peroxide (HO) content and decrease in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity after DM exposure demonstrated the oxidative stress caused by DM. The significantly increased acid phosphatase (ACP), alkaline phosphatase (AKP), LDH activity and LD level indicated hepatopancreatic dysfunction and respiration disruption. The first increased and then decreased expression pattern of immune-related genes indicated the immunosuppression caused by DM. After 7-day decontamination in freshwater, the activity/level of the biomarkers partly recovered. This study revealed the severe toxic effect of DM on Macrobrachium rosenbergii based on multiple biomarkers, providing fundamental knowledge for the establishment of DM toxicity assessment system with proper parameters in freshwater crustaceans.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112067DOI Listing
May 2021

Fungus Regulates CD8 T Cell Exhaustion Through Involvement of T-Bet/Eomes in the Tumor Microenvironment.

Front Pharmacol 2020 8;11:612620. Epub 2021 Jan 8.

The Second Clinical Medical School, Zhejiang Chinese Medical University, Hangzhou, China.

Targeting exhausted T (Tex) cells is a promising strategy for anti-tumour treatment. Previously, we demonstrated that s fungus (HSF) could significantly increase T cell infiltration and the effector T cell ratio in the tumor microenvironment, activating systemic immune responses. However, we do not know how HSF regulates Tex cells in the tumor microenvironment. Here, we explored the mechanism underlying HSF inhibition of Tex cells and tumor growth and metastasis in breast cancer. We examined the effects of HSF on various tumor mouse models using imaging technology. Lung metastasis was detected by H&E staining and the T cell subsets in the tumor microenvironment were assayed with flow cytometry. The proliferation, function and apoptosis of CD8 T cells were measured, as well as the and mRNA expressions. HSF inhibited tumor growth and lung metastasis in the mice, and had significantly higher CD44CD62L and CD44CD62Lpopulations in the tumour-infiltrating CD8 T cells. However, HSF significantly reduced levels of inhibitory receptors, such as PD-1, TIGIT, CTLA-4, and regulatory T cells. , HSF inhibited the CD8 T cell apoptosis rate, and promoted CD8 T cell proliferation and secretion of interferon (IFN)-γ and granzyme B. Furthermore, HSF treatment both and significantly increased Eomes expression, while decreasing T-bet expression. HSF exerted anti-tumour effects mainly through the immune system, by promoting effector/memory T cells and reducing Tex cell production in the tumor microenvironment. The specific mechanisms involved inhibiting T-bet and promoting Eomes to decrease the expression of immune inhibitor receptors and enhance the T cell function, respectively.
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http://dx.doi.org/10.3389/fphar.2020.612620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820905PMC
January 2021

Inhibition of CDC42 reduces macrophage recruitment and suppresses lung tumorigenesis in vivo.

J Recept Signal Transduct Res 2020 Oct 1:1-7. Epub 2020 Oct 1.

Department of Thoracic Surgery, Zhejiang Hospital, Hangzhou, China.

Background: Cell division control (CDC) 42 has been involved in the regulation of diverse cancers. Macrophage recruitment plays an important role in the pathogenesis and development of tumor. However, it remains unclear whether CDC42 contributes to macrophage recruitment and lung tumorigenesis .

Methods: Small interference RNA (siRNA) was used to knock down CDC42 in the Lewis lung carcinoma (LLC)1. The invasion capability of CDC42 knockdown LLC1 cells was evaluated. LLC1 cells with CDC42 targeted small hairpin RNA (shRNA) were inoculated into C57BL/6 mice to establish the tumor-bearing animal model Tumor size and metastasis related proteins were measured. In addition, the invasion of macrophages in the tumor site as well as macrophage chemokine were also determined in the model.

Results: The capacity of invasion and metastasis of LLC1 cells significantly decreased when CDC42 was knocked down. When inoculated with CDC42 knockdown LLC1 cells , the tumor size and metastasis related proteins levels both decreased. The invasion capacity of macrophages and the associated macrophage chemokine were also significantly down-regulated.

Conclusion: Our data suggest that the inhibition of CDC42 expression in lung cancer cells can significantly prevent the pathogenesis and development of tumor in an allograft tumor model , which might provide a novel therapeutic target and potential strategy for lung cancer treatment in the future.
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http://dx.doi.org/10.1080/10799893.2020.1828916DOI Listing
October 2020

Shikonin suppresses NEAT1 and Akt signaling in treating paclitaxel-resistant non-small cell of lung cancer.

Mol Med 2020 04 8;26(1):28. Epub 2020 Apr 8.

Department of Oncology, Zhejiang Hospital, No.12 Lingyin Road, Hangzhou, Zhejiang, 310013, People's Republic of China.

Background: The development of paclitaxel-resistance led to the tumor relapse and treatment failure of non-small cell lung cancer. Shikonin has been demonstrated to show anti-cancer activity in many cancer types. The present study aimed to investigate the anti-cancer activity of shikonin in paclitaxel-resistant non-small cell lung cancer treatment.

Methods: MTT, clonogenic assay, apoptotic cell death analysis, western blot, qRT-PCR, gene knockdown and overexpression, xenograft experiment, immunohistochemistry were performed.

Results: Shikonin decreased paclitaxel-resistant NSCLC cell viability and inhibited the growth of xenograft tumor. Shikonin induced apoptotic cell death of paclitaxel-resistant NSCLC cell lines and suppressed the level of NEAT1 and Akt signaling of paclitaxel-resistant NSCLC cell lines and xenograft tumors. Either low dose or high dose of shikonin considerably suppressed the cell growth and induced the cell apoptotic death in NEAT1 knockdown A549/PTX cells, and p-Akt expression was decreased.

Conclusions: Shikonin could be a promising candidate for paclitaxel-resistant NSCLC treatment.
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http://dx.doi.org/10.1186/s10020-020-00152-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140387PMC
April 2020

EZH2 enhances expression of CCL5 to promote recruitment of macrophages and invasion in lung cancer.

Biotechnol Appl Biochem 2020 Nov 16;67(6):1011-1019. Epub 2020 Apr 16.

Department of Thoracic Surgery, Zhejiang Hospital, Xihu district, Hangzhou, Zhejiang, 310000, China.

EZH2 (enhancer of zeste homolog 2) regulates epigenetic gene silencing and functions as critical regulators in various tumor progression. Macrophages infiltration promotes cancer development via stimulating tumor cell migration and invasion. However, the effect of EZH2 on macrophages infiltration, cell invasion, and migration of lung cancer remains to be investigated. In this study, we found that knockdown of EZH2 inhibited macrophages chemotaxis and decreased chemokine ligand 5 (CCL5). Wound-healing and transwell assays results showed that migration and invasion of lung cancer cells was inhibited by EZH2 deletion. Moreover, EZH2 overexpression increased CCL5 expression. Loss-of functional assay indicated that the promotion ability of EZH2 on macrophages chemotaxis was inhibited by CCL5 knockdown. Mechanistically, the promotion ability of EZH2 on cell migration and invasion of lung cancer was also inhibited by CCL5 knockdown. The in vivo subcutaneous xenotransplanted tumor model also revealed that silence of EZH2 suppressed lung cancer metastasis and macrophages infiltration via regulation of CCL5. In conclusion, our findings indicated that EZH2 promoted lung cancer metastasis and macrophages infiltration via upregulation of CCL5, which might be the underlying mechanism of EZH2-induced lung cancer cell progression.
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http://dx.doi.org/10.1002/bab.1875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818479PMC
November 2020

Computed tomography-guided percutaneous cryoablation for lung ground-glass opacity: A pilot study.

J Cancer Res Ther 2019 ;15(2):370-374

Department of Oncology, First Affiliated Hospital of Jinan University, Guangzhou, China.

Context: Ground-glass opacity (GGO) is a nonspecific imaging parameter for early-stage pulmonary cancer. In these cases, a definite diagnosis and prompt surgery usually yield satisfactory outcomes.

Aims: This study aimed to assess the safety and feasibility of cryoablation treatment for lung GGO.

Subjects And Methods: We reviewed the clinical data of 14 patients (19 lung tumors) with lung GGO and evaluated the adverse events, lung function, and treatment efficacy after cryoablation.

Statistical Analysis Used: Statistical analyses were performed using the Statistical Package for the Social Sciences software (version 13.0; SPSS Inc., Chicago, IL, USA).

Results: None of the patients exhibited serious complications, and lung function recovered to >95% after 1 month. During a follow-up, computed tomography scan at 24 months, the GGO appeared to have been successfully ablated in all patients.

Conclusion: Cryoablation may serve as a safe and feasible option for the treatment of GGO.
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http://dx.doi.org/10.4103/jcrt.JCRT_299_18DOI Listing
July 2019

NEAT1 mediates paclitaxel-resistance of non-small cell of lung cancer through activation of Akt/mTOR signalling pathway.

J Drug Target 2019 12 20;27(10):1061-1067. Epub 2019 Mar 20.

Department of Thoracic Surgery, Zhejiang Hospital , Hangzhou , Zhejiang , PR China.

Development of paclitaxel-resistance is a main problem during non-small cell lung cancer (NSCLC) chemotherapy. Nuclear paraspeckle assembly transcript 1 (NEAT1) is an oncogenic long non-coding RNA (lncRNA) which has been proved to be aberrantly upregulated in many human malignancies. In this study, we investigated the mechanism by which NEAT1 contributed to paclitaxel-resistance in NSCLC. NEAT1 was upregulated significantly in paclitaxel-resistant NSCLC cell line, compared with other NSCLC cell lines and normal bronchial epithelial (BE) cell line. Knockdown of NEAT1 could reverse the paclitaxel-resistance through induction of apoptosis by increasing cleaved PARP and cleaved caspase-3 expression. Moreover, NEAT1 was associated with Akt/mTOR signalling pathway activation by increasing expression of p-Akt, p-mTOR, Bcl-2 and decreasing expression of Bax. In conclusion, these results demonstrated that NEAT1 underlay paclitaxel-resistance in NSCLC.
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http://dx.doi.org/10.1080/1061186X.2019.1585437DOI Listing
December 2019

GRGDS-functionalized chitosan nanoparticles as a potential intravenous hemostat for traumatic hemorrhage control in an animal model.

Nanomedicine 2018 11 5;14(8):2531-2540. Epub 2018 Sep 5.

School of Chemical Engineering and Technology, Guangdong Engineering Technology Research Center for Platform Chemicals from Marine Biomass and Their Functionalization, Sun Yat-sen University, Guangzhou, China. Electronic address:

Hemostats, which are used for immediate intervention during internal hemorrhage in order to reduce resulting mortality and morbidity, are relatively rare. Here, we describe novel intravenous nanoparticles (CPG-NPs-2000) with chitosan succinate (CSS) as cores, polyethylene glycol (PEG-2000) as spacers and a glycine-arginine-glycine-aspartic acid-serine (GRGDS) peptide as targeted, active hemostatic motifs. CPG-NPs-2000 displayed significant hemostatic efficacy, compared to the saline control, CSS nanoparticles, and tranexamic acid in liver trauma rat models. Further studies have demonstrated that CPG-NPs-2000 are effectively cleared from organs and blood, within 2 and 48 h, respectively. In addition, administration of CPG-NPs-2000 does not affect clotting function under normal physiological conditions, indicating their potential safety in vivo. CPG-NPs-2000 exhibit excellent thermal stability, good solubility, and redistribution ability, in addition to being low cost. These characteristics indicate that CPG-NPs-2000 may have strong potential as effective intravenous hemostats for treating severe internal bleeding.
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http://dx.doi.org/10.1016/j.nano.2018.08.007DOI Listing
November 2018

Graft-versus-host disease-like erythroderma: a sign of recurrent thymoma: A case report.

Medicine (Baltimore) 2017 Dec;96(49):e8877

Department of Oncology, The First Affiliated Hospital of Jinan University Department of Traditional Chinese Medicine, The First Affiliated Hospital of Jinan University Department of Central Laboratory, The First Affiliated Hospital of Jinan University Department of Clinical Medicine, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.

Rationale: Thymomas are associated with numerous autoimmune disorders, such as myasthenia gravis (MG), pure red cell aplasia (PRCA), and systemic lupus erythematosus (SLE). However, graft-versus-host disease (GVHD)-like erythroderma is a relatively uncommon paraneoplastic disorder associated with thymomas and signifies a poor prognosis.

Patient Concerns: A 35-year-old woman with medical history significant for stage IVa type AB thymoma presented with patchy erythema over face, trunk, and extremities that failed to respond to topical steroids.

Diagnosis: A contrast-enhanced computerized tomography (CECT) scan of the chest demonstrated tumors in the right mediastinum and right pleura. Percutaneous right mediastinal pleural biopsy confirmed recurrent thymoma (WHO type B3, Masaoka stage IVb). Histopathologic examination of her skin lesions revealed GVHD-like erythroderma.

Interventions: The patient received chemotherapy and local thoracic radiotherapy, as well as corticosteroids.

Outcomes: The eruptions gradually subsided with hyperpigmentation; however the patient eventually died of multiple organ failure.

Lessons: GVHD-like erythroderma is an uncommon paraneoplastic disorder associated with thymomas. Though its pathogenesis still needs further research, prompt diagnosis and appropriate treatment can improve survival rate in patients.
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http://dx.doi.org/10.1097/MD.0000000000008877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728867PMC
December 2017

microRNA-664 enhances proliferation, migration and invasion of lung cancer cells.

Exp Ther Med 2017 Jun 5;13(6):3555-3562. Epub 2017 May 5.

Department of Thoracic Surgery, Zhejiang Hospital, Hangzhou, Zhejiang 310000, P.R. China.

Altered microRNA (miR) expression serves an important role in the development and progression of lung cancer. In the present study, the effect of miR-664 on proliferation, migration and invasion of lung cancer cells was assessed. The proliferation of lung cancer cells with an overexpression of miR-664 was examined via MTT assay. The Caspase-Glo3/7 assay was used to examine the effect of miR-664 on cisplatin-induced apoptosis in lung cancer cells. The migration and invasion of lung cancer cells were assessed by Transwell migration and matrigel invasion assays. Western blot analysis was used to examine the protein expression levels. miR-664 improved the proliferation of lung cancer cells and inhibited cisplatin-induced apoptosis of A549 and A427 cells. Furthermore, altered expression of miR-664 affected migration and invasion of lung cancer cells. In addition, a miR-664 mimic decreased E-cadherin expression and increased vementin and Snail expression in lung cancer cells. Notably, the expression level of protein kinase B in A549 cells was changed following altered expression of miR-664. The results of the present study suggest that miR-664 serves an essential role in tumor development and progression in lung cancer.
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http://dx.doi.org/10.3892/etm.2017.4433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450804PMC
June 2017

Room-Temperature CuI-Catalyzed Amination of Aryl Iodides and Aryl Bromides.

J Org Chem 2017 05 4;82(10):5416-5423. Epub 2017 May 4.

School of Chemical Engineering and Technology and ‡School of Chemistry, Sun Yat-Sen University , Guangzhou 510275, P. R. China.

A general and effective CuI/N',N'-diaryl-1H-pyrrole-2-carbohydrazide catalyst system was developed for the amination of aryl iodides and bromides at room temperature with good chemoselectivity between -OH and -NH groups. Only 5 mol % of CuI and ligands was needed in this protocol to effect the amination of various aryl bromides and aryl iodides with a wide range of aliphatic and aryl amines (1.3 equiv).
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http://dx.doi.org/10.1021/acs.joc.7b00290DOI Listing
May 2017

Ginsenoside Rg3 promotes cytotoxicity of Paclitaxel through inhibiting NF-κB signaling and regulating Bax/Bcl-2 expression on triple-negative breast cancer.

Biomed Pharmacother 2017 May 20;89:227-232. Epub 2017 Feb 20.

Department of Chinese Medicine and Rehabilitation, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR China.

Taxane-based chemotherapy regimen is the most effective therapeutic strategy for triple-negative breast cancer (TNBC) which is an aggressive subtype of breast cancer with high rate of recurrence and distant metastasis. Ginsenoside Rg3 is isolated from Panax ginseng with anti-cancer activity against carcinomas. We aim to evaluate the chemosensitizing effects of Ginsenoside Rg3 on TNBC cells and xenograft and explore the underlying mechanism. Human triple-negative breast cancer lines MDA-MB-231, MDA-MB-453 and BT-549 were used. Cell viability and survival was detected by MTT assay and colony formation assay. Apoptosis was detected by Annexin V/PI assay and TUNEL. Enzyme-linked immunosorbent assay was performed to determine NF-κB activation. The NF-κB p65, Bcl 2, Bax and Caspase-3 protein expression were detected using Western blot analysis. The results showed that Ginsenoside Rg3 promotes cytotoxicity and apoptosis of Paclitaxel on TNBC cell lines and xenograft. Ginsenoside Rg3 combined Paclitaxel inhibited NF-κB activation, decreased NF-κB p65 and Bcl-2 protein expressions, increased Bax and Caspase-3 protein expressions. The ratio of Bax/Bcl-2 was significantly enhanced by the Ginsenoside Rg3 to Paclitaxel. Ginsenoside Rg3 promotes cytotoxicity and apoptosis of Paclitaxel by inhibiting NF-κB signaling and modulating Bax/Bcl-2 expression on TNBC. Ginsenoside Rg3 should be regarded as a good chemosensitizing agent for TNBC treatment.
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http://dx.doi.org/10.1016/j.biopha.2017.02.038DOI Listing
May 2017

Paris Saponin I Sensitizes Gastric Cancer Cell Lines to Cisplatin via Cell Cycle Arrest and Apoptosis.

Med Sci Monit 2016 Oct 18;22:3798-3803. Epub 2016 Oct 18.

Department of Surgery, Huashan Luxeme Medical Cosmetology Hospital, Hangzhou, Zhejiang, China (mainland).

BACKGROUND Dose-related toxicity is the major restriction of cisplatin and cisplatin-combination chemotherapy, and is a challenge for advanced gastric cancer treatment. We explored the possibility of using Paris saponin I as an agent to sensitize gastric cancer cells to cisplatin, and examined the underlying mechanism. MATERIAL AND METHODS Growth inhibition was detected by MTT assay. The cell cycle and apoptosis were detected using flow cytometry and Annexin V/PI staining. The P21waf1/cip1, Bcl-2, Bax, and caspase-3 protein expression were detected using Western blot analysis. RESULTS The results revealed that PSI sensitized gastric cancer cells to cisplatin, with low toxicity. The IC50 value of cisplatin in SGC-7901 cell lines was decreased when combined with PSI. PSI promoted cisplatin-induced G2/M phase arrest and apoptosis in a cisplatin concentration-dependent manner. Bcl-2 protein expression decreased, but Bax, caspase-3, and P21waf1/cip1 protein expression increased with PSI treatment. CONCLUSIONS The underlying mechanism of Paris saponin I may be related to targeting the apoptosis pathway and cell cycle blocking, which suggests that PSI is a potential therapeutic sensitizer for cisplatin in treating gastric cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081239PMC
http://dx.doi.org/10.12659/msm.898232DOI Listing
October 2016

An arch-bridge-type fluorophore for bridging the gap between aggregation-caused quenching (ACQ) and aggregation-induced emission (AIE).

Chem Sci 2016 Jul 29;7(7):4485-4491. Epub 2016 Mar 29.

School of Chemistry and Chemical Engineering , Sun Yat-sen University , Guangzhou 510275 , P. R. China . Email:

Solution and solid dual photoluminescence (PL) molecules fill the substantial gap between ACQ and AIE molecules to explore the mechanism of molecular luminescence in greater detail and to facilitate practical applications. A unique arch-bridge-like thiazolo[5,4-]thieno[3,2-]pyridine moiety is obtained as a stator after the rigidification of rotor 1 by intramolecular H-bonding of -OH or -NH to afford two classes of solid and solution dual PL molecules. As a typical example, is dual PL active. Moreover, the large Stokes shift with high dual PL efficiency ( up to 51% in the solid state, 80% in DMF, 74% in DMSO, and 100% in water), together with the good thermal stability ( > 200 °C and > 200 °C), make it more practical for promising optoelectronic and biological applications.
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http://dx.doi.org/10.1039/c6sc01254jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016330PMC
July 2016

Anticancer Effects of Paris Saponins by Apoptosis and PI3K/AKT Pathway in Gefitinib-Resistant Non-Small Cell Lung Cancer.

Med Sci Monit 2016 Apr 29;22:1435-41. Epub 2016 Apr 29.

Department of Oncology, The First Clinical Medical Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China (mainland).

BACKGROUND Paris saponins have been studied for their anticancer effects in various cancer types, but the mechanisms underlying the cytotoxic effects, especially in EGFR-TKI-resistant cells, are still unclear. We explored the potential mechanism of the antitumor effects of PSI, II, VI, VII in EGFR-TKI-resistant cells and attempted to develop PSI, II, VI, VII as a systemic treatment strategy for EGFR-TKI-resistant lung cancer. MATERIAL AND METHODS Growth inhibition was detected by MTT assay. The apoptosis assay was detected using annexin-V/PI and Hoechst staining. The level of PI3K, pAKT, Bax, Bcl-2, caspase-3, and caspase-9 protein expression were detected using Western blot analysis. RESULTS The results revealed that PSI, II, VI, VII inhibited the proliferation of PC-9-ZD cells. Furthermore, PSI, II, VI, VII induced significant cell apoptosis. The levels of PI3K, pAKT, Bcl-2 protein decreased, while the Bax, caspase-3, and caspase-9 protein was increased by PSI, II, PSVI, PSVII treatment and resulted in increased sensitivity to gefitinib in PC-9-ZD cells. CONCLUSIONS The underlying mechanism of Paris saponins may be related to targeting the PI3K/AKT pathways to cause apoptosis. Our results suggest a therapeutic potential of Paris saponins in clinical settings for gefitinib-resistant NSCLC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917328PMC
http://dx.doi.org/10.12659/msm.898558DOI Listing
April 2016

Direct Arylation of Pyrroles via Indirect Electroreductive C-H Functionalization Using Perylene Bisimide as an Electron-Transfer Mediator.

Org Lett 2016 Feb 22;18(3):544-7. Epub 2016 Jan 22.

School of Chemistry and Chemical Engineering, Sun Yat-Sen University , Guangzhou 510275, P. R. of China.

The indirect electroreductive coupling of aryl halides and pyrroles was successfully conducted using a catalytic amount of perylene bisimide as a mediator in 1-ethyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)imide ([EMIM]NTf2)/DMSO.
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http://dx.doi.org/10.1021/acs.orglett.5b03581DOI Listing
February 2016

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.

Mol Pharmacol 2015 Nov 27;88(5):836-45. Epub 2015 Aug 27.

School of Chemistry and Chemical Engineering (M.H., J.H., X.Z. Yiq.W.), School of Pharmaceutical Sciences (Y.S., Z.L., Yin.W., P.L., H.-B.L.), Sun Yat-Sen University, Guangzhou, PR China; and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina (W.C., B.L., Y.H., H.K.)

Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.
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http://dx.doi.org/10.1124/mol.115.099747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613944PMC
November 2015

Lung cancer cellular apoptosis induced by recombinant human endostatin gold nanoshell-mediated near-infrared thermal therapy.

Int J Clin Exp Med 2015 15;8(6):8758-66. Epub 2015 Jun 15.

Department of Electronic Engineering, Institute of Nano-Chemistry, Jinan University Guangzhou 510632, China.

Aims And Background: Endostatin can inhibit tumor endothelial cell proliferation, angiogenesis, and growth. We aimed to determine the increase in antitumor capabilities of recombinant human endostatin (rhES) when used with a nanocarrier system. The effect of gold nanoshell particles of recombinant human endostatin (G-rhES) with near-infrared (NIR) irradiation on proliferation, inhibition, and apoptosis of A549 lung cancer cells was studied.

Materials And Methods: Gold nanoshell particles were prepared. Endostatin was connected with the bond A-U through surface modification by bioconjugation of core-shell structured gold nanoshells. The drug targeting endostatin and the synthesized G-rhES were successfully connected. G-rhES inhibited proliferation of A549 lung cancer cells, as detected using tetrazolium colorimetric assay. Cellular apoptosis was measured by flow cytometry. Mitochondrial membrane potential was determined using a confocal microscope. Morphological changes were studied by atomic force microscopy.

Results: Under irradiation in the 820 nm NIR, G-rhES significantly inhibited the proliferation of A549 lung cancer cells. The underlying mechanism may be related to heat-induced apoptosis and cytotoxicity by NIR absorption, which kills cells directly, thereby indicating that G-rhES have good biocompatibility and pharmacological potency. Characterization of the local structure of lung cancer cells showed that G-rhES targeted surface receptors that may serve an apoptotic function under NIR exposure. NIR gold nanoshell particles showed synergism with endostatin, which may be related to hyperthermia-increased cytotoxicity and the apoptotic effect of endostatin.

Conclusion: These data suggest that G-rhES can enhance the inhibition of tumor growth. The new treatment strategy of G-rhES combined with thermal therapy may lead to lung cancer remission. The potential benefits of G-rhES are being considered for clinical evaluation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537996PMC
August 2015

Discovery of a phosphodiesterase 9A inhibitor as a potential hypoglycemic agent.

J Med Chem 2014 Dec 8;57(24):10304-13. Epub 2014 Dec 8.

School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, P. R. China.

Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer's disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.
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http://dx.doi.org/10.1021/jm500836hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281101PMC
December 2014

Inhibition of cell proliferation by mild hyperthermia at 43˚C with Paris Saponin I in the lung adenocarcinoma cell line PC-9.

Mol Med Rep 2015 Jan 15;11(1):327-32. Epub 2014 Oct 15.

Department of Thoracic Surgery, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China.

Rhizoma paridis is widely used for cancer therapy due to its potential involvement in the suppression of tumor growth. However, at present there is no clear explanation for the mechanism underlying the inhibitory effects of Rhizoma paridis combined with hyperthermia on tumor growth. The aim of the present study was to evaluate the effects of Paris saponin I (PSI) combined with hyperthermia on a variety of non-small cell lung cancer (NSCLC) cell lines. An MTT assay was used to determine the levels of growth inhibition. The cell cycle was analyzed using flow cytometry and cell apoptosis was analyzed with Annexin V/propidium iodide staining and the Hoechst assay. The morphology of cells during apoptosis was determined using a transmission electron microscope. The expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and caspase-3 proteins were detected using western blotting. The inhibition rates significantly increased with PSI in combination with hyperthermia at 43˚C. PSI with hyperthermia at 43˚C caused G2/M phase arrest and significantly induced apoptosis. The expression level of Bcl-2 decreased, while Bax expression increased following treatment with PSI with hyperthermia at 43˚C. In addition, the protein expression of caspase-3 was significantly enhanced. PSI combined with hyperthermia is a potent antitumor treatment through the inhibition of proliferation of NSCLC cells and may be developed as a new antitumor therapy. PSI combined with hyperthermia significantly induced apoptosis through a multi regulatory process involving G2/M arrest and regulation of Bax, Bcl-2 and caspase-3 expression, resulting in cell death and tumor inhibition.
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http://dx.doi.org/10.3892/mmr.2014.2655DOI Listing
January 2015

Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design.

J Med Chem 2012 Oct 1;55(19):8549-58. Epub 2012 Oct 1.

School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, People's Republic of China.

A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC(50) of 21 nM and 3.3 μM, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.
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http://dx.doi.org/10.1021/jm301189cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469756PMC
October 2012

Pyrrolo[2,3-c]azepine derivatives: a new class of potent protein tyrosine phosphatase 1B inhibitors.

Bioorg Med Chem Lett 2011 Jul 27;21(14):4306-9. Epub 2011 May 27.

School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 West Xin Gang Road, Guangzhou 510275, China.

A series of pyrrolo[2,3-c]azepine derivatives was designed, synthesized, and evaluated as a new class of inhibitors against protein tyrosine phosphatase 1B (PTP1B) in vitro. The results demonstrated that compounds bearing a biphenyl moiety were proved to markedly influence the potency of these inhibitors. Particularly, compounds 29, 35 and 36 showed interesting inhibition with IC(50) value of 16.36, 14.93 and 13.92μM, respectively.
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http://dx.doi.org/10.1016/j.bmcl.2011.05.052DOI Listing
July 2011

Protective effect of tetrandrine on doxorubicin-induced cardiotoxicity in rats.

Tumori 2010 May-Jun;96(3):460-4

Department of Oncology, The First Affiliated Hospital, Jinan University, China.

Aims And Background: Doxorubicin (Dox) is effective in curative and adjuvant chemotherapy of malignant tumors. Cardiotoxicity is the chief toxic effect that limits the clinical use of Dox. We studied the effects of tetrandrine (Tet) on doxorubicin-induced cardiotoxicity in rats and its protective activity.

Materials And Methods: Sprague-Dawley rats were randomly divided into the following 4 groups: a control group (received only saline), Dox group (received only Dox), Tet/Dox group (received Tet plus Dox), and Tet group (received only Tet). Rats were injected intravenously with 2 mg/kg Dox once a week for 7 weeks and 50 mg/kg Tet was administered intraperitoneally weekly for 7 weeks. Measurements of cardiac contractile parameters including LSVP +dP/dt max and -dP/dt max, and assessment of electrocardiograms were carried out. Mitochondrial oxidation and phosphorylation state 3 (S3) and state 4 (S4) respiration were measured. Respiration control rate (RCR) and the ADP/O ratio were calculated. Cardiac ultrastructure was examined by electron microscopy.

Results: Dox induced significant cardiotoxicity in this rat model. The values of LSVP, +dP/dt max, and -dP/dt max in the Tet/Dox group increased as compared to the Dox group (P <0.05). The cardiac contraction and relaxation improved on Tet administration. Tet inhibited the prolonged QT interval on the electrocardiogram in Dox-treated rats. Compared to the Dox group, the values of S3, RCR, and ADP/O increased by more than 28%, 48%, and 27%, respectively, in the Tet/Dox group. Significant cardiac morphological protection was observed in the Tet/Dox-treated rats.

Conclusion: Tet can improve the reduced cardiac function caused by Dox treatment and prevent Dox-induced mitochondrial impairment in rat cardiotoxicity.
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September 2010
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