Shanhua Fang

Shanghai Institute of Materia Medica

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Hu Zhou

University of Chinese Academy of Sciences

Kuifeng Wang

Shandong Geological Sciences Institute

Qian Liu

Chinese Academy of Sciences

Jiansheng Zhu

Wenzhou Medical University

Daming Gao

Chinese Academy of Sciences

Jiasheng Wu

Shanghai University of Traditional Chinese Medicine

Feihong Ji

Ocean University of China

Ping Liu

Shanghai University of Traditional Chinese Medicine

Yueming Ma

Shanghai University of Traditional Chinese Medicine

Hongwen Zhu

Guangzhou University

Cooperative Institutions

Chinese Academy of Sciences

University of Chinese Academy of Sciences

Shanghai Institute of Materia Medica

Center for Excellence in Molecular Cell Science

Tongji University

Shanghai Pulmonary Hospital

Sun Yat-sen University

Zhejiang University

Shanghai University of Traditional Chinese Medicine

Shanghai Jiao Tong University

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Carbohydrate Strengthens the Immunotherapeutic Effect of Small-Molecule PD-L1 Inhibitors

Journal of Medicinal Chemistry (2023)

Qian Dong Mengya Tong Xiaolu Yu Lei Wang Jiwei Ao

PD-1/PD-L1 checkpoint blockade has demonstrated great success in cancer immunotherapy. Small-molecule PD-L1 inhibitors also attract significant research interests but remain challenging in the efficacy and safety. Carbohydrate moiety and carbohydrate-binding proteins (lectins) play important roles in immune modulation including antigen recognition and presenting. Herein, we reported a novel strategy to strengthen the immunotherapeutic effect of small-molecule PD-L1 inhibitors by introducing sugar motifs, which may utilize the carbohydrate-mediated immune enhancement for cancer treatment. The data revealed that glycoside compounds containing mannose or N-acetylglucosamine exhibited the best results in IFN-γ secretion. Moreover, compared to the nonglycosylated compounds, glycosides C3 and C15 demonstrated significant lower cytotoxicity and effective in vivo antitumor potency in the CT26 and melanoma B16-F10 tumor models with good tolerance. Notably, tumor-infiltrating lymphocyte (TIL) analysis validated increased CD3+, CD4+, CD8+, and granzyme B+ T cells after glycoside treatments. This work presents a new concept to improve the immunotherapy.

Cancer Immunotherapy

10.1021/acs.jmedchem.2c01347

Cite

Citations (5)

Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies

Cell (2024)

Qian Liu Jing Zhang Chenchen Guo Mengcheng Wang Chenfei Wang

Omics

10.1016/j.cell.2023.12.004

Cite

Citations (60)

SGLT2 promotes cardiac fibrosis following myocardial infarction and is regulated by miR‑141

Experimental and Therapeutic Medicine (2021)

Gang Li Congchun Zhao Shanhua Fang

Cardiac fibrosis is a primary event during myocardial infarction (MI) progression, which impairs cardiac function. The present study aimed to investigate the effect of SGLT2 on cardiac fibrosis following MI. To validate the role of SGLT2 in the regulation of cardiac fibrosis in vivo, an MI rat model was established. Echocardiography was performed to determine cardiac function at 4 weeks post‑MI. MI model rats were transfected with short hairpin RNA (sh)‑SGLT2 or sh‑negative control lentiviruses to investigate the effect of SGLT2 on rat heart function post‑MI. Subsequently, the effects of SGLT2 on the cardiac fibrosis of infarcted hearts were assessed by performing Masson's trichrome staining. To further clarify the effect of SGLT2 on cardiac fibroblast proliferation, TGFβ was used to stimulate primary cardiac fibroblasts in vitro. The results demonstrated that SGLT2 served a key role in cardiac fibrosis. SGLT2 expression levels in infarct tissues were significantly increased at week 1 post‑MI compared with the sham group. Compared with the control group, SGLT2 knockdown attenuated cardiac fibrosis by inhibiting the expression of collagen I and collagen III in cardiac fibroblasts in vitro and in vivo. Furthermore, the results indicated that SGLT2 expression was modulated by miR‑141 in cardiac fibroblasts. In summary, the present study indicated that upregulated SGLT2 expression in cardiac fibrosis following MI was regulated by miR‑141 and SGLT2 that knockdown reduced cardiac fibrosis and improved cardiac function after MI.

Cardiac Fibrosis

Myocardial fibrosis

Masson's trichrome stain

10.3892/etm.2021.10147

Cite

Citations (11)

TGF-β1/P65/MAT2A Pathway Regulates Liver Fibrogenesis via Intracellular SAM

SSRN Electronic Journal (2019)

Kuifeng Wang Shanhua Fang Qian Liu Jing Gao Xiaoning Wang

Background: Hepatic stellate cell (HSC) activation induced by transforming growth factor β1 (TGF-β1) plays a pivotal role in fibrogenesis, while the complex downstream mediators of TGF-β1 in such process are largely unknown. Methods: We performed proteomic profiling of mice liver tissues from control, carbon tetrachloride (CCl4)-induced fibrosis and NPLC0393 administrated groups. Our target Mat2a was overexpressed and knocked down in vivo by tail vein injection of AAV vectors. We examined NF-κB transcriptional and MAT2A promoter activation via luciferase assay. Intracellular SAM contents were analyzed by LC/MS method. Findings: We found that methionine adenosyltransferase 2A (MAT2A) is significantly upregulated in the CCl4-induced fibrosis mice model and application of NPLC0393, a known small molecule inhibitor of TGF-β1 signaling pathway, inhibits the upregulation of MAT2A. Mechanistically, TGF-β1 induces phosphorylation of p65 and activation of NF-κB, thereby promoting mRNA transcription and protein expression of MAT2A and reduces S-adenosylmethionine (SAM) concentration in HSCs. Consistently, in vivo and in vitro knockdown of MAT2A alleviates CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitates hepatic fibrosis and abolishes therapeutic effect of NPLC0393. Interpretation: This study identifies TGF-β1/p65/MAT2A pathway that is involved in the regulation of intracellular SAM concentration and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis. Funding: This work was supported by National Natural Science Foundation of China (No. 81500469, 81573873 and 81774196), Zhejiang Provincial Natural Science Foundation of China (No. Y15H030004), the National Key Research and Development Program from the Ministry of Science and Technology of China (No. 2017YFC1700200) and the Key Program of National Natural Science Foundation of China (No. 8153000502). Declaration of Interest: The authors declare no conflict of interest.Ethical Approval: The animal experiment was approved by Science and Technology Commission of Shanghai Municipality, and all experimental procedures were performed according to the ethical guidelines of Animal care and use committee, Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

10.2139/ssrn.3335024

Cite

Citations (0)

The Active Constituent From Gynostemma Pentaphyllum Prevents Liver Fibrosis Through Regulation of the TGF-β1/NDRG2/MAPK Axis

Frontiers in Genetics (2020)

Hui Huang Kuifeng Wang Qian Liu Feihong Ji Hu Zhou

Liver fibrosis resulting from chronic liver damage constitutes a major health care burden worldwide; however, no antifibrogenic agents are currently available. Our previous study reported that the small molecule NPLC0393 extracted from the herb Gynostemma pentaphyllum exerts efficient antifibrotic effects both in vivo and in vitro. In this study, a TMT-based quantitative proteomic study using a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was performed to identify the potential target of NPLC0393. Combining this study with bioinformatic analysis of differentially ex-pressed proteins between the CCl4 model and NPLC0393 treatment groups, we focused on the function of N-myc downstream-regulated gene 2 (NDRG2) involved in cell dif-ferentiation. In vitro studies showed that NPLC0393 prevented the TGF-β1 stimula-tion-induced decrease in the NDRG2 level in hepatic stellate cells (HSCs). Functional studies indicated that NDRG2 can inhibit the activation of HSCs by preventing the phosphorylation of ERK and JNK. Furthermore, knockdown of NDRG2 abolished the ability of NPLC0393 to inhibit HSC activation. In conclusion, these results provide in-formation on the mechanism underlying the antifibrotic effect of NPLC0393 and shed new light on the potential therapeutic function of the TGF-β1/NDRG2/MAPK signaling axis in liver fibrosis.

Hepatic stellate cell

CCL4

Hepatic fibrosis

10.3389/fgene.2020.594824

Cite

Citations (9)

Quantitative Proteomics Reveals the Protective Effects of Huangqi Decoction Against Acute Cholestatic Liver Injury by Inhibiting the NF-κB/IL-6/STAT3 Signaling Pathway

Journal of Proteome Research (2019)

Jiasheng Wu Qian Liu Shanhua Fang Xing Liu Min Zheng

Intrahepatic cholestasis (IC) is a common syndrome that affects the liver, with treatment options being limited. Huangqi decoction (HQD), a classic herbal medicine, has shown protective effects against IC. In this study, isobaric tags for relative and absolute quantification-based quantitative proteomics was performed to investigate the potential mechanism of action of HQD on α-naphthylisothiocyanate (ANIT)-induced IC, resulting in 2796 quantified proteins across all samples, including 270 differentially expressed proteins under HQD treatment. Fuzzy c-means clustering analysis of these 270 proteins assigned the proinflammatory proteins, such as LCN2, SAA1, FGG, FGA, and FGB, to Cluster 1 (upregulated by ANIT, and downregulated by HQD). Functional bioinformatics and protein-protein interaction network analyses indicated that these proinflammatory proteins were involved in the STAT3 signaling pathway. Further real-time PCR and Western blot experiments confirmed that the expression of these proteins was consistent with the proteomic results. Moreover, HQD treatment decreased the phosphorylation of STAT3, induced by ANIT. Western blot experiments revealed that HQD treatment decreased phosphorylation of NF-κB and downregulated the expression of the inflammatory gene IL-6 and therefore inhibited the IL-6/STAT3 signaling pathway. In summary, the present study suggested that HQD may ameliorate acute cholestatic liver injury via inhibition of the NF-κB/IL-6/STAT3 signaling pathway.

Decoction

10.1021/acs.jproteome.9b00563

Cite

Citations (12)

UQ eSpace

Shanhua Fang

ESPACE

10.14264/1b23d27

Cite

Citations (0)

Quantitative Proteomic Study Reveals Up-Regulation of cAMP Signaling Pathway-Related Proteins in Mild Traumatic Brain Injury

Journal of Proteome Research (2017)

Hai Song Shanhua Fang Jing Gao Jiaxong Wang Zhenzhen Cao

Traumatic brain injury (TBI), as a neurological injury, becomes a leading cause of disability and mortality due to lacking effective therapy. About 75% of TBI is mild traumatic brain injury (mTBI). However, the complex molecular mechanisms underlying mTBI pathophysiology remains to be elucidated. In this study, iTRAQ-based quantitative proteomic approach was employed to measure temporal-global proteome changes of rat brain tissues from different time points (1 day, 7 day and 6 months) post single mTBI (smTBI) and repetitive mTBI (rmTBI). A total of 5169 proteins were identified, of which, 237 proteins were significantly changed between control rats and mTBI model rats. Fuzzy c-means (FCM) clustering analysis classified these 237 proteins into six clusters according to their temporal pattern of protein abundance. Functional bioinformatics analysis and protein-protein interaction (PPI) network mapping of these FCM clusters showed that phosphodiesterase 10A (Pde10a) and guanine nucleotide-binding protein G (olf) subunit alpha (Gnal) were the node proteins in the cAMP signaling pathway. Other biological processes, such as cell adhesion, autophagy, myelination, microtubule depolymerization and brain development, were also over-represented in FCM clusters. Further Western Blot experiments confirmed that Pde10a and Gnal were acutely up-regulated in severity-dependent manner by mTBI, but these two proteins could not be down-regulated to basal level at the time point of 6 months post repetitive mTBI. Our study demonstrated that different severity of mTBI cause significant temporal profiling change at the proteomic level and pointed out the cAMP signaling pathway-related proteins, Pde10a and Gnal, may play important roles in the pathogenesis and recovery of mTBI.

10.1021/acs.jproteome.7b00618

Cite

Citations (21)

Discovery of a Potential Plasma Protein Biomarker Panel for Acute-on-Chronic Liver Failure Induced by Hepatitis B Virus

Frontiers in Physiology (2017)

Ni Zhou Kuifeng Wang Shanhua Fang Xiaoyu Zhao Tingting Huang

Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF), characterized by an acute deterioration of liver function in the patients with chronic hepatitis B (CHB), is lack of predicting biomarkers for prognosis. Plasma is an ideal sample for biomarker discovery due to inexpensive and minimally invasive sampling and good reproducibility. In this study, immuno-depletion of high-abundance plasma proteins followed by iTRAQ-based quantitative proteomic approach was employed to analyze plasma samples from 20 healthy control people, 20 CHB patients and 20 HBV-ACLF patients, respectively. As a result, a total of 427 proteins were identified from these samples, and 42 proteins were differentially expressed in HBV-ACLF patients as compared to both CHB patients and healthy controls. According to bioinformatics analysis results, 6 proteins related to immune response (MMR), inflammatory response (OPN, HPX), blood coagulation (ATIII) and lipid metabolism (APO-CII, GP73) were selected as biomarker candidates. Further ELISA analysis confirmed the significant up-regulation of GP73, MMR, OPN and down-regulation of ATIII, HPX, APO-CII in HBV-ACLF plasma samples (p < 0.01). Moreover, receiver operating characteristic (ROC) curve analysis revealed high diagnostic value of these candidates in assessing HBV-ACLF. In conclusion, present quantitative proteomic study identified 6 novel HBV-ACLF biomarker candidates and might provide fundamental information for development of HBV-ACLF biomarker.

Hepatitis B

Biomarker Discovery

10.3389/fphys.2017.01009

Cite

Citations (26)

TGF-β1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM

EBioMedicine (2019)

Kuifeng Wang Shanhua Fang Qian Liu Jing Gao Xiaoning Wang

Hepatic stellate cell (HSC) activation induced by transforming growth factor β1 (TGF-β1) plays a pivotal role in fibrogenesis, while the complex downstream mediators of TGF-β1 in such process are largely unknown.We performed pharmacoproteomic profiling of the mice liver tissues from control, carbon tetrachloride (CCl4)-induced fibrosis and NPLC0393 administrated groups. The target gene MAT2A was overexpressed or knocked down in vivo by tail vein injection of AAV vectors. We examined NF-κB transcriptional activity on MAT2A promoter via luciferase assay. Intracellular SAM contents were analyzed by LC-MS method.We found that methionine adenosyltransferase 2A (MAT2A) is significantly upregulated in the CCl4-induced fibrosis mice, and application of NPLC0393, a known small molecule inhibitor of TGF-β1 signaling pathway, inhibits the upregulation of MAT2A. Mechanistically, TGF-β1 induces phosphorylation of p65, i.e., activation of NF-κB, thereby promoting mRNA transcription and protein expression of MAT2A and reduces S-adenosylmethionine (SAM) concentration in HSCs. Consistently, in vivo and in vitro knockdown of MAT2A alleviates CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitates hepatic fibrosis and abolishes therapeutic effect of NPLC0393.This study identifies TGF-β1/p65/MAT2A pathway that is involved in the regulation of intracellular SAM concentration and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis. FUND: This work was supported by National Natural Science Foundation of China (No. 81500469, 81573873, 81774196 and 31800693), Zhejiang Provincial Natural Science Foundation of China (No. Y15H030004), the National Key Research and Development Program from the Ministry of Science and Technology of China (No. 2017YFC1700200) and the Key Program of National Natural Science Foundation of China (No. 8153000502).

Hepatic stellate cell

Hepatic fibrosis

10.1016/j.ebiom.2019.03.058

Cite

Citations (46)