My long-term goals involve the development of a full understanding of key molecular mechanisms and the identification of corresponding therapeutics for human diseases. My research training and academic experience have provided me with an excellent background necessary in multiple fields including molecular biology, cell biology, medicinal chemistry, and biochemical pharmacology. As an undergraduate, I have learned numerous biology and physiology courses, which let me appreciate and understand biological diversity. As a predoctoral student, my research focused on the identification and evaluation of fusion proteins, gene therapy-based biologics, molecular modifiers and inhibitors to treat tissue injury or cancer. We first revealed a novel mechanism underscoring the regulation of metabolic profiles and mitochondrial function of epithelial cells by IL-22 during cell injury, which might provide useful insights from the bench to the clinic in treating and preventing more diseases, especially acute stroke/traumatic brain injuries. We subsequently demonstrated that autophagy was induced to play cytoprotective roles in numerous cells, which highlighted the potential therapeutic strategies for CNS neurodegeneration diseases or cancer by targeting autophagy. During my undergraduate and graduate careers, I also received several academic awards, including two times National Scholarship. For my postdoctoral training, I will continue to build on my previous researches in metabolic profiles and mitochondrial function regulations by concentrating on determining the role of mitochondrial thioredoxin metabolism in neuronal survival. These new scientific issues will allow me to address additional problems regarding the molecular basis of neurodegeneration and develop a neuroprotective gene therapy strategy to protect CNS neurodegenerative diseases/injuries.
Honors & Awards
Excellent Graduates in Shanghai, Shanghai Municipal Education Commission (2019)
“Warm heart” Scholarship, China Gut Festival 2019 (2019)
National Scholarship, Ministry of Education of the People's Republic of China (2018)
National Scholarship, Ministry of Education of the People's Republic of China (2017)
Excellence Award, International Academic and Industrial Forum of Precision Medicine at 2017 (2017)
Ph.D., Fudan University (2019)
Yang Hu, Postdoctoral Faculty Sponsor
Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production
CELL DEATH & DISEASE
2019; 10: 626
Lung adenocarcinoma (LUAD), which comprises over 50% of all cases of non-small-cell lung cancer, has a poor prognosis and requires novel therapeutic approaches. The sonic Hedgehog (Shh) pathway, which plays a crucial role in differentiation, proliferation, and survival of cancer cells, is likely to be activated in LUADs, suggesting the Shh pathway as a potential therapeutic target for LUAD treatment. In this study, we reported that vismodegib, an inhibitor of the Shh pathway, only elicited minor antitumor efficacy in A549 and NCI-H1975 LUAD cells as well as in the xenograft tumors, with overexpressed GLI2 and increased autophagic activity. The aberrant autophagy in LUAD cells was further confirmed by the three main stages of autophagic flux, including the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Furthermore, inhibition of autophagy by siRNA against ATG5 or ATG7 rescued the sensitivity of A549 and NCI-H1975 LUAD cells to vismodegib in vitro. Meanwhile, administration of the pharmaceutical inhibitor of autophagy, chloroquine, contributed to the enhanced anti-LUAD efficacy of vismodegib in vivo, probably through overproduction of ROS, acceleration of apoptosis, and suppression of GLI2 in LUAD tissues. In summary, our research revealed that downregulating autophagy facilitated the anti-LUAD efficacy of the Shh pathway suppression, thus highlighting a potential approach for LUAD therapy via simultaneously targeting the Shh signaling and autophagy pathway.
View details for DOI 10.1038/s41419-019-1840-6
View details for Web of Science ID 000481965800004
View details for PubMedID 31427566
View details for PubMedCentralID PMC6700102
<bold>Recombinant human arginase I elicited immunosuppression in activated macrophages through inhibiting autophagy</bold>
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
2019; 103 (12): 4825–38
Arginase I has been documented to impair T cell function and attenuate cellular immunity, however, there is little evidence to reveal the effect of arginase I on macrophage function. Recently, recombinant human arginase I (rhArg) has been developed for cancer therapy and is in clinical trial for hepatocellular carcinoma, whereas the potential immunosuppression induced by rhArg limited its therapeutic efficacy. To improve the clinical outcome of rhArg, addressing the immune suppression appears to be particularly important. In this study, we found that rhArg attenuated macrophage functions, including inhibiting macrophage cell proliferation, nitric oxide (NO) and reactive oxygen species (ROS) production, cytokine secretion, MHC-II surface expression, and phagocytosis, thereby inducing immunosuppression in lipopolysaccharides (LPS)/interferon-γ (IFN-γ)-activated macrophages. Notably, we observed that rhArg downregulated autophagy in activated macrophages. Moreover, application of trehalose (an autophagy inducer) significantly restored the impaired immune function in activated macrophages, suggesting the essential role of autophagy in rhArg-induced immunosuppression. To further illustrate the effect of autophagy in immunosuppression, we then observed the effect of 3-MA (an autophagy inhibitor) on the immune function of macrophages. As expected, inhibiting autophagy by 3-MA attenuated immune functions in activated macrophages. Collectively, this study elucidated that rhArg induced immunosuppression in activated macrophages via inhibiting autophagy, providing potential strategy to ameliorate the immune suppression which is of great significance to cancer therapy and facilitating the development of rhArg as a potential therapy for malignant carcinomas.
View details for DOI 10.1007/s00253-019-09832-w
View details for Web of Science ID 000469192100014
View details for PubMedID 31053913
GSDMD membrane pore is critical for IL-1β release and antagonizing IL-1β by hepatocyte-specific nanobiologics is a promising therapeutics for murine alcoholic steatohepatitis.
2019; 227: 119570
Excessive release of interleukin-1β (IL-1β) is well-known to provoke cascades of inflammatory responses thus contributing to the pathogenesis of alcohol-induced steatohepatitis (ASH), but the cellular mechanism that regulates IL-1β release during ASH remains unclear. Herein, we identified that gasdermin D (GSDMD) membrane pore is critical in mediating IL-1β hypersecretion from chronic ethanol or acetaldehyde-stimulated macrophages. Deletion of GSDMD reduced IL-1β release and ameliorated alcoholic steatohepatitis in vivo. These findings uncovered a novel mechanism regarding the IL-1β release in ASH, and also indicated the therapeutic potential of IL-1β blockade. Interleukin-1 receptor antagonist (IL-1Ra) is protective to ASH by blocking IL-1β, but it has a short biological half-life (4-6 h) and lower liver concentrations. Thus, we constructed a therapeutic plasmid pVAX1-IL-1Ra-ApoAI (pVAX1-IA) encoding IL-1Ra anchored to the liver-targeting protein apolipoprotein A-I (ApoAI), and developed hepatocyte-specific nanobiologics (Glipo-pVAX1-IA) by galactose functionalization for local and prolonged expression of IL-1Ra in liver. Data presented here showed that Glipo-pVAX1-IA facilitated efficient uptake of gene cargos by hepatocytes. The biodistribution studies confirmed a predominant hepatocytes internalization, but a minimal kupffer cells uptake of Glipo-pVAX1-IA following intravenous injection. The locally secreted IL-1Ra attenuated alcohol-induced steatohepatisis and infiltration of inflammatory cells. Together, our results unraveled the critical role of GSDMD membrane pore in IL-1β hypersecretion and highlighted the hepatocyte-specific Glipo-pVAX1-IA nanobiologics as a promising therapeutic strategy for ASH.
View details for DOI 10.1016/j.biomaterials.2019.119570
View details for PubMedID 31670032
Interleukin-22 attenuated renal tubular injury in aristolochic acid nephropathy via suppressing activation of NLRP3 inflammasome
View details for DOI 10.3389/fimmu.2019.02277
Curdione ameliorated doxorubicin-induced cardiotoxicity through suppressing oxidative stress and activating Nrf2/HO-1 pathway.
Journal of Cardiovascular Pharmacology
2019; 74 (2): 118-127
View details for DOI 10.1097/FJC.0000000000000692
Targeting PARP and autophagy evoked synergistic lethality in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC), one of the most lethal malignancies worldwide, has limited efficient therapeutic options. Here, we first demonstrated that simultaneously targeting poly (ADP-ribose) polymerase (PARP) and autophagy could evoke striking synergistic lethality in HCC cells. Specifically, we found that the PARP inhibitor Niraparib induced cytotoxicity accompanied by significant autophagy formation and autophagic flux in HCC cells. Further experiments showed that Niraparib induced suppression of the Akt/mTOR pathway and activation of the Erk1/2 cascade, two typical signaling pathways related to autophagy. In addition, the accumulation of reactive oxygen species (ROS) was triggered, which was involved in Niraparib-induced autophagy. Blocking autophagy by chloroquine (CQ) in combination with Niraparib further enhanced cytotoxicity, induced apoptosis and inhibited colony formation in HCC cells. Synergistic inhibition was also observed in Huh7 xenografts in vivo. Mechanistically, we showed that autophagy inhibition abrogated Niraparib-induced cell cycle arrest and checkpoint activation. Cotreatment with CQ and Niraparib promoted the formation of γ-H2AX foci while inhibiting the recruitment of the homologous recombination (HR) repair protein RAD51 to double-strand break (DSB) sites. Thus, the present study developed a novel promising strategy for the management of HCC in the clinic and highlighted a potential approach to expand the application of PARP inhibitors.
View details for DOI 10.1093/carcin/bgz104
View details for PubMedID 31175354
- Targeted Interleukin-22 Gene Delivery in the Liver by Poly-Metformin and Penetratin-Based Hybrid Nanoparticles to Treat Non-Alcoholic Fatty Liver Disease. ACS applied materials & interfaces 2019
In vivo hepatocellular expression of interleukin-22 using penetratin-based hybrid nanoparticles as potential anti-hepatitis therapeutics
2018; 187: 66–80
Hepatocellular injury is the pathological hallmark of hepatitis and a crucial driver for the progression of liver diseases, while the treatment options are commonly restricted. Interleukin-22 (IL-22) has attracted special attention as a potent survival factor for hepatocytes that both prevents and repairs the injury of hepatocytes through activation of STAT3 signaling pathway. We hypothesized that the ability to generate potent expression of IL-22 locally for the treatment of severe hepatocellular injury in hepatitis was a promising strategy to enhance efficacy and overcome off-target effects. Accordingly, we developed a polypeptide penetratin-based hybrid nanoparticle system (PDPIA) carrying IL-22 gene by a self-assembly process. This nanocomplex modified with penetratin featured direct translocation across the cellular or endosomal membrane but mild zeta-potential to facilitate the high cellular internalization and endosomal escape of the gene cargos as well as scarcely Kupffer cells uptake. More importantly, PDPIA afforded preferential liver accumulation and predominant hepatocytes internalization following systemic administration, which showed pharmacologically suitable organ and sub-organ-selective properties. Subsequent studies confirmed a considerable protective role of PDPIA in a model of severe hepatitis induced by concanavalin A, evidenced by reduced hepatocellular injury and evaded immune response. The locally expressed IL-22 by PDPIA activated STAT3/Erk signal transduction, and thus promoted hepatocyte regeneration, inhibited reactive oxygen species (ROS) accumulation as well as prevented the dysfunction of mitochondrial. In addition, this system did not manifest side effects or systemic toxicity in mice. Collectively, the high versatility of PDPIA rendered its promising applications might be an effective agent to treat various hepatic disorders.
View details for DOI 10.1016/j.biomaterials.2018.09.046
View details for Web of Science ID 000449446000008
View details for PubMedID 30296739
Activating Autophagy Enhanced the Antitumor Effect of Antibody Drug Conjugates Rituximab-Monomethyl Auristatin E
FRONTIERS IN IMMUNOLOGY
2018; 9: 1799
Antibody drug conjugate (ADC) showed potent therapeutic efficacy in several types of cancers. The role of autophagy in antitumor effects of ADC remains unclear.In this study, the ADC, Rituximab-monomethyl auristatin E (MMAE) with a Valine-Citrulline cleavable linker, was designed to investigate its therapeutic efficacy against non-Hodgkin lymphoma (NHL) as well as the underlying mechanisms. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) was used to detect growth inhibition in B-cell lymphoma cell lines, Ramos and Daudi cells, which were treated by Rituximab-MMAE alone or combined with autophagy conditioner. Apoptosis was detected by flow cytometry and immunohistochemistry, and apoptosis inhibitor was employed to discover the relationship between autophagy and apoptosis during the Rituximab-MMAE treatment. Autophagy was determined by three standard techniques which included confocal microscope, transmission electron microscope, and western blots. Ramos xenograft tumors in BALB/c nude mice were established to investigate the antitumor effect of combination use of Rituximab-MMAE and autophagy conditioner in B-NHL therapy.Our results showed that Rituximab-MMAE elicited caspase-3-dependent apoptosis in NHL cells and exhibited potent therapeutic efficacy in vivo. Autophagy, which was characterized by upregulated light chain 3-II expression, and accumulation of autophagosomes, was triggered during the Rituximab-MMAE treatment. Meanwhile, inactivation of Akt/mTOR pathway was shown to be involved in the autophagy triggered by Rituximab-MMAE, indicating a probable mechanism of the ADC-initiated autophagy. Importantly, inhibition of autophagy by chloroquine suppressed the Rituximab-MMAE-induced apoptosis, while activating autophagy by rapamycin significantly enhanced the therapeutic effect of Rituximab-MMAE both in vitro and in vivo.Our data elucidated the critical relationship between autophagy and apoptosis in Rituximab-MMAE-based therapy and highlighted the potential approach for NHL therapy by combined administration of the ADC and autophagy activator.
View details for DOI 10.3389/fimmu.2018.01799
View details for Web of Science ID 000440722400004
View details for PubMedID 30123222
View details for PubMedCentralID PMC6085421
Inhibition of autophagy potentiated the anti-tumor effects of VEGF and CD47 bispecific therapy in glioblastoma
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
2018; 102 (15): 6503–13
Glioblastoma, characterized by extensive microvascular proliferation and invasive tumor growth, is one of the most common and lethal malignancies in adults. Benefits of the conventional anti-angiogenic therapy were only observed in a subset of patients and limited by diverse relapse mechanism. Fortunately, recent advances in cancer immunotherapy have offered new hope for patients with glioblastoma. Herein, we reported a novel dual-targeting therapy for glioblastoma through simultaneous blockade of VEGF and CD47 signaling. Our results showed that VEGFR1D2-SIRPαD1, a VEGF and CD47 bispecific fusion protein, exerted potent anti-tumor effects via suppressing VEGF-induced angiogenesis and activating macrophage-mediated phagocytosis. Meanwhile, autophagy was activated by VEGFR1D2-SIRPαD1 through inactivating Akt/mTOR and Erk pathways in glioblastoma cells. Importantly, autophagy inhibitor or knockdown of autophagy-related protein 5 potentiated VEGFR1D2-SIRPαD1-induced macrophage phagocytosis and cytotoxicity against glioblastoma cells. Moreover, suppression of autophagy led to increased macrophage infiltration, angiogenesis inhibition, and tumor cell apoptosis triggered by VEGF and CD47 dual-targeting therapy, thus eliciting enhanced anti-tumor effects in glioblastoma. Our data revealed that VEGFR1D2-SIRPαD1 alone or in combination with autophagy inhibitor could effectively elicit potent anti-tumor effects, highlighting potential therapeutic strategies for glioblastoma through disrupting angiogenetic axis and CD47-SIRPα anti-phagocytic axis alone or in combination with autophagy inhibition.
View details for DOI 10.1007/s00253-018-9069-3
View details for Web of Science ID 000438606100019
View details for PubMedID 29754163
Mesoporous silica nanoparticles induced hepatotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis
2018; 10 (19): 9141–52
Increased biomedical applications of mesoporous silica nanoparticles (MSNs) raise considerable attention concerning their toxicological effects; the toxicities of MSNs are still undefined and the underlying mechanisms are unknown. We conducted this study to determine the hepatotoxicity of continuous administration of MSNs and the potential mechanisms. MSNs caused cytotoxicity in hepatic L02 cells in a dose- and time-dependent manner. Then, MSNs were shown to elicit NOD-like receptor protein 3 (NLRP3) inflammasome activation in hepatocytes, leading to caspase-1-dependent pyroptosis, a novel manner of cell death. In vivo MSN administration triggered hepatotoxicity as indicated by increased histological injury, serum alanine aminotransferase and serum aspartate aminotransferase. Notably, NLRP3 inflammasome and pyroptosis were also activated during the treatment. Meanwhile, in NLRP3 knockout mice and caspase-1 knockout mice, MSN-induced liver inflammation and hepatotoxicity could be abolished. Furthermore, experiments indicated that MSNs induced mitochondrial reactive oxygen species (ROS) generation, and the ROS scavenger could attenuate the MSN-activated NLRP3 inflammasomes and pyroptosis in the liver. Collectively, these data suggested that MSNs triggered liver inflammation and hepatocyte pyroptosis through NLRP3 inflammasome activation, which was caused by MSN-induced ROS generation. Our study provided novel insights into the hepatotoxicity of MSNs and the underlying mechanisms, and facilitated the potential approach to increase the biosafety of MSNs.
View details for DOI 10.1039/c8nr00554k
View details for Web of Science ID 000437007700024
View details for PubMedID 29722780
Disrupting CD47-SIRP alpha axis alone or combined with autophagy depletion for the therapy of glioblastoma
2018; 39 (5): 689–99
CD47-targeting immune checkpoint inhibitors have been investigated for immunotherapy of several cancers, glioblastoma, one of the most common tumors in brain, was still a challenge for CD47-targeting therapy. Herein, we reported novel strategies for glioblastoma therapy via blocking CD47-signal regulatory protein-α (SIRPα) by SIRPα-Fc alone or in combination with autophagy inhibition. Our results showed that SIRPα-Fc increased macrophages-triggered cytotoxicity and phagocytosis of glioblastoma cells then elicited potent anti-tumor efficacy. During the treatment, SIRPα-Fc induced autophagy and autophagic flux in glioblastoma cells and Akt/mammalian target of rapamycin (mTOR) inactivation was participated in the autophagy activation. Inhibition of autophagy by pharmacological agents or small-interfering RNA increased SIRPα-Fc-triggered macrophage phagocytosis and cytotoxicity. Importantly, when compared with SIRPα-Fc treatment, blocking both CD47/SIRPα and autophagy significantly increased infiltration of macrophages and apoptosis of tumor cells, triggering potentiated anti-glioblastoma effect and extended median survival. Further experiments showed that adaptive immune response, including CD8+ T-cell subsets, was also played a crucial role in SIRPα-Fc-induced glioblastoma rejection. Our results indicated that SIRPα-Fc alone or combined with autophagy inhibitors elicited potent anti-glioblastoma effect, highlighting potential therapeutic strategies of glioblastoma via blocking CD47/SIRPα alone or in combination with autophagy inhibitor.
View details for DOI 10.1093/carcin/bgy041
View details for Web of Science ID 000434120600006
View details for PubMedID 29538621
NOD-Like Receptor Protein 3 Inflammasome-Dependent IL-1 beta Accelerated ConA-Induced Hepatitis
FRONTIERS IN IMMUNOLOGY
2018; 9: 758
Autoimmune hepatitis (AIH) is a progressive inflammatory disorders of unknown etiology, characterized by immune-mediated destruction of hepatocytes and massive production of cytokines. Interleukin-1β is a pleiotropic proinflammatory cytokine and well known to be critical in a variety of autoimmune diseases. However, the role of interleukin-1β (IL-1β) in AIH is still indistinct. Here, we first investigated the significance of NOD-like receptor protein 3 (NLRP3) inflammasome-dependent IL-1β in the pathogenesis of AIH with a murine model of immune-mediated hepatitis induced by Concanavalin A (ConA). In ConA-treated mice, pathogenic elevated NLRP3, Cleaved caspase-1 and IL-1β levels, as well as an inflammatory cell death known as pyroptosis predominantly occurred in the livers. Strikingly, NLRP3-/- and caspase-1-/- mice were broadly protected from hepatitis as determined by decreased histological liver injury, serum aminotransferase (ALT)/aspartate transaminase levels, and pyroptosis. In vivo intervention with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) strongly suppressed ConA-induced hepatitis by decreasing tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) secretion, and inflammatory cell infiltration into livers. Additionally, rhIL-1Ra-pretreated mice developed significantly reduced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation. Scavenging of ROS by N-acetyl-cysteine also attenuated NLRP3 inflammasome activation and liver inflammation, indicating that the essential role of ROS in mediating NLRP3 inflammasome activation in ConA-induced hepatitis. In conclusion, our results demonstrated that NLRP3 inflammasome-dependent IL-1β production was crucial in the pathogenesis of ConA-induced hepatitis, which shed light on the development of promising therapeutic strategies for AIH by blocking NLRP3 inflammasome and IL-1β.
View details for DOI 10.3389/fimmu.2018.00758
View details for Web of Science ID 000429583500001
View details for PubMedID 29692782
View details for PubMedCentralID PMC5902503
- Quantum Dots Elicit Hepatotoxicity through Lysosome-Dependent Autophagy Activation and Reactive Oxygen Species Production ACS BIOMATERIALS SCIENCE & ENGINEERING 2018; 4 (4): 1418–27
Kidney protection effects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP3 inflammasome
2018; 41: 45–53
Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is acknowledged as an independent risk factor for cardiovascular disease, which underlines the urgent need for new medications to DN. Dihydroquercetin (DHQ), an important natural dihydroflavone, exerts significant antioxidant, anti-inflammatory, and antifibrotic properties, but its effects on DN have not been investigated yet.We aimed to explore the kidney protection effects of DHQ on DN rats induced by high-fat diet/streptozotocin in vivo and the underlying mechanisms of DHQ on renal cells including HBZY-1 and HK2 exposed to high glucose in vitro.Major biochemical indexes were measured including urine microalbumin, fasting serum glucose, serum levels of creatinine, total cholesterol and low density lipoprotein cholesterol. Renal histologic sections were stained with hematoxylin-eosin, periodic acid-Schiff and Masson. The cell proliferation was assessed by MTT assay. Reactive oxygen species (ROS) generation was detected by DCFH-DA assay and laser scanning confocal microscope. Expression of all proteins was examined by western-blot.In high-fat diet/streptozotocin-induced DN rats, DHQ at the dose of 100 mg/kg/day significantly attenuated the increasing urine microalbumin excretion, hyperglycemia and lipid metabolism disorders, and mitigated renal histopathological lesions. In in vitro studies, DHQ significantly suppressed cell proliferation and the excessive ROS generation, and alleviated the activation of nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and the expression of renal fibrosis-associated proteins in renal cells exposed to high glucose.The results revealed that DHQ possesses kidney protection effects including attenuating urine microalbumin excretion, hyperglycemia and lipid metabolism disorders, and mitigating renal histopathological lesions on DN, and one of the possible renal-protective mechanisms is suppressing ROS and NLRP3 inflammasome.
View details for DOI 10.1016/j.phymed.2018.01.026
View details for Web of Science ID 000427463700006
View details for PubMedID 29519318
Dihydroquercetin ameliorated acetaminophen-induced hepatic cytotoxicity via activating JAK2/STAT3 pathway and autophagy
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
2018; 102 (3): 1443–53
Acetaminophen (APAP) overdose is currently the leading cause of acute liver disease, but therapeutic treatment strategies are commonly limited. Although dihydroquercetin (DHQ) is an attractive botanical antioxidant, its protective potential for liver disease remains elusive. The present study investigated the protective effects of DHQ against APAP-induced hepatic cytotoxicity. Primary mouse hepatocytes were treated with different concentrations of DHQ followed by APAP administration. Our data showed that DHQ relieved APAP-induced growth inhibition and lactate dehydrogenase (LDH) release in a dose-dependent manner, as well as inhibited APAP-induced necrosis and extracellular signal regulated kinase-c-Jun-N-terminal kinase (ERK-JNK) stress. In addition, reactive oxygen species (ROS) accumulation and mitochondria dysfunction were also reversed by DHQ treatment. Further study revealed that DHQ induced phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) cascade and thus modulated expression of anti-apoptotic Bcl-2 family proteins. Moreover, DHQ induced autophagy which mediated its protective effects in hepatocytes. The protection was abrogated through pharmacological blockage of autophagy by chloroquine (CQ). These studies demonstrated, for the first time, that DHQ possessed hepatocellular protective effects in the context of APAP-induced cytotoxicity and subsequently revealed that the mechanisms comprised activation of JAK2/STAT3 signaling pathway and autophagy. These altogether highlighted the significant therapeutic potential of this agent during acute liver failure and other types of liver diseases.
View details for DOI 10.1007/s00253-017-8686-6
View details for Web of Science ID 000423110400033
View details for PubMedID 29243082
A novel therapeutic approach for glioblastoma: blocking CD47-SIRPa axis alone or combined with autophagy inhibitor
View details for DOI 10.1093/annonc/mdy375.032
Dual NAMPT/HDAC Inhibitors as a New Strategy for Multitargeting Antitumor Drug Discovery
ACS MEDICINAL CHEMISTRY LETTERS
2018; 9 (1): 34–38
Novel dual nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC) inhibitors were designed by a pharmacophore fusion approach. The thiazolocarboxamide inhibitors were highly active for both targets. In particular, compound 7f (NAMPT IC50 = 15 nM, HDAC1 IC50 = 2 nM) showed potent in vivo antitumor efficacy in the HCT116 xenograft model. The study offers a new strategy for multitarget antitumor drug discovery by simultaneously acting on cancer metabolism and epigenetics.
View details for DOI 10.1021/acsmedchemlett.7b00414
View details for Web of Science ID 000422813500008
View details for PubMedID 29348808
View details for PubMedCentralID PMC5767891
Autophagy inhibition improves CD47-blocking immunotherapy in laryngeal squamous cell carcinoma.
View details for DOI 10.1093/annonc/mdy375.030
- Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo ONCOTARGET 2017; 8 (53): 91052–66
Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors
JOURNAL OF MEDICINAL CHEMISTRY
2017; 60 (19): 7965–83
Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM). It could effectively induce cell apoptosis and autophagy and ultimately led to cell death. Importantly, compound 35 showed excellent in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept study demonstrates the feasibility of discovering an inhibitor targeting cancer metabolism and epigenetics and provides an efficient strategy for multitarget antitumor drug discovery.
View details for DOI 10.1021/acs.jmedchem.7b00467
View details for Web of Science ID 000413131400003
View details for PubMedID 28885834
Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury
2017; 7 (17): 4135–48
Increasing evidence indicates that interleukin-22 (IL-22) holds tremendous potential as a protective agent in preventing liver injury, but its pleiotropic effects and pathogenic role in carcinogenesis, rheumatoid arthritis and psoriasis restrict its systemic application. Here, we first developed a nanoparticle (liposIA) as a liver-targeted agent through IL-22 tethered to apolipoprotein A-I (ApoA-I) in a gene therapy vector. LiposIA was prepared using thin film dispersion method and the complexes exhibited desirable nanoparticle size, fine polydisperse index, highly efficient transfection, and excellent serum and storage stability. Biodistribution and hepatic STAT3 phosphorylation studies revealed that IL-22 tethered to ApoA-I led to highly efficient liver targeting. More importantly, our studies showed that a single-dose of liposIA was able to protect mice against acetaminophen-induced liver injury and did not initiate inflammatory response or systemic toxicity in vivo. During this process, activated STAT3/Erk and Akt/mTOR signaling transductions were observed, as well as inhibition of reactive oxygen species (ROS) generation, which prevented mitochondrial dysfunction. These studies demonstrated that IL-22 tethered to apolipoprotein A-I could target and ameliorate acetaminophen-induced acute liver injury, which highlighted that a targeted strategy for IL-22 delivery might have broad utility for the protection of hepatocellular damage.
View details for DOI 10.7150/thno.20955
View details for Web of Science ID 000412296800005
View details for PubMedID 29158815
View details for PubMedCentralID PMC5695002
Identification of benzothiophene amides as potent inhibitors of human nicotinamide phosphoribosyltransferase
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
2016; 26 (3): 765–68
Nicotinamide phosphoribosyltransferase (Nampt) is an attractive therapeutic target for cancer. A Nampt inhibitor with novel benzothiophene scaffold was discovered by high throughput screening. Herein the structure-activity relationship of the benzothiophene Nampt inhibitor was investigated. Several new inhibitors demonstrated potent activity in both biochemical and cell-based assays. In particular, compound 16b showed good Nampt inhibitory activity (IC50=0.17 μM) and in vitro antitumor activity (IC50=3.9 μM, HepG2 cancer cell line). Further investigation indicated that compound 16b could efficiently induce cancer cell apoptosis. Our findings provided a good starting point for the discovery of novel antitumor agents.
View details for DOI 10.1016/j.bmcl.2015.12.101
View details for Web of Science ID 000368797600013
View details for PubMedID 26755394
Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors
ACS MEDICINAL CHEMISTRY LETTERS
2015; 6 (3): 239–43
Designing multitarget drugs remains a significant challenge in current antitumor drug discovery. Because of the synergistic effect between topoisomerase and HDAC inhibitors, the present study reported the first-in-class triple inhibitors of topoisomerase I/II and HDAC. On the basis of 3-amino-10-hydroxylevodiamine and SAHA, a series of hybrid molecules was successfully designed and synthesized. In particular, compound 8c was proven to be a potent inhibitor of topoisomerase I/II and HDAC with good antiproliferative and apoptotic activities. This proof-of-concept study also validated the effectiveness of discovering triple topoisomerase I/II and HDAC inhibitors as novel antitumor agents.
View details for DOI 10.1021/ml500327q
View details for Web of Science ID 000351193100003
View details for PubMedID 25815139
View details for PubMedCentralID PMC4360171
Scaffold hopping of sampangine: Discovery of potent antifungal lead compound against Aspergillus fumigatus and Cryptococcus neoformans
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
2014; 24 (17): 4090–94
Discovery of novel antifungal agents against Aspergillus fumigatus and Cryptococcus neoformans remains a significant challenge in current antifungal therapy. Herein the antifungal natural product sampangine was used as the lead compound for novel antifungal drug discovery. A series of D-ring scaffold hopping derivatives were designed and synthesized to improve antifungal activity and water solubility. Among them, the thiophene derivative S2 showed broad-spectrum antifungal activity, particularly for Aspergillus fumigatus and Cryptococcus neoformans. Moreover, compound S2 also revealed better water solubility than sampangine, which represents a promising antifungal lead compound for further structural optimization.
View details for DOI 10.1016/j.bmcl.2014.07.064
View details for Web of Science ID 000341339300004
View details for PubMedID 25115626