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8. The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.

Author

Zhu, Ziang, Luo, Ying, Lou, Guohua, Yihunie, Kiddist, Wizzard, Safuwra, DeVilbiss, Andrew W., Muh, Sarah, Ma, Chaoyu, Shinde, Sejal S., Hoar, Jonathan, Hu, Taidou, Zhang, Nu, Biswal, Shyam, DeBerardinis, Ralph J., Wu, Tuoqi, and Yao, Chen

Subjects
IMMUNE checkpoint proteins, T-cell exhaustion, T cell receptors, T cells, METABOLIC reprogramming
Abstract

During persistent antigen stimulation, exhausted CD8+ T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8+ T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell–intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8+ T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8+ GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8+ T cells and long-term T cell immunity during chronic antigen exposure. Editor's summary: Oxidative stress activates the protective KEAP1-NRF2 pathway and expression of antioxidant genes, but this pathway's function in T cells is not fully understood. Using mouse models of acute and chronic viral infection, Zhu et al. found that the KEAP1-mediated suppression of NRF2 was required for optimal expansion of CD8+ T cells during chronic antigen exposure. KEAP1 enabled beneficial T cell adaptations including appropriate T cell receptor activation, metabolic reprogramming, and generation of stem-like T cells that support long-term immunity. KEAP1 also promoted expansion of chimeric antigen receptor (CAR) T cells exposed to persistent CAR signaling. Thus, the redox sensor KEAP1 supports T cell adaptations needed for productive responses during chronic antigen exposure. —Claire Olingy [ABSTRACT FROM AUTHOR]

Published
2024
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14. FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells

Author

Zhu, Ziang, primary, Lou, Guohua, additional, Teng, Xiao-Lu, additional, Wang, Haixia, additional, Luo, Ying, additional, Shi, Wangke, additional, Yihunie, Kiddist, additional, Hao, Shumeng, additional, DeGolier, Kole, additional, Liao, Chengheng, additional, Huang, Huocong, additional, Zhang, Qing, additional, Fry, Terry, additional, Wang, Tao, additional, Yao, Chen, additional, and Wu, Tuoqi, additional

Published
2023
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19. Author Correction: BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells

Author

Yao, Chen, Lou, Guohua, Sun, Hong-Wei, Zhu, Ziang, Sun, Yi, Chen, Zeyu, Chauss, Daniel, Moseman, E. Ashley, Cheng, Jun, D’Antonio, Marc A., Shi, Wangke, Shi, Junwei, Kometani, Kohei, Kurosaki, Tomohiro, Wherry, E. John, Afzali, Behdad, Gattinoni, Luca, Zhu, Yuwen, McGavern, Dorian B., O’Shea, John J., Schwartzberg, Pamela L., and Wu, Tuoqi

Published
2021
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31. Anti-metastasis traditional Chinese medicine monomer screening system based on perinucleolar compartment analysis in hepatocellular carcinoma cells

Author

Liu, Feifei, Lou, Guohua, Zhang, Tianbao, Chen, Senzhong, Xu, Jia, Xu, Lichen, Huang, Chunhong, Liu, Yanning, and Chen, Zhi

Subjects
Original Article, neoplasms, digestive system diseases
Abstract

Hepatocellular Carcinoma (HCC) lacks effective anti-metastasis drugs. Traditional Chinese Medicine (TCM) monomers have shown anti-proliferation activity in HCC, but few of them are specifically anti-metastasis. Therefore, further clarifying the indicators of HCC metastasis and screening TCM monomers based on the indicators, will effectively guide the development of novel anti-HCC drugs. The perinucleolar compartment (PNC), existing in the nuclear of tumor cells, is closely correlated with metastasis of several tumors. In this study, we found positive correlation between higher PNC prevalence and metastasis in HCC tissue of patients. The PNC prevalence was also positively correlated with the malignancy of HCC cell lines. On this premise, we established a PNC-based screening system for anti-metastasis TCM monomers and obtained Camptothecin (CPT), Evodiamine and Isoglycyrrhizin, the three most effective TCM monomers from a TCM monomer library to reduce the PNC prevalence in Huh7 cells. The anti-metastasis effect of these TCM monomers was positively correlated with their PNC inhibitor effect. Our data further revealed that CPT reduced metastasis of Huh7 cells possibly by inhibiting Epithelial-Mesenchymal Transition by upregulating the expression of ZO-1, E-cadherin and Claudin-1. The PNC-based screening system is effective and it may provide an effective technical platform for the development of anti-metastasis drugs.

Published
2019

34. Neddylation inhibitor MLN4924 has anti‐HBV activity via modulating the ERK‐HNF1α‐C/EBPα‐HNF4α axis.

Author

Xie, Mingjie, Guo, Huiting, Lou, Guohua, Yao, Jiping, Liu, Yanning, Sun, Yi, Yang, Zhenggang, and Zheng, Min

Subjects
VIRAL antigens, HEPATITIS B virus, TRANSCRIPTION factors, EXTRACELLULAR signal-regulated kinases, HEPATOCELLULAR carcinoma
Abstract

Hepatitis B virus (HBV) infection is a major public health problem. The high levels of HBV DNA and HBsAg are positively associated with the development of secondary liver diseases, including hepatocellular carcinoma (HCC). Current treatment with nucleos(t)ide analogues mainly reduces viral DNA, but has minimal, if any, inhibitory effect on the viral antigen. Although IFN reduces both HBV DNA and HBsAg, the serious associated side effects limit its use in clinic. Thus, there is an urgent demanding for novel anti‐HBV therapy. In our study, viral parameters were determined in the supernatant of HepG2.2.15 cells, HBV‐expressing Huh7 and HepG2 cells which transfected with HBV plasmids and in the serum of HBV mouse models with hydrodynamic injection of pAAV‐HBV1.2 plasmid. RT‐qPCR and Southern blot were performed to detect 35kb mRNA and cccDNA. RT‐qPCR, Luciferase assay and Western blot were used to determine anti‐HBV effects of MLN4924 and the underlying mechanisms. We found that treatment with MLN4924, the first‐in‐class neddylation inhibitor currently in several phase II clinical trials for anti‐cancer application, effectively suppressed production of HBV DNA, HBsAg, 3.5kb HBV RNA as well as cccDNA. Mechanistically, MLN4924 blocks cullin neddylation and activates ERK to suppress the expression of several transcription factors required for HBV replication, including HNF1α, C/EBPα and HNF4α, leading to an effective blockage in the production of cccDNA and HBV antigen. Our study revealed that neddylation inhibitor MLN4924 has impressive anti‐HBV activity by inhibiting HBV replication, thus providing sound rationale for future MLN4924 clinical trial as a novel anti‐HBV therapy. [ABSTRACT FROM AUTHOR]

Published
2021
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37. BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+T cells

Author

Yao, Chen, Lou, Guohua, Sun, Hong-Wei, Zhu, Ziang, Sun, Yi, Chen, Zeyu, Chauss, Daniel, Moseman, E. Ashley, Cheng, Jun, D’Antonio, Marc A., Shi, Wangke, Shi, Junwei, Kometani, Kohei, Kurosaki, Tomohiro, Wherry, E. John, Afzali, Behdad, Gattinoni, Luca, Zhu, Yuwen, McGavern, Dorian B., O’Shea, John J., Schwartzberg, Pamela L., and Wu, Tuoqi

Abstract

During chronic infection and cancer, a self-renewing CD8+T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8+T cells diverge from other CD8+subsets early after chronic viral infection. However, pathways guarding stem-like CD8+T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8+T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8+T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8+T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8+lineage and prevents an alternative terminally exhausted cell fate.

Published
2021
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40. 6‐Methoxyethylamino‐numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib

Author

Liu, Yanning, primary, Lou, Guohua, additional, Norton, John T., additional, Wang, Chen, additional, Kandela, Irawati, additional, Tang, Shuai, additional, Shank, Nathaniel I., additional, Gupta, Pankaj, additional, Huang, Min, additional, Avram, Michael J., additional, Green, Richard, additional, Mazar, Andrew, additional, Appella, Daniel, additional, Chen, Zhi, additional, and Huang, Sui, additional

Published
2017
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43. The Sterile Inflammation in the Exacerbation of HBV-Associated Liver Injury

Author

Yang, Qiao, Shi, Yu, Yang, Ying, Lou, Guohua, and Chen, Zhi

Subjects
Article Subject
Abstract

Exacerbation of hepatitis B virus-associated liver injury is characterized by abnormal immune response which not only mobilizes specific antiviral effects but also poses a potentially lethal nonspecific sterile inflammation to the host. How nonspecific sterile inflammation is triggered after the preexisting injury caused by specific immune injury remains elusive. In the setting of sterile inflammation, endogenous damage-associated molecular patterns are released by stressed and dying hepatocytes, which alarm the immune system through their potential pattern recognition receptors and related signaling pathways, orchestrate the influx of diverse cytokines, and ultimately amplify liver destruction. This review highlights current knowledge about the sterile hepatic inflammation in the exacerbation of chronic hepatitis B.

Published
2015
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46. SPAG9 is involved in hepatocarcinoma cell migration and invasion via modulation of ELK1 expression

Author

Yan,Qiuyue, Lou,Guohua, Qian,Ying, Qin,Bo, Xu,Xiuping, Wang,Yanan, Liu,Yanning, Dong,Xuejun, Yan,Qiuyue, Lou,Guohua, Qian,Ying, Qin,Bo, Xu,Xiuping, Wang,Yanan, Liu,Yanning, and Dong,Xuejun

Abstract

Qiuyue Yan,1,2 Guohua Lou,3 Ying Qian,1 Bo Qin,1 Xiuping Xu,1,2 Yanan Wang,1,2 Yanning Liu,3 Xuejun Dong1 1Shaoxing People’s Hospital, Shaoxing Hospital Zhejiang University, Shaoxing, Zhejiang, 2The Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, 3State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Background: Sperm-associated antigen 9 (SPAG9) is upregulated in several malignancies and its overexpression is positively correlated with cancer cell malignancies. However, the specific biological roles of SPAG9 in hepatocellular carcinoma (HCC) are less understood. Methods: We analyzed SPAG9 and ETS-like gene 1, tyrosine kinase (ELK1) expression in 50 paired HCC specimens and adjacent noncancerous liver specimens using immunohistochemistry. SPAG9 small interfering RNA (siRNA) was used to knockdown SPAG9 expression in HCCLM3 and HuH7 cell lines. We used plasmids to upregulate ELK1 expression and siRNA to downregulate ELK1 expression in HuH7 cells. Quantitative real-time polymerase chain reaction and Western blot were used to evaluate the expression of SPAG9 and ELK1 at the mRNA and protein level, respectively. Wound healing, matrigel migration, and invasion analyses were performed to determine the effect of SPAG9 and ELK1 on HCC metastasis. Results: SPAG9 and ELK1 were overexpressed in HCC tissue specimens and their expressions were higher in HCCLM3 and HuH7 cells compared to the low-metastatic HepG2 cells. Overexpression of SPAG9 was positively associated with tumor-node-metastasis staging (P=0.032), metastasis parameters (P=0.018) of HCC patients, and ELK1 expression (r=0.422, P<0.001) in HCC tissue specimen

Published
2016

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