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3. Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing

Author

Vollmann, Elisabeth H, Cao, Lizhi, Amatucci, Aldo, Reynolds, Taylor, Hamann, Stefan, Dalkilic-Liddle, Isin, Cameron, Thomas O, Hossbach, Markus, Kauffman, Kevin J, Mir, Faryal F, Anderson, Daniel G, Novobrantseva, Tatiana, Koteliansky, Victor, Kisseleva, Tatiana, Brenner, David, Duffield, Jeremy, and Burkly, Linda C

Subjects
Biochemistry and Cell Biology, Biological Sciences, Liver Disease, Digestive Diseases, Biotechnology, Genetics, Chronic Liver Disease and Cirrhosis, 2.1 Biological and endogenous factors, Aetiology, Egr2, LNP, fibrosis, in vivo gene silencing, myofibroblast, siRNA, Clinical Sciences, Biochemistry and cell biology
Abstract

Fibrotic diseases contribute to 45% of deaths in the industrialized world, and therefore a better understanding of the pathophysiological mechanisms underlying tissue fibrosis is sorely needed. We aimed to identify novel modifiers of tissue fibrosis expressed by myofibroblasts and their progenitors in their disease microenvironment through RNA silencing in vivo. We leveraged novel biology, targeting genes upregulated during liver and kidney fibrosis in this cell lineage, and employed small interfering RNA (siRNA)-formulated lipid nanoparticles technology to silence these genes in carbon-tetrachloride-induced liver fibrosis in mice. We identified five genes, Egr2, Atp1a2, Fkbp10, Fstl1, and Has2, which modified fibrogenesis based on their silencing, resulting in reduced Col1a1 mRNA levels and collagen accumulation in the liver. These genes fell into different groups based on the effects of their silencing on a transcriptional mini-array and histological outcomes. Silencing of Egr2 had the broadest effects in vivo and also reduced fibrogenic gene expression in a human fibroblast cell line. Prior to our study, Egr2, Atp1a2, and Fkbp10 had not been functionally validated in fibrosis in vivo. Thus, our results provide a major advance over the existing knowledge of fibrogenic pathways. Our study is the first example of a targeted siRNA assay to identify novel fibrosis modifiers in vivo.

Published
2017

10. Abstract CT034: GLIMMER-01: initial results from a phase 1 dose escalation trial of a first-in-class bi-sialidase (E-602) in solid tumors

Author

Luke, Jason J., primary, Johnson, Melissa, additional, Tolcher, Anthony, additional, Chen, Christopher T., additional, Dai, Tong, additional, Curti, Brendan D., additional, El-Khoueiry, Anthony, additional, Sznol, Mario, additional, Henick, Brian S., additional, Horak, Christine, additional, Jayaraman, Pushpa, additional, Cole, Christopher B., additional, Wilson, Dawn, additional, Cao, Lizhi, additional, Peng, Li, additional, Feltquate, David, additional, Lathers, Deanne, additional, and Sharma, Manish R., additional

Published
2023
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12. Long-term pegylated growth hormone for children with growth hormone deficiency: a large, prospective, real-world study

Author

Hou, Ling, primary, Huang, Ke, additional, Gong, Chunxiu, additional, Luo, Feihong, additional, Wei, Haiyan, additional, Liang, Liyang, additional, Du, Hongwei, additional, Zhang, Jianping, additional, Zhong, Yan, additional, Chen, Ruimin, additional, Chen, Xinran, additional, Pan, Jiayan, additional, Jin, Xianjiang, additional, Zeng, Ting, additional, Liao, Wei, additional, Liu, Deyun, additional, Lan, Dan, additional, Zhu, Shunye, additional, Dong, Zhiya, additional, Ma, Huamei, additional, Yang, Yu, additional, Xiong, Feng, additional, MB, Ping Lu, additional, Cheng, Shengquan, additional, Gu, Xuefan, additional, Jin, Runming, additional, Liu, Yu, additional, Wu, Jinzhun, additional, Xu, Xu, additional, Chen, Linqi, additional, Dong, Qin, additional, Pan, Hui, additional, Su, Zhe, additional, Liu, Lijun, additional, Luo, Xiaoming, additional, Ni, Shining, additional, Chen, Zhihong, additional, Hu, Yuhua, additional, Wang, Chunlin, additional, Liu, Jing, additional, Liu, Li, additional, Lu, Biao, additional, Wang, Xinli, additional, Wang, Yunfeng, additional, Yang, Fan, additional, Zhang, Manyan, additional, Cao, Lizhi, additional, Liu, GeLi, additional, Yao, Hui, additional, Zhang, Yaqin, additional, Dai, Mingjuan, additional, Li, Guimei, additional, Li, Li, additional, Liu, Yanjie, additional, Wang, Kan, additional, Xiao, Yanfeng, additional, Zhang, Xingxing, additional, Dong, Junhua, additional, Gu, Zaiyan, additional, Ying, Lirong, additional, Huang, Feng, additional, Liu, Yanling, additional, Liu, Zheng, additional, Ye, Jin, additional, Zhao, Dongmei, additional, Hu, Xu, additional, Jiang, Zhihong, additional, Ye, Kan, additional, Zhu, Hong, additional, Chen, Shaoke, additional, Chen, Xiaobo, additional, Wan, Naijun, additional, Xu, Zhuangjian, additional, Yin, Qingjin, additional, Zhang, Hongxiao, additional, Huang, Xiaodong, additional, Yin, Jianying, additional, Zhang, Huifeng, additional, Li, Pin, additional, Yin, Ping, additional, Fu, Junfen, additional, and Luo, XiaoPing, additional

Published
2023
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13. 772 A phase 1/2 dose escalation/expansion study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of E-602, a bi-sialidase fusion protein, in advanced cancer (GLIMMER-01)

Author

Sharma, Manish, primary, Lathers, Deanne, additional, Johnson, Melissa, additional, Luke, Jason, additional, Puzanov, Igor, additional, Curti, Brendan, additional, Chen, Christopher, additional, El-Khoueiry, Anthony, additional, Henick, Brian, additional, Callahan, Margaret, additional, Sznol, Mario, additional, Patel, Sandip, additional, Wilson, Dawn, additional, Ricker, Melissa, additional, Cao, Lizhi, additional, Jayaraman, Pushpa, additional, Che, Jenny, additional, Peng, Li, additional, Feltquate, David, additional, and Tolcher, Anthony, additional

Published
2022
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17. Short-term efficacy and safety of a lower dose of polyethylene glycol recombinant human growth hormone in children with growth hormone deficiency: A randomized, dose-comparison study

Author

Jiang, Zhouhong, primary, Chen, Xuefeng, additional, Dong, Guanping, additional, Lou, Yin, additional, Zhang, Jianping, additional, Cheng, Xinran, additional, Pan, Jiayan, additional, Liao, Wei, additional, Wu, Jinzhun, additional, Huang, Xiaodong, additional, Jin, Xianjiang, additional, Liu, Deyun, additional, Zeng, Ting, additional, Zhu, Shunye, additional, Dong, Qin, additional, Luo, Xiaoming, additional, Lan, Dan, additional, Cao, Lizhi, additional, Zhang, Xingxing, additional, Liu, Jing, additional, Dai, Mingjuan, additional, Zhang, Manyan, additional, Liu, Li, additional, Dong, Junhua, additional, Zhao, Dongmei, additional, Ni, Shaoqing, additional, and Fu, Junfen, additional

Published
2022
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22. Long-term Pegylated GH for Children With GH Deficiency: A Large, Prospective, Real-world Study

Author

Hou, Ling, Huang, Ke, Gong, Chunxiu, Luo, Feihong, Wei, Haiyan, Liang, Liyang, Du, Hongwei, Zhang, Jianping, Zhong, Yan, Chen, Ruimin, Chen, Xinran, Pan, Jiayan, Jin, Xianjiang, Zeng, Ting, Liao, Wei, Liu, Deyun, Lan, Dan, Zhu, Shunye, Dong, Zhiya, Ma, Huamei, Yang, Yu, Xiong, Feng, Lu, Ping, Cheng, Shengquan, Gu, Xuefan, Jin, Runming, Liu, Yu, Wu, Jinzhun, Xu, Xu, Chen, Linqi, Dong, Qin, Pan, Hui, Su, Zhe, Liu, Lijun, Luo, Xiaoming, Ni, Shining, Chen, Zhihong, Hu, Yuhua, Wang, Chunlin, Liu, Jing, Liu, Li, Lu, Biao, Wang, Xinli, Wang, Yunfeng, Yang, Fan, Zhang, Manyan, Cao, Lizhi, Liu, GeLi, Yao, Hui, Zhan, Yaqin, Dai, Mingjuan, Li, Guimei, Li, Li, Liu, Yanjie, Wang, Kan, Xiao, Yanfeng, Zhang, Xingxing, Dong, Junhua, Gu, Zaiyan, Ying, Lirong, Huang, Feng, Liu, Yanling, Liu, Zheng, Ye, Jin, Zhao, Dongmei, Hu, Xu, Jiang, Zhihong, Ye, Kan, Zhu, Hong, Chen, Shaoke, Chen, Xiaobo, Wan, Naijun, Xu, Zhuangjian, Yin, Qingjin, Zhang, Hongxiao, Huang, Xiaodong, Yin, Jianying, Zhang, Huifeng, Li, Pin, Yin, Ping, Fu, Junfen, and Luo, XiaoPing

Published
2023
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23. 843 Development and engineering of human sialidase for degradation of immunosuppressive sialoglycans to treat cancer

Author

Peng Li, Das Abhishek, Xu Lihui, Nerle Sujata, Che Jenny, Autumn Turner, Hui Xu, Sandip A. Shelke, James Broderick, Gatlin Wayne, Cao Lizhi, Robert LeBlanc, and Zakir Siddiquee

Subjects
Pharmacology, Cancer Research, biology, Chemistry, medicine.medical_treatment, Immunology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Sialidase, Mixed lymphocyte reaction, Acquired immune system, Immune system, Cytokine, Oncology, Antigen, Immunity, biology.protein, Cancer research, medicine, Molecular Medicine, Immunology and Allergy, Antibody, RC254-282
Abstract

BackgroundSialoglycans, a type of glycans with a terminal sialic acid, have emerged as a critical glyco-immune checkpoint that impairs antitumor response by inhibiting innate and adaptive immunity. Upregulation of sialoglycans on tumors has been observed for decades and correlates with poor clinical outcomes across many tumor types. We previously showed that targeted desialylation of tumors using a bifunctional sialidase x antibody molecule, consisting of sialidase and a tumor-associated antigen (TAA)-targeting antibody, has led to robust single-agent efficacy in mouse tumor models. In addition to tumor cells, most immune cells present substantially more abundant sialoglycans than non-hematological healthy cells, which may also contribute to immunosuppression. Therefore, we studied the impact of immune cell desialylation and evaluated the therapeutic potential of a newly developed sialidase-Fc fusion (Bi-Sialidase), which lacks a TAA-targeting moiety and consists of engineered human neuraminidase 2 (Neu2) and human IgG1 Fc region, in preclinical mouse tumor models.MethodsThe first generation Neu2 variant was further optimized to improve titers and stability to constructed Bi-Sialidase. Bi-Sialidase’s desialylation potency and impact on immune responses were studied in vitro using various human immune functional assays, including T-cell activation, allogeneic mixed lymphocyte reaction, antibody-dependent cellular cytotoxicity, macrophages polarization/activation, neutrophil activation, and peripheral blood mononuclear cell (PBMC) cytokine release assays. We evaluated its antitumor efficacy in mouse tumor models. Bi-Sialidase’s safety profile was characterized by conducting rat and non-human primate (NHP) toxicology studies.ResultsThe optimized Bi-Sialidase achieved a titer of 2.5 g/L from a 15-day fed-batch Chinese hamster ovary cell culture; in contrast, the wild-type and first-generation Neu2 had no production or a low titer (ConclusionsBi-Sialidase with an optimized Neu2 offers a novel immunomodulatory approach to enhancing T-cell immunity by desialylating immunosuppressive sialoglycans for cancer treatment.

Published
2021

25. Salvianolic Acid B Improves Chronic Mild Stress-Induced Depressive Behaviors in Rats: Involvement of AMPK/SIRT1 Signaling Pathway

Author

Liao,Dehua, Chen,Yun, Guo,Yujin, Wang,Changshui, Liu,Ni, Gong,Qian, Fu,Yingzhou, Fu,Yilan, Cao,Lizhi, Yao,Dunwu, and Jiang,Pei

Subjects
Journal of Inflammation Research
Abstract

Dehua Liao,1,2,* Yun Chen,1,* Yujin Guo,3 Changshui Wang,4 Ni Liu,1 Qian Gong,1 Yingzhou Fu,1 Yilan Fu,1 Lizhi Cao,1 Dunwu Yao,1 Pei Jiang3 1Department of Pharmacy, Hunan Cancer Hospital, Changsha, Hunan 410013, People’s Republic of China; 2Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 3Institute of Clinical Pharmacy & Pharmacology, Jining First People’s Hospital, Jining, Shandong 272000, People’s Republic of China; 4Department of Clinical Translational Medicine, Jining Life Science Center, Jining, Shandong 272000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pei Jiang Tel/ Fax + 86 537 2106208Email jiangpeicsu@sina.comIntroduction: Depression is one of the most common neuropsychiatric illnesses which leads to a huge social and economic burden on modern society. So, it is necessary to develop an effective and safe pharmacological intervention for depression. Accumulating evidence has shown that adenosine monophosphate-activated protein kinase/sirtuin 1 (AMPK/SIRT1) signaling pathway plays a pivotal role in the development of depression. Our present study aimed to investigate the antidepressant effect and possible mechanisms of salvianolic acid B (SalB) in a chronic mild stress (CMS)-induced depression model in rats.Materials and Methods: The rats were randomly divided into three groups: control group with no stressor, CMS group and CMS+SalB (30 mg/kg/d) group. After administration for 28 consecutive days, the behavior tests were performed. The rats were sacrificed after behavior tests, and the brain tissues were collected for biochemical analysis.Results: It was observed that the administration of SalB for 28 consecutive days successfully corrected the depressive-like behaviors in CMS-treated rats. SalB could effectively reduce the gene expression of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α), as well as nuclear factor-kappa B (NF-κB) p65 protein. In addition, inhibitor of NF-κB (IκB) protein expression was significantly increased after the administration of SalB. Moreover, SalB could effectively decrease protein expression of oxidative stress markers such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) and increase the activity of catalase (CAT). SalB treatment also reversed CMS-induced inhibition of Nrf2 signaling pathway, along with increasing the mRNA expression of NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1 (HO-1). Regarding the endoplasmic reticulum (ER) stress markers, the protein expressions of C/EBP-homologous protein (CHOP) and glucose-regulated protein 78 kD (GRP78) were also significantly reduced after SalB administration. Furthermore, the supplementation of SalB could effectively activate the AMPK/SIRT1 signaling pathway, which indicated significant increase in pAMPK/AMPK ratio and SIRT1 protein expression.Conclusion: Our study demonstrated that SalB relieved CMS-induced depressive-like state through the mitigation of inflammatory status, oxidative stress, and the activation of AMPK/SIRT1 signaling pathway.Keywords: SalB, depression, CMS, AMPK/SIRT1

Published
2020

29. Polymorphisms of Drug-Metabolizing Enzymes and Transporters Contribute to the Individual Variations of Erlotinib Steady State Trough Concentration, Treatment Outcomes, and Adverse Reactions in Epidermal Growth Factor Receptor–Mutated Non-Small Cell Lung Cancer Patients

Author

Liao, Dehua, primary, Liu, Zhigang, additional, Zhang, Yongchang, additional, Liu, Ni, additional, Yao, Dunwu, additional, Cao, Lizhi, additional, Chen, Yun, additional, Fu, Yilan, additional, Yang, Nong, additional, and Xiang, Daxiong, additional

Published
2020
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31. TMEM173 Drives Lethal Coagulation in Sepsis

Author

Zhang, Hui, primary, Zeng, Ling, additional, Xie, Min, additional, Liu, Jiao, additional, Zhou, Borong, additional, Wu, Runliu, additional, Cao, Lizhi, additional, Kroemer, Guido, additional, Wang, Haichao, additional, Billiar, Timothy R., additional, Zeh, Herbert J., additional, Kang, Rui, additional, Jiang, Jianxin, additional, Yu, Yan, additional, and Tang, Daolin, additional

Published
2020
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35. Abstract PR18: A novel immunomodulatory strategy of targeting glyco-immune checkpoints using EAGLE technology to treat cancer

Author

Adam Petrone, James Broderick, Cao Lizhi, and Peng Li

Subjects
Eagle, Cancer Research, Tumor microenvironment, biology, medicine.drug_class, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunosuppression, Immunotherapy, medicine.disease, Monoclonal antibody, Immune system, Immunity, biology.animal, medicine, Cancer research, business
Abstract

Cancer therapy has been revolutionized by inhibiting immune checkpoints to harness the power of the immune system in fighting cancer. However, the majority of patients are resistant to the current immuno-oncology drugs. There is a strong need to identify novel mechanisms of immune evasion in cancer and explore novel therapeutic modalities. Recently, glyco-immune checkpoints have been identified as an important modulator in cancer immune escape. Upon ligation of cancer-specific sialylated glycans, glyco-immune checkpoints suppress multiple facets of cancer immunity, including cancer antigen release, cancer antigen presentation, and priming and activation anticancer T-cell immunity. However, due to the complexity and heterogeneity of cancer sialylated glycans and the profound species differences of the glyco-immune checkpoints between human and mouse, this immunomodulatory pathway remains unexplored for therapeutic interventions. Here we described a novel multifunctional antibody-like therapeutic modality, named EAGLE (Enzyme-Antibody Glyco-Ligand Editing), to target this glyco-immune checkpoint axis. EAGLE overcomes the complexity of cancer glycans and specifically cleaves the immunosuppression-mediating key sugar moieties, the terminal sialic acids of various sialylated glycans on tumor cells. We hypothesized that EAGLE could block the immunosuppressive glyco-immune checkpoints in the tumor microenvironment and potentiate innate and adaptive immune responses to treat cancer. Indeed, systematic delivery of an EAGLE molecule decreased the levels of immunosuppressive sialic acids on tumor cells, and increased T-cell infiltration and activation in syngeneic tumor models. EAGLE treatment led to 50% complete regressions of established tumors as a monotherapy, and 100% cures in combination with anti-PD1 mAb. Furthermore, cured mice from EAGLE treatment completely rejected the rechallenge of tumor cells, suggesting that EAGLE induced antitumor immunologic memory. In summary, we demonstrated that this novel therapeutic modality, EAGLE, can release glyco-immune checkpoint-mediated immunosuppression in the tumor microenvironment and potentiate innate and adaptive antitumor immunity, which offers a novel and promising immunomodulatory strategy to treat cancer. This abstract is also being presented as Poster A91. Citation Format: Li Peng, Adam Petrone, Lizhi Cao, James Broderick. A novel immunomodulatory strategy of targeting glyco-immune checkpoints using EAGLE technology to treat cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR18.

Published
2020

37. Abstract LB-109: A novel therapeutic modality of inhibiting the glyco-immune checkpoint axis to treat cancer

Author

Cao, Lizhi, primary, Petrone, Adam, additional, Gatlin, Wayne, additional, Che, Jenny, additional, Das, Abhishek, additional, LeBlanc, Robert, additional, Siddiquee, Zakir, additional, Nerle, Sujata, additional, Stanczak, Michal, additional, Mayo, Michele, additional, Xu, Lihui, additional, Normington, Karl, additional, Brown, Jeff, additional, Yao, Wei, additional, Bertozzi, Carolyn, additional, Broderick, James, additional, Läubli, Heinz, additional, and Peng, Li, additional

Published
2019
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41. Extracellular matrix rigidity modulates neuroblastoma cell differentiation and N-myc expression

Author

Umesh Vaibhavi, Cao Lizhi, Lam Wilbur A, Keung Albert J, Sen Shamik, and Kumar Sanjay

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Neuroblastoma is a pediatric malignancy characterized by tremendous clinical heterogeneity, in which some tumors are extremely aggressive while others spontaneously differentiate into benign forms. Because the degree of differentiation correlates with prognosis, and because differentiating agents such as retinoic acid (RA) have proven to decrease mortality, much effort has been devoted to identifying critical regulators of neuroblastoma differentiation in the cellular microenvironment, including cues encoded in the extracellular matrix (ECM). While signaling between tumor cells and the ECM is classically regarded to be based purely on biochemical recognition of ECM ligands by specific cellular receptors, a number of recent studies have made it increasingly clear that the biophysical properties of the ECM may also play an important role in this cross-talk. Given that RA-mediated neuroblastoma differentiation is accompanied by profound changes in cell morphology and neurite extension, both of which presumably rely upon mechanotransductive signaling systems, it occurred to us that mechanical cues from the ECM might also influence RA-mediated differentiation, which in turn might regulate clinically-relevant aspects of neuroblastoma biology. In this study, we tested this hypothesis by subjecting a series of neuroblastoma culture models to ECM microenvironments of varying mechanical stiffness and examined the regulatory role of ECM stiffness in proliferation, differentiation, and expression of tumor markers. We find that increasing ECM stiffness enhances neuritogenesis and suppresses cell proliferation. Remarkably, increasing ECM stiffness also reduces expression of N-Myc, a transcription factor involved in multiple aspects of oncogenic proliferation that is used for evaluating prognosis and clinical grading of neuroblastoma. Furthermore, the addition of RA enhances all of these effects for all ECM stiffnesses tested. Together, our data strongly support the notion that the mechanical signals from the cellular microenvironment influence neuroblastoma differentiation and do so synergistically with RA. These observations support further investigation of the role of microenvironmental mechanical signals in neuroblastoma proliferation and differentiation and suggest that pharmacological agents that modulate the underlying mechanotransductive signaling pathways may have a role in neuroblastoma therapy.

Published
2010
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42. Dysregulation of Neuregulin-1/ErbB signaling in the hippocampus of rats after administration of doxorubicin

Author

Liao,Dehua, Guo,Yujin, Xiang,Daxiong, Dang,Ruili, Xu,Pengfei, Cai,Hualin, Cao,Lizhi, Jiang,Pei, Liao,Dehua, Guo,Yujin, Xiang,Daxiong, Dang,Ruili, Xu,Pengfei, Cai,Hualin, Cao,Lizhi, and Jiang,Pei

Abstract

Dehua Liao,1,2 Yujin Guo,3 Daxiong Xiang,2 Ruili Dang,3 Pengfei Xu,3 Hualin Cai,2 Lizhi Cao,1 Pei Jiang3 1Department of Pharmacy, Hunan Cancer Hospital, 2Department of Pharmacy, Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha, 3Department of Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining, People’s Republic of China Objective: Long-term use of doxorubicin (Dox) can cause neurobiological side effects associated with depression, but the underlying mechanisms remain equivocal. While recent evidence has indicated that Neuregulin-1 (NRG1) and its ErbB receptors play an essential role in neural function, much is still unknown concerning the biological link between the NRG1/ErbB pathway and the Dox-induced neurotoxicity. Therefore, we examined the protein expression of NRG1 and ErbB receptors in the hippocampus of rats following Dox treatment.Materials and methods: The drug was administered every 2 days at a dose of 2.5 mg/kg, and the animals in different groups were treated with intraperitoneal injection for three or seven times, respectively.Results: Our data showed that the rats treated with Dox for seven times (DoxL group) exhibited depression-like behaviors, whereas the short-term treatment (DoxS group) had no effect on the behavioral changes. Dox treatment also induced the neural apoptosis with more severe neurotoxicity. Intriguingly, the expression of NRG1 and the ratio of pErbB4/ErbB4 and pErbB2/ErbB2 were significantly decreased in the DoxL group, but enhanced activation of ErbB receptors was observed in the DoxS group. In parallel, administration of Dox for seven times suppressed the downstream Akt and ERK phosphorylation, while the Akt phosphorylation was enhanced with the administration of Dox for three times.Conclusion: Our data first showed the Dox-induced alterations of the NRG1/ErbB system in the hippocampus, indicating the po

Published
2018

43. Involvement of neurotrophic signaling in doxorubicin-induced cardiotoxicity.

Author

Liao, Dehua, Zhang, Chen, Liu, Ni, Cao, Lizhi, Wang, Changshui, Feng, Qingyan, Yao, Dunwu, Long, Minghui, and Jiang, Pei

Subjects
BRAIN-derived neurotrophic factor, NERVE growth factor, PROTEIN kinase B, CARDIOTOXICITY, ASPARTATE aminotransferase, NEUROTROPHINS
Abstract

Dose dependent cardiotoxicity is the primary side effect of doxorubicin (DOX), but the underlying molecular mechanisms remain unclear. An increasing amount of evidence has demonstrated that neurotrophic signaling plays a pivotal role in both neurons and the heart, but the biological association between neurotrophic signaling and DOX-induced cardiotoxicity remains unknown. The present study determined the level of neurotrophins and their receptors in the heart of rats following DOX administration. DOX was administered 7 times at a dose of 2.5 mg/kg once every 2 days via intraperitoneal injection. The present study revealed that cardiac injury parameters, such as creatine kinase (CK), creatine kinase-myocardial bound, lactate dehydrogenase, troponin T and aspartate transaminase in serum were significantly increased in the DOX group. Both the gene and protein expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the heart were markedly decreased following DOX treatment. Notably, the protein level of BDNF in the serum was inhibited in DOX-treated rats, whereas DOX induced a significant increase in the protein level of NGF in the serum. DOX induced a significant decrease in the level of tropomyosin-associated kinase A (TrkA) and the ratio of pTrkA/TrkA and pTrkB/TrkB. Furthermore, the administration of DOX suppressed downstream protein kinase B and extracellular signal regulated kinase phosphorylation. The present study first demonstrated that BDNF/TrkB signaling and NGF/TrkA signaling were altered by DOX, which indicated that neurotrophic signaling was involved in DOX-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Published
2020
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47. The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis

Author

Deng, Wenjun, primary, Zhu, Shan, additional, Zeng, Ling, additional, Liu, Jiao, additional, Kang, Rui, additional, Yang, Minghua, additional, Cao, Lizhi, additional, Wang, Haichao, additional, Billiar, Timothy R., additional, Jiang, Jianxin, additional, Xie, Min, additional, and Tang, Daolin, additional

Published
2018
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48. Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis

Author

Kang, Rui, primary, Zeng, Ling, additional, Zhu, Shan, additional, Xie, Yangchun, additional, Liu, Jiao, additional, Wen, Qirong, additional, Cao, Lizhi, additional, Xie, Min, additional, Ran, Qitao, additional, Kroemer, Guido, additional, Wang, Haichao, additional, Billiar, Timothy R., additional, Jiang, Jianxin, additional, and Tang, Daolin, additional

Published
2018
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