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The roles and mechanisms of SREBP1 in cancer development and drug response

Genes & Diseases 2024年第4期11卷 258-269页

作者： Ying He Shasha Qi Lu Chen Jinyu Zhu Linda Liang Xudong Chen Hao Zhang Lvjia Zhuo Shujuan Zhao Shuiping Liu Tian Xie School of Pharmacy Hangzhou Normal UniversityHangzhouZhejiang 311121China key laboratory of elemene class anti-cancer chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhouZhejiang 311121China laboratory of cancer Genomics Division of Cellular and Molecular ResearchNational Cancer Centre SingaporeSingapore 169610Singapore

cancer occurrence and development are closely related to increased lipid produc-tion and glucose *** are the basic component of the cell membrane and play a significant role in cancer cell processes such as cell-to-cell recognition,signal transduction,and energy supply,which are vital for cancer cell rapid proliferation,invasion,and *** regulatory element-binding transcription factor 1(SREBP1)is a key transcription factor regulating the expression of genes related to cholesterol biosynthesis,lipid homeostasis,and fatty acid *** addition,SREBP1 and its upstream or downstream target genes are implicated in various metabolic diseases,particularly ***,no review of sREBP1 in cancer biology has yet been ***,we summarized the roles and mechanisms of SREBP1 biological processes in cancer cells,including SREBP1 modification,lipid metabolism and reprogramming,glucose and mitochondrial metabolism,immunity,and tumor microenvi-ronment,epithelial-mesenchymal transition,cell cycle,apoptosis,and ***-ally,we discussed the potential role of SREBP1 in cancer prognosis,drug response such as drug sensitivity to chemotherapy and radiotherapy,and the potential drugs targeting SREBP1 and its corresponding pathway,elucidating the potential clinical application based on SREBP1 and its corresponding signal pathway.

关键词： cancer Drug Lipid metabolism reprogramming Resistance SREBP1

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Lipid metabolism, amino acid metabolism, and prostate cancer: a crucial metabolic journey

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Asian Journal of Andrology 2024年第2期26卷 123-134页

作者： Lin Chen Yu-Xin Xu Yuan-Shuo Wang Jian-Liang Zhou School of Pharmacy Hangzhou Normal UniversityHangzhou 311121China key laboratory of elemene class anti-cancer chinese medicines Collaborative Innovation Center of Traditional chinese medicines of Zhejiang Province Hangzhou Normal UniversityHangzhou 311121China School of Pharmacy Guangxi Medical UniversityNanning530021China

Prostate cancer(PCa)is one of the most common malignancies in males worldwide,and its development and progression involve the regulation of multiple metabolic *** in lipid metabolism affect the proliferation and metastatic capabilities of PCa *** cells increase lipid synthesis and regulate fatty acid oxidation to meet their growth and energy ***,changes occur in amino acid metabolism in *** cells exhibit an increased demand for specific amino acids,and they regulate amino acid transport and metabolic pathways to fulfill their proliferation and survival *** changes are closely associated with disease progression and treatment response in PCa ***,a comprehensive investigation of the metabolic characteristics of PCa is expected to offer novel insights and approaches for the early diagnosis and treatment of this disease.

关键词： amino acid metabolism lipid metabolism metabolic pathways prostate cancer treatment strategies

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elemene antitumor Drugs Development Based on "Molecular Compatibility Theory" and Clinical Application: A Retrospective and Prospective Outlook

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chinese Journal of Integrative Medicine 2024年第1期30卷 62-74页

作者： JIANG Xiao-ying SHI Li-ping ZHU Jun-long BAI Ren-ren XIE Tian School of Pharmacy Hangzhou Normal UniversityHangzhou(311121)China key laboratory of elemene class anti-cancer chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhou(311121)China Good Clinical Practice Center Affliliated Hospital of Nanjing University of Chinese MedicineNanjing(210000)China

elemene, derived from Curcuma wenyujin, one of the "8 famous genuine medicinal materials of Zhejiang province," exhibits remarkable antitumor activity. It has gained wide recognition in clinical practice for effectiveness on tumors. Dr. XIE Tian introduced the innovative concept of "molecular compatibility theory" by combining chinese medicine principles, specifically the "monarch, minister, assistant, and envoy" theory, with modern biomedical technology. This groundbreaking approach, along with a systematic analysis of chinese medicine and modern biomedical knowledge, led to the development of elemene nanoliposome formulations. These novel formulations offer numerous advantages, including low toxicity, well-defined composition, synergistic effects on multiple targets, and excellent biocompatibility. Following the principles of the "molecular compatibility theory", further exploration of cancer treatment strategies and methods based on elemene was undertaken. This comprehensive review consolidates the current understanding of elemene's potential antitumor mechanisms, recent clinical investigations, advancements in drug delivery systems, and structural modifications. The ultimate goal of this review is to establish a solid theoretical foundation for researchers, empowering them to develop more effective antitumor drugs based on the principles of "molecular compatibility theory".

关键词： molecular compatibility theory chinese integrative medicine elemene antitumor activity drug delivery structural modification

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The Wnt-dependent and Wnt-independent functions of BCL9 in development,tumorigenesis,and immunity:Implications in therapeutic opportunities

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Genes & Diseases 2024年第2期11卷 701-710页

作者： Minjie Wu Heng Dong Chao Xu Mengqing Sun Haojin Gao Fangtian Bu Jianxiang Chen College of Pharmacy and Department of Hepatology Institute of Hepatology and Metabolic DiseasesThe Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhouZhejiang 311121China laboratory of cancer Genomics Division of Cellular and Molecular ResearchNational Cancer CentreSingapore 169610Singapore key laboratory of elemene class anti-cancer chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhouZhejiang 311121China

B-cell CLL/lymphoma 9(BCL9)is considered a key developmental regulator and a well-established oncogenic driver in multiple cancer types,mainly through potentiating the Wnt/β-catenin ***,increasing evidences indicate that BCL9 also plays multiple Wnt-independent ***,we summarized the updates of the canonical and non-canonical functions of BCL9 in cellular,physiological,or pathological ***,we also concluded that the targeted inhibitors disrupt the interaction ofβ-catenin with BCL9 reported recently.

关键词： BCL9 Development Immunity Multifaceted functions Therapeutic target Tumorigenesis

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LH-Nts Neurons Regulate VTA Calcium Dynamics Via Releasing GABA and Nts

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Neuroscience Bulletin 2024年第4期40卷 550-552页

作者： Danni Chen Yinfeng Yuan Zhihui Huang Yongjie Wang School of Pharmacy Hangzhou Normal UniversityHangzhou311121ZhejiangChina key laboratory of Element class anti-cancer chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhou311121ZhejiangChina

The peripheral and central nervous systems have numerous examples of two or more neuroactive products co-existing in the same neuron[1],which can simultaneously be released as both fast-acting neurotransmitters and slow-acting regulatory neuropeptides[2].For example,neurons in the lateral hypothalamus(LH)release both irritant neurotensin(Nts)and inhibitory-aminobutyric acid(GABA),two counterproductive substances[3].LH-Nts neurons project to the ventral tegmental area(VTA)and form synaptic connections with dopamine(DA)neurons to regulate reward[4-6].More critically,VTA-DA neurons express the Nts receptor Ntsrl and play a crucial role in cognition,anesthesia,reward,and disgust[4,7,8].Nevertheless,a mechanistic understanding of how stimulation and inhibition work together to control the output of neural circuits remains *** is very difficult to selectively isolate these signaling pathways in cell and circuit-specific manners.

关键词： anesthesia stimulation dopamine

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Monotropein Induced Apoptosis and Suppressed Cell Cycle Progression in Colorectal cancer Cells

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chinese Journal of Integrative Medicine 2024年第1期30卷 25-33页

作者： GAO Quan LI Lin ZHANG Qi-man SHENG Qin-song ZHANG Ji-liang JIN Li-jun SHANG Rui-yan School of Pharmacy and Department of Medical Oncology the Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhou(311121)China key laboratory of elemene class anti-cancer chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhou(311121)China Department of Colorectal Surgery the First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina Beijing Tong Ren Tang chinese Medicine Co. Ltd.Beijing(100000)China Department of Traditional chinese Medicine Hangzhou Shangcheng District People's HospitalHangzhou(310006)China Department of Gynecology Hangzhou Women's HospitalHangzhou(310008)China

Objective: To determine whether monotropein has an anticancer effect and explore its potential mechanisms against colorectal cancer(CRC) through network pharmacology and molecular docking combined with experimental verification. Methods: Network pharmacology and molecular docking were used to predict potential targets of monotropein against CRC. Cell counting kit assay, plate monoclonal assay and microscopic observation were used to investigate the antiproliferative effects of monotropein on CRC cells HCT116, HT29 and LoVo. Flow cytometry and scratch assay were used to analyze apoptosis and cell cycle, as well as cell migration, respectively in HCT116, HT29, and LoVo cells. Western blotting was used to detect the expression of proteins related to apoptosis, cell cycle, and cell migration, and the expression of proteins key to the Akt pathway. Results: The Gene Ontology and Reactome enrichment analyses indicated that the anticancer potential of monotropein against CRC might be involved in multiple cancer-related signaling pathways. Among these pathways, RAC-beta serine/threonine-protein kinase(Akt1, Akt2), cyclin-dependent kinase 6(CDK6), matrix metalloproteinase-9(MMP9), epidermal growth factor receptor(EGFR), cell division control protein 42 homolog(CDC42) were shown as the potential anticancer targets of monotropein against CRC. Molecular docking suggested that monotropein may interact with the 6 targets(Akt1, Akt2, CDK6, MMP9, EGFR, CDC42). Subsequently, cell activity of HCT116, HT29 and LoVo cell lines were significantly suppressed by monotropein(Pcancer by decreasing the expressions of CyclinD1, CDK4 and CDK6, inhibited cell migration by suppressing the expressions of CDC42 and MMP9(Panticancer role through Akt signaling pathway. Conclusions: Monotropein exerts its antitumor

关键词： monotropein chinese medicine anticancer activity colorectal cancer cells network pharmacology

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STING signaling in islet macrophages impairs insulin secretion in obesity

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Science China(Life Sciences) 2024年第2期67卷 345-359页

作者： Ze Hong Saihua Chen Jing Sun Dan Cheng Hanli Guo Jiahao Mei Xiang Zhang Munire Maimaiti Haiping Hao Peng Cao Haiyang Hu Chen Wang School of Pharmacy Nanjing University of Chinese MedicineNanjing 210023China State key laboratory of Natural medicines Department of Life Science and TechnologyChina Pharmaceutical UniversityNanjing 211198China School of Life Sciences Westlake UniversityHangzhou 310012China

The innate immune regulator stimulator of interferon genes(STING)mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines,which promotes the progression of various inflammatory and autoimmune *** immune system plays a critical role in regulating obesity-induced islet dysfunction,whereas the potential effect of STING signaling is not fully ***,we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet(HFD)***^(-/-)alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of ***,palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in ***,STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment ofβcell insulin secretory *** inhibiting STING activation enhances insulin secretion to control ***,our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in dietinduced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.

关键词： STING obesity type 2 diabetes insulin macrophages islet

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A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT

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chinese Journal of Natural medicines 2024年第2期22卷 112-126页

作者： REN Boxue LI Yang DI Lei CHENG Ranran LIU Lijuan LI Hongmei LI Yi TANG Zhangrui YAN Yongming LU Tao FU Rong CHENG Yongxian WU Zhaoqiu State key laboratory of Natural medicines Department of PharmacologySchool of PharmacyChina Pharmaceutical UniversityNanjing 211198China Institute for Inheritance-Based Innovation of chinese Medicine School of Pharmaceutical SciencesShenzhen University Health Science CenterShenzhen 518060China

The tumor suppressor protein p53 is central to cancer biology,with its pathway reactivation emerging as a promising therapeutic strategy in *** study introduced LZ22,a novel compound that selectively inhibits the growth,migration,and metastasis of tumor cells expressing wild-type p53,demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant ***22’s mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 *** interaction disrupted the MDM2-p53 binding,consequently stabilizing p53 by shielding it from proteasomal ***22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling ***,LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT,effectively reducing tumor cell migration and distal ***,LZ22 administration in tumor-bearing mice did not manifest notable side *** findings position LZ22 as a structurally unique reactivator of p53,offering therapeutic promise for the management of human cancers with wild-type TP53.

关键词： LZ22 Wild-type p53 p53 Reactivator Snail-driven EMT Tumor growth and metastasis

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Discovery and bioassay of disubstituted β-elemene-NO donor conjugates:synergistic enhancement in the treatment of leukemia

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chinese Journal of Natural medicines 2023年第12期21卷 916-926页

作者： ZHU Junlong JIANG Xiaoying LUO Xinyu GAO Yuan ZHAO Rui LI Junjie CAI Hong DANG Xiawen YE Xiangyang BAI Renren XIE Tian School of Pharmacy Hangzhou Normal UniversityHangzhou 311121China key laboratory of elemene class anti-cancer chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhou 311121China

Natural products are essential sources of antitumor *** such molecule,β-elemene,is a potent antitumor compound extracted from Curcuma *** the present investigation,a series of novel 13,14-disubstituted nitric oxide(NO)-donorβelemene derivatives were designed,withβ-elemene as the foundational compound,and subsequently synthesized to evaluate their therapeutic potential against ***,the derivative labeled as compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line,with a high NO *** vivo studies indicated that compound 13d could effectively inhibit tumor growth,exhibiting no discernible toxic ***,a significant tumor growth inhibition rate of 62.9%was observed in the K562 xenograft tumor mouse *** accumulated data propound the potential therapeutic application of compound 13d in the management of leukemia.

关键词： antitumor activity Chronic myeloid leukemia β-elemene Nitric oxide donor Structural modification

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Loss of C9orf72 in Microglia Drives Neuronal Injury by Enhancing Synaptic Pruning in Aged and Alzheimer’s Disease Mice

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Neuroscience Bulletin 2022年第3期38卷 327-330页

作者： Mengmeng Wang Yuanyuan Jiang Zhihui Huang School of Pharmacy Hangzhou Normal UniversityHangzhou311121China key laboratory of elemene class anti-cancer chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhou311121China

Many diseases are caused by the expansion of simple sequence repeats scattered throughout the human genome;they are defined as repeat expansion *** size of the repeat unit ranges from trinucleotides(the vast majority)to tetranucleotides,pentanucleotides,hexan cleotides,and even dodecanucleotides[1].Expansions of the hexanucleotide GGGGCC in the C9orf72 gene are the most frequent genetic cause of amyotrophic lateral sclero・sis(ALS)and frontotemporal dementia(FTD)[2].In addition to ALS and FTD,C9orf72 repeat expansions may also be associated with Alzheimer's disease(AD),since the rate of such expansions in AD cases(0.57%)is higher than normal(0.11%)[3].However,the exact role of C9orf72 in AD is still unclear.

关键词： C9orf72 Alzheimer diseases

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