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Current therapeutic modalities and chemopreventive role of natural products in liver cancer:Progress and promise

World Journal of Hepatology 2023年第1期15卷 1-18页

作者： Amit Kumar Singh Shiv Vardan Singh Ramesh Kumar Shashank Kumar Sabyasachi Senapati Abhay K Pandey Department of Botany Government Naveen Girls CollegeBalod(Hemchand Yadav University)DurgChattisgarhIndia Department of Biochemistry University of AllahabadPrayagraj 211002Uttar PradeshIndia Department of Biochemistry School of Basic and Applied SciencesCentral University of PunjabBathinda 151401PunjabIndia Department of Human Genetics and Molecular Medicine Central University of PunjabBathinda 151401PunjabIndia

Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year,with an estimated 5-year survival rate of 30%–35%after diagnosis.Hepatocellular carcinoma(HCC)constitutes a significant subtype of liver cancer(approximate75%)and is considered primary liver cancer.Treatment for liver cancer mainly depends on the stage of its progression,where surgery including,hepatectomy and liver transplantation,and ablation and radiotherapy are the prime choice.For advanced liver cancer,various drugs and immunotherapy are used as first-line treatment,whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins.Sorafenib and lenvatinib are first-line therapies,while regorafenib and ramucirumab are secondline therapy.Various metabolic and signaling pathways such as Notch,JAK/STAT,Hippo,TGF-β,and Wnt have played a critical role during HCC progression.Dysbiosis has also been implicated in liver cancer.Drug-induced toxicity is a key obstacle in the treatment of liver cancer,necessitating the development of effective and safe medications,with natural compounds such as resveratrol,curcumin,diallyl sulfide,and others emerging as promising anticancer agents.This review highlights the current status of liver cancer research,signaling pathways,therapeutic targets,current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.

关键词： Liver cancer Hepatocellular carcinoma signaling pathways Therapeutic targets Natural products Chemopreventive

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Small-molecule chemical probes for the potential therapeutic targets in alcoholic liver diseases

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Liver Research 2023年第3期7卷 177-188页

作者： Ashish Dogra Feng Li Center for Drug Discovery Department of Pathology&ImmunologyBaylor College of MedicineHoustonTXUSA NMR and Drug Metabolism Core Advanced Technology CoresBaylor College of MedicineHoustonTXUSA Department of Biochemistry&Molecular Pharmacology&Chemical Biology Baylor College of MedicineHoustonTXUSA

Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.

关键词： Alcoholic liver disease(ALD) signaling pathways Pathogenesis Therapeutic target chemical probe Small-molecule probe

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ATF4/TXNIP/REDD1/mTOR signaling mediates the antitumor activities of liver X receptor in pancreatic cancers

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Cancer Innovation 2022年第1期1卷 55-69页

作者： Zhikang Chen Xiaobo Lai Hui Ding Aijun Zhang Yufei Sun Jianhua Ling Paul J.Chiao Zihua Chen Xuefeng Xia The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor ChangshaHunanChina Department of General Surgery Xiangya HospitalCentral South UniversityChangshaHunanChina International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment&Standardization ChangshaHunanChina National Clinical Research Center for Geriatric Disorders Xiangya HospitalChangshaHunanChina Guangzhou First People's Hospital The Second Affiliated Hospital of South China University of TechnologyGuangzhouGuangdongChina Hainan Eye Hospital and Key Laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-Sen UniversityHaikouHainanChina Houston Methodist Research Institute HoustonTexasUSA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA GenePlus‐Beijing Institute BeijingChina

Background:Limited by difficulties in early detection and availabilities of effective treatments,pancreatic cancer is a highly malignant disease with poor prognosis.Nuclear receptors are a family of ligand‐dependent transcription factors that are highly druggable therapeutic targets playing critical roles in human physiological and pathological development,including cancer.In this study,we explored the therapeutic potential as well as the molecular mechanisms of liver X receptor(LXR)agonist GW3965 in pancreatic cancer.Methods:Soft‐agar colony formation assay,xenograft tumors,Oligonucleotide microarray,Reverse transcription real‐time polymerase chain reaction,Western immunoblotting and Immunohistochemistry were used in this study.Results:We demonstrated pleotropic in vitro activities of GW3965 in pancreatic cell lines MIA PaCa‐2 and BXPC3 including reduction of cell viability,inhibition of cell proliferation,stimulation of cell death,and suppression of colony formation,which translated to significant inhibition of xenograft tumor growth in vitro.By mapping the gene expression profiles,we identified the up‐regulations of 188 and the down‐regulations of 92 genes common to both cell lines following GW3965 treatment.Genes responsive to GW3965 represent a variety of biological pathways vital for multiple cellular functions.Specifically,we identified that the activating transcription factor 4/thioredoxin‐interacting protein/regulated in development and DNA damage responses 1/mechanistic target of rapamycin(ATF4/TXNIP/REDD1/mTOR)signaling critically controls GW3965‐mediated regulation of cell proliferation/death.The significance of the ATF4/TXNIP/REDD1/mTOR pathway was further supported by associated expressions in xenograft tumors as well as human pancreatic cancer samples.Conclusions:This study provides the pre‐clinical evidence that LXR agonist is a promising therapy for pancreatic cancer.

关键词： GW3965 liver X receptor nuclear receptors pancreatic cancer signaling pathways

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Dual Functions of Microglia in Ischemic Stroke

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Neuroscience Bulletin 2019年第5期35卷 921-933页

作者： Chuan Qin Luo-Qi Zhou Xiao-Tong Ma Zi-Wei Hu Sheng Yang Man Chen Dale B. Bosco Long-Jun Wu Dai-Shi Tian Department of Neurology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China Department of Neurology Mayo Clinic Rochester MN 55905 USA

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Resident microglia are the principal immune cells of the brain, and the first to respond to the pathophysiological changes induced by ischemic stroke. Traditionally, it has been thought that microglial activation is deleterious in ischemic stroke, and therapies to suppress it have been intensively explored. However,increasing evidence suggests that microglial activation is also critical for neurogenesis, angiogenesis, and synaptic remodeling, thereby promoting functional recovery after cerebral ischemia. Here, we comprehensively review the dual role of microglia during the different phases of ischemic stroke, and the possible mechanisms controlling the post-ischemic activity of microglia. In addition, we discuss the dynamic interactions between microglia and other cells, such as neurons, astrocytes, oligodendrocytes,and endothelial cells within the brain parenchyma and the neurovascular unit.

关键词： Microglia Inflammation Ischemic stroke signaling pathways

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Transcriptomic study of the red palm weevil Rhynchophorus ferrugineus embryogenesis

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Insect Science 2015年第1期22卷 65-82页

作者： An Yin Linlin Pan Xiaowei Zhang Lei Wang Yuxin Yin Shangang Jia Wanfei Liu Chengqi Xin Kan Liu Xiaoguang Yu Gaoyuan Sun Khalid AI-hudaib Son qnian Hu Ibrahim S. AI-Mssallem Jun Yu joint Center for Genomics Research (JCGR) King Abdulaziz City for Science and Technology (KACST) and Chinese Academy ofSciences (CAS) Riyadh Kingdom of Saudi Arabia CAS Key Laboratory of Genome Sciences and Information Beijing Institute ofGenomics Chinese Academy of Sciences Beijing China University of Chinese Academy of Sciences Beijing China plant ProtectionDepartment Department of Biotechnology College of Agriculture and Food Sciences King Faisal University AI-Hssa HofufKingdom of Saudi Arabia

The red palm weevil （RPW）, Rhynchophorus ferrugineus （Coleoptera： Cur- culionidae）, is an invasive, concealed and destructive tissue borer, and it becomes a lethal pest of the palm family of plants and has been reported to attack 20 palm species around the globe. Here we report a systematic transcriptomic study on embryogenesis of RPW, where we analyze the transcriptomes across five developmental stages of RPW embryogenesis, involving four embryonic stages （El, E2, E3 and E4） and one larval stage （L1）. Using the RNA-seq and next-generation platforms, we generated 80 to 91 million reads for each library and assemble 22 532 genes that are expressed at different embryonic stages. Among the total transcripts from the five embryonic development stages, we found that 30.45 % are differentially expressed, 10.10 % show stage-specificity and even a larger fraction, 62.88 %, exhibit constitutive expression in all the stages. We also analyzes the expression dynamics of several conserved signaling pathways （such as Hedgehog, JAK-STAT, Notch, TGF-β, Ras/MAPK and Writ）, as well as key developmental genes, including those related to apoptosis, axis formation, Hox complex, neurogenesis and segmentation. The datasets provide an essential resource for gene annotation and RPW functional genomics, including studies by using tools and concepts from multiple disciplines, such as development, physiology, biochemistry, molecular biology and genetics.

关键词： insect embryogenesis red palm weevil Rhynchophorusferrugineus RNAseq signaling pathways transcriptome

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Role of Wnt and Notch signaling in regulating hair cell regeneration in the cochlea

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Frontiers of Medicine 2016年第3期10卷 237-249页

作者： Muhammad Waqas Shasha Zhang Zuhong He Mingliang Tang Renjie Chai Key Laboratory for Developmental Genes and Human Disease Ministry of Education Institute of Life Sciences Southeast University Nanjing 210096 China Co-Innovation Center of Neuroregeneration Nantong University Nantong 226001 China

Sensory hair cells in the inner ear are responsible for sound recognition. Damage to hair cells in adult mammals causes permanent hearing impairment because these cells cannot regenerate. By contrast, newborn mammals possess limited regenerative capacity because of the active participation of various signaling pathways, including Wnt and Notch signaling. The Wnt and Notch pathways are highly sophisticated and conserved signaling pathways that control multiple cellular events necessary for the formation of sensory hair cells. Both signaling pathways allow resident supporting cells to regenerate hair cells in the neonatal cochlea. In this regard, Wnt and Notch signaling has gained increased research attention in hair cell regeneration. This review presents the current understanding of the Wnt and Notch signaling pathways in the auditory portion of the inner ear and discusses the possibilities of controlling these pathways with the hair cell fate determiner Atohl to regulate hair cell regeneration in the mammalian cochlea.

关键词： inner ear cochlea hair cell regeneration Wnt Notch signaling pathways

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Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

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Cellular & Molecular Immunology 2016年第6期13卷 828-838页

作者： Olga Romanets-Korbut Larysa M. Kovalevska Tsukasa Seya Svetlana P. Sidorenko Branka Horvat CIRI International Center for Infectiology Research IblVteam Universite de Lyon Lyon France Inserm U1111 Lyon France CNRS UMR5308 Lyon France Universite Lyon 1 Lyon France Ecole Normale Superieure de Lyon Lyon France R.E. Kavetsky Institute of Experimental Pathology Oncology and Radiobiology NASU Kyiv Ukraine and 7Department of Microbiology and Immunology Graduate School of Medicine Hokkaido University Kita-ku Sapporo Japan Department ofMicrobiologyand Immunology Graduate School of Medicine Hokkaido University Kita-kuSapporo Japan

Measles virus （MV） is highly contagious pathogen, which causes a profound immunosuppression, resulting in high infant mortality. This virus infects dendritic cells （DCs） following the binding of MV hemagglutinin （MV-H） to CD150 receptor and alters DC functions by a mechanism that is not completely understood. We have analyzed the effect of MV-H interaction with CD150-expressing DCs on the DC signaling pathways and consequent phenotypic and functional changes in the absence of infectious context. We demonstrated that contact between CD150 on human DCs and MV-H expressed on membrane of transfected CHO cells was sufficient to modulate the activity of two major regulatory pathways of DC differentiation and function： to stimulate Akt and inhibit p38 MAPK phosphorylation, without concomitant ERK1/2 activation. Furthermore, interaction with MV-H decreased the expression level of DC activation markers CD80, CD83, CD86, and HLA-DR and strongly downregulated IL-12 production but did not modulate IL-IO secretion. Moreover, contact with MV-H suppressed DC-mediated T-cell alloproliferation, demonstrating profound alteration of DC maturation and functions. Finally, engagement of CD150 by MV-H in mice transgenic for human CD150 decreased inflammatory responses, showing the immunosuppressive effect of CD150-MV-H interaction in vivo. Altogether, these results uncover novel mechanism of MV-induced immunosuppression, implicating modulation of cell signaling pathways following MV-H interaction with CD150-expressing DCs and reveal anti-inflammatory effects of CD150 stimulation.

关键词： dendritic cells measles virus signaling pathways SLAM/CD150

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Expression profiles of long noncoding RNAs in retinopathy of prematurity

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Neural Regeneration Research 2020年第10期15卷 1962-1968页

作者： Yue Wang Xue Wang Yuan Ma Yue-Xia Wang Yu Di Department of Ophthalmology Shengjing Hospital of China Medical University

Long noncoding RNA(lncRNA)regulates the proliferation and migration of human retinal endothelial cells,as well as retinal neovascularization in diabetic retinopathy.Based on similarities between the pathogenesis of retinopathy of prematurity(ROP)and diabetic retinopathy,lncRNA may also play a role in ROP.Seven-day-old mice were administered 75±2% oxygen for 5 days and normoxic air for another 5 days to establish a ROP model.Expression of lncRNA and mRNA in the retinal tissue of mice was detected by high-throughput sequencing technology,and biological functions of the resulted differentially expressed RNAs were evaluated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses.The results showed that compared with the control group,57 lncRNAs were differentially expressed,including 43 upregulated and 14 downregulated,in the retinal tissue of ROP mice.Compared with control mice,42 mRNAs were differentially expressed in the retinal tissue of ROP mice,including 24 upregulated and 18 downregulated mRNAs.Differentially expressed genes were involved in ocular development and related metabolic pathways.The differentially expressed lncRNAs may regulate ROP in mice via microRNAs and multiple signaling pathways.Our results revealed that these differentially expressed lncRNAs may be therapeutic targets for ROP treatment.This study was approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University on February 25,2016(approval No.2016PS074K).

关键词： bioinformatics gene therapy long noncoding RNA microglial neurovascular disease optic neuropathy retinal development retinal neovascularization retinopathy of prematurity signaling pathways

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miRNA targeted signaling pathway in the early stage of denervated fast and slow muscle atrophy

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Neural Regeneration Research 2016年第8期11卷 1293-1303页

作者： Gang Li Qing-shan Li Wen-bin Li Jian Wei Wen-kai Chang Zhi Chen Hu-yun Qiao Ying-wei Jia Jiang-hua Tian Bing-sheng Liang Department of Orthopedics Second Affiliated Hospital of Shanxi Medical University

Denervation often results in skeletal muscle atrophy.Different mechanisms seem to be involved in the determination between denervated slow and fast skeletal muscle atrophy.At the epigenetic level,mi RNAs are thought to be highly involved in the pathophysiological progress of denervated muscles.We used mi RNA microarrays to determine mi RNA expression profiles from a typical slow muscle（soleus muscle） and a typical fast muscle（tibialis anterior muscle） at an early denervation stage in a rat model.Results showed that mi R-206,mi R-195,mi R-23 a,and mi R-30 e might be key factors in the transformation process from slow to fast muscle in denervated slow muscles.Additionally,certain mi RNA molecules（mi R-214,mi R-221,mi R-222,mi R-152,mi R-320,and Let-7e） could be key regulatory factors in the denervated atrophy process involved in fast muscle.Analysis of signaling pathway networks revealed the mi RNA molecules that were responsible for regulating certain signaling pathways,which were the final targets（e.g.,p38 MAPK pathway; Pax3/Pax7 regulates Utrophin and follistatin by HDAC4; IGF1/PI3K/Akt/m TOR pathway regulates atrogin-1 and Mu RF1 expression via Fox O phosphorylation）.Our results provide a better understanding of the mechanisms of denervated skeletal muscle pathophysiology.

关键词： nerve regeneration microRNA expression profile denervated skeletal muscle gene functions signaling pathways neural regeneration

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Hericium Erinaceus (Bull.:Fr.) Pers.,A Medicinal Mushroom,Activates Peripheral Nerve Regeneration

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Chinese Journal of Integrative Medicine 2016年第10期22卷 759-767页

作者： Kah-Hui Wong Gowri Kanagasabapathy Murali Naidu Pamela David Vikineswary Sabaratnam Department of Anatomy Faculty of Medicine University of Malaya Mushroom Research Centre University of Malaya Institute of Biological Sciences Faculty of Science University of Malaya

Objective： To study the ability of aqueous extract of Hericium erinaceus mushroom in the treatment of nerve injury following peroneal nerve crush in Sprague-Dawley rats. Methods： Aqueous extract of Hericium erinaceus was given by daily oral administration following peroneal nerve crush injury in Sprague- Dawley rats. The expression of protein kinase B （Akt） and mitogen-activated protein kinase （MAPK） signaling pathways; and c-Jun and c-Fos genes were studied in dorsal root ganglia （DRG） whereas the activity of protein synthesis was assessed in peroneal nerves by immunohistochemical method. Results： Peripheral nerve injury leads to changes at the axonal site of injury and remotely located DRG containing cell bodies of sensory afferent neurons. Immunofluorescence studies showed that DRG neurons ipsilateral to the crush injury in rats of treated groups expressed higher immunoreactivities for Ak＇t, MAPK, c-Jun and c-Fos as compared with negative control group （P〈0.05）. The intensity of nuclear ribonucleoprotein in the distal segments of crushed nerves of treated groups was significantly higher than in the negative control group （P〈0.05）. Conclusion： H. erinaceus is capable of promoting peripheral nerve regeneration after injury. Potential signaling pathways include Akt, MAPK, c-Jun, and c-Fos, and protein synthesis have been shown to be involved in its action.

关键词： Hericium erinaceus dorsal root ganglia signaling pathways gene expression protein synthesis machinery peripheral nerve regeneration

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