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Start Over Descriptor "TFEB, transcription factor EB" Journal acta pharmaceutica sinica b
13 results on '"TFEB, transcription factor EB"'

1. Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218

Author

Po Hu, Hongzheng Wang, Xiaoxuan Yu, Wenzhuo Sun, Hui Hui, Hui Li, Mengyuan Zhu, Zhanyu Wang, Jingyan Xu, Qinglong Guo, and Yingjie Qing

Subjects
NPC, Niemann-Pick type disease C, Cathepsin D, ATG, autophagy related, NH4Cl, ammonium chloride, Lysosomal damage, Calcium in biology, Hematological malignancies, 0302 clinical medicine, RAB7A, RAS-related protein RAB-7a, K48, lysine 48, LC3, microtubule-associated protein 1 light chain 3, TFEB, transcription factor EB, General Pharmacology, Toxicology and Pharmaceutics, 0303 health sciences, RT-qPCR, real time quantitative PCR, Chemistry, LCD, lysosome-dependent cell death, CaN, calcineurin, P62/SQSTM1, sequestosome 1, Cell biology, TRPML1, transient receptor potential mucolipin 1, medicine.anatomical_structure, Cholesterol, 030220 oncology & carcinogenesis, shRNA, short hairpin RNA, Original Article, CsA, cyclosporine A, DAPI, 4′,6-diamidino-2-phenylindole dihydrochloride, Programmed cell death, AO, acridine orange, CTSD, cathepsin D, LW-218, PBS, phosphate-buffered saline, CTSB, cathepsin B, LMP, lysosome membrane permeabilization, EGTA, ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid, RM1-950, Lysosome-dependent cell death, 03 medical and health sciences, Dex, dexamethasone, ROS, reactive oxygen species, FBS, fetal bovine serum, Lysosome, NPC1, NPC intracellular cholesterol transporter 1, medicine, BAF A1, bafilomycin A1, 030304 developmental biology, Cathepsin, PBMCs, peripheral blood mononuclear cells, Lysosomal membrane permeabilization, K63, lysine 63, Cell growth, DCFH-DA, 2,7-dichlorodi-hydrofluorescein diacetate, Autophagy, BID, BH3-interacting domain death agonist, Lysophagy, OD, optical density, TFEB, CCK8, Cell Counting Kit, Therapeutics. Pharmacology, LAMPs, lysosomal-associated membrane proteins
Abstract

The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth in vivo. Thus, the necessary impact of integral lysosomal function in cell rescue and death were illustrated., Graphical abstract LW-218-induced cholesterol accumulation on lysosomes via NPC1 binding can elicit lysosomal damage followed by lysophagy and lysosome-dependent cell death in hematological malignancies cells.Image 1

Published
2021

2. Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease

Author

Lu Feng, Kai Zhang, Bo Liu, Tingting Jiang, Liang Ouyang, Guan Wang, Jiamei Li, Shiou Zhu, and Junping Pei

Subjects
Target, ONRs, orphan nuclear receptors, Parkinson's disease, Small-molecule compound, MPP+, 1-methyl-4-phenylpyridinium, Autolysosome, GAPDH, glyceraldehyde 3-phosphate dehydrogenase, GBA, glucocerebrosidase β acid, Review, MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, Disease, mTORC1, mTOR, the mammalian target of rapamycin, PD, Parkinson's disease, 0302 clinical medicine, CL, clearance rate, DAT, dopamine transporter, HDAC6, histone deacetylase 6, PD therapy, A2A, adenosine 2A, MYCBP2, MYC-binding protein 2, TFEB, transcription factor EB, AUTAC, autophagy targeting chimera, General Pharmacology, Toxicology and Pharmaceutics, SAS, solvent accessible surface, 0303 health sciences, α-syn, α-synuclein, ALP, autophagy-lysosomal pathway, AADC, aromatic amino acid decarboxylase, DJ-1, Parkinson protein 7, PI3K, phosphatidylinositol 3-kinase, COMT, catechol-O-methyltransferase, LUHMES, lund human mesencephalic, LRRK2, CMA, chaperone-mediated autophagy, KI, knockin, 030220 oncology & carcinogenesis, LRS, leucyl-tRNA synthetase, BBB, blood−brain barrier, SN, substantia nigra, IMPase, inositol monophosphatase, IPPase, inositol polyphosphate 1-phosphatase, HSPA8, heat shock 70 kDa protein 8, MAO-B, monoamine oxidase B, PREP, prolyl oligopeptidase, Parkinson's disease (PD), DR, dopamine receptor, PDE4, phosphodiesterase 4, AMPK, 5ʹAMP-activated protein kinase, 5-HT2C, serotonin 2C, SNCA, α-synuclein gene, TSC2, tuberous sclerosis complex 2, RM1-950, LIMP-2, lysosomal integrated membrane protein-2, CNS, central nervous system, 5-HT2A, Serotonin 2A, ER, endoplasmic reticulum, ATG, autophagy related protein, 03 medical and health sciences, PLC, phospholipase C, ROS, reactive oxygen species, ERRα, estrogen-related receptor alpha, SAR, structure–activity relationship, ULK1, UNC-51-like kinase 1, medicine, Autophagy, NMDA, N-methyl-d-aspartic acid, mAChR, muscarinic acetylcholine receptor, GWAS, genome-wide association study, LAMP2A, lysosome-associated membrane protein 2 A, Lamp2a, type 2A lysosomal-associated membrane protein, 030304 developmental biology, Parkin, parkin RBR E3 ubiquitin−protein ligase, PINK1, PTEN-induced kinase 1, ATTEC, autophagosome-tethering compound, ATP13A2, ATPase cation transporting 13A2, business.industry, ULK1, medicine.disease, LC3, light chain 3, PI3P, phosphatidylinositol 3-phosphate, SYT11, synaptotagmin 11, AUC, the area under the curve, UPS, ubiquitin−proteasome system, TFEB, DA, dopamine, Therapeutics. Pharmacology, business, BAF, bafilomycinA1, HSC70, heat shock cognate 71 kDa protein, Neuroscience, 3-MA, 3-methyladenine, F, oral bioavailability, LRRK2, leucine-rich repeat sequence kinase 2
Abstract

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERRα, C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future., Graphical abstract In this review, we summarize the mechanism of autophagy in the pathogenesis of Parkinson's disease (PD). We focus on several cytoprotective autophagy-regulated targets, such as LRRK2, C-Abelson, GCase, TFEB, ERRα, mTORC1, AMPK, ULK1, beclin-1, and IMPase. At the meantime, their relevant small-molecule compounds in PD models are listed.Image 1

Published
2021

3. Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management

Author

Hai-Yong Chen, Yibin Feng, Cheng Zhang, Ning Wang, Sha Li, and Guoyi Tang

Subjects
LOX1, lectin-like oxidized LDL receptor 1, BUN, blood urea nitrogen, TGBM, thickness of glomerular basement membrane, NQO1, NAD(P)H:quinone oxidoreductase 1, STAT, signal transducers and activators of transcription, N/O, not observed, p62, sequestosome 1 protein, p-IRS1, phospho-IRS1, Review, NOX-4, nicotinamide adenine dinucleotide phosphate-oxidase-4, OCP, oxidative carbonyl protein, Traditional Chinese medicine, AGEs, advanced glycation end-products, N/A, not applicable, TRAF5, tumor-necrosis factor receptor-associated factor 5, Health problems, 0302 clinical medicine, ESRD, end-stage renal disease, LDL, low-density lipoprotein, BMP-7, bone morphogenetic protein-7, TGFβR-I/II, TGF-β receptor I/II, Medicine, P70S6K, 70-kDa ribosomal protein S6 kinase, General Pharmacology, Toxicology and Pharmaceutics, SOCS, suppressor of cytokine signaling proteins, HO-1, heme oxygenase-1, 0303 health sciences, TG, triglyceride, BW, body weight, HDL-C, high density lipoprotein-cholesterol, RASI, renin-angiotensin system inhibitor, ATK, protein kinase B, TBARS, thiobarbituric acid-reactive substance, BCL-XL, B-cell lymphoma-extra large, Gαq, Gq protein alpha subunit, GCK, glucokinase, PI3K, phosphatidylinositol 3 kinases, Systematic review, TLR-2/4, toll-like receptor 2/4, IR, insulin receptor, PERK, protein kinase RNA-like eukaryotic initiation factor 2A kinase, 030220 oncology & carcinogenesis, CRP, C-reactive protein, IRS, insulin receptor substrate, AM, mesangial area, JAK, Janus kinase, FBG, fasting blood glucose, ETAR, endothelium A receptor, LDL-C, low density lipoprotein-cholesterol, CD2AP, CD2-associated protein, eIF2α, eukaryotic initiation factor 2α, RM1-950, mTOR, mammalian target of rapamycin, CHOP, C/EBP homologous protein, STZ, streptozotocin, 03 medical and health sciences, ADE, adverse event, PKC, protein kinase C, LC3, microtubule-associated protein light chain 3, ORP150, 150-kDa oxygen-regulated protein, PGE2, prostaglandin E2, IL-1β/6, interleukin 1β/6, Diabetic kidney disease, IGF-1, insulin-like growth factor 1, EP, E-prostanoid receptor, FN, fibronectin, eGFR, estimated GFR, MDA, malondialdehyde, Chinese medicine, MMP-2, matrix metallopeptidase 2, XBP-1, spliced X box-binding protein 1, TGF-β, tumor growth factor β, GRB 10, growth factor receptor-bound protein 10, medicine.disease, Clinical trial, GRP78, glucose-regulated protein 78, UP, urinary protein, IGF-1R, insulin-like growth factor 1 receptor, ACEI, angiotensin-converting enzyme inhibitor, BCL-2, B-cell lymphoma 2, EMT, epithelial-to-mesenchymal transition, MAPK, mitogen-activated protein kinase, MYD88, myeloid differentiation primary response 88, PBG, postprandial blood glucose, RCT, randomized clinical trial, N/R, not reported, COL-I/IV, collagen I/IV, PINK1, PTEN-induced putative kinase 1, UACR, urinary albumin to creatinine ratio, C, control group, Diabetic nephropathy, GPX, glutathione peroxidase, ICAM-1, intercellular adhesion molecule-1, Bioinformatics, VCAM-1, vascular cell adhesion molecule-1, AMPKα, adenosine monophosphate-activated protein kinase α, DM, diabetes mellitus, TFEB, transcription factor EB, TNF-α, tumor necrosis factor α, Molecular target, IKK-β, IκB kinase β, Signaling pathway, GLUT4, glucose transporter type 4, BAX, BCL-2-associated X protein, NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells, PARP, poly(ADP-Ribose) polymerase, SMURF-2, SMAD ubiquitination regulatory factor 2, AREs, antioxidant response elements, MD, mean difference, SMAD, small mothers against decapentaplegic, MCP-1, monocyte chemotactic protein-1, VEGF, vascular endothelial growth factor, cAMP, cyclic adenosine monophosphate, ARB, angiotensin receptor blocker, PAI-1, plasminogen activator inhibitor-1, SMD, standard mean difference, JNK, c-Jun N-terminal kinase, NRF2, nuclear factor erythroid 2-related factor 2, IκB-α, inhibitory protein α, Herbal medicine, TCM, traditional Chinese medicine, DG, glomerular diameter, GSK-3, glycogen synthase kinase 3, SIRT1, sirtuin 1, D, duration, HbA1c, glycosylated hemoglobin, WMD, weight mean difference, CTGF, connective tissue growth factor, ER, endoplasmic reticulum, DN, diabetic nephropathy, ROS, reactive oxygen species, CCR, creatinine clearance rate, SOD, superoxide dismutase, Diabetes mellitus, PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α, ET-1, endothelin-1, UMA, urinary microalbumin, SCr, serum creatinine, IRE-1α, inositol-requiring enzyme-1α, 030304 developmental biology, TII, tubulointerstitial injury index, RAGE, receptors of AGE, business.industry, GFR, glomerular filtration rate, PTEN, phosphatase and tensin homolog, CI, confidence interval, TC, total cholesterol, SD-rat, Sprague–Dawley rat, UAER, urinary albumin excretion rate, DKD, diabetic kidney disease, T, treatment group, Molecular targets, Therapeutics. Pharmacology, α-SMA, α smooth muscle actin, SD, standard deviation, business, DAG, diacylglycerol, GCLC, glutamate-cysteine ligase catalytic subunit, Kidney disease
Abstract

Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensin-aldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN., Graphical abstract Diabetic nephropathy is one of the most severe complications of diabetes mellitus. Chinese medicines have been intensively studied in treating diabetic nephropathy. This review comprehensively summarizes and discusses the clinical efficacies and underlying mechanisms of Chinese medicines for diabetic nephropathy, providing deep insights and profound perspectives into this field.Image 1

Published
2021
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4. Gene therapy for neurodegenerative disorders: advances, insights and prospects

Author

Dianwen Ju, Yang Hu, and Wei Chen

Subjects
CHOP, CCAAT/enhancer binding homologous protein, Genetic enhancement, AAVs, adeno-associated viruses, BCSFB, blood–cerebrospinal fluid barrier, SMN, survival motor neuron, Review, Disease, Bioinformatics, CSF, cerebrospinal fluid, PD, Parkinson's disease, IDS, iduronate 2-sulfatase, ASOs, antisense oligonucleotides, Bip, glucose regulated protein 78, UPR, unfolded protein response, 0302 clinical medicine, Medicine, HD, Huntington's disease, TFEB, transcription factor EB, General Pharmacology, Toxicology and Pharmaceutics, BBB, blood–brain barrier, Therapeutic strategy, GAD, glutamic acid decarboxylase, TPP1, tripeptidyl peptidase 1, 0303 health sciences, RNAi, RNA interference, SUMF, sulfatase-modifying factor, RPE, retinal pigmented epithelial, 030220 oncology & carcinogenesis, AADC, aromatic-l-amino-acid, AD, Alzheimer's disease, LVs, retrovirus/lentivirus, AD - Alzheimer's disease, GDNF, glial derived neurotrophic factor, NGF, nerve growth factor, GAA, lysosomal acid α-glucosidase, HTT, mutant huntingtin, mTOR, mammalian target of rapamycin, ARSA, arylsulfatase A, CNS, central nervous system, ER, endoplasmic reticulum, 03 medical and health sciences, Gene therapy, SOD, superoxide dismutase, TREM2, triggering receptor expressed on myeloid cells 2, ASPA, aspartoacylase, Adeno-associated viruses, 030304 developmental biology, Lamp2a, lysosomal-associated membrane protein 2a, PGRN, Progranulin, Adv, adenovirus, BRB, blood–retina barrier, PD - Parkinson's disease, CLN6, ceroidlipofuscinosis neuronal protein 6, business.industry, lcsh:RM1-950, Delivery routes, PINK1, putative kinase 1, PTEN, phosphatase and tensin homolog, RGCs, retinal ganglion cells, Clinical trial, FDA, U.S. Food and Drug Administration, SGSH, lysosomal heparan-N-sulfamidase gene, lcsh:Therapeutics. Pharmacology, Central nervous system, HSPGs, heparin sulfate proteoglycans, siRNA, small interfering RNA, Neurodegenerative disorders, business, ZFPs, zinc finger proteins, CSF - Cerebrospinal fluid
Abstract

Gene therapy is rapidly emerging as a powerful therapeutic strategy for a wide range of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Some early clinical trials have failed to achieve satisfactory therapeutic effects. Efforts to enhance effectiveness are now concentrating on three major fields: identification of new vectors, novel therapeutic targets, and reliable of delivery routes for transgenes. These approaches are being assessed closely in preclinical and clinical trials, which may ultimately provide powerful treatments for patients. Here, we discuss advances and challenges of gene therapy for neurodegenerative disorders, highlighting promising technologies, targets, and future prospects., Graphical abstract Gene therapy for neurodegenerative disorders has made the unprecedented progress. This review summarizes advances and challenges of gene therapy for neurodegenerative disorders, highlighting promising technologies, targets, and future prospects with the authors’ insights and experience.Image 1

Published
2020
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5. Targeting autophagy-related protein kinases for potential therapeutic purpose

Author

Jifa Zhang, Bo Liu, Liang Ouyang, Honggang Xiang, Congcong Lin, and Lan Zhang

Subjects
PINK1, PTEN-induced putative kinase 1, Review, PROTAC, proteolysis targeting chimeras, PTMs, post-translational modifications, Protein aggregation, PKCα, protein kinase C alpha type, AKT1, AKT serine/threonine kinase 1, PD, Parkinson's disease, Autophagy-related kinase, DAPK, death associated protein kinase, PKD1, polycystin-1, GAP, GTPase-activating protein, PKACα, a protein kinase cAMP-activated catalytic subunit alpha, 0302 clinical medicine, Human disease, TNBC - Triple-negative breast cancer, Protein kinases, LC3, microtubule-associated protein 1 light chain 3, UVRAG, ultraviolet resistance-associated gene, TFEB, transcription factor EB, Phosphorylation, General Pharmacology, Toxicology and Pharmaceutics, Rheb, the RAS homolog enriched in brain, TAK1, transforming growth factor activated kinase-1, 0303 health sciences, Kinase, mTORC1, mammalian target of rapamycin complex 1, PI3 kinase, phosphoinositide 3-kinase, Cell biology, GSK3α, glycogen synthase kinase 3 alpha, HMGB1, high mobility group protein B1, AMBRA1, autophagy/beclin-1 regulator 1, ULK complex, ULK1–mATG13–FIP200–ATG101 complex, ARF, auxin response factor gene, 030220 oncology & carcinogenesis, TSC1/2, tuberous sclerosis complex proteins 1/2, PIM2, proviral insertion in murine lymphomas 2, LPS, lipopolysaccharide, PI3P, phosphatidylinositol triphosphate, Small-molecule kinase inhibitors/activators, JNK1, C-Jun N-terminal kinase, mTOR, mammalian target of rapamycin, ULK1, unc-51-like kinase 1, Biology, PPIs, protein–protein interactions, PI, phosphatidylinositol, TNBC, triple-negative breast cancer, FIP200, FAK family kinase-interacting protein of 200 kDa, 03 medical and health sciences, 4E-BP1, eukaryotic translation initiation factor 4E-binding protein, Organelle, Autophagy, LRRK2, leucine rich repeat kinase 2, ATG, autophagy-related protein, GO, gene ontology, 030304 developmental biology, PD - Parkinson's disease, lcsh:RM1-950, CaMKK2, calcium/calmodulin-dependent protein kinase kinase 2, Human disease therapy, AMPK, AMP-activated protein kinase, lcsh:Therapeutics. Pharmacology, PIP2, phosphatidylinositol-4,5-bisphosphate, LKB1, serine/threonine-protein kinase stk11
Abstract

Autophagy, defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes, plays a significant role in the quality control of macromolecules and organelles. Since protein kinases are integral to the autophagy process, it is critically important to understand the role of kinases in autophagic regulation. At present, intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease, especially cancer. In this review, we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation. We also summarize the small-molecule kinase inhibitors/activators of these targets, highlighting the opportunities of these new therapeutic agents., Graphical abstract This review elaborates in detail the role of some autophagy-related kinase targets and phosphorylation in autophagy regulation, and further summarizes the application of small-molecule kinase inhibitors/activators for autophagy inhibition and induction. Understanding how these autophagy-related kinases regulate autophagy machinery is critical for the potential therapeutic application of autophagy.Image 1

Published
2020

6. Inactivation of TFEB and NF-κB by marchantin M alleviates the chemotherapy-driven pro-tumorigenic senescent secretion

Author

Bin Sun, Huanmin Niu, Hong-Xiang Lou, Fang Wang, Huiqing Yuan, Qian Wang, Xiao-Tian Ji, Effat Un Nesa, Wenjian Liu, Lilin Qian, and Yanhai Luo

Subjects
BUN, blood urea nitrogen, medicine.medical_treatment, DMSO, dimethyl sulfoxide, SASP, AST, transaminase, NF-κB, Doc, docetaxel, Doxo, doxorubicin, MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, chemistry.chemical_compound, 0302 clinical medicine, CI, combinatory index, TFEB, transcription factor EB, General Pharmacology, Toxicology and Pharmaceutics, 0303 health sciences, CM, conditioned media, PGPH, peptidylglutamyl hydrolyzing, Chemistry, CDDP, cisplatin, ALT, glutamic-pyruvic transaminase, EdU, 5-ethynyl-2′-deoxyuridine, Phenotype, Sv, starvation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Toxicity, LPS, lipopolysaccharide, medicine.drug, Original article, TCGA, the Cancer Genome Atlas, NF-κB, nuclear factor-κB, SASP, senescence-associated secretory phenotype, PI, propidium iodide, Mar-M, Marchantin M, 03 medical and health sciences, ROS, reactive oxygen species, medicine, Doxorubicin, Secretion, Fibroblast, 030304 developmental biology, TFEB, Chemotherapy, lcsh:RM1-950, fungi, Marchantin M, CREA, creatinine, lcsh:Therapeutics. Pharmacology, CT-like, both chymotrypsin-like, Drug resistance, Tg, thapsigargin, Cancer research, SA-β-gal, senescence-associated β-galactosidase
Abstract

It is critical to regulate the senescence-associated secretory phenotype (SASP) due to its effect on promoting malignant phenotypes and limiting the efficiency of cancer therapy. In this study, we demonstrated that marchantin M (Mar-M, a naturally occurring bisbibenzyl) suppressed pro-inflammatory SASP components which were elevated in chemotherapy-resistant cells. Mar-M treatment attenuated the pro-tumorigenic effects of SASP and enhanced survival in drug-resistant mouse models. No toxicity was detected on normal fibroblast cells or in animals following this treatment. Inactivation of transcription factor EB (TFEB) and nuclear factor-κB (NF-κB) by Mar-M significantly accounted for its suppression on the components of SASP. Furthermore, inhibition of SASP by Mar-M contributed to a synergistic effect during co-treatment with doxorubicin to lower toxicity and enhance antitumor efficacy. Thus, chemotherapy-driven pro-inflammatory activity, seen to contribute to drug-resistance, is an important target for Mar-M. By decreasing SASP, Mar-M may be a potential approach to overcome tumor malignancy., Graphical abstract A naturally-occurring bisbibenzyl of marchantin M (Mar-M) can induce cellular senescence and transcriptionally suppress the senescence-associated secretary phenotype (SASP) through inactivation of TFEB and NF-κB in drug-resistant cells instead of normal fibroblast cells at low dose. Mar-M can alleviate the chemotherapy-driven pro-tumorigenic senescent secretion, leading to tumor regressions and prolonged survival with no detectable toxicity in drug-resistant mouse models. Mar-M synergistically cooperated with doxorubicin to remarkably lower its toxicity and enhance the antitumor efficacy.Image 1

Published
2019
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7. Autophagy enhanced by curcumin ameliorates inflammation in atherogenesis via the TFEB-P300-BRD4 axis.

Author

Li X, Zhu R, Jiang H, Yin Q, Gu J, Chen J, Ji X, Wu X, Fu H, Wang H, Tang X, Gao Y, Wang B, Ji Y, and Chen H

Abstract

Disturbance of macrophage-associated lipid metabolism plays a key role in atherosclerosis. Crosstalk between autophagy deficiency and inflammation response in foam cells (FCs) through epigenetic regulation is still poorly understood. Here, we demonstrate that in macrophages, oxidized low-density lipoprotein (ox-LDL) leads to abnormal crosstalk between autophagy and inflammation, thereby causing aberrant lipid metabolism mediated through a dysfunctional transcription factor EB (TFEB)-P300-bromodomain-containing protein 4 (BRD4) axis. ox-LDL led to macrophage autophagy deficiency along with TFEB cytoplasmic accumulation and increased reactive oxygen species generation. This activated P300 promoted BRD4 binding on the promoter regions of inflammatory genes, consequently contributing to inflammation with atherogenesis. Particularly, ox-LDL activated BRD4-dependent super-enhancer associated with liquid-liquid phase separation (LLPS) on the regulatory regions of inflammatory genes. Curcumin (Cur) prominently restored FCs autophagy by promoting TFEB nuclear translocation, optimizing lipid catabolism, and reducing inflammation. The consequences of P300 and BRD4 on super-enhancer formation and inflammatory response in FCs could be prevented by Cur. Furthermore, the anti-atherogenesis effect of Cur was inhibited by macrophage-specific Brd4 overexpression or Tfeb knock-out in Apoe knock-out mice via bone marrow transplantation. The findings identify a novel TFEB-P300-BRD4 axis and establish a new epigenetic paradigm by which Cur regulates autophagy, inhibits inflammation, and decreases lipid content., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2022
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8. The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation.

Author

Fan Z, Wu C, Chen M, Jiang Y, Wu Y, Mao R, and Fan Y

Abstract

The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000-5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3'UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2022
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9. Role of farnesoid X receptor and bile acids in alcoholic liver disease

Author

Wen-Xing Ding and Sharon Manley

Subjects
WT, wild type, Alcoholic liver disease, Cirrhosis, NTCP, sodium taurocholate cotransporting polypeptide, IR-1, inverted repeat-1, Review, TLR4, toll-like receptor 4, SHP, small heterodimer partner, 0302 clinical medicine, NAD+, nicotinamide adenine dinucleotide, 6ECDCA, 6α-ethyl-chenodeoxycholic acid, TFEB, transcription factor EB, General Pharmacology, Toxicology and Pharmaceutics, Liver injury, FGFR4, fibroblast growth factor receptor 4, MRP4, multidrug resistance protein 4, 0303 health sciences, CA, cholic acid, SQSTM, sequestome-1, FGF15/19, fibroblast growth factor 15/19, 3. Good health, Atg, autophagy-related, WAY, WAY-362450, Hepatocellular carcinoma, CREBH, cAMP response element-binding protein, hepatocyte specific, FoxO3, FOXO3, CYP, cytochrome P450, 030211 gastroenterology & hepatology, FoxO3a, forkhead box-containing protein class O3a, BAAT, bile acid CoA:amino acid N-acyltransferase, RXRα, retinoid X receptor-alpha, BACS, bile acid CoA synthetase, medicine.medical_specialty, ALD, alcoholic liver disease, GGT, gamma-glutamyltranspeptidase, TCA, taurocholic acid, ASBT, apical sodium dependent bile acid transporter, Biology, PE, phosphatidylethanolamine, AKT, protein kinase B, ADH, alcohol dehydrogenase, UDCA, ursodeoxycholic acid, CDCA, chenodeoxycholic acid, 03 medical and health sciences, FXR, farnesoid X receptor, ROS, reactive oxygen species, Cholestasis, Farnesoid X receptor, TUDCA, tauro-ursodeoxycholic acid, Internal medicine, ALT, alanine aminotransferase, AF, activation function, medicine, Autophagy, BSEP, bile salt export pump, 030304 developmental biology, KO, knockout, PPARα, peroxisome proliferator-activated receptor alpha, SREBP1, sterol regulatory element-binding protein 1, lcsh:RM1-950, CB1R, cannabinoid receptor type 1, CRTC2, CREB regulated transcription coactivator 2, medicine.disease, Bile acids, LC3, light chain 3, OSTα/β, organic solute transporter α/β, Endocrinology, lcsh:Therapeutics. Pharmacology, DCA, deoxycholic acid, DR1, direct repeat 1, LRH-1, liver receptor homolog 1, CREB, cAMP response element-binding protein, Steatosis, LXR, liver X receptor, HCC, hepatocellular carcinoma, Sirt1, sirtuin 1
Abstract

Alcoholic liver disease (ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a) and PPARα (peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure., Graphical abstract This review discusses the effects of alcohol consumption on farnesoid X receptor (FXR), bile acids and gut microbiome as well as their impacts on alcoholic liver disease. Moreover, we summarize the findings on FXR, forkhead box-containing protein class O3a and peroxisome proliferator-activated receptor alpha in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.

Published
2015
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10. Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease.

Author

Zhang K, Zhu S, Li J, Jiang T, Feng L, Pei J, Wang G, Ouyang L, and Liu B

Abstract

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERR α , C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future., Competing Interests: The authors have no conflicts of interest to declare., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2021
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11. Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218.

Author

Hu P, Li H, Sun W, Wang H, Yu X, Qing Y, Wang Z, Zhu M, Xu J, Guo Q, and Hui H

Abstract

The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth in vivo . Thus, the necessary impact of integral lysosomal function in cell rescue and death were illustrated., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2021
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12. Natural compounds modulate the autophagy with potential implication of stroke.

Author

Ahsan A, Liu M, Zheng Y, Yan W, Pan L, Li Y, Ma S, Zhang X, Cao M, Wu Z, Hu W, Chen Z, and Zhang X

Abstract

Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment., Competing Interests: The authors declare no conflicts of interest., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2021
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13. Targeting autophagy-related protein kinases for potential therapeutic purpose.

Author

Xiang H, Zhang J, Lin C, Zhang L, Liu B, and Ouyang L

Abstract

Autophagy, defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes, plays a significant role in the quality control of macromolecules and organelles. Since protein kinases are integral to the autophagy process, it is critically important to understand the role of kinases in autophagic regulation. At present, intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease, especially cancer. In this review, we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation. We also summarize the small-molecule kinase inhibitors/activators of these targets, highlighting the opportunities of these new therapeutic agents., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2020
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