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  1. Article ; Online: Mitochondrial complex III: Tuner of autophagy.

    Jin, Shengkan

    Chemistry & biology

    2011  Volume 18, Issue 11, Page(s) 1348–1349

    Abstract: Using chemical approaches, Ma et al. in this issue of Chemistry & Biology identify mitochondrial complex III as a specific positive regulator of autophagy. This study brings us a step closer to understanding the mechanism by which basal autophagy is ... ...

    Abstract Using chemical approaches, Ma et al. in this issue of Chemistry & Biology identify mitochondrial complex III as a specific positive regulator of autophagy. This study brings us a step closer to understanding the mechanism by which basal autophagy is coupled to cellular energy flux.
    Language English
    Publishing date 2011-11-23
    Publishing country United States
    Document type Comment ; Journal Article
    ZDB-ID 917827-2
    ISSN 1879-1301 ; 1074-5521
    ISSN (online) 1879-1301
    ISSN 1074-5521
    DOI 10.1016/j.chembiol.2011.11.004
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  2. Article: Autophagy, mitochondrial quality control, and oncogenesis.

    Jin, Shengkan

    Autophagy

    2006  Volume 2, Issue 2, Page(s) 80–84

    Abstract: Cancer is a disease associated with aging. More than 80% of human cancers are diagnosed in people aged 55 years or older. Autophagy has recently been demonstrated to be a novel mechanism of tumor suppression. Interestingly, autophagy also plays an ... ...

    Abstract Cancer is a disease associated with aging. More than 80% of human cancers are diagnosed in people aged 55 years or older. Autophagy has recently been demonstrated to be a novel mechanism of tumor suppression. Interestingly, autophagy also plays an important role in the control of aging. Here we summarize the genetic studies of autophagy in tumorigenesis and aging, and propose that autophagy may suppress tumor development and prevent aging through a common mechanism involving mitochondrial surveillance.
    MeSH term(s) Animals ; Autophagy ; Cell Transformation, Neoplastic ; Cellular Senescence/genetics ; Cellular Senescence/physiology ; DNA, Mitochondrial/genetics ; DNA, Mitochondrial/physiology ; Humans ; Mitochondria/genetics ; Mitochondria/physiology ; Mutation ; Neoplasms/genetics ; Neoplasms/pathology ; Reactive Oxygen Species/metabolism
    Chemical Substances DNA, Mitochondrial ; Reactive Oxygen Species
    Language English
    Publishing date 2006-04-29
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2454135-7
    ISSN 1554-8635 ; 1554-8627
    ISSN (online) 1554-8635
    ISSN 1554-8627
    DOI 10.4161/auto.2.2.2460
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  3. Article ; Online: The bioluminescent imaging of spontaneously occurring tumors in immunocompetent ODD-luciferase bearing transgenic mice.

    Goldman, Scott J / Jin, Shengkan

    Methods in molecular biology (Clifton, N.J.)

    2014  Volume 1098, Page(s) 129–143

    Abstract: The imaging of spontaneously occurring tumors in mice poses many technical and logistical problems. Recently a mouse model was generated in which a chimeric protein consisting of HIF-1α oxygen-dependent degradation domain (ODD) fused to luciferase was ... ...

    Abstract The imaging of spontaneously occurring tumors in mice poses many technical and logistical problems. Recently a mouse model was generated in which a chimeric protein consisting of HIF-1α oxygen-dependent degradation domain (ODD) fused to luciferase was ubiquitously expressed in all tissues. Hypoxic stress leads to the accumulation of ODD-luciferase in the tissues of this mouse model which can be identified by noninvasive bioluminescence measurement. Crossing this transgenic mouse with tumorigenic mice yields solid tumors with hypoxic cores that may be successfully imaged and characterized using the technique described herein.
    MeSH term(s) Animals ; Hypoxia-Inducible Factor 1, alpha Subunit/chemistry ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Image Processing, Computer-Assisted ; Immunocompetence ; Luciferases/genetics ; Luciferases/metabolism ; Luminescent Measurements ; Mice ; Mice, Transgenic ; Molecular Imaging/methods ; Neoplasms/pathology ; Oxygen/metabolism ; Protein Structure, Tertiary/genetics ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism
    Chemical Substances Hypoxia-Inducible Factor 1, alpha Subunit ; Recombinant Fusion Proteins ; Luciferases (EC 1.13.12.-) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2014
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-62703-718-1_11
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  4. Article ; Online: Mitochondrial uncoupler MB1-47 is efficacious in treating hepatic metastasis of pancreatic cancer in murine tumor transplantation models.

    Alasadi, Amer / Cao, Bin / Guo, Jingjing / Tao, Hanlin / Collantes, Juan / Tan, Victor / Su, Xiaoyang / Augeri, David / Jin, Shengkan

    Oncogene

    2021  Volume 40, Issue 12, Page(s) 2285–2295

    Abstract: Pancreatic ductal adenocarcinoma (PDA) is aggressive cancer characterized by rapid progression, metastatic recurrence, and highly resistant to treatment. PDA cells exhibit aerobic glycolysis, or the Warburg effect, which reduces the flux of pyruvate into ...

    Abstract Pancreatic ductal adenocarcinoma (PDA) is aggressive cancer characterized by rapid progression, metastatic recurrence, and highly resistant to treatment. PDA cells exhibit aerobic glycolysis, or the Warburg effect, which reduces the flux of pyruvate into mitochondria. As a result, more glycolytic metabolites are shunted to pathways for the production of building blocks (e.g., ribose) and reducing agents (e.g., NADPH) for biosynthesis that are necessary for cell proliferation. In addition, PDA cells are highly addicted to glutamine for both maintaining biosynthetic pathways and achieving redox balance. Mitochondrial uncoupling facilitates proton influx across the mitochondrial inner membrane without generating ATP, leading to a futile cycle that consumes glucose metabolites and glutamine. We synthesized a new mitochondrial uncoupler MB1-47 and tested its effect on cancer cell metabolism and the anticancer activity in pancreatic cancer cell models and murine tumor transplantation models. MB1-47 uncouples mitochondria in the pancreatic cancer cells, resulting in: (1) the acceleration of pyruvate oxidation and TCA turnover; (2) increases in AMP/ATP and ADP/AMP ratios; and (3) a decrease in the synthesis rate of nucleotides and sugar nucleotides. Moreover, MB1-47 arrests cell cycle at G
    MeSH term(s) Adenocarcinoma/genetics ; Adenocarcinoma/metabolism ; Adenocarcinoma/pathology ; Adenosine Diphosphate/genetics ; Adenosine Monophosphate/genetics ; Adenosine Triphosphate/genetics ; Animals ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Cell Cycle Checkpoints/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; Citric Acid Cycle/genetics ; Disease Models, Animal ; Glucose/metabolism ; Glycolysis/genetics ; Heterografts ; Humans ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Liver Neoplasms/secondary ; Mice ; Mitochondria/genetics ; Mitochondria/metabolism ; Pyruvic Acid/metabolism
    Chemical Substances Adenosine Monophosphate (415SHH325A) ; Adenosine Diphosphate (61D2G4IYVH) ; Pyruvic Acid (8558G7RUTR) ; Adenosine Triphosphate (8L70Q75FXE) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-03-01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-021-01688-7
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  5. Article: p53, Autophagy and tumor suppression.

    Jin, Shengkan

    Autophagy

    2005  Volume 1, Issue 3, Page(s) 171–173

    Abstract: Autophagy was recently established as a novel tumor suppression mechanism, which stimulated a wave of investigations that were aimed at understanding exactly how autophagy prevents tumorigenesis, as well as to determine to what extent autophagy is ... ...

    Abstract Autophagy was recently established as a novel tumor suppression mechanism, which stimulated a wave of investigations that were aimed at understanding exactly how autophagy prevents tumorigenesis, as well as to determine to what extent autophagy is implicated in human cancers. Autophagy might exert its tumor suppression function at the subcellular level by removing defective cytoplasmic components, such as damaged mitochondria. In addition, it might function at the cellular level by helping in the orderly removal of damaged cells. Previous studies indicated that autophagy is compromised in human breast, ovarian and prostate cancers. Recent research revealed that autophagy is activated by p53, a critical tumor suppressor that is involved in most, if not all, tumorigenesis. This study places autophagy in a broader context of human cancers. Future work elucidating the role of autophagy in the p53 circuit and p53 function might provide more insight into tumorigenesis and targeted cancer chemotherapy.
    MeSH term(s) Autophagy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Female ; Genes, Tumor Suppressor ; Humans ; Male ; Mutation ; Neoplasms/metabolism ; Neoplasms/pathology ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Tumor Suppressor Protein p53
    Language English
    Publishing date 2005-10-21
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2454135-7
    ISSN 1554-8635 ; 1554-8627
    ISSN (online) 1554-8635
    ISSN 1554-8627
    DOI 10.4161/auto.1.3.2051
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  6. Article ; Online: New methods for monitoring mitochondrial biogenesis and mitophagy in vitro and in vivo.

    Williams, Jessica A / Zhao, Katrina / Jin, Shengkan / Ding, Wen-Xing

    Experimental biology and medicine (Maywood, N.J.)

    2017  Volume 242, Issue 8, Page(s) 781–787

    Abstract: Removal of damaged mitochondria through mitophagy is critical for maintaining cellular homeostasis and functions. Increasing evidence implicates mitophagy in red blood cell differentiation, neurodegeneration, macrophage-mediated inflammation, ischemia, ... ...

    Abstract Removal of damaged mitochondria through mitophagy is critical for maintaining cellular homeostasis and functions. Increasing evidence implicates mitophagy in red blood cell differentiation, neurodegeneration, macrophage-mediated inflammation, ischemia, adipogenesis, drug-induced tissue injury, and cancer. Considerable progress has been made toward understanding the biochemical mechanisms involved in mitophagy regulation. However, few reliable assays to monitor and quantify mitophagy have been developed, particularly in vivo. In this review, we summarize the recent development of three assays, MitoTimer, mt-Keima and mito-QC, for monitoring and quantifying mitophagy in cells and in animal tissues. We also discuss the advantages and limitations of these three assays when using them to monitor and quantify mitophagy. Impact statement Removal of damaged mitochondria through mitophagy is critical for maintaining cellular homeostasis and functions. However, reliable quantitative assays to monitor mitophagy, particularly in vivo, are just emerging. This review will summarize the current novel quantitative assays to monitor mitophagy in vivo.
    MeSH term(s) Flow Cytometry/methods ; Microscopy, Fluorescence/methods ; Mitochondria/ultrastructure ; Mitochondrial Degradation ; Mitochondrial Proteins/analysis
    Chemical Substances Mitochondrial Proteins
    Language English
    Publishing date 2017-04
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 4015-0
    ISSN 1535-3699 ; 1525-1373 ; 0037-9727
    ISSN (online) 1535-3699 ; 1525-1373
    ISSN 0037-9727
    DOI 10.1177/1535370216688802
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  7. Article ; Online: Niclosamide piperazine prevents high-fat diet-induced obesity and diabetic symptoms in mice.

    Guo, Jingjing / Tao, Hanlin / Alasadi, Amer / Huang, Qingrong / Jin, Shengkan

    Eating and weight disorders : EWD

    2017  Volume 24, Issue 1, Page(s) 91–96

    Abstract: Purpose: Obesity and type 2 diabetes (T2D) have become the major public health challenges globally. Mitochondrial uncoupling, which reduces intracellular lipid loads and corrects the underlying cause of insulin resistance, has emerged as a promising ... ...

    Abstract Purpose: Obesity and type 2 diabetes (T2D) have become the major public health challenges globally. Mitochondrial uncoupling, which reduces intracellular lipid loads and corrects the underlying cause of insulin resistance, has emerged as a promising anti-obese and anti-diabetic intervention. Niclosamide is an anthelmintic drug approved by the US FDA with the mechanism of action that uncouples mitochondria of parasitic worms. Recently, niclosamide ethanolamine salt (NEN) was found to be a safe and effective hepatic mitochondrial uncoupler for the prevention and treatment of obesity and T2D in mouse models. The striking features of NEN prompt us to examine the anti-obese and anti-diabetic efficacy of other salt forms of niclosamide, with the ultimate goal to identify a suitable salt formulation for future clinical development. Here, we report the study with niclosamide piperazine salt (NPP), another salt form of niclosamide with documented safety profile.
    Methods: Mitochondrial uncoupling activity of NEN and NPP were determined by oxygen consumption assay with Seahorse XF24e Analyzer, as well as by mitochondrial membrane potential measurement in cultured cells. The in vivo anti-diabetic and anti-obesity activities were determined in C57BL/6J mice fed high-fat diet (HFD) or HFD containing 2000 ppm. NPP for 11 weeks.
    Results: Niclosamide piperazine salt showed a comparable mitochondrial uncoupling activity to NEN. Oral administration of NPP significantly reduced HFD-induced obesity, hyperglycemia and hepatic steatosis, and sensitized the insulin responses in mice.
    Conclusions: Niclosamide piperazine salt may hold the promise to become an alternative to NEN as a drug lead for the treatment of obesity and T2D. No level of evidence Animal study.
    MeSH term(s) Animals ; Diabetes Mellitus, Type 2/etiology ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/prevention & control ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Insulin Resistance/physiology ; Mice ; Mitochondria/drug effects ; Mitochondria/metabolism ; Niclosamide/pharmacology ; Niclosamide/therapeutic use ; Obesity/etiology ; Obesity/metabolism ; Obesity/prevention & control ; Oxygen Consumption/drug effects
    Chemical Substances Niclosamide (8KK8CQ2K8G)
    Language English
    Publishing date 2017-08-05
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2038625-4
    ISSN 1590-1262 ; 1124-4909
    ISSN (online) 1590-1262
    ISSN 1124-4909
    DOI 10.1007/s40519-017-0424-7
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  8. Article ; Online: Development and Characterization of a Modular CRISPR and RNA Aptamer Mediated Base Editing System.

    Collantes, Juan Carlos / Tan, Victor M / Xu, Huiting / Ruiz-Urigüen, Melany / Alasadi, Amer / Guo, Jingjing / Tao, Hanlin / Su, Chi / Tyc, Katarzyna M / Selmi, Tommaso / Lambourne, John J / Harbottle, Jennifer A / Stombaugh, Jesse / Xing, Jinchuan / Wiggins, Ceri M / Jin, Shengkan

    The CRISPR journal

    2021  Volume 4, Issue 1, Page(s) 58–68

    Abstract: Conventional CRISPR approaches for precision genome editing rely on the introduction of DNA double-strand breaks (DSB) and activation of homology-directed repair (HDR), which is inherently genotoxic and inefficient in somatic cells. The development of ... ...

    Abstract Conventional CRISPR approaches for precision genome editing rely on the introduction of DNA double-strand breaks (DSB) and activation of homology-directed repair (HDR), which is inherently genotoxic and inefficient in somatic cells. The development of base editing (BE) systems that edit a target base without requiring generation of DSB or HDR offers an alternative. Here, we describe a novel BE system called Pin-point
    MeSH term(s) Animals ; Aptamers, Nucleotide ; Bacteria/genetics ; Bacteria/metabolism ; CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats ; Gene Editing ; Green Fluorescent Proteins/genetics ; HEK293 Cells ; Humans ; INDEL Mutation ; RNA Editing ; RNA, Guide, CRISPR-Cas Systems/genetics ; Recombinational DNA Repair ; Exome Sequencing
    Chemical Substances Aptamers, Nucleotide ; RNA, Guide, CRISPR-Cas Systems ; Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2021-02-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3017891-5
    ISSN 2573-1602 ; 2573-1599
    ISSN (online) 2573-1602
    ISSN 2573-1599
    DOI 10.1089/crispr.2020.0035
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  9. Article ; Online: A role for ABCG2 beyond drug transport: Regulation of autophagy.

    Ding, Rui / Jin, Shengkan / Pabon, Kirk / Scotto, Kathleen W

    Autophagy

    2016  Volume 12, Issue 5, Page(s) 737–751

    Abstract: The ABC drug transporters, including ABCG2, are well known for their ability to efflux a wide spectrum of chemotherapeutic agents, thereby conferring a multidrug-resistant phenotype. However, studies over the past several years suggest that the ABC ... ...

    Abstract The ABC drug transporters, including ABCG2, are well known for their ability to efflux a wide spectrum of chemotherapeutic agents, thereby conferring a multidrug-resistant phenotype. However, studies over the past several years suggest that the ABC transporters may play additional role(s) in cell survival in the face of stress inducers that are not ABCG2 substrates (i.e., nutrient deprivation, ionizing radiation, rapamycin). The mechanism by which this occurs is largely unknown. In the present study, using several cancer cell lines and their ABCG2-overexpressing sublines, we show that cells overexpressing ABCG2 were more resistant to these stressors. This resistance was associated with an elevated level of autophagy flux, as measured by a higher rate of SQSTM1/p62 degradation and greater accumulation of LC3-II when compared to parental cells. Knockdown of ABCG2 reduced autophagic activity in resistant cells to a level similar to that observed in parental cells, confirming that the enhanced autophagy was ABCG2-dependent. Moreover, using cell viability, apoptosis, and clonogenic assays, we demonstrated that the ABCG2-expressing cells were more resistant to amino acid starvation and radiation-induced cell death. Importantly, knockdown of the critical autophagy factors ATG5 and ATG7 greatly reduced cell survival, verifying that enhanced autophagy was critical for this effect. Taken together, these data indicate that autophagy induced by various stressors is enhanced/accelerated in the presence of ABCG2, resulting in delayed cell death and enhanced cell survival. This defines a new role for this transporter, one with potential clinical significance.
    Language English
    Publishing date 2016-05-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2454135-7
    ISSN 1554-8635 ; 1554-8627
    ISSN (online) 1554-8635
    ISSN 1554-8627
    DOI 10.1080/15548627.2016.1155009
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  10. Article ; Online: A novel and highly effective mitochondrial uncoupling drug in T-cell leukemia.

    da Silva-Diz, Victoria / Cao, Bin / Lancho, Olga / Chiles, Eric / Alasadi, Amer / Aleksandrova, Maya / Luo, Shirley / Singh, Amartya / Tao, Hanlin / Augeri, David / Minuzzo, Sonia / Indraccolo, Stefano / Khiabanian, Hossein / Su, Xiaoyang / Jin, Shengkan / Herranz, Daniel

    Blood

    2021  Volume 138, Issue 15, Page(s) 1317–1330

    Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy. Despite recent advances in treatments with intensified chemotherapy regimens, relapse rates and associated morbidities remain high. In this context, metabolic ... ...

    Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy. Despite recent advances in treatments with intensified chemotherapy regimens, relapse rates and associated morbidities remain high. In this context, metabolic dependencies have emerged as a druggable opportunity for the treatment of leukemia. Here, we tested the antileukemic effects of MB1-47, a newly developed mitochondrial uncoupling compound. MB1-47 treatment in T-ALL cells robustly inhibited cell proliferation via both cytostatic and cytotoxic effects as a result of compromised mitochondrial energy and metabolite depletion, which severely impaired nucleotide biosynthesis. Mechanistically, acute treatment with MB1-47 in primary leukemias promoted adenosine monophosphate-activated serine/threonine protein kinase (AMPK) activation and downregulation of mammalian target of rapamycin (mTOR) signaling, stalling anabolic pathways that support leukemic cell survival. Indeed, MB1-47 treatment in mice harboring either murine NOTCH1-induced primary leukemias or human T-ALL patient-derived xenografts (PDXs) led to potent antileukemic effects with a significant extension in survival without overlapping toxicities. Overall, our findings demonstrate a critical role for mitochondrial oxidative phosphorylation in T-ALL and uncover MB1-47-driven mitochondrial uncoupling as a novel therapeutic strategy for the treatment of this disease.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; Mice ; Mitochondria/drug effects ; Mitochondria/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Uncoupling Agents/pharmacology ; Uncoupling Agents/therapeutic use
    Chemical Substances Antineoplastic Agents ; Uncoupling Agents
    Language English
    Publishing date 2021-05-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2020008955
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