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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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Zs.A 2218: Show issues

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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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Zs.A 5566: Show issues

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Article ; Online: Prevention of Obesity and Type 2 Diabetes with Aged Citrus Peel (Chenpi) Extract.

Guo, Jingjing / Tao, Hanlin / Cao, Yong / Ho, Chi-Tang / Jin, Shengkang / Huang, Qingrong

Journal of agricultural and food chemistry

2016 Volume 64, Issue 10, Page(s) 2053–2061

Abstract: Chenpi is the dry peel of the plant Citrus reticulata Blanco after an aging processing. It has been used as an antidigestive and anti-inflammatory traditional medicine, as well as culinary seasoning and dietary supplement, in China. However, its efficacy ...

Abstract	Chenpi is the dry peel of the plant Citrus reticulata Blanco after an aging processing. It has been used as an antidigestive and anti-inflammatory traditional medicine, as well as culinary seasoning and dietary supplement, in China. However, its efficacy and underlying scientific mechanism have not been sufficiently investigated. Chenpi is uniquely enriched with a high content of 5-demethylated polymethoxyflavones (5-OH PMFs). The effect of chenpi extract on improving metabolic features was examined using high-fat diet (HFD)-induced obesity/diabetes mouse model. Oral administration of 0.25 and 0.5% chenpi extract in food over 15 weeks markedly prevented HFD-induced obesity, hepatic steatosis, and diabetic symptoms. The beneficial effect is associated with 5'-adenosine monophosphate-activated protein kinase (AMPK) activation in adipose tissue. Our results indicate that 5-OH PMFs-enriched chenpi extract is effective in preventing obesity and type 2 diabetes, and its effect might be related to improvement in lipid metabolism associated with activation of the AMPK pathway.
MeSH term(s)	Animals ; Blood Glucose/metabolism ; Citrus/chemistry ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/prevention & control ; Drugs, Chinese Herbal/administration & dosage ; Drugs, Chinese Herbal/chemistry ; Fruit/chemistry ; Humans ; Insulin/blood ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/drug therapy ; Obesity/prevention & control
Chemical Substances	Blood Glucose ; Drugs, Chinese Herbal ; Insulin ; chenpi (JU3D414057)
Language	English
Publishing date	2016-03-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	241619-0
ISSN	1520-5118 ; 0021-8561
ISSN (online)	1520-5118
ISSN	0021-8561
DOI	10.1021/acs.jafc.5b06157
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Zs.A 1172: Show issues

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Article ; Online: Effect of mitochondrial uncouplers niclosamide ethanolamine (NEN) and oxyclozanide on hepatic metastasis of colon cancer.

Alasadi, Amer / Chen, Michael / Swapna, G V T / Tao, Hanlin / Guo, Jingjing / Collantes, Juan / Fadhil, Noor / Montelione, Gaetano T / Jin, Shengkan

Cell death & disease

2018 Volume 9, Issue 2, Page(s) 215

Abstract: Metabolism of cancer cells is characterized by aerobic glycolysis, or the Warburg effect. Aerobic glycolysis reduces pyruvate flux into mitochondria, preventing a complete oxidation of glucose and shunting glucose to anabolic pathways essential for cell ... ...

Abstract	Metabolism of cancer cells is characterized by aerobic glycolysis, or the Warburg effect. Aerobic glycolysis reduces pyruvate flux into mitochondria, preventing a complete oxidation of glucose and shunting glucose to anabolic pathways essential for cell proliferation. Here we tested a new strategy, mitochondrial uncoupling, for its potential of antagonizing the anabolic effect of aerobic glycolysis and for its potential anticancer activities. Mitochondrial uncoupling is a process that facilitates proton influx across the mitochondrial inner membrane without generating ATP, stimulating a futile cycle of acetyl- CoA oxidation. We tested two safe mitochondrial uncouplers, NEN (niclosamide ethanolamine) and oxyclozanide, on their metabolic effects and anti-cancer activities. We used metabolomic NMR to examine the effect of mitochondrial uncoupling on glucose metabolism in colon cancer MC38 cells. We further tested the anti-cancer effect of NEN and oxyclozanide in cultured cell models, APC
MeSH term(s)	Animals ; Antinematodal Agents/pharmacology ; Antinematodal Agents/therapeutic use ; Colonic Neoplasms/complications ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/pathology ; Ethanolamine/pharmacology ; Ethanolamine/therapeutic use ; Humans ; Liver Neoplasms/pathology ; Liver Neoplasms/secondary ; Mice ; Niclosamide/pharmacology ; Niclosamide/therapeutic use ; Oxyclozanide/pharmacology ; Oxyclozanide/therapeutic use
Chemical Substances	Antinematodal Agents ; Oxyclozanide (1QS9G4876X) ; Ethanolamine (5KV86114PT) ; Niclosamide (8KK8CQ2K8G)
Language	English
Publishing date	2018-02-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-017-0092-6
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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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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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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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Zs.A 7195: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 119: Show issues

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Article ; Online: Niclosamide ethanolamine-induced mild mitochondrial uncoupling improves diabetic symptoms in mice.

Tao, Hanlin / Zhang, Yong / Zeng, Xiangang / Shulman, Gerald I / Jin, Shengkan

Nature medicine

2014 Volume 20, Issue 11, Page(s) 1263–1269

Abstract: Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom of the disease but are not effective in correcting its underlying cause. One important causal factor of T2D is ectopic accumulation ...

Abstract	Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom of the disease but are not effective in correcting its underlying cause. One important causal factor of T2D is ectopic accumulation of lipids in metabolically sensitive organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, is an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an anthelmintic drug approved by the US Food and Drug Administration that uncouples the mitochondria of parasitic worms. Here we show that niclosamide ethanolamine salt (NEN) uncouples mammalian mitochondria at upper nanomolar concentrations. Oral NEN increases energy expenditure and lipid metabolism in mice. It is also efficacious in preventing and treating hepatic steatosis and insulin resistance induced by a high-fat diet. Moreover, it improves glycemic control and delays disease progression in db/db mice. Given the well-documented safety profile of NEN, our study provides a potentially new and practical pharmacological approach for treating T2D.
MeSH term(s)	Administration, Oral ; Animals ; Blood Glucose/metabolism ; Cell Respiration/drug effects ; Diabetes Mellitus, Experimental/blood ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Experimental/pathology ; Diet, High-Fat ; Disease Models, Animal ; Energy Metabolism/drug effects ; Fasting/blood ; Fatty Liver/complications ; Fatty Liver/drug therapy ; Fatty Liver/pathology ; Glucose Clamp Technique ; Hep G2 Cells ; Humans ; Hyperglycemia/blood ; Hyperglycemia/complications ; Hyperglycemia/drug therapy ; Hyperglycemia/pathology ; Insulin Resistance ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Liver/ultrastructure ; Male ; Mammals/metabolism ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; NIH 3T3 Cells ; Niclosamide/administration & dosage ; Niclosamide/chemistry ; Niclosamide/pharmacology ; Niclosamide/therapeutic use ; Uncoupling Agents/administration & dosage ; Uncoupling Agents/chemistry ; Uncoupling Agents/pharmacology ; Uncoupling Agents/therapeutic use
Chemical Substances	Blood Glucose ; Uncoupling Agents ; Niclosamide (8KK8CQ2K8G)
Keywords	covid19
Language	English
Publishing date	2014-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.3699
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 39: Show issues

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Article: Damage of PS II during senescence of Spirodela polyrrhiza explants under long-day conditions and its prevention by 6-benzyladenine.

Liu, Qingdai / Zhu, Yerong / Tao, Hanlin / Wang, Ningning / Wang, Yong

Journal of plant research

2006 Volume 119, Issue 2, Page(s) 145–152

Abstract: The chlorophyll a (Chl a) fluorescence technique was applied to investigate damage of PS II during senescence of excised half-fronds in Spirodela polyrrhiza P143. The green explants showed a typical Chl a fluorescence transient, OJIP. After cultivation ... ...

Abstract	The chlorophyll a (Chl a) fluorescence technique was applied to investigate damage of PS II during senescence of excised half-fronds in Spirodela polyrrhiza P143. The green explants showed a typical Chl a fluorescence transient, OJIP. After cultivation of explants under long-day conditions for 8 days, all the J, I, and P steps disappeared, but a clear K band, an indication of senescence, was observed. JIP-test showed that at this time point, the photosynthetic performance index (PI) dropped to zero and the active reaction center (RC) per leaf cross-section (RC/CS) declined to 18%. As the oxygen-evolving complex (OEC) and the chlorophyll content all remained above 42%, it is proposed that the decline in RC contributes more to the appearance of the K band. Supplementation of 6-benzyladenine (6-BA) into the medium at the beginning of cultivation caused dramatic increase in PI, OEC, RC/CS, and chlorophyll content, and at any time before the 8th day reversed the senescence process of the explants. When 6-BA was added after 8 days of cultivation, the PI did not increase anymore, RC/CS and OEC were maintained at 22% and above 40%, respectively, and chlorophyll content decreased continuously further. These data support a view that the decline in RC is crucial for initiation of the irreversible senescence phase of explants cultivated under long-day conditions.
MeSH term(s)	Benzyl Compounds ; Chlorophyll ; Fluorescence ; Kinetin/physiology ; Magnoliopsida/physiology ; Photosystem II Protein Complex/physiology ; Purines
Chemical Substances	Benzyl Compounds ; Photosystem II Protein Complex ; Purines ; Chlorophyll (1406-65-1) ; benzylaminopurine (KXG6A989PS) ; Kinetin (P39Y9652YJ) ; chlorophyll a (YF5Q9EJC8Y)
Language	English
Publishing date	2006-03
Publishing country	Japan
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2077362-6
ISSN	1618-0860 ; 0918-9440
ISSN (online)	1618-0860
ISSN	0918-9440
DOI	10.1007/s10265-006-0259-1
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Article ; Online: Vaccinia virus leads to ATG12–ATG3 conjugation and deficiency in autophagosome formation.

Moloughney, Joseph G / Monken, Claude E / Tao, Hanlin / Zhang, Haiyan / Thomas, Janice D / Lattime, Edmund C / Jin, Shengkan

Autophagy

2011 Volume 7, Issue 12, Page(s) 1434–1447

Abstract: The interactions between viruses and cellular autophagy have been widely reported. On the one hand, autophagy is an important innate immune response against viral infection. On the other hand, some viruses exploit the autophagy pathway for their survival ...

Abstract	The interactions between viruses and cellular autophagy have been widely reported. On the one hand, autophagy is an important innate immune response against viral infection. On the other hand, some viruses exploit the autophagy pathway for their survival and proliferation in host cells. Vaccinia virus is a member of the family of Poxviridae which includes the smallpox virus. The biogenesis of vaccinia envelopes, including the core envelope of the immature virus (IV), is not fully understood. In this study we investigated the possible interaction between vaccinia virus and the autophagy membrane biogenesis machinery. Massive LC3 lipidation was observed in mouse fibroblast cells upon vaccinia virus infection. Surprisingly, the vaccinia virus induced LC3 lipidation was shown to be independent of ATG5 and ATG7, as the atg5 and atg7 null mouse embryonic fibroblasts (MEFs) exhibited the same high levels of LC3 lipidation as compared with the wild-type MEFs. Mass spectrometry and immunoblotting analyses revealed that the viral infection led to the direct conjugation of ATG3, which is the E2-like enzyme required for LC3-phosphoethanonamine conjugation, to ATG12, which is a component of the E3-like ATG12–ATG5-ATG16 complex for LC3 lipidation. Consistently, ATG3 was shown to be required for the vaccinia virus induced LC3 lipidation. Strikingly, despite the high levels of LC3 lipidation, subsequent electron microscopy showed that vaccinia virus-infected cells were devoid of autophagosomes, either in normal growth medium or upon serum and amino acid deprivation. In addition, no autophagy flux was observed in virus-infected cells. We further demonstrated that neither ATG3 nor LC3 lipidation is crucial for viral membrane biogenesis or viral proliferation and infection. Together, these results indicated that vaccinia virus does not exploit the cellular autophagic membrane biogenesis machinery for their viral membrane production. Moreover, this study demonstrated that vaccinia virus instead actively disrupts the cellular autophagy through a novel molecular mechanism that is associated with aberrant LC3 lipidation and a direct conjugation between ATG12 and ATG3.
MeSH term(s)	Amino Acid Sequence ; Animals ; Autophagy ; Autophagy-Related Protein 12 ; Autophagy-Related Protein 5 ; Autophagy-Related Protein 7 ; Autophagy-Related Proteins ; DNA, Viral/metabolism ; Fibroblasts/metabolism ; Fibroblasts/virology ; Immunoprecipitation ; Lipids/chemistry ; Mass Spectrometry ; Mice ; Microtubule-Associated Proteins/metabolism ; Molecular Sequence Data ; NIH 3T3 Cells ; Phagosomes/metabolism ; Proteins/chemistry ; Proteins/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Vaccinia/metabolism ; Vaccinia/virology ; Vaccinia virus/growth & development ; Vaccinia virus/metabolism
Chemical Substances	Atg12 protein, mouse ; Atg5 protein, mouse ; Atg7 protein, mouse ; Autophagy-Related Protein 12 ; Autophagy-Related Protein 5 ; Autophagy-Related Proteins ; DNA, Viral ; Lipids ; Map1lc3b protein, mouse ; Microtubule-Associated Proteins ; Proteins ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Autophagy-Related Protein 7 (EC 6.2.1.45) ; Atg3 protein, mouse (EC 6.3.2.-)
Keywords	covid19
Language	English
Publishing date	2011-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.7.12.17793
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Article: Synthesis and herbicidal activity of novel alpha,alpha,alpha-trifluoro-m-tolyl pyridazinone derivatives.

Xu, Han / Zou, Xiao-Mao / Zhu, You-Quan / Liu, Bin / Tao, Han-Lin / Hu, Xu-Hong / Song, Hai-Bin / Hu, Fang-Zhong / Wang, Yong / Yang, Hua-Zheng

Pest management science

2006 Volume 62, Issue 6, Page(s) 522–530

Abstract: A series of novel alpha,alpha,alpha-trifluoro-m-tolyl pyridazinone derivatives was synthesised. Herbicidal activities of the two intermediate compounds and 15 pyridazinone derivatives were evaluated through barnyardgrass and rape cup tests and Spirodela ... ...

Abstract	A series of novel alpha,alpha,alpha-trifluoro-m-tolyl pyridazinone derivatives was synthesised. Herbicidal activities of the two intermediate compounds and 15 pyridazinone derivatives were evaluated through barnyardgrass and rape cup tests and Spirodela polyrrhiza (L.) Schleiden tests. Selected compounds were also evaluated under greenhouse conditions. Bleaching activities were observed at 10 microg ml(-1) and some compounds exhibited herbicidal activities at a rate of 300 g ha(-1). The relationship between crystal structures and herbicidal activities is discussed through a comparison of two compounds (5a and 5f).
MeSH term(s)	Brassica/drug effects ; Brassica/growth & development ; Echinochloa/drug effects ; Echinochloa/growth & development ; Herbicides/chemical synthesis ; Herbicides/chemistry ; Herbicides/pharmacology ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Plants/drug effects ; Pyridazines/chemical synthesis ; Pyridazines/chemistry ; Pyridazines/pharmacology
Chemical Substances	Herbicides ; Pyridazines
Language	English
Publishing date	2006-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2001705-4
ISSN	1526-4998 ; 1526-498X
ISSN (online)	1526-4998
ISSN	1526-498X
DOI	10.1002/ps.1195
Database	MEDical Literature Analysis and Retrieval System OnLINE

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