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- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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- Xie, Sisi, et al.
(författare)
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Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia
- 2022
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 14:673
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Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating beta-hydroxybutyrate (beta-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-beta-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked beta-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a non-toxic, low-cost dietary intervention for combating CIT.
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- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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- Liu, Yong, et al.
(författare)
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Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-kappa B activity
- 2017
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Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889 .- 2041-4889. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of L-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor kappa B (NF-kappa B) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-kappa B activation and less release of TNF-alpha and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that inhibition of XIAP represents a potential therapeutic strategy for the treatment of acute pancreatitis.
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- Liu, Zhao-Di, et al.
(författare)
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Influence of the central metal on the crystal structures and electronic structures of biferrocene trinuclear complexes
- 2011
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Ingår i: Polyhedron. - : Elsevier. - 0277-5387 .- 1873-3719. ; 30:2, s. 279-283
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Tidskriftsartikel (refereegranskat)abstract
- Five metal-bridged biferrocene complexes of the Schiff-base ligand (HL = S-benzyl-N-(ferrocenyl-1-methyl-methylidene)dithiocarbazate) have been studied by single crystal X-ray diffraction and 57Fe Mössbauer spectroscopy. The crystal structures of the complexes show that the central metal ions are tetra-coordinated by two ligands in two modes: the central d8 transition metal ions (Ni2+, Pd2+, and Pt2+) are nearly square-planar coordinated and the d10 transition metal ions (Zn2+ and Cd2+) are tetrahedrally coordinated. Interestingly, the isomer shifts in 57Fe Mössbauer spectroscopy are also of two kinds: d8 transition metal ions (0.097–0.247 mm/s) and d10 transition metal ions (0.416–0.435 mm/s).
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- Tian, Yu-peng, et al.
(författare)
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Synthesis, crystal structure and NLO properties of a novel ruthenium(II) complex with unusual coordination mode
- 2005
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Ingår i: Transition metal chemistry (Weinheim). - : Kluwer Academic Publishers. - 0340-4285 .- 1572-901X. ; 30:7, s. 778-785
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Tidskriftsartikel (refereegranskat)abstract
- A new Schiff base 4-[N-hydroxyethyl-N-(methyl)amino]benzaldehyde S-methyl dithiocarbazate (HL, where H is a dissociable proton) and the ruthenium complex [Ru(bpy)2L]PF6 (bpy = 2,2′-bipyridine) have been synthesized. The structural determinations of the ligand and its ruthenium complex, by X-ray crystallography, show that the ligand is coordinated as a monoanionic bidentate N, S-donor, forming a four-member chelate ring with a bite angle of 65.91°. The complex shows intense MLCT transitions in the visible region. Fluorescent and electrochemical properties have been also studied. The complex in DMF solution exhibited a strong two-photon absorption (t.p.a.) at 532 nm nanosecond laser pulses. The t.p.a. coefficient β, t.p.a. cross-section σ and the third-order optical nonlinearity χ(3) of the complex and the ligand have been determined by the Z-scan technique.
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