scholarly journals Formation of Mallory Body-like Inclusions and Cell Death Induced by Deregulated Expression of Keratin 18

2002 ◽  
Vol 13 (10) ◽  
pp. 3441-3451 ◽  
Author(s):  
Ikuo Nakamichi ◽  
Shigetsugu Hatakeyama ◽  
Keiichi I. Nakayama
Keyword(s):  
Cell Death ◽  
Important Determinant ◽  
Cellular Model ◽  
Microtubule Network ◽  
Cytoplasmic Inclusions ◽  
Mallory Bodies ◽  
Keratin 18 ◽  
Intracellular Aggregates

Mallory bodies (MBs) are cytoplasmic inclusions that contain keratin 8 (K8) and K18 and are present in hepatocytes of individuals with alcoholic liver disease, nonalcoholic steatohepatitis, or benign or malignant hepatocellular neoplasia. Mice fed long term with griseofulvin are an animal model of MB formation. However, the lack of a cellular model has impeded understanding of the molecular mechanism of this process. Culture of HepG2 cells with griseofulvin has now been shown to induce both the formation of intracellular aggregates containing K18 as well as an increase in the abundance of K18 mRNA. Overexpression of K18 in HepG2, HeLa, or COS-7 cells also induced the formation of intracellular aggregates that stained with antibodies to ubiquitin and with rhodamine B (characteristics of MBs formed in vivo), eventually leading to cell death. The MB-like aggregates were deposited around centrosomes and disrupted the microtubular array. Coexpression of K8 with K18 restored the normal fibrous pattern of keratin distribution and reduced the toxicity of K18. In contrast, an NH2-terminal deletion mutant of K8 promoted the formation of intracellular aggregates even in the absence of K18 overexpression. Deregulated expression of K18, or an imbalance between K8 and K18, may thus be an important determinant of MB formation, which compromises the function of centrosomes and the microtubule network and leads to cell death.

Neurofilament phosphorylation

1995 ◽  
Vol 73 (9-10) ◽  
pp. 575-592 ◽  
Author(s):  
Harish C. Pant ◽  
Veeranna
Keyword(s):  
Molecular Weight ◽  
Nervous System ◽  
Nervous Tissue ◽  
Important Determinant ◽  
Neurofilament Proteins ◽  
Neurofilament Phosphorylation ◽  
Axonal Compartment

Neurofilament proteins (NFPs) are highly phosphorylated molecules in the axonal compartment of the adult nervous system. The phosphorylation of NFP is considered an important determinant of filament caliber, plasticity, and stability. This process reflects the function of NFs during the lifetime of a neuron from differentiation in the embryo through long-term activity in the adult until aging and environmental insult leads to pathology and ultimately death. NF function is modulated by phosphorylation–dephosphorylation in each of these diverse neuronal states. In this review, we have summarized some of these properties of NFP in adult nervous tissue, mostly from work in our own laboratory. Identification of sites phosphorylated in vivo in high molecular weight NFP (NF-H) and properties of NF-associated and neural-specific kinases phosphorylating specific sites in NFP are described. A model to explain the role of NF phosphorylation in determining filament caliber, plasticity, and stability is proposed.Key words: neurofilament proteins, phosphorylation, kinases, phosphatases, regulators, inhibitors, multimesic complex, domains.

Glucose regulates lipid metabolism in fasting king penguins

2003 ◽  
Vol 285 (2) ◽  
pp. R313-R320 ◽  
Author(s):  
Servane F. Bernard ◽  
Jord Orvoine ◽  
René Groscolas
Keyword(s):  
Lipid Metabolism ◽  
Plasma Concentration ◽  
Energy Production ◽  
Important Determinant ◽  
Plasma Concentrations ◽  
Glucose Infusion ◽  
Nonesterified Fatty Acids ◽  
Fat Stores

This study aims to determine whether glucose intervenes in the regulation of lipid metabolism in long-term fasting birds, using the king penguin as an animal model. Changes in the plasma concentration of various metabolites and hormones, and in lipolytic fluxes as determined by continuous infusion of [2-3H]glycerol and [1-14C]palmitate, were examined in vivo before, during, and after a 2-h glucose infusion under field conditions. All the birds were in the phase II fasting status (large fat stores, protein sparing) but differed by their metabolic and hormonal statuses, being either nonstressed (NSB; n = 5) or stressed (SB; n = 5). In both groups, glucose infusion at 5 mg·kg-1·min-1 induced a twofold increase in glycemia. In NSB, glucose had no effect on lipolysis (maintenance of plasma concentrations and rates of appearance of glycerol and nonesterified fatty acids) and no effect on the plasma concentrations of triacylglycerols (TAG), glucagon, insulin, or corticosterone. However, it limited fatty acid (FA) oxidation, as indicated by a 25% decrease in the plasma level of β-hydroxybutyrate (β-OHB). In SB, glucose infusion induced an ∼2.5-fold decrease in lipolytic fluxes and a large decrease in FA oxidation, as reflected by a 64% decrease in the plasma concentration of β-OHB. There were also a 35% decrease in plasma TAG, a 6.5- and 2.8-fold decrease in plasma glucagon and corticosterone, respectively, and a threefold increase in insulinemia. These data show that in fasting king penguins, glucose regulates lipid metabolism (inhibition of lipolysis and/or of FA oxidation) and affects hormonal status differently in stressed vs. nonstressed individuals. The results also suggest that in birds, as in humans, the availability of glucose, not of FA, is an important determinant of the substrate mix (glucose vs. FA) that is oxidized for energy production.

scholarly journals Efficacy, long-term toxicity, and mechanistic studies of gold nanorods photothermal therapy of cancer in xenograft mice

2017 ◽  
Vol 114 (15) ◽  
pp. E3110-E3118 ◽  
Author(s):  
Moustafa R. K. Ali ◽  
Mohammad Aminur Rahman ◽  
Yue Wu ◽  
Tiegang Han ◽  
Xianghong Peng ◽  
...  
Keyword(s):  
Cell Death ◽  
Mechanism Of Action ◽  
Gold Nanorods ◽  
Photothermal Therapy ◽  
Near Infrared ◽  
Infrared Light ◽  
Mouse Tumor ◽  
Maximal Induction

Gold nanorods (AuNRs)-assisted plasmonic photothermal therapy (AuNRs-PPTT) is a promising strategy for combating cancer in which AuNRs absorb near-infrared light and convert it into heat, causing cell death mainly by apoptosis and/or necrosis. Developing a valid PPTT that induces cancer cell apoptosis and avoids necrosis in vivo and exploring its molecular mechanism of action is of great importance. Furthermore, assessment of the long-term fate of the AuNRs after treatment is critical for clinical use. We first optimized the size, surface modification [rifampicin (RF) conjugation], and concentration (2.5 nM) of AuNRs and the PPTT laser power (2 W/cm2) to achieve maximal induction of apoptosis. Second, we studied the potential mechanism of action of AuNRs-PPTT using quantitative proteomic analysis in mouse tumor tissues. Several death pathways were identified, mainly involving apoptosis and cell death by releasing neutrophil extracellular traps (NETs) (NETosis), which were more obvious upon PPTT using RF-conjugated AuNRs (AuNRs@RF) than with polyethylene glycol thiol-conjugated AuNRs. Cytochrome c and p53-related apoptosis mechanisms were identified as contributing to the enhanced effect of PPTT with AuNRs@RF. Furthermore, Pin1 and IL18-related signaling contributed to the observed perturbation of the NETosis pathway by PPTT with AuNRs@RF. Third, we report a 15-month toxicity study that showed no long-term toxicity of AuNRs in vivo. Together, these data demonstrate that our AuNRs-PPTT platform is effective and safe for cancer therapy in mouse models. These findings provide a strong framework for the translation of PPTT to the clinic.

scholarly journals Lessons from Keratin 18 Knockout Mice: Formation of Novel Keratin Filaments, Secondary Loss of Keratin 7 and Accumulation of Liver-specific Keratin 8-Positive Aggregates

1998 ◽  
Vol 140 (6) ◽  
pp. 1441-1451 ◽  
Author(s):  
Thomas M. Magin ◽  
Rolf Schröder ◽  
Sabine Leitgeb ◽  
Frederique Wanninger ◽  
Kurt Zatloukal ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Alcoholic Hepatitis ◽  
Liver Pathology ◽  
Secondary Loss ◽  
Mallory Bodies ◽  
Keratin Filaments ◽  
Keratin 18 ◽  
Keratin 7 ◽  
Human Alcoholic

Here, we report on the analysis of keratin 18 null mice. Unlike the ablation of K8, which together with K18 is expressed in embryonic and simple adult epithelia, K18 null mice are viable, fertile, and show a normal lifespan. In young K18 null mice, hepatocytes were completely devoid of keratin filaments. Nevertheless, typical desmosomes were formed and maintained. Old K18 null mice, however, developed a distinctive liver pathology with abnormal hepatocytes containing K8-positive aggregates. These stained positively for ubiquitin and MM120-1 and were identified as Mallory bodies, one hallmark of human alcoholic hepatitis. This is the first demonstration that the ablation of one keratin leads to the accumulation of its single partner. Another striking finding was the absence or drastic down regulation of K7 in several tissues despite its ongoing transcription. Moreover, K18 null mice revealed new insights in the filament-forming capacity of the tail-less K19 in vivo. Due to the unexpected secondary loss of K7, only K8/19 are expressed in the uterine epithelium of K18 null mice. Immunoelectron microscopy of this tissue demonstrated the presence of typical K8/19 IF, thus highlighting in vivo that K19 is a fully competent partner for K8.

In vivo imaging of myocardial cell death using a peptide probe and assessment of long-term heart function

2013 ◽  
Vol 172 (1) ◽  
pp. 367-373 ◽  
Author(s):  
Bodhraj Acharya ◽  
Kai Wang ◽  
In-San Kim ◽  
WoongChol Kang ◽  
Chanil Moon ◽  
...  
Keyword(s):  
Cell Death ◽  
In Vivo Imaging ◽  
Heart Function ◽  
Myocardial Cell ◽  
Peptide Probe

Programmed cell death with a necrotic-like phenotype

2013 ◽  
Vol 4 (3) ◽  
pp. 259-275 ◽  
Author(s):  
Michael J. Morgan ◽  
Zheng-gang Liu
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Mammalian Development ◽  
Programmed Necrosis ◽  
Physiological Processes ◽  
Molecular Events ◽  
Regulated Necrosis

AbstractProgrammed cell death is the process by which an individual cell in a multicellular organism commits cellular ‘suicide’ to provide a long-term benefit to the organism. Thus, programmed cell death is important for physiological processes such as development, cellular homeostasis, and immunity. Importantly, in this process, the cell is not eliminated in response to random events but in response to an intricate and genetically defined set of internal cellular molecular events or ‘program’. Although the apoptotic process is generally very well understood, programmed cell death that occurs with a necrotic-like phenotype has been much less studied, and it is only within the past few years that the necrotic program has begun to be elucidated. Originally, programmed necrosis was somewhat dismissed as a nonphysiological phenomenon that occurs in vitro. Recent in vivo studies, however, suggest that regulated necrosis is an authentic classification of cell death that is important in mammalian development and other physiological processes, and programmed necrosis is now considered a significant therapeutic target in major pathological processes as well. Although the RIP1-RIP3-dependent necrosome complex is recognized as being essential for the execution of many instances of programmed necrosis, other downstream and related necrotic molecules and pathways are now being characterized. One of the current challenges is understanding how and under what conditions these pathways are linked together.

scholarly journals Fructose-a double edged sword for cell death versus differentiation and long-term survival of NSC-34 motor neuron like cells in vitro

2021 ◽  
Author(s):  
Divya Lodha ◽  
Jamuna R. Subramaniam
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Motor Neurons ◽  
Response Regulator ◽  
Nuclear Staining ◽  
Term Survival ◽  
High Fructose

Abstract In various neurological and neurodegenerative diseases (ND), motor neurons (MN) of the spinal cord are affected leading to movement impairments. The ND, Amyotrophic Lateral Sclerosis (ALS), is caused due to MN degeneration. ALS afflicts athletes and other major sports personalities, who generally consume fructose enriched sports drinks. Recently, we have reported that high fructose (F5%) impairs the metabolic activity in the NSC-34, MN cell line and reduces the healthspan of C. elegans. But how fructose impacts the MNs either in vitro or in vivo in the long term is not understood. Here we report, to our surprise, that high fructose (F5%) treatment of NSC-34 leads to differentiation of 1-2% of cells with progressive neurite extension. They could be maintained for 80 days in vitro with 5% CO2 and O2 at 18.8%. On the contrary, 5% fructose significantly reduced cell viability by ~85% and inhibited cell proliferation by Day10. Nuclear staining displayed multiple nuclei in the cells indicative of cytokinesis inhibition which led to the lack of cell proliferation. Further, F5% significantly increased ROS levels (^~34%), the potential cause for reduced viability. In addition, no induction of expression of the master oxidative stress response regulator, the transcription factor, nrf-2, or the downstream effector, sod1, was evident. Despite the adverse effects, in the absence of any, F5% is a potential strategy to maintain at least a small percentage of MNs for a long time, ~45 days in vitro, which also reinforces the Redox-Cell death versus cell survival conundrum.

Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice

2020 ◽  
Vol 12 (530) ◽  
pp. eaax1337 ◽  
Author(s):  
Ke Lai ◽  
Xing-Lei Song ◽  
Hao-Song Shi ◽  
Xin Qi ◽  
Chun-Yan Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebrospinal Fluid ◽  
Lactate Dehydrogenase ◽  
Neonatal Hyperbilirubinemia ◽  
Bilirubin Concentration ◽  
Acid Sensing Ion Channels ◽  
Intracellular Ca ◽  
Prevailing View

Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory and complex sensorimotor functions in vivo, which are largely attenuated in ASIC1a null mice. These findings suggest that targeting acidosis and ASICs may attenuate neonatal hyperbilirubinemia complications.

Immunofluorescence of peritoneal phagocytes after infection in vivo with egg-attenuated Chlamydia psittaci 6BC

1973 ◽  
Vol 19 (11) ◽  
pp. 1425-1429 ◽  
Author(s):  
Nonna Kordová ◽  
Caroline Martin ◽  
John C. Wilt ◽  
Wally Meyer
Keyword(s):  
Giemsa Stain ◽  
Chlamydia Psittaci ◽  
Specific Staining ◽  
Cytoplasmic Inclusions ◽  
Peritoneal Cells ◽  
Epitheloid Cells ◽  
Chlamydial Antigen

The present studies on the fluorescence of Chlamydiae-infected peritoneal cells have demonstrated considerable variation in the morphology, distribution, and localization of antigen in the phagocytes of the mononuclear series. In addition, diffuse or patchy fluorescence was detected in the cytoplasm of apparently intact polymorphonuclear phagocytes (PMN's). Small lymphocytes "coated" with a thin layer of diffuse fluorescence appeared to be firmly attached to macrophages, which exhibited specific staining. A marked increase of chlamydial antigen was present in peritoneal cells (infected in vivo) after they were kept in vitro. Epitheloid cells were evident in long-term cultures and demonstrated strong specific fluorescence, which was associated with intracellular membranes and enlarged nucleoli; cytoplasmic inclusions stained only faintly. In contrast Giemsa-stain demonstrated classical chlamydial inclusions. The significance of localization and persistence of chlamydial antigens in phagocytes is discussed.

scholarly journals Recombinant Lactaptin Induces Immunogenic Cell Death and Creates an Antitumor Vaccination Effect in Vivo with Enhancement by an IDO Inhibitor

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2804 ◽  
Author(s):  
Olga Troitskaya ◽  
Mikhail Varlamov ◽  
Anna Nushtaeva ◽  
Vladimir Richter ◽  
Olga Koval
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Ethyl Pyruvate ◽  
High Mobility ◽  
Cytotoxic Agents ◽  
Phagocytic Cells ◽  
Syngeneic Mouse Model

Natural compounds of various origins are intensively investigated for their antitumor activity. Potential benefits of antitumor therapy can be achieved when cytotoxic agents kill cancer cells and these dying cancer cells drive adoptive immunity to the tumor. This strategy was successfully demonstrated for chemotherapeutic drugs that induce immunogenic type of cell death (ICD) with release of DAMPs (danger associated molecular patterns) and exposure of “eat me” signals. In this study, we demonstrated that recombinant human milk peptide lactaptin (RL2) induces death of cancer cells with ICD hallmarks in vitro with the release of ATP and high-mobility group box 1 protein (HMGB1) and exposure of calreticulin and HSP70 on the external cell membrane. RL2-treated cancer cells were efficiently engulfed by phagocytic cells. Using the syngeneic mouse model, we demonstrated that RL2-treated MX-7 rhabdomyosarcoma cells confer long-term immune-mediated protection against challenge with live MX-7 cells. We also analyzed the combinatorial antitumor effect of vaccination with RL2-treated cells and the inhibition of indoleamine 2,3-dioxygenase (IDO) with ethyl pyruvate. Compared to solo anti-tumor immunization with RL2-treated cells, additional chemical inhibition of IDO demonstrated better long-term antitumor responses than vaccination alone.

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