Alterations to the structure of Leishmania major induced by N-arylisoquinolines correlate with compound accumulation and disposition

Naphthylisoquinoline alkaloids equipped with a N,C-hetero-‘biaryl’ axis, and, in particular, simplified synthetic analogues thereof, kill intracellular Leishmania major at concentrations in the low submicromolar range, while being significantly less toxic to their major host cell, the macrophage, at the same concentrations. To further investigate their mechanism of action we evaluated the morphological and ultrastructural changes induced by specific N-arylisoquinolines in L. major, and the correlation of these changes with compound accumulation and disposition by the parasite. After 24 h of treatment with the synthetic arylisoquinolinium salts 3 or 4, dramatic structural changes and cell death were observed. Furthermore, the auto-fluorescent derivative salt 3 accumulates continually in intracellular compartments. Our results thus suggest that the leishmanicidal effect of arylisoquinolinium salts may involve their ability to accumulate and precipitate in intracellular organelles, form a huge vacuole and eventually promote cell lysis.

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Ultrastructural changes associated with induced systemic resistance of cucumber to disease: host response and development of Colletotrichum lagenarium in systemically protected leaves

Canadian Journal of Botany ◽

10.1139/b88-148 ◽

1988 ◽

Vol 66 (6) ◽

pp. 1028-1038 ◽

Cited By ~ 39

Author(s):

X. L. Xuei ◽

U. Järlfors ◽

J. Kuć

Keyword(s):

Electron Microscopy ◽

Host Cell ◽

Host Response ◽

Structural Changes ◽

Induced Systemic Resistance ◽

Light And Electron Microscopy ◽

Systemic Resistance ◽

Ultrastructural Changes ◽

Mesophyll Cells ◽

Before And After

Systemic resistance to anthracnose caused by Colletotricum lagenarium was induced in cucumber by inoculation with fungal conidia. Control and immunized leaves were examined by both light and electron microscopy before and after subsequent challenge with the fungus. Penetration through the epidermal wall was evident 36 h after challenge and was followed by hyphal proliferation and host-cell destruction in control tissues. Penetration was rarely seen in immunized tissues before 72 h, but at 24 h, invaginations of the appressorial wall were observed, as well as highly electron opaque epidermal walls beneath the appressoria. At 72 h, thin penetration pegs were seen within the dense host wall, and at 96 h, the peg was embedded within the underlying papilla and aggregates of callose-like material. Penetration through the epidermis was rare in immunized tissue, but when it was observed, development appeared to be similar to that in control leaves. Evidence is presented to show that ultra-structural changes in immunized tissues as well as in the fungus occur within 24 h after challenge of the host. There appears to be a correlation between the comparatively few lesions observed macroscopically in immunized leaves and the sparsity of successful penetrations into host mesophyll cells.

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Fine Structural Changes in the Microvasculature of the Mouse Pinna: Aging and Radiation Injury

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050287 ◽

1974 ◽

Vol 32 ◽

pp. 54-55

Author(s):

S. Phyllis Steamer ◽

Rosemarie L. Devine

Keyword(s):

Structural Changes ◽

Radiation Treatment ◽

Arterial Stenosis ◽

Ultrastructural Changes ◽

Vascular Effects ◽

Microvascular Changes ◽

Surrounding Connective Tissue ◽

Fission Neutrons ◽

Total Body

The importance of radiation damage to the skin and its vasculature was recognized by the early radiologists. In more recent studies, vascular effects were shown to involve the endothelium as well as the surrounding connective tissue. Microvascular changes in the mouse pinna were studied in vivo and recorded photographically over a period of 12-18 months. Radiation treatment at 110 days of age was total body exposure to either 240 rad fission neutrons or 855 rad 60Co gamma rays. After in vivo observations in control and irradiated mice, animals were sacrificed for examination of changes in vascular fine structure. Vessels were selected from regions of specific interest that had been identified on photomicrographs. Prominent ultrastructural changes can be attributed to aging as well as to radiation treatment. Of principal concern were determinations of ultrastructural changes associated with venous dilatations, segmental arterial stenosis and tortuosities of both veins and arteries, effects that had been identified on the basis of light microscopic observations. Tortuosities and irregularly dilated vein segments were related to both aging and radiation changes but arterial stenosis was observed only in irradiated animals.

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Faculty Opinions recommendation of Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13988977.15445089 ◽

2012 ◽

Author(s):

Thierry Soldati ◽

Sonia Arafah

Keyword(s):

Cell Death ◽

Mycobacterium Tuberculosis ◽

Host Cell ◽

Host Cell Death

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Discovery of fungal surface NADases predominantly present in pathogenic species

Nature Communications ◽

10.1038/s41467-021-21307-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Øyvind Strømland ◽

Juha P. Kallio ◽

Annica Pschibul ◽

Renate H. Skoge ◽

Hulda M. Harðardóttir ◽

...

Keyword(s):

Cell Death ◽

Aspergillus Fumigatus ◽

Neurospora Crassa ◽

Binding Site ◽

Host Cell ◽

Nicotinamide Adenine Dinucleotide ◽

Catalytic Mechanism ◽

Pathogenic Species ◽

X Ray ◽

Cellular Bioenergetics

AbstractNicotinamide adenine dinucleotide (NAD) is a key molecule in cellular bioenergetics and signalling. Various bacterial pathogens release NADase enzymes into the host cell that deplete the host’s NAD+ pool, thereby causing rapid cell death. Here, we report the identification of NADases on the surface of fungi such as the pathogen Aspergillus fumigatus and the saprophyte Neurospora crassa. The enzymes harbour a tuberculosis necrotizing toxin (TNT) domain and are predominately present in pathogenic species. The 1.6 Å X-ray structure of the homodimeric A. fumigatus protein reveals unique properties including N-linked glycosylation and a Ca2+-binding site whose occupancy regulates activity. The structure in complex with a substrate analogue suggests a catalytic mechanism that is distinct from those of known NADases, ADP-ribosyl cyclases and transferases. We propose that fungal NADases may convey advantages during interaction with the host or competing microorganisms.

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Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

Cell Death Discovery ◽

10.1038/s41420-020-00366-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Ayushi Chaurasiya ◽

Swati Garg ◽

Ashish Khanna ◽

Chintam Narayana ◽

Ved Prakash Dwivedi ◽

...

Keyword(s):

Cell Death ◽

Host Cell ◽

Nicotinamide Adenine Dinucleotide ◽

Malaria Parasite ◽

Host Cells ◽

Nicotinamide Adenine ◽

Targeted Therapeutics ◽

Nad Metabolism ◽

Host Cell Death ◽

Nanomolar Range

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

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Establishment of an in vitro model for analyzing mitochondrial ultrastructure in PRKN-mutated patient iPSC-derived dopaminergic neurons

Molecular Brain ◽

10.1186/s13041-021-00771-0 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Mutsumi Yokota ◽

Soichiro Kakuta ◽

Takahiro Shiga ◽

Kei-ichi Ishikawa ◽

Hideyuki Okano ◽

...

Keyword(s):

Electron Microscopy ◽

Dopaminergic Neurons ◽

Structural Changes ◽

In Vitro Model ◽

Induced Pluripotent Stem Cell ◽

Substantia Nigra Pars Compacta ◽

Ultrastructural Changes ◽

Mitochondrial Morphology ◽

Vitro Model

AbstractMitochondrial structural changes are associated with the regulation of mitochondrial function, apoptosis, and neurodegenerative diseases. PRKN is known to be involved with various mechanisms of mitochondrial quality control including mitochondrial structural changes. Parkinson’s disease (PD) with PRKN mutations is characterized by the preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta, which has been suggested to result from the accumulation of damaged mitochondria. However, ultrastructural changes of mitochondria specifically in dopaminergic neurons derived from iPSC have rarely been analyzed. The main reason for this would be that the dopaminergic neurons cannot be distinguished directly among a mixture of iPSC-derived differentiated cells under electron microscopy. To selectively label dopaminergic neurons and analyze mitochondrial morphology at the ultrastructural level, we generated control and PRKN-mutated patient tyrosine hydroxylase reporter (TH-GFP) induced pluripotent stem cell (iPSC) lines. Correlative light-electron microscopy analysis and live cell imaging of GFP-expressing dopaminergic neurons indicated that iPSC-derived dopaminergic neurons had smaller and less functional mitochondria than those in non-dopaminergic neurons. Furthermore, the formation of spheroid-shaped mitochondria, which was induced in control dopaminergic neurons by a mitochondrial uncoupler, was inhibited in the PRKN-mutated dopaminergic neurons. These results indicate that our established TH-GFP iPSC lines are useful for characterizing mitochondrial morphology, such as spheroid-shaped mitochondria, in dopaminergic neurons among a mixture of various cell types. Our in vitro model would provide insights into the vulnerability of dopaminergic neurons and the processes leading to the preferential loss of dopaminergic neurons in patients with PRKN mutations.

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Suppression of cell proliferation and programmed cell death by dexamethasone during postnatal lung development

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00406.2000 ◽

2002 ◽

Vol 282 (3) ◽

pp. L477-L483 ◽

Cited By ~ 31

Author(s):

Cédric Luyet ◽

Peter H. Burri ◽

Johannes C. Schittny

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Programmed Cell Death ◽

Lung Development ◽

Structural Changes ◽

Tissue Transglutaminase ◽

Lung Parenchyma ◽

Lung Maturation ◽

Morphological Criteria ◽

Postnatal Lung Development

Prematurely born babies are often treated with glucocorticoids. We studied the consequences of an early postnatal and short dexamethasone treatment (0.1–0.01 μg/g, days 1–4) on lung development in rats, focusing on its influence on peaks of cell proliferation around day 4 and of programmed cell death at days 19–21. By morphological criteria, we observed a dexamethasone-induced premature maturation of the septa ( day 4), followed by a transient septal immatureness and delayed alveolarization leading to complete rescue of the structural changes. The numbers of proliferating (anti-Ki67) and dying cells (TdT-mediated dUTP nick end labeling) were determined and compared with controls. In dexamethasone-treated animals, both the peak of cell proliferation and the peak of programmed cell death were reduced to baseline, whereas the expression of tissue transglutaminase (transglutaminase-C), another marker for postnatal lung maturation, was not significantly altered. We hypothesize that a short neonatal course of dexamethasone leads to severe but transient structural changes of the lung parenchyma and influences the balance between cell proliferation and cell death even in later stages of lung maturation.

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