Bacterial and Viral Pathogens, Molecular Mechanisms and Cellular Toxicity

Nutraceuticals, including vitamin D, vitamin A, zinc, lactoferrin, polyphenols coenzyme Q, magnesium, and selenium, are implicated in the modulation of the complex molecular pathways involved in the immune response against viral pathogens. A common element of the activity of nutraceuticals is their ability to enhance the innate immune response against pathogens by acting on the major cellular subsets and inducing the release of pro-inflammatory cytokines and antimicrobial peptides. In some cases, this action is accompanied by a direct antimicrobial effect, as evidenced in the specific case of lactoferrin. Furthermore, nutraceuticals act through complex molecular mechanisms to minimize the damage caused by the activation of the immune system against pathogens, reducing the oxidative damage, influencing the antigen presentation, enhancing the differentiation and proliferation of regulatory T cells, driving the differentiation of lymphocyte subsets, and modulating the production of pro-inflammatory cytokines. In this paper, we review the main molecular mechanisms responsible for the immunomodulatory function of nutraceuticals, focusing on the most relevant aspects for the prevention and treatment of viral infections.

Download Full-text

Establishing Cell Models to Understand Cellular Toxicity: Lessons Learned from an Unconventional Cell Type

Toxins ◽

10.3390/toxins14010054 ◽

2022 ◽

Vol 14 (1) ◽

pp. 54

Author(s):

Tino Vollmer ◽

Bernd Stegmayr

Keyword(s):

Molecular Mechanisms ◽

Cell Model ◽

Physiological State ◽

Animal Experiments ◽

Lessons Learned ◽

Protective Effects ◽

Cellular Toxicity ◽

Cellular Models ◽

Organ Systems

The syndrome of uremic toxicity comprises a complex toxic milieu in-vivo, as numerous uremic substances accumulate and harm the organ systems. Among these substances, toxic and non-toxic players differently interfere with human cells. However, results from animal experiments are not always compatible with the expected reactions in human patients and studies on one organ system are limited in capturing the complexity of the uremic situation. In this narrative review, we present aspects relevant for cellular toxicity research based on our previous establishment of a human spermatozoa-based cell model, as follows: (i) applicability to compare the effects of more than 100 uremic substances, (ii) detection of the protective effects of uremic substances by the cellular responses towards the uremic milieu, (iii) inclusion of the drug milieu for cellular function, and (iv) transferability for clinical application, e.g., hemodialysis. Our technique allows the estimation of cell viability, vitality, and physiological state, not only restricted to acute or chronic kidney toxicity but also for other conditions, such as intoxications of unknown substances. The cellular models can clarify molecular mechanisms of action of toxins related to human physiology and therapy. Identification of uremic toxins retained during acute and chronic kidney injury enables further research on the removal or degradation of such products.

Download Full-text

Evolutionary conflicts and adverse effects of antiviral factors

eLife ◽

10.7554/elife.65243 ◽

2021 ◽

Vol 10 ◽

Author(s):

Daniel Sauter ◽

Frank Kirchhoff

Keyword(s):

Cell Death ◽

Adverse Effects ◽

Antiviral Activity ◽

Host Cell ◽

Molecular Mechanisms ◽

Viral Infections ◽

Restriction Factors ◽

Viral Pathogens ◽

Trade Off ◽

Viral Spread

Human cells are equipped with a plethora of antiviral proteins protecting them against invading viral pathogens. In contrast to apoptotic or pyroptotic cell death, which serves as ultima ratio to combat viral infections, these cell-intrinsic restriction factors may prevent or at least slow down viral spread while allowing the host cell to survive. Nevertheless, their antiviral activity may also have detrimental effects on the host. While the molecular mechanisms underlying the antiviral activity of restriction factors are frequently well investigated, potential undesired effects of their antiviral functions on the host cell are hardly explored. With a focus on antiretroviral proteins, we summarize in this review how individual restriction factors may exert adverse effects as trade-off for efficient defense against attacking pathogens.

Download Full-text

Peroxisome biogenesis and the formation of multivesicular peroxisomes during tombusvirus infection: a role for ESCRT?This review is one of a selection of papers published in the Special Issue on Plant Cell Biology.

Canadian Journal of Botany ◽

10.1139/b06-005 ◽

2006 ◽

Vol 84 (4) ◽

pp. 551-564 ◽

Cited By ~ 8

Author(s):

Robert T. Mullen ◽

Andrew W. McCartney ◽

C. Robb Flynn ◽

Graham S.T. Smith

Keyword(s):

Cell Biology ◽

Molecular Mechanisms ◽

Protein Sorting ◽

Multivesicular Body ◽

Peroxisomal Membrane ◽

Viral Pathogens ◽

Endosomal Sorting ◽

Metabolic Functions ◽

Membrane Bound ◽

Vacuolar Protein

Peroxisomes are highly dynamic organelles with regard to their metabolic functions, shapes, distribution, movements, and biogenesis. They are also important as sites for the development of some viral pathogens. It has long been known that certain members of the tombusvirus family recruit peroxisomes for viral RNA replication and that this process is accompanied by dramatic changes in peroxisome morphology, the most remarkable of which is the extensive inward vesiculation of the peroxisomal boundary membrane leading to the formation of a peroxisomal multivesicular body (pMVB). While it is unclear how the internal vesicles of a pMVB form, they appear to serve in effectively concentrating viral membrane-bound replication complexes and protecting nascent viral RNAs from host-cell defences. Here, we review briefly the biogenesis of peroxisomes and pMVBs and discuss recent studies that have begun to shed light on how components of the tombusvirus replicase exploit the molecular mechanisms involved in peroxisome membrane protein sorting. We also address the question of what controls invagination and vesicle formation at the peroxisomal membrane during pMVB biogenesis. We propose that tombusviruses exploit protein constituents of the class E vacuolar protein-sorting pathway referred to as ESCRT (endosomal sorting complex required for transport) in the formation of pMVBs. This new pMVB–ESCRT hypothesis reconciles current paradigms of pMVB biogenesis with the role of ESCRT in endosomal multivesicular body formation and the ability of enveloped RNA viruses, including HIV, to appropriate the ESCRT machinery to execute their budding programme from cells.

Download Full-text

Redefining Memory: Building the Case for Adaptive NK Cells

Journal of Virology ◽

10.1128/jvi.00169-17 ◽

2017 ◽

Vol 91 (20) ◽

Cited By ~ 35

Author(s):

Silke Paust ◽

Catherine A. Blish ◽

R. Keith Reeves

Keyword(s):

Nk Cells ◽

Molecular Mechanisms ◽

Nk Cell ◽

Murine Cytomegalovirus ◽

The Novel ◽

Antigen Specificity ◽

Cell Memory ◽

Viral Pathogens ◽

Adaptive Capabilities ◽

Cell Subpopulations

ABSTRACT Classically, natural killer (NK) cells have been defined by nonspecific innate killing of virus-infected and tumor cells. However, burgeoning evidence suggests that the functional repertoire of NK cells is far more diverse than has been previously appreciated, thus raising the possibility that there may be unexpected functional specialization and even adaptive capabilities among NK cell subpopulations. Some of the first evidence that NK cells respond in an antigen-specific fashion came from experiments revealing that subpopulations of murine NK cells were able to respond to a specific murine cytomegalovirus (MCMV) protein and that in the absence of T and B cells, murine NK cells also mediated adaptive immune responses to a secondary challenge with specific haptens. These data have been followed by demonstrations of NK cell memory of viruses and viral antigens in mice and primates. Herein, we discuss different forms of NK cell antigen specificity and how these responses may be tuned to specific viral pathogens, and we provide assessment of the current literature that may explain molecular mechanisms of the novel phenomenon of NK cell memory.

Download Full-text

Elevated phosphate mediates extensive cellular toxicity: from abnormal proliferation to excessive cell death

10.1101/2020.01.02.892638 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ping He ◽

Olivia Mann-Collura ◽

Jacob Fling ◽

Naga Edara ◽

Mohammed S. Razzaque

Keyword(s):

Cell Death ◽

Er Stress ◽

Molecular Mechanisms ◽

Tissue Injury ◽

Control Cell ◽

Mapk Signaling ◽

Dependent Manner ◽

Physiological Level ◽

Cellular Toxicity ◽

Mesenchymal Transition

AbstractInorganic phosphate (Pi) is an essential nutrient for human health. Due to our change in dietary pattern, dietary Pi overload engenders systematic phosphotoxicity, including excessive Pi related vascular calcification and chronic tissue injury. The molecular mechanisms of the seemingly distinct phenotypes remain elusive. In this study, we found that Pi directly mediates diverse cellular toxicity in a dose-dependent manner on a cell-based model. At moderately higher than physiological level, extracellular Pi promotes cell proliferation by activating AKT and extracellular signal-regulated kinase 1/2 (ERK1/2) cascades. By introducing additional Pi, we observed significant cell damage caused by the interwoven Pi related biological processes, including activation of mitogen-activated protein kinase (MAPK) signaling, endoplasmic reticulum (ER) stress, epithelial-mesenchymal transition (EMT) and apoptosis. Taken together, elevated extracellular Pi results in a broad spectrum of toxicity by rewiring complicated signaling networks that control cell growth, cell death, ER stress, and cell mobility.

Download Full-text

The Diagnosis of Viral Disease by Electron Microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010005398x ◽

1982 ◽

Vol 40 ◽

pp. 270-273

Author(s):

William B. McCombs ◽

Cameron E. McCoy

Keyword(s):

Electron Microscopy ◽

Hospital Stay ◽

Viral Infections ◽

Medical Profession ◽

Bacterial Pathogens ◽

Viral Disease ◽

Viral Pathogens ◽

Academic Interest ◽

The Past

Recent years have brought a reversal in the attitude of the medical profession toward the diagnosis of viral infections. Identification of bacterial pathogens was formerly thought to be faster than identification of viral pathogens. Viral identification was dismissed as being of academic interest or for confirming the presence of an epidemic, because the patient would recover or die before this could be accomplished. In the past 10 years, the goal of virologists has been to present the clinician with a viral identification in a matter of hours. This fast diagnosis has the potential for shortening the patient's hospital stay and preventing the administering of toxic and/or expensive antibiotics of no benefit to the patient.

Download Full-text

Transcription factor/DNA interactions visualized by electron spectroscopic imaging

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100122654 ◽

1992 ◽

Vol 50 (1) ◽

pp. 450-451

Author(s):

David P. Bazett-Jones ◽

Mark L. Brown

Keyword(s):

Transcription Factor ◽

Dna Sequences ◽

Transcription Initiation ◽

Molecular Mechanisms ◽

Phosphorus Content ◽

Spectroscopic Imaging ◽

Electron Spectroscopic Imaging ◽

Dna Backbone ◽

Two Parameters ◽

High Level

A multisubunit RNA polymerase enzyme is ultimately responsible for transcription initiation and elongation of RNA, but recognition of the proper start site by the enzyme is regulated by general, temporal and gene-specific trans-factors interacting at promoter and enhancer DNA sequences. To understand the molecular mechanisms which precisely regulate the transcription initiation event, it is crucial to elucidate the structure of the transcription factor/DNA complexes involved. Electron spectroscopic imaging (ESI) provides the opportunity to visualize individual DNA molecules. Enhancement of DNA contrast with ESI is accomplished by imaging with electrons that have interacted with inner shell electrons of phosphorus in the DNA backbone. Phosphorus detection at this intermediately high level of resolution (≈lnm) permits selective imaging of the DNA, to determine whether the protein factors compact, bend or wrap the DNA. Simultaneously, mass analysis and phosphorus content can be measured quantitatively, using adjacent DNA or tobacco mosaic virus (TMV) as mass and phosphorus standards. These two parameters provide stoichiometric information relating the ratios of protein:DNA content.

Download Full-text

Dissection of the molecular mechanisms of protein targeting to the peroxisome using immunofluorescence and immunocryoelectron microscopies

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100157760 ◽

1990 ◽

Vol 48 (3) ◽

pp. 44-45

Author(s):

G-A. Keller ◽

S. J. Gould ◽

S. Subramani ◽

S. Krisans

Keyword(s):

Mammalian Cells ◽

Molecular Mechanisms ◽

Protein Targeting ◽

Firefly Luciferase ◽

Peroxisomal Enzyme ◽

Transfected Cells ◽

Peroxisomal Targeting ◽

Targeting Signal ◽

Series Of Experiments ◽

Peroxisomal Targeting Signal

Subcellular compartments within eukaryotic cells must each be supplied with unique sets of proteins that must be directed to, and translocated across one or more membranes of the target organelles. This transport is mediated by cis- acting targeting signals present within the imported proteins. The following is a chronological account of a series of experiments designed and carried out in an effort to understand how proteins are targeted to the peroxisomal compartment.-We demonstrated by immunocryoelectron microscopy that the enzyme luciferase is a peroxisomal enzyme in the firefly lantern. -We expressed the cDNA encoding firefly luciferase in mammalian cells and demonstrated by immunofluorescence that the enzyme was transported into the peroxisomes of the transfected cells. -Using deletions, linker insertions, and gene fusion to identify regions of luciferase involved in its transport to the peroxisomes, we demonstrated that luciferase contains a peroxisomal targeting signal (PTS) within its COOH-terminal twelve amino acid.

Download Full-text