scholarly journals Gram-Negative Bacterial Endotoxin LPS Induces NeuGc Loss through Ets1-Dependent Downregulation of Intestine-Specific pcmah Transcript in Porcine Intestinal Cells

2020 ◽  
Vol 21 (14) ◽  
pp. 4892
Author(s):  
Choong-Hwan Kwak ◽  
Kwon-Ho Song ◽  
Cheorl-Ho Kim
Keyword(s):  
Bacterial Infections ◽  
Defense Mechanism ◽  
Bacterial Endotoxin ◽  
Microbial Infection ◽  
Gram Negative ◽  
Acetylneuraminic Acid ◽  
Host Defense Mechanism ◽  
Small Intestinal ◽  
Underlying Mechanisms ◽  
Insight Into

N-glycolylneuraminic acid (NeuGc), a non-human sialic acid derivative synthesized by cytidine-5′-monophospho-N-acetylneuraminic acid hydroxylase (CMAH), plays a crucial role in mediating infections by certain pathogens. Although it has been postulated that NeuGc biosynthesis and CMAH expression are downregulated during microbial infection, the underlying mechanisms remain unclear. The present study showed that exposure to lipopolysaccharide (LPS), a Gram-negative bacterial endotoxin, leads to loss of NeuGc biosynthesis in pig small intestinal I2I-2I cells. This LPS-induced NeuGc loss was accompanied by decreased CMAH transcript levels, especially intestine-specific 5′pcmah-1. Furthermore, LPS suppressed the activity of the Pi promoter responsible for 5′pcmah-1 by inhibiting DNA binding of Est1. These findings provide insight into the regulatory mechanisms of Neu5Gc biosynthesis during pathogenic infectious events, which may represent a host defense mechanism that protects the self against pathogenic bacterial infections even in non-sanitary environments.

Platelet factor 4 binds to bacteria, inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1370-1378 ◽  
Author(s):  
Krystin Krauel ◽  
Christian Pötschke ◽  
Claudia Weber ◽  
Wolfram Kessler ◽  
Birgitt Fürll ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Defense Mechanism ◽  
Platelet Factor 4 ◽  
Cross Sectional ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Host Defense Mechanism ◽  
Heparin Complexes ◽  
Major Antigen

AbstractA clinically important adverse drug reaction, heparin-induced thrombocytopenia (HIT), is induced by antibodies specific for complexes of the chemokine platelet factor 4 (PF4) and the polyanion heparin. Even heparin-naive patients can generate anti-PF4/heparin IgG as early as day 4 of heparin treatment, suggesting preimmunization by antigens mimicking PF4/heparin complexes. These antibodies probably result from bacterial infections, as (1) PF4 bound charge-dependently to various bacteria, (2) human heparin-induced anti-PF4/heparin antibodies cross-reacted with PF4-coated Staphylococcus aureus and Escherichia coli, and (3) mice developed anti-PF4/heparin antibodies during polymicrobial sepsis without heparin application. Thus, after binding to bacteria, the endogenous protein PF4 induces antibodies with specificity for PF4/polyanion complexes. These can target a large variety of PF4-coated bacteria and enhance bacterial phagocytosis in vitro. The same antigenic epitopes are expressed when pharmacologic heparin binds to platelets augmenting formation of PF4 complexes. Boosting of preformed B cells by PF4/heparin complexes could explain the early occurrence of IgG antibodies in HIT. We also found a continuous, rather than dichotomous, distribution of anti-PF4/heparin IgM and IgG serum concentrations in a cross-sectional population study (n = 4029), indicating frequent preimmunization to modified PF4. PF4 may have a role in bacterial defense, and HIT is probably a misdirected antibacterial host defense mechanism.

scholarly journals Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Blood ◽  
2012 ◽  
Vol 120 (16) ◽  
pp. 3345-3352 ◽  
Author(s):  
Krystin Krauel ◽  
Claudia Weber ◽  
Sven Brandt ◽  
Ulrich Zähringer ◽  
Uwe Mamat ◽  
...  
Keyword(s):  
Lipid A ◽  
Defense Mechanism ◽  
Binding Activity ◽  
Platelet Factor 4 ◽  
Gram Negative Bacteria ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Gram Negative ◽  
Host Defense Mechanism ◽  
Heparin Complexes

AbstractThe positively charged chemokine platelet factor 4 (PF4) forms immunogenic complexes with heparin and other polyanions. Resulting antibodies can induce the adverse drug effect heparin-induced thrombocytopenia. PF4 also binds to bacteria, thereby exposing the same neoantigen(s) as with heparin. In this study, we identified the negatively charged lipopolysaccharide (LPS) as the PF4 binding structure on Gram-negative bacteria. We demonstrate by flow cytometry that mutant bacteria with progressively truncated LPS structures show increasingly enhanced PF4 binding activity. PF4 bound strongest to mutants lacking the O-antigen and core structure of LPS, but still exposing lipid A on their surfaces. Strikingly, PF4 bound more efficiently to bisphosphorylated lipid A than to monophosphorylated lipid A, suggesting that phosphate residues of lipid A mediate PF4 binding. Interactions of PF4 with Gram-negative bacteria, where only the lipid A part of LPS is exposed, induce epitopes on PF4 resembling those on PF4/heparin complexes as shown by binding of human anti-PF4/heparin antibodies. As both the lipid A on the surface of Gram-negative bacteria and the amino acids of PF4 contributing to polyanion binding are highly conserved, our results further support the hypothesis that neoepitope formation on PF4 after binding to bacteria is an ancient host defense mechanism.

scholarly journals ER-Phagy and Microbial Infection

2021 ◽  
Vol 9 ◽  
Author(s):  
Jiahui Li ◽  
Enfeng Gao ◽  
Chenguang Xu ◽  
Hongna Wang ◽  
Yongjie Wei
Keyword(s):  
Host Defense ◽  
Defense Mechanism ◽  
Membrane Lipids ◽  
Regulatory Mechanisms ◽  
Secretory Proteins ◽  
Microbial Infection ◽  
Er Quality Control ◽  
Host Defense Mechanism ◽  
Survival And Growth ◽  
Microbial Defense

The endoplasmic reticulum (ER) is an essential organelle in cells that synthesizes, folds and modifies membrane and secretory proteins. It has a crucial role in cell survival and growth, thus requiring strict control of its quality and homeostasis. Autophagy of the ER fragments, termed ER-phagy or reticulophagy, is an essential mechanism responsible for ER quality control. It transports stress-damaged ER fragments as cargo into the lysosome for degradation to eliminate unfolded or misfolded protein aggregates and membrane lipids. ER-phagy can also function as a host defense mechanism when pathogens infect cells, and its deficiency facilitates viral infection. This review briefly describes the process and regulatory mechanisms of ER-phagy, and its function in host anti-microbial defense during infection.

scholarly journals Ciprofloxacin reduces tenocyte viability and proteoglycan synthesis in short-term explant cultures of equine tendon

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12003
Author(s):  
Stuart James ◽  
Johannes Schuijers ◽  
John Daffy ◽  
Jill Cook ◽  
Tom Samiric
Keyword(s):  
Cell Viability ◽  
Bacterial Infections ◽  
Recovery Period ◽  
Proteoglycan Synthesis ◽  
Rna Expression ◽  
Increased Risk ◽  
Discontinuation Of Treatment ◽  
Superficial Digital Flexor Tendon ◽  
Underlying Mechanisms ◽  
Insight Into

Fluoroquinolones are an effective, broad-spectrum antibiotic used to treat an array of bacterial infections. However, they are associated with an increased risk of tendinopathy and tendon rupture even after discontinuation of treatment. This condition is known as fluoroquinolone-associated tendinopathy, the underlying mechanisms of which are poorly understood. While many factors may be involved in the pathophysiology of tendinopathies in general, changes in tenocyte metabolism and viability, as well as alteration of proteoglycan metabolism are prominent findings in the scientific literature. This study investigated the effects of ciprofloxacin, a common fluoroquinolone, on cell viability, proteoglycan synthesis, and proteoglycan mRNA expression in equine superficial digital flexor tendon explants after 96 h treatment with between 1–300 µg/mL ciprofloxacin, and again after 8 days discontinuation of treatment. Ciprofloxacin caused significant reductions in cell viability by between 25–33% at all dosages except 10 µg/mL, and viability decreased further after 8 days discontinuation of treatment. Proteoglycan synthesis significantly decreased by approximately 50% in explants treated with 100 µg/mL and 300 µg/mL, however this effect reversed after 8 days in the absence of treatment. No significant mRNA expression changes were observed after the treatment period with the exception of versican which was down-regulated at the highest concentration of ciprofloxacin. After the recovery period, aggrecan, biglycan and versican genes were all significantly downregulated in explants initially treated with 1–100 µg/mL. Results from this study corroborate previously reported findings of reduced cell viability and proteoglycan synthesis in a whole tissue explant model and provide further insight into the mechanisms underlying fluoroquinolone-associated tendinopathy and rupture. This study further demonstrates that certain ciprofloxacin induced cellular changes are not rapidly reversed upon cessation of treatment which is a novel finding in the literature.

Insight into innate immunity of the uterine cervix as a host defense mechanism against infection and preterm birth

2009 ◽  
Vol 4 (1) ◽  
pp. 9-15 ◽  
Author(s):  
Catalin S Buhimschi ◽  
Margaret A Baumbusch ◽  
Katherine H Campbell ◽  
Antonette T Dulay ◽  
Irina A Buhimschi
Keyword(s):  
Innate Immunity ◽  
Preterm Birth ◽  
Host Defense ◽  
Uterine Cervix ◽  
Defense Mechanism ◽  
Host Defense Mechanism ◽  
Insight Into

Removal of Anti---Galactosyl Antibodies Elicits Protective Immunity Against Gram-Negative Bacterial Infections

2018 ◽  
Author(s):  
Daniel Bello-Gil ◽  
Magdiel Perez-Cruz ◽  
Cristina Costa ◽  
Mariana Camoez ◽  
Angeles Dominguez ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Bacterial Infections ◽  
Gram Negative

Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

2020 ◽  
Vol 20 (3) ◽  
pp. 192-208 ◽  
Author(s):  
Talita Odriane Custodio Leite ◽  
Juliana Silva Novais ◽  
Beatriz Lima Cosenza de Carvalho ◽  
Vitor Francisco Ferreira ◽  
Leonardo Alves Miceli ◽  
...  
Keyword(s):  
In Silico ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Mass Spectrometry Analysis ◽  
World Health ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Dione Derivative ◽  
In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

A Review of Phytochemical and Pharmacological Studies of Inula Species

2020 ◽  
Vol 16 (5) ◽  
pp. 557-567
Author(s):  
Aparoop Das ◽  
Anshul Shakya ◽  
Surajit Kumar Ghosh ◽  
Udaya P. Singh ◽  
Hans R. Bhat
Keyword(s):  
Bacterial Infections ◽  
Chemical Constituents ◽  
Valuable Insight ◽  
Important Ingredient ◽  
Pharmacological Activities ◽  
Medicinal Uses ◽  
The Family ◽  
Pharmacological Studies ◽  
Perennial Herbs ◽  
Insight Into

Background: Plants of the genus Inula are perennial herbs of the family Asteraceae. This genus includes more than 100 species, widely distributed throughout Europe, Africa and Asia including India. Many of them are indicated in traditional medicine, e.g., in Ayurveda. This review explores chemical constituents, medicinal uses and pharmacological actions of Inula species. Methods: Major databases and research and review articles retrieved through Scopus, Web of Science, and Medline were consulted to obtain information on the pharmacological activities of the genus Inula published from 1994 to 2017. Results: Inula species are used either alone or as an important ingredient of various formulations to cure dysfunctions of the cardiovascular system, respiratory system, urinary system, central nervous system and digestive system, and for the treatment of asthma, diabetes, cancers, skin disorders, hepatic disease, fungal and bacterial infections. A range of phytochemicals including alkaloids, essential and volatile oils, flavonoids, terpenes, and lactones has been isolated from herbs of the genus Inula, which might possibly explain traditional uses of these plants. Conclusion: The present review is focused on chemical constituents, medicinal uses and pharmacological actions of Inula species and provides valuable insight into its medicinal potential.

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