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1.
Antimicrob Agents Chemother ; 65(7): e0001321, 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1476381

ABSTRACT

The SOS response to DNA damage is a conserved stress response in Gram-negative and Gram-positive bacteria. Although this pathway has been studied for years, its relevance is still not familiar to many working in the fields of clinical antibiotic resistance and stewardship. Under some conditions, the SOS response favors DNA repair and preserves the genetic integrity of the organism. On the other hand, the SOS response also includes induction of error-prone DNA polymerases, which can increase the rate of mutation, called the mutator phenotype or "hypermutation." As a result, mutations can occur in genes conferring antibiotic resistance, increasing the acquisition of resistance to antibiotics. Almost all of the work on the SOS response has been on bacteria exposed to stressors in vitro. In this study, we sought to quantitate the effects of SOS-inducing drugs in vivo, in comparison with the same drugs in vitro. We used a rabbit model of intestinal infection with enteropathogenic Escherichia coli strain E22. SOS-inducing drugs triggered the mutator phenotype response in vivo as well as in vitro. Exposure of E. coli strain E22 to ciprofloxacin or zidovudine, both of which induce the SOS response in vitro, resulted in increased antibiotic resistance to 3 antibiotics: rifampin, minocycline, and fosfomycin. Zinc was able to inhibit the SOS-induced emergence of antibiotic resistance in vivo, as previously observed in vitro. Our findings may have relevance in reducing the emergence of resistance to new antimicrobial drugs.


Subject(s)
Escherichia coli , SOS Response, Genetics , Animals , Anti-Bacterial Agents/pharmacology , Ciprofloxacin/pharmacology , Drug Resistance, Microbial , Escherichia coli/genetics , Mutation , Rabbits
2.
Int J Mol Sci ; 22(11)2021 May 26.
Article in English | MEDLINE | ID: covidwho-1244042

ABSTRACT

Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and IL-6. Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated the roles of the integrated stress response (ISR) and activator protein-1 (AP-1) family proteins in regulating coronavirus-induced IL-8 and IL-6 upregulation. The mRNA expression of IL-8 and IL-6 was significantly induced in cells infected with infectious bronchitis virus (IBV), a gammacoronavirus, and porcine epidemic diarrhea virus, an alphacoronavirus. Overexpression of a constitutively active phosphomimetic mutant of eukaryotic translation initiation factor 2α (eIF2α), chemical inhibition of its dephosphorylation, or overexpression of its upstream double-stranded RNA-dependent protein kinase (PKR) significantly enhanced IL-8 mRNA expression in IBV-infected cells. Overexpression of the AP-1 protein cJUN or its upstream kinase also increased the IBV-induced IL-8 mRNA expression, which was synergistically enhanced by overexpression of cFOS. Taken together, this study demonstrated the important regulatory roles of ISR and AP-1 proteins in IL-8 production during coronavirus infection, highlighting the complex interactions between cellular stress pathways and the innate immune response.


Subject(s)
Coronavirus Infections/metabolism , Endoplasmic Reticulum Stress/genetics , Eukaryotic Initiation Factor-2/metabolism , Interleukin-8/metabolism , Unfolded Protein Response/genetics , Alphacoronavirus/metabolism , Alphacoronavirus/pathogenicity , Animals , Cell Line , Chlorocebus aethiops , Coronavirus Infections/genetics , Gammacoronavirus/metabolism , Gammacoronavirus/pathogenicity , Gene Expression Regulation , Humans , Immunity, Innate , Infectious bronchitis virus/metabolism , Infectious bronchitis virus/pathogenicity , Interleukin-8/genetics , Phosphorylation , Porcine epidemic diarrhea virus/metabolism , Porcine epidemic diarrhea virus/pathogenicity , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , Signal Transduction/genetics , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , Up-Regulation , Vero Cells , eIF-2 Kinase/genetics , eIF-2 Kinase/metabolism
3.
Int J Mol Sci ; 22(8)2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1196033

ABSTRACT

Amyloidoses are a group of diseases associated with the formation of pathological protein fibrils with cross-ß structures. Approximately 5-10% of the cases of these diseases are determined by amyloidogenic mutations, as well as by transmission of infectious amyloids (prions) between organisms. The most common group of so-called sporadic amyloidoses is associated with abnormal aggregation of wild-type proteins. Some sporadic amyloidoses are known to be induced only against the background of certain pathologies, but in some cases the cause of amyloidosis is unclear. It is assumed that these diseases often occur by accident. Here we present facts and hypotheses about the association of sporadic amyloidoses with vascular pathologies, trauma, oxidative stress, cancer, metabolic diseases, chronic infections and COVID-19. Generalization of current data shows that all sporadic amyloidoses can be regarded as a secondary event occurring against the background of diseases provoking a cellular stress response. Various factors causing the stress response provoke protein overproduction, a local increase in the concentration or modifications, which contributes to amyloidogenesis. Progress in the treatment of vascular, metabolic and infectious diseases, as well as cancers, should lead to a significant reduction in the risk of sporadic amyloidoses.


Subject(s)
Amyloidosis/etiology , Stress, Physiological , Brain Injuries/complications , Communicable Diseases/complications , Humans , Metabolic Diseases/complications , Neoplasms/complications , Oxidative Stress , Vascular Diseases/complications
4.
Diabetol Metab Syndr ; 13(1): 23, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1112450

ABSTRACT

BACKGROUND: Our understanding of the pathophysiology of the COVID-19 manifestations and evolution has improved over the past 10 months, but the reasons why evolution is more severe in obese and diabetic patients are not yet completely understood. MAIN TEXT: In the present review we discuss the different mechanisms that may contribute to explain the pathophysiology of COVID-19 including viral entrance, direct viral toxicity, endothelial dysfunction, thromboinflammation, dysregulation of the immune response, and the renin-angiotensin-aldosterone system. CONCLUSIONS: We show that the viral infection activates an integrated stress response, including activations of serine kinases such as PKR and PERK, which induce IRS-1 serine phosphorylation and insulin resistance. In parallel, we correlate and show the synergy of the insulin resistance of COVID-19 with this hormonal resistance of obesity and diabetes, which increase the severity of the disease. Finally, we discuss the potential beneficial effects of drugs used to treat insulin resistance and diabetes in patients with COVID-19.

5.
J Obsessive Compuls Relat Disord ; 28: 100615, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-997177

ABSTRACT

The COVID Stress Scales (CSS) were designed to assess stress related to the COVID-19 pandemic. Emerging evidence indicates that people with anxiety disorders (ADs) and obsessive-compulsive disorder (OCD) may be more negatively impacted by COVID-19 than those with mood disorders or healthy individuals. Accordingly, this study sought to validate the Persian CSS (Persian-CSS) and to compare COVID-19-related stress reactions among patients with specific ADs and OCD. Patients with OCD (n = 300) and ADs (n = 310) completed the Persian-CSS and other scales developed to assess anxiety-related traits and COVID-19-related distress. The Persian-CSS replicated a five-factor structure similar to the original CSS in OCD and ADs. The total CSS and its scales had good reliability and validity. Patients with generalized anxiety disorder, panic disorder, and OCD had higher COVID-19 stress reactions than patients with social anxiety disorder and specific phobia. Patients with panic disorder had higher danger and contamination fears and xenophobia than patients with OCD. The study suggests that the Persian-CSS is a valid scale to be used in patients with OCD and ADs, each of whom differs in their specific patterns of COVID-19-related stress reactions.

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