scholarly journals Microbiome engineering could select for more virulent pathogens

2015 ◽  
Author(s):  
Luke McNally ◽  
Pedro F Vale ◽  
Sam P Brown
Keyword(s):  
Infectious Diseases ◽  
Virulence Factors ◽  
Human Microbiome ◽  
Careful Consideration ◽  
Promising Alternative ◽  
Pathogen Evolution ◽  
Evolutionary Response ◽  
Damage Limitation ◽  
Inflammatory Drugs

Recent insights into the human microbiome offer the hope of manipulating its composition to help fight infectious diseases. While this strategy has shown huge potential, its consequences for pathogen evolution have not been explored. Here we show that manipulating the microbiome to increase the competition that pathogens face could lead to the evolution of increased production of virulence factors that pathogens use to combat commensals, an evolutionary response that can increase total disease induced mortality in the long-term. However, if treatment with microbiome engineering is sufficiently aggressive this evolutionary response can be avoided and the pathogen eradicated. Furthermore, we show that using damage limitation therapies (e.g. anti-virulence and anti-inflammatory drugs) in combination with microbiome manipulation increases the potential for pathogen eradication. While manipulating our microbiota offers a promising alternative to antibiotics, our results show that these treatments must be designed with careful consideration of the potential evolutionary responses of target pathogens.

scholarly journals Transdermal delivery of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): a mini review

2020 ◽  
Vol 4 (2) ◽  
Author(s):  
Raditya Weka Nugraheni
Keyword(s):  
Drug Administration ◽  
Oral Route ◽  
The Body ◽  
Promising Alternative ◽  
Non Invasive ◽  
Gastrointestinal Side Effects ◽  
Inflammatory Drugs ◽  
Foreign Materials ◽  
Transdermal Route

The transdermal route has several advantages over the oral route, especially for the drugs which significantly experience the first-pass effect in the liver. Another advantage of drug administration via the transdermal route is its non-invasive way and can be used by patients themselves. Also, it allows long-term use, thereby increasing patient compliance and is generally inexpensive. The development of transdermal preparation itself is not easy because of the permeability factor of drug ingredients through the skin is relatively low compared to the gastrointestinal route or mucous membrane because the skin is part of the body's defense system and prevents foreign materials to entering the body. The biggest challenge for drug administration via the transdermal route is that the limitations of drugs can be administrated through this route. NSAIDs are drugs that are widely used in chronic conditions and can cause serious gastrointestinal side effects. Therefore the transdermal route is expected to be a promising alternative in the future. The drug-loaded nanoparticle delivered using the iontophoresis method can improve the bioavailability of NSAIDs via the transdermal route.

NF-κB as a Key Mediator of Brain Inflammation in Alzheimer’s Disease

2019 ◽  
Vol 18 (1) ◽  
pp. 3-10 ◽  
Author(s):  
Chul Ju Hwang ◽  
Dong-Young Choi ◽  
Mi Hee Park ◽  
Jin Tae Hong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Treatment Strategies ◽  
Close Correlation ◽  
Specific Protein ◽  
Brain Inflammation ◽  
Cytokines And Chemokines ◽  
Inflammatory Drugs ◽  
Peptide Fibrils

Alzheimer’s disease is the most common form of dementia. It is characterized by betaamyloid peptide fibrils which are extracellular deposition of a specific protein, accompanied by extensive neuroinflammation. Various studies show the presence of a number of inflammation markers in the AD brain: elevated inflammatory cytokines and chemokines, and an accumulation of activated microglia in the damaged regions. NF-κB is a family of redox sensitive transcriptional factors, and it is known that NF-κB has binding sites in the promoter region of the genes involved in amyloidogenesis and inflammation. Long-term use of non-steroidal anti-inflammatory drugs prevents progression of AD and delays its onset, suggesting that there is a close correlation between NF-κB and AD pathogenesis. This study aims to (1) assess the association between NF-κB activity and AD through discussion of a variety of experimental and clinical studies on AD and (2) review treatment strategies designed to treat or prevent AD with NF-κB inhibitors.

scholarly journals Pseudomonas aeruginosa PA80 is a cystic fibrosis isolate deficient in RhlRI quorum sensing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Syed A. K. Shifat Ahmed ◽  
Michelle Rudden ◽  
Sabrina M. Elias ◽  
Thomas J. Smyth ◽  
Roger Marchant ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Genomic Islands ◽  
Clinical Strain ◽  
Whole Genome ◽  
Synonymous Mutations ◽  
Wide Range

AbstractPseudomonas aeruginosa uses quorum sensing (QS) to modulate the expression of several virulence factors that enable it to establish severe infections. The QS system in P. aeruginosa is complex, intricate and is dominated by two main N-acyl-homoserine lactone circuits, LasRI and RhlRI. These two QS systems work in a hierarchical fashion with LasRI at the top, directly regulating RhlRI. Together these QS circuits regulate several virulence associated genes, metabolites, and enzymes in P. aeruginosa. Paradoxically, LasR mutants are frequently isolated from chronic P. aeruginosa infections, typically among cystic fibrosis (CF) patients. This suggests P. aeruginosa can undergo significant evolutionary pathoadaptation to persist in long term chronic infections. In contrast, mutations in the RhlRI system are less common. Here, we have isolated a clinical strain of P. aeruginosa from a CF patient that has deleted the transcriptional regulator RhlR entirely. Whole genome sequencing shows the rhlR locus is deleted in PA80 alongside a few non-synonymous mutations in virulence factors including protease lasA and rhamnolipid rhlA, rhlB, rhlC. Importantly we did not observe any mutations in the LasRI QS system. PA80 does not appear to have an accumulation of mutations typically associated with several hallmark pathoadaptive genes (i.e., mexT, mucA, algR, rpoN, exsS, ampR). Whole genome comparisons show that P. aeruginosa strain PA80 is closely related to the hypervirulent Liverpool epidemic strain (LES) LESB58. PA80 also contains several genomic islands (GI’s) encoding virulence and/or resistance determinants homologous to LESB58. To further understand the effect of these mutations in PA80 QS regulatory and virulence associated genes, we compared transcriptional expression of genes and phenotypic effects with isogenic mutants in the genetic reference strain PAO1. In PAO1, we show that deletion of rhlR has a much more significant impact on the expression of a wide range of virulence associated factors rather than deletion of lasR. In PA80, no QS regulatory genes were expressed, which we attribute to the inactivation of the RhlRI QS system by deletion of rhlR and mutation of rhlI. This study demonstrates that inactivation of the LasRI system does not impact RhlRI regulated virulence factors. PA80 has bypassed the common pathoadaptive mutations observed in LasR by targeting the RhlRI system. This suggests that RhlRI is a significant target for the long-term persistence of P. aeruginosa in chronic CF patients. This raises important questions in targeting QS systems for therapeutic interventions.

scholarly journals Baicalin Represses Type Three Secretion System of Pseudomonas aeruginosa through PQS System

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1497
Author(s):  
Pansong Zhang ◽  
Qiao Guo ◽  
Zhihua Wei ◽  
Qin Yang ◽  
Zisheng Guo ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Mammalian Cells ◽  
Secretion System ◽  
Chinese Herbs ◽  
Infection Model ◽  
Lung Pathology ◽  
Promising Alternative ◽  
The Impact

Therapeutics that target the virulence of pathogens rather than their viability offer a promising alternative for treating infectious diseases and circumventing antibiotic resistance. In this study, we searched for anti-virulence compounds against Pseudomonas aeruginosa from Chinese herbs and investigated baicalin from Scutellariae radix as such an active anti-virulence compound. The effect of baicalin on a range of important virulence factors in P. aeruginosa was assessed using luxCDABE-based reporters and by phenotypical assays. The molecular mechanism of the virulence inhibition by baicalin was investigated using genetic approaches. The impact of baicalin on P. aeruginosa pathogenicity was evaluated by both in vitro assays and in vivo animal models. The results show that baicalin diminished a plenty of important virulence factors in P. aeruginosa, including the Type III secretion system (T3SS). Baicalin treatment reduced the cellular toxicity of P. aeruginosa on the mammalian cells and attenuated in vivo pathogenicity in a Drosophila melanogaster infection model. In a rat pulmonary infection model, baicalin significantly reduced the severity of lung pathology and accelerated lung bacterial clearance. The PqsR of the Pseudomonas quinolone signal (PQS) system was found to be required for baicalin’s impact on T3SS. These findings indicate that baicalin is a promising therapeutic candidate for treating P. aeruginosa infections.

scholarly journals The Abstruse Side of Type I Interferon Immunotherapy for COVID-19 Cases with Comorbidities

2021 ◽  
Vol 1 (1) ◽  
pp. 49-59
Author(s):  
Selvakumar Subbian
Keyword(s):  
Infectious Diseases ◽  
Disease Severity ◽  
Type I Interferon ◽  
Host Factors ◽  
Type I ◽  
The Novel ◽  
Inflammatory Drugs ◽  
Precautionary Measures ◽  
Inducible Genes

The Coronavirus Disease-2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed 1.2 million people globally since December 2019. Although the host factors underpinning COVID-19 pathology are not fully understood, type I interferon (IFN-I) response is considered crucial for SARS-CoV-2 pathogenesis. Perturbations in IFN-I signaling and associated interferon-inducible genes (ISG) are among the primary disease severity indicators in COVID-19. Consequently, IFN-I therapy, either alone or in- combination with existing antiviral or anti-inflammatory drugs, is tested in many ongoing clinical trials to reduce COVID-19 mortality. Since signaling by the IFN-I family of molecules regulates host immune response to other infectious and non-infectious diseases, any imbalance in this family of cytokines would impact the clinical outcome of COVID-19, as well as other co-existing diseases. Therefore, it is imperative to evaluate the beneficial-versus-detrimental effects of IFN-I immunotherapy for COVID-19 patients with divergent disease severity and other co-existing conditions. This review article summarizes the role of IFN-I signaling in infectious and non-infectious diseases of humans. It highlights the precautionary measures to be considered before administering IFN-I to COVID-19 patients having other co-existing disorders. Finally, suggestions are proposed to improve IFN-I immunotherapy to COVID-19.

scholarly journals MICRONUTRIENT CONTENTS IN THE PROFILE OF A RECOVERED SOIL WITH SEWAGE SLUDGE AND NATIVE SPECIES OF ATLANTIC FOREST

FLORESTA ◽  
2019 ◽  
Vol 49 (3) ◽  
pp. 485
Author(s):  
Lívia Mara Lima Goulart ◽  
Marianne Fidalgo de Faria ◽  
Grasiela Spada ◽  
Thiago Tássio de Souza Silva ◽  
Iraê Amaral Guerrini
Keyword(s):  
Sewage Sludge ◽  
Atlantic Forest ◽  
Soil Profile ◽  
Native Species ◽  
Control Treatment ◽  
Mineral Fertilization ◽  
Promising Alternative ◽  
Final Destination ◽  
Potassium Supplementation

The use of sewage sludge in agriculture and recovery of degraded areas has been shown as a promising alternative for its final destination. Studies on micronutrient levels after sludge application are necessary to avoid soil contamination at toxic levels. The objective of this work was to verify the micronutrient contents in the soil profile and pH, up to one-meter-deep, nine years after the application of sewage sludge and planting of native species of the Atlantic Forest. The experiment was implemented in a degraded Quartzeneic Neosol and conducted in randomized blocks with four replicates and eight treatments, consisting of six doses of sewage sludge (0, 2.5, 5, 10, 15 and 20 Mg ha-1, with supplementation of potassium due to low concentration in the residue), besides the control treatment, mineral fertilization and only potassium supplementation. After nine years, the contents of all micronutrients evaluated presented a significant response to the application of the treatments, and the application of sewage sludge provided an increase in their contents. Soil pH remained stable at sites receiving mineral fertilization and potassium supplementation. Only manganese and zinc showed mobility in the soil profile. The application of sewage sludge in degraded soil increases the micronutrient content and decreases its movement in the soil profile, and the application of the maximum dose of the residue does not provide toxic levels of these elements in the soil in the long term.

Natural inhibitors against potential targets of cyclooxygenase, lipoxygenase and leukotrienes

2021 ◽  
Vol 25 ◽  
Author(s):  
Rishita Dey ◽  
Sudatta Dey ◽  
Asmita Samadder ◽  
Anil Saxena ◽  
Sisir Nandi
Keyword(s):  
Rheumatoid Arthritis ◽  
Arachidonic Acid ◽  
Side Effects ◽  
Extensive Study ◽  
Alternative Medicines ◽  
Great Acceptance ◽  
Inflammatory Drugs ◽  
Lox Inhibitors ◽  
Natural Inhibitors

Background: The cyclooxygenase (COX) and lipoxygenase (LOX) enzymes catalyze the production of pain mediators like prostaglandins (PGs) and leukotrienes (LTs) respectively from arachidonic acid. Introduction: The COX and LOX enzyme modulators are responsible for the major PGs and LTs mediated complications like asthma, osteoarthritis, rheumatoid arthritis, cancer, Alzheimer’s disease, neuropathy and cardiovascular syndromes (CVS). Many synthetic nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment have serious side effects like nausea, vomiting, hyperacidity, gastrointestinal ulcers, CVS, etc. Methods: The natural inhibitors of pain mediators have great acceptance worldwide due to fewer side effects on long-term uses. The present review is an extensive study of the advantages of plant-based vs synthetic inhibitors. Results: These natural COX and LOX inhibitors control inflammatory response without causing side-effect-related complicacy. Conclusion: Therefore, the natural COX and LOX inhibitors may be used as alternative medicines for the management of pain and inflammation due to their less toxicity and resistivity.

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