Epithelial Barrier Hypothesis and Its Comparison with the Hygiene Hypothesis

Chronic inflammatory conditions including allergic, autoimmune, metabolic, and neuropsychiatric disorders are constantly increasing and leading to a high burden, especially in more industrialized countries. The prevalence is still on the rise in developing countries. The start of the steep increase in asthma, atopic dermatitis, and allergic rhinitis dates to the 1960s, whereas a second wave with an increase in eosinophilic gastrointestinal disease, food allergy, and drug hypersensitivity started after the 2000s. These diseases also started to appear more with neuropsychiatric and autoimmune conditions during the last few decades. Many theories have been proposed to explain this outbreak. The hygiene hypothesis was consolidated by "old friends" and biodiversity, although some gaps remained unresolved. The introduction of the epithelial barrier hypothesis gave us a new perspective to explain the effects of industrialization without environment control and health concerns creeping into our daily lives. The present review touches on the possible explanations of why epithelial barrier hypothesis covers all previous ones, which are not contradictory but mostly complementary

Advances and recent developments in asthma in 2020

In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis, and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis, and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping, and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers, are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2, and COVID-19

Biochemistry, genetics and regulation of bacilysin biosynthesis and its significance more than an antibiotic

Bacillus subtilis has the capacity to produce more than two dozen bioactive compounds with an amazing variety of chemical structures. Among them, bacilysin is a non-ribosomally synthesized dipeptide antibiotic consisting of L-alanine residue at the N terminus and a non-proteinogenic amino acid, L-anticapsin, at the C terminus. In spite of its simple structure, it is active against a wide range of bacteria and fungi. As a potent antimicrobial agent, we briefly review the biochemistry and genetics as well as the regulation of bacilysin biosynthesis within the frame of peptide pheromones-based control of secondary activities. Biological functions of bacilysin in the producer B. subtilis beyond its antimicrobial activity as well as potential biotechnological use of the biosynthetic enzyme L-amino acid ligase (Lal) are also discussed

Akut astım fare modeli üzerinde pluripotent kök hücrelerin etkisinin araştırılması

Astımda hava yolu inflamasyonunu baskılayacak ve hava yolu yeniden yapılanmasını önleyecek veya tersine çevirebilecek yeni stratejilere ihtiyaç duyulmaktadır. Yeniden programlanmış uyarılmış pluripotent kök hücreler (uPKH), embriyonik kök hücre (EKH) potansiyeline sahiptir ve kök hücre bazlı kullanım için kaynak sağlamaktadır. Bu çalışmada, allojenik olarak uygulanan EKH ve uPKH’lerin akut astım modeli oluşturulmuş fareler üzerinde histopatolojik ve immünmodülatuar etkilerinin araştırılması amaçlandı. Bu amaçla, akut astım fare modeli, BALB/c farelerin i.p. olarak OVA proteini ile duyarlılaştırılması ve %1 OVA’nın nebulize yolla verilmesi sonucu oluşturuldu. Son nebülizasyon günü, EKH ve uPKH’ler intranazal (i.n.) yolla 5x105 hücre olacak şekilde uygulandı. Fareler 24 saat sonra sakrifiye edilerek, serum spesifik antikor miktarı, hava yolu yeniden yapılanması, sitokin miktarları, BAL sıvısındaki hücre miktarı, lenfositlerin proliferasyon ve apoptoz tayini yapıldı. Kontrol grubuna (PBS) göre, astım grubunda (OVA) daha fazla EKH ve uPKH’nin akciğerde toplandığı belirlendi. Hava yolu yeniden yapılanmasında meydana gelen epitel, düz kas ve bazal membranda artışın ve aynı zamanda goblet hücre hiperplazisinin distal ve proksimal hava yollarında pluripotent kök hücrelerin uygulanması sonucu anlamlı derecede baskılandığı gözlendi. BAL sıvısında eozinofil yüzdesinin anlamlı derecede azaldığı saptandı. Serumda allerjen-spesifik IgE’nin baskılandığı ve IL-4’ün akciğer süpernatanında azaldığı, aynı zamanda, regülatör sitokin olan IL-10’un arttığı tesbit edildi. Özellikle EKH’nin uygulanması ile, akciğerde Treg hücre alt grupları yüzdesinin anlamlı şekilde arttığı ve akciğer lenfosit hücre proliferasyonunun ve apoptozunun anlamlı olarak baskılandığı gözlendi. Bu çalışmada elde edilen sonuçlar, i.n. olarak uygulanan EKH ve uPKH’lerin akut astım fare modeli ile ilişkili hava yolu inflamasyonu üzerine iyileştirici etkiler sağladığını ve ayrıca, bu hücrelerin farelerde in vivo immünmodülasyon etkinliğinin benzer olduğunu göstermektedir. Anahtar Sözcükler: Astım, BALB/c, EKH, İmmünomodülasyon, uPKH SUMMARY Investigation on the Effect of Pluripotent Stem Cells on Murine Model of Acute Asthma New strategies are needed to supress airway inflammation and prevent or reverse airway remodeling in asthma. Reprogramming induced pluripotent stem cells (iPSCs) has the potential of embryonic stem cells (ESCs) and provide a resource for stem cell-based utility. The aim of this study was to evaluate the histopathologic and immunomodulatory effects of ESCs and iPSCs for potential allogenic application in a murine model of acute asthma. For this aim, BALB/c mice wre sensitized with alum-absorbed ovalbumin (OVA) and then challenged with aerosolized 1% OVA. 5x105 ESCs and iPSCs were administrated intranasally on the last day of nebulization. Mice were sacrified after 24 hours, and serum allergen spesific antibody level, airway remodeling, cytokine levels in lung supernatants, cellular distribution in BAL fluid, lymphocyte proliferation and apoptosis assays were then examined. More ESC and iPSCs integrated into the lungs of mice OVA groups than those of the control mice. Epithelial, smooth muscle and basal membrane thicknesses as well as goblet cell hyperplasia occurring in airway remodeling were suppressed significantly by pluripotent stem cells in both distal and proximal airways. Percentage of eosinophyls decreased significantly in BAL fluid. Reduction in serum allergen-spesific IgE level as well as IL-4 level in lung supernatatnts was observed. Meanwhile, regulatory cytokine, IL-10, was enhanced. Application of especially ESCs significantly increased percentage of Treg subsets and supressed proliferation and apoptosis of lung lymphocyte cells. Our results showed that i.n. delivery of ESCs and iPSCs provide a benefical effect to attenuate airway inflammation related with acute asthma murine model, and these cells also have similar immunomodulatory effectiveness in mice. Key Words: Asthma, BALB/c, ESCs, Immunomodulation, iPSC

Advances and highlights in biomarkers of allergic diseases

During the past years, there has been a global outbreak of allergic diseases, presenting a considerable medical and socioeconomical burden. A large fraction of allergic diseases is characterized by a type 2 immune response involving Th2 cells, type 2 innate lymphoid cells, eosinophils, mast cells, and M2 macrophages. Biomarkers are valuable parameters for precision medicine as they provide information on the disease endotypes, clusters, precision diagnoses, identification of therapeutic targets, and monitoring of treatment efficacies. The availability of powerful omics technologies, together with integrated data analysis and network-based approaches can help the identification of clinically useful biomarkers. These biomarkers need to be accurately quantified using robust and reproducible methods, such as reliable and point-of-care systems. Ideally, samples should be collected using quick, cost-efficient and noninvasive methods. In recent years, a plethora of research has been directed toward finding novel biomarkers of allergic diseases. Promising biomarkers of type 2 allergic diseases include sputum eosinophils, serum periostin and exhaled nitric oxide. Several other biomarkers, such as pro-inflammatory mediators, miRNAs, eicosanoid molecules, epithelial barrier integrity, and microbiota changes are useful for diagnosis and monitoring of allergic diseases and can be quantified in serum, body fluids and exhaled air. Herein, we review recent studies on biomarkers for the diagnosis and treatment of asthma, chronic urticaria, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, food allergies, anaphylaxis, drug hypersensitivity and allergen immunotherapy. In addition, we discuss COVID-19 and allergic diseases within the perspective of biomarkers and recommendations on the management of allergic and asthmatic patients during the COVID-19 pandemic

The effects of twelve quorum-sensing gene products on the expression of bacabcde operon in bacillus subtilis

In Bacillus subtilis, genetic competence, sporulation and antibiotic production are controlled by quorum-sensing global regulatory mechanism. Bacilysin, being produced and excreted by certain strains of Bacillus subtilis, is a dipeptide antibiotic composed of L-alanine and L-anticapsin. We showed that the biosynthesis of bacilysin is under the control of quorum sensing global regulatory pathway through the action of ComQ/ComX, PhrC (CSF), ComP/ComA in a Spo0K (Opp)-dependent manner. Recently, the ywfBCDEF genes of B. subtilis 168 were shown to carry biosynthetic core function and renamed as bacABCDE operon. The objective of the present study is to elucidate the effects of previously-identified genes srfA, oppA, comA, phrC, phrF, phrK, comQ (comX), comP, spo0H, spo0A, abrB and codY on the expression of bacilysin biosynthetic operon bacABCDE. In order to monitor the expression of bac operon a B. subtilis strain, namely OGU1, containing a transcriptional bacA-lacZ fusion at bacA locus was constructed. Subsequently, each of the above-mentioned genes of cell density signaling was insertionally inactivated by transforming the competent cells of OGU1 with chromosomal DNA of the corresponding blocked mutant strains. The resulting strains and OGU1 as the control were cultured in PA medium and bacA-directed β-galactosidase activities were monitored. bacA-lacZ expression was severely impaired in the srfA, oppA, comA, phrC, phrF, phrK, comQ (comX), comP, spo0H and spo0A disrupted mutants. On the other hand, in the abrB single mutant bacA expression level increased nearly 2-fold during exponential growth and in the codY mutant it severely decreased during the stationary phase.M.S. - Master of Scienc

Dysregulation of the epithelial barrier by environmental and other exogenous factors

The epithelial barrier hypothesis proposes that the exposure to various epithelial barrier-damaging agents linked to industrialization and urbanization underlies the increase in allergic diseases. The epithelial barrier constitutes the first line of physical, chemical, and immunological defense against environmental factors. Recent reports have shown that industrial products disrupt the epithelial barriers. Innate and adaptive immune responses play an important role in epithelial barrier damage. In addition, recent studies suggest that epithelial barrier dysfunction plays an essential role in the pathogenesis of the atopic march by allergen sensitization through the transcutaneous route. It is evident that external factors interact with the immune system, triggering a cascade of complex reactions that damage the epithelial barrier. Epigenetic and microbiome changes modulate the integrity of the epithelial barrier. Robust and simple measurements of the skin barrier dysfunction at the point-of-care are of significant value as a biomarker, as recently reported using electrical impedance spectroscopy to directly measure barrier defects. Understanding epithelial barrier dysfunction and its mechanism is key to developing novel strategies for the prevention and treatment of allergic diseases. The aim of this review is to summarize recent studies on the pathophysiological mechanisms triggered by environmental factors that contribute to the dysregulation of epithelial barrier function

Akut astım fare modeli üzerinde pluripotent kök hücrelerin etkisinin araştırılması

ÖZETAstımda hava yolu inflamasyonunu baskılayacak ve hava yolu yeniden yapılanmasını önleyecek veya tersine çevirebilecek yeni stratejilere ihtiyaç duyulmaktadır. Yeniden programlanmış uyarılmış pluripotent kök hücreler (uPKH), embriyonik kök hücre (EKH) potansiyeline sahiptir ve kök hücre bazlı kullanım için kaynak sağlamaktadır. Bu çalışmada, allojenik olarak uygulanan EKH ve uPKH’lerin akut astım modeli oluşturulmuş fareler üzerinde histopatolojik ve immünmodülatuar etkilerinin araştırılması amaçlandı. Bu amaçla, akut astım fare modeli, BALB/c farelerin i.p. olarak OVA proteini ile duyarlılaştırılması ve %1 OVA’nın nebulize yolla verilmesi sonucu oluşturuldu. Son nebülizasyon günü, EKH ve uPKH’ler intranazal (i.n.) yolla 5x105 hücre olacak şekilde uygulandı. Fareler 24 saat sonra sakrifiye edilerek, serum spesifik antikor miktarı, hava yolu yeniden yapılanması, sitokin miktarları, BAL sıvısındaki hücre miktarı, lenfositlerin proliferasyon ve apoptoz tayini yapıldı. Kontrol grubuna (PBS) göre, astım grubunda (OVA) daha fazla EKH ve uPKH’nin akciğerde toplandığı belirlendi. Hava yolu yeniden yapılanmasında meydana gelen epitel, düz kas ve bazal membranda artışın ve aynı zamanda goblet hücre hiperplazisinin distal ve proksimal hava yollarında pluripotent kök hücrelerin uygulanması sonucu anlamlı derecede baskılandığı gözlendi. BAL sıvısında eozinofil yüzdesinin anlamlı derecede azaldığı saptandı. Serumda allerjen-spesifik IgE’nin baskılandığı ve IL-4’ün akciğer süpernatanında azaldığı, aynı zamanda, regülatör sitokin olan IL-10’un arttığı tesbit edildi. Özellikle EKH’nin uygulanması ile, akciğerde Treg hücre alt grupları yüzdesinin anlamlı şekilde arttığı ve akciğer lenfosit hücre proliferasyonunun ve apoptozunun anlamlı olarak baskılandığı gözlendi. Bu çalışmada elde edilen sonuçlar, i.n. olarak uygulanan EKH ve uPKH’lerin akut astım fare modeli ile ilişkili hava yolu inflamasyonu üzerine iyileştirici etkiler sağladığını ve ayrıca, bu hücrelerin farelerde in vivo immünmodülasyon etkinliğinin benzer olduğunu göstermektedir.Anahtar Sözcükler: Astım, BALB/c, EKH, İmmünomodülasyon, uPKHSUMMARYInvestigation on the Effect of Pluripotent Stem Cells on Murine Model of Acute AsthmaNew strategies are needed to supress airway inflammation and prevent or reverse airway remodeling in asthma. Reprogramming induced pluripotent stem cells (iPSCs) has the potential of embryonic stem cells (ESCs) and provide a resource for stem cell-based utility. The aim of this study was to evaluate the histopathologic and immunomodulatory effects of ESCs and iPSCs for potential allogenic application in a murine model of acute asthma. For this aim, BALB/c mice wre sensitized with alum-absorbed ovalbumin (OVA) and then challenged with aerosolized 1% OVA. 5x105 ESCs and iPSCs were administrated intranasally on the last day of nebulization. Mice were sacrified after 24 hours, and serum allergen spesific antibody level, airway remodeling, cytokine levels in lung supernatants, cellular distribution in BAL fluid, lymphocyte proliferation and apoptosis assays were then examined. More ESC and iPSCs integrated into the lungs of mice OVA groups than those of the control mice. Epithelial, smooth muscle and basal membrane thicknesses as well as goblet cell hyperplasia occurring in airway remodeling were suppressed significantly by pluripotent stem cells in both distal and proximal airways. Percentage of eosinophyls decreased significantly in BAL fluid. Reduction in serum allergen-spesific IgE level as well as IL-4 level in lung supernatatnts was observed. Meanwhile, regulatory cytokine, IL-10, was enhanced. Application of especially ESCs significantly increased percentage of Treg subsets and supressed proliferation and apoptosis of lung lymphocyte cells. Our results showed that i.n. delivery of ESCs and iPSCs provide a benefical effect to attenuate airway inflammation related with acute asthma murine model, and these cells also have similar immunomodulatory effectiveness in mice.Key Words: Asthma, BALB/c, ESCs, Immunomodulation, iPSC

Biochemistry, genetics and regulation of bacilysin biosynthesis and its significance more than an antibiotic

Bacillus subtilis has the capacity to produce more than two dozen bioactive compounds with an amazing variety of chemical structures. Among them, bacilysin is a non-ribosomally synthesized dipeptide antibiotic consisting of l-alanine residue at the N terminus and a non-proteinogenic amino acid, l-anticapsin, at the C terminus. In spite of its simple structure, it is active against a wide range of bacteria and fungi. As a potent antimicrobial agent, we briefly review the biochemistry and genetics as well as the regulation of bacilysin biosynthesis within the frame of peptide pheromones-based control of secondary activities. Biological functions of bacilysin in the producer B. subtilis beyond its antimicrobial activity as well as potential biotechnological use of the biosynthetic enzyme l-amino acid ligase (Lal) are also discussed. © 2015 Elsevier B.V