Relationship between Asthma and Rhinitis: Epidemiologic, Pathophysiologic, and Therapeutic Aspects

Over the last few years, the evidence of links between rhinitis and asthma has been strengthened. This has led to the introduction of the concept of united airway disease. Rhinitis and asthma appear to be interrelated at the epidemiologic level and at the pathophysiologic level. This article reviews current epidemiologic and pathophysiologic evidence of the relationship between rhinitis and asthma and discusses the effect of treatment of one site on the other site

Small airway inflammation in asthma

Asthma was originally described as an inflammatory disease that predominantly involves the central airways. Pathological and physiological evidence reported during the past few years suggests that the inflammatory process extends beyond the central airways to the peripheral airways and the lung parenchyma. The small airways are capable of producing T-helper-2 cytokines, as well as chemokines, and they have recently been recognized as a predominant site of airflow obstruction in asthmatic persons. The inflammation at this distal site has been described as more severe than large airway inflammation. These findings are of great clinical significance, and highlight the need to consider the peripheral airways as a target in any therapeutic strategy for treatment of asthma

MLH1 mediates cytoprotective nucleophagy to resist 5-Fluorouracil-induced cell death in colorectal carcinoma

Colorectal Cancer (CRC) with Microsatellite instability (MSI) and mutLhomolog-1 (MLH1) gene deficiency are less aggressive than MLH1 proficient cancers. MLH1 is involved in several cellular processes, but its connection with the autophagy-dependent cellular response towards anticancer drugs remains unclear. In this study, we aimed to investigate the interaction between MLH1 and the autophagy marker LC3, which facilitated nucleophagy induction, and its potential role in determining sensitivity to 5-Fluorouracil (5-FU) induced cell death. To examine the role of MLH1 in DNA-damage-induced nucleophagy in CRC cells, we utilized a panel of MLH1 deficient and MLH1 proficient CRC cell lines. We included a parental HCT116 cell line (MLH1−/−) and its isogenic cell line HCT116 MLH1+/− in which a single allele of the MLH1 gene was introduced using CRISPR-Cas9 gene editing. We observed that MLH1 proficient cells were less sensitive to the 5-FU-induced cytotoxic effect. The 5-FU induced DNA damage led to LC3 up-regulation, which was dependent on MLH1 overexpression. Moreover, immunofluorescence and immunoprecipitation data showed LC3 and MLH1 were colocalized in CRC cells. Consequently, MLH1 dependent 5-FU-induced DNA damage contributed to the formation of micronuclei. These micronuclei colocalize with autolysosome, indicating a cytoprotective role of MLH1 dependent nucleophagy. Interestingly, siRNA knockdown of MLH1 in HCT116 MLH1+/− prevented LC3 upregulation and micronuclei formation. These novel data are the first to show an essential role of MLH1 in mediating the chemoresistance and survival of cancer cells by increasing the LC3 expression and inducing nucleophagy in 5-FU treated CRC cells.</p

The Role of Systems Biology in Deciphering Asthma Heterogeneity

Asthma is one of the most common and lifelong and chronic inflammatory diseases characterized by inflammation, bronchial hyperresponsiveness, and airway obstruction episodes. It is a heterogeneous disease of varying and overlapping phenotypes with many confounding factors playing a role in disease susceptibility and management. Such multifactorial disorders will benefit from using systems biology as a strategy to elucidate molecular insights from complex, quantitative, massive clinical, and biological data that will help to understand the underlying disease mechanism, early detection, and treatment planning. Systems biology is an approach that uses the comprehensive understanding of living systems through bioinformatics, mathematical, and computational techniques to model diverse high-throughput molecular, cellular, and the physiologic profiling of healthy and diseased populations to define biological processes. The use of systems biology has helped understand and enrich our knowledge of asthma heterogeneity and molecular basis; however, such methods have their limitations. The translational benefits of these studies are few, and it is recommended to reanalyze the different studies and omics in conjugation with one another which may help understand the reasons for this variation and help overcome the limitations of understanding the heterogeneity in asthma pathology. In this review, we aim to show the different factors that play a role in asthma heterogeneity and how systems biology may aid in understanding and deciphering the molecular basis of asthma

Luxury in jewelry design

The current research dealt with the presence of ornaments and jewelry since ancient times، which express the social، religious or emotional status of the person who adorns them، in addition to being distinguished by a distinct aesthetic and luxury، that is، in a sense closely related to the social and economic status of people، and we note that jewelry is considered a symbol of luxury and luxury، and hence The need to study luxury appeared in the design of ornaments and jewelry because it refers to the adornment elements that are made of metals and precious stones، which actually indicate signs of status or position that distinguish social classes from each other. The problem was identified by the following question: Determine the effectiveness of luxury in the design of jewelry and jewelry? The research included two important topics. We will address them successively. Below are some results and conclusions: 1. Luxury is of great importance in the field of distinguished and luxurious creativity of the industrial designer and industrial production institutions in the modern industrial world. 2. The emergence of luxury led to the fulfillment of the requests of users with trends and class of the velvet class of the rich، political figures، aristocratic classes and the global bourgeoisie

Current Status of Baricitinib as a Repurposed Therapy for COVID-19

The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of preclinical and initial safety studies. BenevolentAI’s large knowledge graph repository of structured medical information suggested baricitinib, a Janus-associated kinase inhibitor, as a potential repurposed medicine with a dual mechanism; hindering SARS-CoV2 entry and combatting the cytokine storm; the leading cause of mortality in COVID-19. However, the recently-published Adaptive COVID-19 Treatment Trial-2 (ACTT-2) positioned baricitinib only in combination with remdesivir for treatment of a specific category of COVID-19 patients, whereas the drug is not recommended to be used alone except in clinical trials. The increased pace of data output in all life sciences fields has changed our understanding of data processing and manipulation. For the purpose of drug design, development, or repurposing, the integration of different disciplines of life sciences is highly recommended to achieve the ultimate benefit of using new technologies to mine BIG data, however, the final say remains to be concluded after the drug is used in clinical practice. This review demonstrates different bioinformatics, chemical, pharmacological, and clinical aspects of baricitinib to highlight the repurposing journey of the drug and evaluates its placement in the current guidelines for COVID-19 treatment

Asthma severity as a contributing factor to cancer incidence: A cohort study

BACKGROUND: A putative link between asthma and asthma severity with the occurrence of cancer has been suggested but has not been fully investigated. The objective of this study is to assess the incidence of all types of cancer in a cohort of asthmatic patients. METHODS AND FINDINGS: A single center cohort retrospective study was conducted to investigate the role of asthma as a potential risk factor for various cancers. Participants were followed for a period of 9 years from 01/01/2010 to 30/12/2018 and cancer incidence and its determinants were collected in asthmatic patients and controls from the same population source but without any respiratory disease. Overall, 2,027 asthma patients and 1,637 controls were followed up for an average of 9 years. The statistical analysis showed that 2% of asthma patients were diagnosed with various cancers, resulting in an incidence rate of cancer of 383.02 per 100,000 persons per year which is significantly higher than the 139.01 per 100,000 persons per year observed in matched controls (p-value < 0.001). The top four cancers reported among asthmatics were breast, colon, lung and prostate cancer. Lung cancer in asthmatics had the longest diagnosis period with a mean of 36.6 years compared to the shortest with prostate cancer with 16.5 years. CONCLUSIONS: This study shows that asthma patients are at increased risk of different types of cancers with asthma severity and goiter as the main factors that may increase the risk of developing cancers among asthmatic patients

MiR-365-3p is a negative regulator in IL-17-mediated asthmatic inflammation

BackgroundInterleukin-17, the major proinflammatory cytokine secreted by Th17 cells, makes essential contribution to pathogenesis of severe asthma, while the detailed mechanisms, especially the involvement of microRNAs which are also important participants in asthma progression, remains largely unclear.MethodsIn this study, we established a house dust mite (HDM) extract-induced murine asthmatic models and the miRNA expression in the lung tissues of mice were profiled by miRNA microarray assay. The effect of miR-365-3p on IL-17-mediated inflammation was examined by qRT-PCR and immunoblotting analysis. The involvement of ARRB2 as target gene of miR-365-3p was verified by overexpression or RNA interference.ResultsHDM extract-induced asthmatic inflammation was proved to be IL17-mediated and miR-365-3p was screened out to be the only miRNA exclusively responsive to IL-17. miR-365-3p, whose expression was significantly downregulated upon IL-17 stimulation, was demonstrated to exert remarkable anti-inflammatory effect to decrease IL-17-provoked inflammatory cytokines (KC/IL-8 and IL-6) in both airway epithelial cells and macrophages of murine and human origins, verifying its universal antagonizing activity against IL-17-initiated inflammation across the two species. ARRB2 was characterized as the key target of miR-365-3p to negate IL-17-induced inflammatory cytokines.ConclusionTaken together, our data supported the notion that miR-365-3p, which was diminished by IL-17 in murine and human asthmatic pathogenesis, functioned as an essential negative mediator in IL-17-stimuated inflammatory response by targeting ARRB2, which would shed new light to the understanding and therapeutics thereof of asthmatic inflammation

Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology

BACKGROUND: The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients. AIM: To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction. METHODS: The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR. RESULTS: Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction. CONCLUSION: Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction