Van Eerdewegh P, Little RD, Dupuis J, et al Nature 2002;418:426–430 

To identify novel genetic polymorphisms associated with bronchial hyperresponsiveness (BHR) in asthma

Four hundred sixty white affected sib-pair families from the United States and the United Kingdom with current asthma

A genetic linkage analysis was performed for current asthma and BHR Case-control, transmission disequilibrium, and haplotype analyses were conducted to identify the gene(s) most commonly associated with asthma Novel genes of interest were …

Association of the adam33 gene with asthma and bronchial hyperresponsiveness

The growing environmental concerns due to the excessive use of non-renewable petroleum based products have raised interest for the sustainable synthesis of bio-based value added products and chemicals. Recently, nanocellulose has attracted wide attention because of its unique properties such as high surface area, tunable surface chemistry, excellent mechanical strength, biodegradability and renewable nature. It serves wide range of applications in paper making, biosensor, hydrogel and aerogel synthesis, water purification, biomedical industry and food industry. Variations in selection of source, processing technique and subsequent chemical modifications influence the size, morphology, and other characteristics of nanocellulose and ultimately their area of application. The current review is focused on extraction/synthesis of nanocellulose from different sources such as bacteria and lignocellulosic biomass, by using various production techniques ranging from traditional harsh chemicals to green methods. Further, the challenges in nanocellulose production, physio-chemical properties and applications are discussed with future opportunities. Finally, the sustainability of nanocellulose product as well as processes is reviewed by taking a systems view. The impact of chemicals, energy use, and waste generated can often negate the benefit of a bio-based product. These issues are evaluated and future research needs are identified.

Nanocellulose: Resources, Physio-Chemical Properties, Current Uses and Future Applications

A review of the ethnobotanical value, phytochemistry, pharmacology, toxicity and quality control of Tussilago farfara L. (coltsfoot).

Asthma is a chronic respiratory disease that affects 339 million people worldwide and has a considerable impact on the pediatric population. Asthma symptoms can be controlled by pharmacological treatment. However, some patients do not respond to therapy and continue suffering from symptoms, which impair the quality of life of patients and limit their daily activity. Genetic variation has been shown to have a role in treatment response. The aim of this review is to update the main findings described in pharmacogenetic studies of pediatric asthma published from January 1, 2018 to December 31, 2019. During this period, the response to short-acting beta-agonists and inhaled corticosteroids in childhood asthma has been evaluated by eleven candidate-gene studies, one meta-analysis of a candidate gene, and six pharmacogenomic studies. The findings have allowed validating the association of genes previously related to asthma treatment response (ADRB2, GSDMB, FCER2, VEGFA, SPAT2SL, ASB3, and COL2A1), and identifying novel associations (PRKG1, DNAH5, IL1RL1, CRISPLD2, MMP9, APOBEC3B-APOBEC3C, EDDM3B, and BBS9). However, some results are not consistent across studies, highlighting the need to conduct larger studies in diverse populations with more homogeneous definitions of treatment response. Once stronger evidence was established, genetic variants will have the potential to be applied in clinical practice as biomarkers of treatment response enhancing asthma management and improving the quality of life of asthma patients.

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Pharmacogenetics of Pediatric Asthma: Current Perspectives

Ceramide, a bioactive lipid, plays an essential role in the development of several pulmonary inflammatory diseases. Matrix metallopeptidase 9 (MMP-9) regulates the synthesis and degradation of extracellular matrix, and is associated with airway remodeling and tissue injury. This study was conducted to investigate the effects and underlying mechanisms of ceramide on MMP-9 expression in airway epithelium. BEAS-2B cells, normal human bronchial epithelium cell lines, were pretreated with AG490, a selective janus tyrosine kinase 2 (JAK2) inhibitor, or Stattic, a selective signal transducer and activator of transcription 3 (STAT3) inhibitor. The cells were then stimulated with C6-ceramide. The levels of MMP-9 were determined by ELISA and real-time quantitative PCR (RT-qPCR). JAK2, phosphorylated JAK2 (p-JAK2), STAT3, and phosphorylated STAT3 (p-STAT3) expression was examined by Western blotting. BALB/c mice were pretreated with AG490 or Stattic before intratracheally instillated with C6-ceramide. Pathological changes in lung tissues were examined by Hematoxylin and Eosin staining, Periodic-acid Schiff staining, and Masson’s trichrome staining. MMP-9, JAK2, p-JAK2, STAT3, and p-STAT3 expression in the lung tissues was examined by Western blotting. The expression of MMP-9, p-JAK2 and p-STAT3 in BEAS-2B cells was significantly increased after the treatment of C6-ceramide. Furthermore, the increased expression of MMP-9 induced by C6-ceramide was inhibited by AG490 and Stattic. Similar results were obtained in the lung tissues of C6-ceramide-exposed mice which were treated with AG490 or Stattic. Ceramide could up-regulate MMP-9 expression through the activation of the JAK2/STAT3 pathway in airway epithelium. Targeted modulation of the ceramide signaling pathway may offer a potential therapeutic approach for inhibiting MMP-9 expression. This study points to a potentially novel approach to alleviating airway remodeling in inflammatory airway diseases.

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Ceramide induces MMP-9 expression through JAK2/STAT3 pathway in airway epithelium

Metastatic colorectal cancer (mCRC) patients are treated with standard chemotherapeutic drugs in the form of FOLFOX and FOLFIRI regimens. There are no reliable markers that could predict response to chemotherapy for mCRC. TGF-β signaling which interacts with microRNA (miRNA) network has important roles in tumor progression and chemotherapy resistance, thus the interplay between TGF-β signaling and miRNAs could be crucial for treatment response. The aim of this study was to analyze the effect of chemotherapy for mCRC on TGF-β signaling and related miRNAs. Hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p were selected out of 316 miRNAs with multiple targets within the TGF-β signaling by in silico analysis. SW620 cells were treated with chemotherapeutic drugs for mCRC for 1, 3 and 6 days and expression of selected miRNAs, PAI-1, CDH1 and VIM was measured. Expression of TGF-β signaling-related hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p was time-dependently altered in SW620 cells treated with chemotherapeutics for mCRC. The expression of hsa-miR-93-5p remained downregulated after 6 days under combined treatments FOX and FIRI as well as the hsa-miR-17-5p expression under FIRI. Chemotherapy regimens for mCRC increased expression of a major TGF-β signaling target gene PAI-1, independently of the selected miRNAs expression. These treatments also increased the expression of epithelial-mesenchymal transition (EMT) markers CDH1 and VIM on day 3 resulting in decrease of mesenchymal-like characteristics. However, their expression returned close to basal level on day 6. In conclusion, after initial response to chemotherapeutic drugs SW620 cells start to return close to the basal mesenchymal state while the long-term downregulated expression pattern of hsa-miR-93-5p and hsa-miR-17-5p makes them candidates worth testing as biomarkers for monitoring combined chemotherapeutic treatments therapy response in mCRC patients.

Effects of Chemotherapy for Metastatic Colorectal Cancer on the TGF-β Signaling and Related miRNAs hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p.

Inhaled β2 adrenergic receptor (β2-AR) agonists are the mainstay of asthma therapy. The β2-AR protein is encoded by the ADRB2 gene and variants within this gene can have significant consequences for modulating the response to asthma therapy. This cross-sectional study performed at the University Children's Hospital in Belgrade, included 54 children with asthma. The subjects were genotyped for ADRB2 +46A>G (Arg16Gly, rs1042713) and +79C>G (Gln27Glu, rs 1042714) polymorphisms and the association with asthma severity and response to inhaled salbutamol was examined. In Serbian asthmatic children, allele +46A was detected with a frequency of 41.7% and allele +79G was detected with a frequency of 23.1%. Allele +46G was found to be associated with a better response to inhaled salbutamol (p G may be a determinant of asthma severity and response to salbutamol in children with asthma. We did not find any association of +79C>G polymorphisms with the asthma severity and bronchodilator response to inhaled salbutamol. The results of this study can be potentially useful for personalization of asthma treatment.

/pdf/adrb2-gene-polymorphisms-and-salbutamol-responsiveness-in-fl6yl3eepu.pdf

ADRB2 gene polymorphisms and salbutamol responsiveness in Serbian children with asthma

BACKGROUND Asthma is a chronic respiratory disease caused by a combination of genetic and environmental factors. Transforming growth factor beta 1 (TGFB1) is a multifunctional cytokine that plays an important role in airway remodeling in asthma. OBJECTIVES The aim of this study was to analyze common TGFB1 gene promoter polymorphisms C-509T and G-800A in Serbian asthmatics and to investigate their association with exacerbations. MATERIAL AND METHODS The study involved 102 asthmatics and 58 healthy individuals from Serbia, age and gender matched. An analysis of the TGFB1 promoter was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS For polymorphism C-509T a significant difference in the allele frequency was observed between the patients and the controls (p = 0.011), while the genotype distribution was similar in the analyzed groups, with statistical significance near the borderline (p = 0.061). For the polymorphism G-800A no difference was observed between the groups. The frequency of the -509TT genotype was higher in patients with exacerbations compared to patients without exacerbations (36.4% vs. 17.0%), with statistical significance near the borderline (p = 0.080). CONCLUSIONS The results suggest that polymorphism C-509T may be associated with asthma and disease exacerbations, while G-800A is not significant for the etiology and clinical course of the disease. These findings should be confirmed in a larger study group, and since the TGFB1 promoter is highly complex and very responsive to environmental factors, future studies should also take other genetic and non-genetic factors into consideration.

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TGFB1 Gene Promoter Polymorphisms in Serbian Asthmatics.

The maintaining of asthma control is difficult due to high variability in response to therapy among patients. Since matrix metalloproteinase 9 (MMP9) is implicated in inflammation and remodeling of asthmatic airways, it could be associated with adequate response to asthma therapy. The aim of this study was to investigate whether variants in 3′ end of the MMP9 gene are associated with clinical phenotype and responsiveness to treatment in children with asthma. The study included 127 asthmatic children from Slovenia. Variants in the 3′ end of the MMP9 gene were analyzed by direct DNA sequencing and the obtained results were correlated with clinical parameters. Two variants were detected, rs13925 and rs20544. For the variant rs20544, statistically significant difference in airway hyperresponsiveness (p = 0.011) and asthma control (p = 0.049) between genotypes was found. Patients with TT genotype had lower airway sensitivity, and after 12 months of treatment showed significant improvement in Asthma Control Test (ACT) scores compared to CC and CT genotype. For the variant rs13925, the association with lung function was observed. The carriers of A allele showed noticeable improvement of lung function after the first 6 months of treatment in comparison to the carriers of G allele (p = 0.046). The main finding of our study is the association of MMP9 genotypes rs20544 TT and rs13925 AA and AG with better asthma control, and indirectly better response to treatment. Based on these results, MMP9 deserves further research as a potential predictive biomarker for asthma.

Sandra Dragicevic

Papers

Effects of Chemotherapy for Metastatic Colorectal Cancer on the TGF-β Signaling and Related miRNAs hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p.

ADRB2 gene polymorphisms and salbutamol responsiveness in Serbian children with asthma

TGFB1 Gene Promoter Polymorphisms in Serbian Asthmatics.

The Variants in the 3′ Untranslated Region of the Matrix Metalloproteinase 9 Gene as Modulators of Treatment Outcome in Children with Asthma

SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response.