Altered respiratory microbiota composition and functionality associated with asthma early in life.

BACKGROUND: The microbiota of the respiratory tract has an important role in maintaining respiratory health. However, little is known on the respiratory microbiota in asthmatic patients among Middle Eastern populations. This study investigated the respiratory microbiota composition and functionality associated with asthma in Emirati subjects. METHODS: We performed 16S rRNA and ITS2-gene based microbial profiling of 40 expectorated sputum samples from adult and pediatric Emirati individuals averaging 52 and 7 years of age, respectively with or without asthma. RESULTS: We report bacterial difference belonging to Bacteroidetes, Firmicutes, Fusobacteria and Proteobacteria phyla between asthmatic and non-asthmatic controls. Similarly, fungal difference belonging to Ascomycota, Basidiomycota phyla and other unclassified fungi. Differential abundance testing among asthmatic individuals with relation to Asthma Control Test show a significant depletion of Penicillium aethiopicum and Alternaria spp., among poorly controlled asthmatics. Moreover, data suggest a significant expansion of Malassezia spp. and other unclassified fungi in the airways of those receiving steroids and leukotriene receptor antagonists' combination therapy, in contrast to those receiving steroids alone. Functional profiling from 16S data showed marked differences between pediatric asthmatic and non-asthmatic controls, with pediatric asthmatic patients showing an increase in amino acid (p-value < 5.03 × 10- 7), carbohydrate (p-value < 4.76 × 10- 7), and fatty acid degradation (p-value < 6.65 × 10- 7) pathways, whereas non-asthmatic controls are associated with increase in amino acid (p-value < 8.34 × 10- 7), carbohydrate (p-value < 3.65 × 10- 7), and fatty acid (p-value < 2.18 × 10- 6) biosynthesis pathways in concordance with enterotype composition. CONCLUSIONS: These differences provide an insight into respiratory microbiota composition in Emirati population and its possible role in the development of asthma early in life. This study provides important information that may eventually lead to the development of screening biomarkers to predict early asthma development and novel therapeutic approaches.

Immunohistochemical assessment of Survivin and Bcl3 expression as potential biomarkers for NF-κB activation in the Barrett metaplasia-dysplasia-adenocarcinoma sequence.

Non-dysplastic Barrett's oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro-oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF-κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF-κB activation along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Survivin is an NF-κB-inducible anti-apoptotic protein, and Bcl3 is a negative regulator of NF-κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Bcl3 expression was upregulated in non-dysplastic Barrett's oesophagus, low-grade, high-grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barrett's stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF-κB activation. In addition, the study suggests that NF-κB activation may infer resistance to apoptosis through the expression of anti-apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barrett's metaplasia.

Circulating microRNAs as potential biomarkers of early vascular damage in vitamin D deficiency, obese, and diabetic patients.

Vitamin D3 deficiency, obesity, and diabetes mellitus (DM) have been shown to increase the risk of cardiovascular diseases (CVDs). However, the early detection of vascular damage in those patients is still difficult to ascertain. MicroRNAs (miRNAs) are recognized to play a critical role in initiation and pathogenesis of vascular dysfunction. Herein, we aimed to identify circulating miRNA biomarkers of vascular dysfunction as early predictors of CVDs. We have recruited 23 middle-aged Emiratis patients with the following criteria: A healthy control group with vitamin D ≥ 20ng, and BMI < 30 (C1 group = 11 individuals); A vitamin D deficiency (Vit D level ≤ 20 ng) and obese (BMI ≥ 30) group (A1 group = 9 patients); A vitamin D deficiency, obese, plus DM (A2 group = 3 patients). Arterial stiffness via pulse wave velocity (PWV) was measured and the whole transcriptome analysis with qPCR validation for miRNA in plasma samples were tested. PWV relative to age was significantly higher in A1 group 19.4 ± 4.7 m/s and A2 group 18.3 ± 1.3 m/s compared to controls 14.7 ± 2.1 m/s (p < 0.05). Similar patterns were also observed in the Augmentation pressure (AP) and Alx%. Whole RNA-Sequencing revealed miR-182-5p; miR-199a-5p; miR-193a-5p; and miR-155-5p were differentially over-expressed (logFC > 1.5) in high-risk patients for CVDs vs healthy controls. Collectively, our result indicates that four specific circulating miRNA signature, may be utilized as non-invasive, diagnostic and prognostic biomarkers for early vascular damage in patients suffering from vitamin D deficiency, obesity and DM.

The Essential Role of 17-Octadecynoic Acid in the Pathogenesis of Periapical Abscesses.

INTRODUCTION: Periapical abscesses are 1 of the most frequent pathologic lesions in the alveolar bone. Recently, we have identified 17-octadecynoic acid (17-ODYA) as the highest unique metabolite in periapical abscesses. Therefore, the aim of this study was to investigate the immunologic and pathophysiological roles of this metabolite in the initiation and development of periapical abscesses. METHODS: Periodontal ligament fibroblasts and peripheral blood mononuclear cells were treated with 17-ODYA. Gene expression analysis and interleukin (IL)-8 release were determined using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Macrophage polarization and cytokine release were also determined using flow cytometry and Luminex bioassay (R&D Systems, Minneapolis, MN), respectively. RESULTS: In periodontal ligament fibroblasts, 17-ODYA caused significant (P < .0001) up-regulation of IL-1α, IL-1ß, IL-6, matrix metalloproteinase-1, and monocyte chemoattractant protein-1 at 10 µmol/L after 6 days of treatment and up-regulation of platelet-derived growth factor alpha and vascular endothelial growth factor alpha at all tested concentrations after 2 days of treatment. In peripheral blood mononuclear cells, 17-ODYA significantly increased the expression of IL-1α, IL-1ß, IL-6, matrix metalloproteinase-1, and monocyte chemoattractant protein-1 at 10 µmol/L (P < .0001) and vascular endothelial growth factor alpha and platelet-derived growth factor alpha at 1 µmol/L 17-ODYA (P < .0001). 17-ODYA polarized macrophages toward a proinflammatory phenotype (M1) and suppressed the release of pro- and anti-inflammatory cytokines. 17-ODYA significantly enhanced the release of IL-8. CONCLUSIONS: This study was the first to identify the pathologic role of 17-ODYA in the development of periapical abscesses. The results of this study are important in shedding light on the pathogenesis of periapical abscesses in relation to microbial metabolites.

Molecular pathogenicity of 1-nonadecene and L-lactic acid, unique metabolites in radicular cysts and periapical granulomas.

Recently, 1-nonadecene and L-lactic acid were identified as unique metabolites in radicular cysts and periapical granuloma, respectively. However, the biological roles of these metabolites were unknown. Therefore, we aimed to investigate the inflammatory and mesenchymal-epithelial transition (MET) effects of 1-nonadecene, and the inflammatory and collagen precipitation effects of L-lactic acid on both periodontal ligament fibroblasts (PdLFs) and peripheral blood mononuclear cells (PBMCs). PdLFs and PBMCs were treated with 1-nonadecene and L-lactic acid. Cytokines' expression was measured using quantitative real-time polymerase chain reaction (qRT-PCR). E-cadherin, N-cadherin, and macrophage polarization markers were measured using flow cytometry. The collagen, matrix metalloproteinase (MMP)-1, and released cytokines were measured using collagen assay, western blot, and Luminex assay, respectively. In PdLFs, 1-nonadecene enhances inflammation through the upregulation of some inflammatory cytokines including IL-1ß, IL-6, IL-12A, monocyte chemoattractant protein (MCP)-1, and platelet-derived growth factor (PDGF) α. 1-Nonadecene also induced MET through the upregulation of E-cadherin and the downregulation of N-cadherin in PdLFs. 1-Nonadecene polarized macrophages to a pro-inflammatory phenotype and suppressed their cytokines' release. L-lactic acid exerted a differential impact on the inflammation and proliferation markers. Intriguingly, L-lactic acid induced fibrosis-like effects by enhancing collagen synthesis, while inhibiting MMP-1 release in PdLFs. These results provide a deeper understanding of 1-nonadecene and L-lactic acid's roles in modulating the microenvironment of the periapical area. Consequently, further clinical investigation can be employed for target therapy.

Unveiling the molecular Culprit of arterial stiffness in vitamin D deficiency and obesity: Potential for novel therapeutic targets.

Cardiovascular diseases (CVDs) are highly associated with both vitamin D deficiency and obesity, two prevalent health conditions worldwide. Arterial stiffness, an independent predictor of CVDs, is particularly elevated in both conditions, yet the molecular mechanisms underlying this phenomenon remain elusive, hindering effective management of CVDs in this population. We recruited 20 middle-aged Emiratis, including 9 individuals with vitamin D deficiency (Vit D level ≤20 ng) and obesity (BMI ≥30) and 11 individuals as control with Vit D level >20 ng and BMI <30. We measured arterial stiffness using pulse wave velocity (PWV) and performed whole transcriptome sequencing to identify differentially expressed genes (DEGs) and enriched pathways. We validated these findings using qRT-PCR, Western blot, and multiplex analysis. PWV was significantly higher in the vitamin D deficient and obese group relative to controls (p ≤ 0.05). The DEG analysis revealed that pathways related to interleukin 1 (IL-1), nitrogen metabolism, HIF-1 signaling, and MAPK signaling were over-activated in the vitamin D deficient and obese group. We found that HIF-1alpha, NOX-I, NOX-II, IL-1b, IL-8, IL-10, and VEGF were significantly upregulated in the vitamin D deficient and obese group (p < 0.05). Our study provides new insights into the molecular mechanisms of arterial stiffness in vitamin D deficiency and obesity, demonstrating the role of oxidative stress and inflammation in this process. Our findings suggest that these biomarkers may serve as potential therapeutic targets for early prevention of CVDs. Further studies are needed to investigate these pathways and biomarkers with larger cohort.

MGMT CpG island is invariably methylated in adult astrocytic and oligodendroglial tumors with IDH1 or IDH2 mutations.

We have previously identified a region containing 16 CpGs within the MGMT CpG islands which is critical for the transcriptional control of MGMT (Malley, Acta Neuropathol 2011). To investigate the patterns and incidence of MGMT methylation in astrocytic and oligodendroglial tumors, we quantitatively assessed methylation at these 16 CpGs using bisulfite modification followed by pyrosequencing of 362 gliomas not treated with temozolomide, and correlated the findings with previously identified patterns of genetic abnormalities, patients' age and survival. The MGMT gene was considered to be methylated when the mean methylation of the 16 CpGs was 10% or higher. This cut-off value distinguished diffuse astrocytomas with high and low MGMT expression. Within each tumor type, the patterns of methylation were highly variable and also highly heterogeneous across the 16 CpGs. A high incidence of MGMT methylation was observed in all subtypes of gliomas included in this study. Among a subset of 97 tumors where conventional methylation-specific PCR (MSP) was also applied, methylation was detected by both methods in 54 tumors, while the pyrosequencing results identified a further 17 tumors. No additional cases were found using MSP alone, indicating that pyrosequencing is a robust method for methylation analysis. All tumors with IDH1/IDH2 mutations except two had MGMT methylation, while there were many tumors with MGMT methylation, particularly primary glioblastomas, which had no mutations of IDH1/2. We suggest that MGMT methylation may be one of the earliest events in the development of astrocytic and oligodendroglial tumors.

A20 inactivation in ocular adnexal MALT lymphoma.

Recent studies showed A20 inactivation by deletion, mutation and promoter methylation in ocular adnexal mucosa-associated lymphoid tissue lymphoma. However, the incidences of A20 abnormalities and their clinical impact remain for the most part unknown. It is also unknown whether ABIN-1 and ABIN-2, the components of the A20 NF-κB inhibitor complex, are inactivated by genetic changes in ocular adnexal mucosa-associated lymphoid tissue lymphoma. A total of 105 cases were investigated for A20 mutation/deletion, ABIN-1/2 mutation, MALT1 and IGH involved translocation. Somatic mutation was seen frequently in A20 (28.6%) but rarely in ABIN-1 (1%) and ABIN-2 (1%). A20 mutations were significantly associated with A20 heterozygous deletion, and both were mutually exclusive from the MALT1 or IGH involved translocations. A20 mutation/deletion was also significantly associated with increased expression of the NF-κB target genes CCR2, TLR6 and BCL2. The cases with A20 mutation/deletion required significantly higher radiation dosages to achieve complete remission than those without these abnormalities.

BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas.

The genetics and pathogenesis of splenic marginal zone lymphoma are poorly understood. The lymphoma lacks chromosome translocation, and approximately 30% of cases are featured by 7q deletion, but the gene targeted by the deletion is unknown. A recent study showed inactivation of A20, a "global" NF-κB negative regulator, in 1 of 12 splenic marginal zone lymphomas. To investigate further whether deregulation of the NF-κB pathway plays a role in the pathogenesis of splenic marginal zone lymphoma, we screened several NF-κB regulators for genetic changes by PCR and sequencing. Somatic mutations were found in A20 (6/46=13%), MYD88 (6/46=13%), CARD11 (3/34=8.8%), but not in CD79A, CD79B and ABIN1. Interestingly, these genetic changes are largely mutually exclusive from each other and MYD88 mutation was also mutually exclusive from 7q deletion. These results strongly suggest that deregulation of the TLR (toll like receptor) and BCR (B-cell receptor) signaling pathway may play an important role in the pathogenesis of splenic marginal zone lymphoma.

ACE2 polymorphisms impact COVID-19 severity in obese patients.

A strong association between obesity and COVID-19 complications and a lack of prognostic factors that explain the unpredictable severity among these patients still exist despite the various vaccination programs. The expression of angiotensin converting enzyme 2 (ACE2), the main receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is enhanced in obese individuals. The occurrence of frequent genetic single nucleotide polymorphisms (SNPs) in ACE2 is suggested to increase COVID-19 severity. Accordingly, we hypothesize that obesity-associated ACE2 polymorphisms increase the severity of COVID-19. In this study, we profiled eight frequently reported ACE2 SNPs in a cohort of lean and obese COVID-19 patients (n = 82). We highlight the significant association of rs2285666, rs2048683, rs879922, and rs4240157 with increased severity in obese COVID-19 patients as compared to lean counterparts. These co-morbid-associated SNPs tend to positively correlate, hence proposing possible functional cooperation to ACE2 regulation. In obese COVID-19 patients, rs2285666, rs879922, and rs4240157 are significantly associated with increased blood nitrogen urea and creatinine levels. In conclusion, we highlight the contribution of ACE2 SNPs in enhancing COVID-19 severity in obese individuals. The results from this study provide a basis for further investigations required to shed light on the underlying mechanisms of COVID-19 associated SNPs in COVID-19 obese patients.

Travel ban effects on SARS-CoV-2 transmission lineages in the UAE as inferred by genomic epidemiology.

Global and local whole genome sequencing of SARS-CoV-2 enables the tracing of domestic and international transmissions. We sequenced Viral RNA from 37 sampled Covid-19 patients with RT-PCR-confirmed infections across the UAE and developed time-resolved phylogenies with 69 local and 3,894 global genome sequences. Furthermore, we investigated specific clades associated with the UAE cohort and, their global diversity, introduction events and inferred domestic and international virus transmissions between January and June 2020. The study comprehensively characterized the genomic aspects of the virus and its spread within the UAE and identified that the prevalence shift of the D614G mutation was due to the later introductions of the G-variant associated with international travel, rather than higher local transmissibility. For clades spanning different emirates, the most recent common ancestors pre-date domestic travel bans. In conclusion, we observe a steep and sustained decline of international transmissions immediately following the introduction of international travel restrictions.

A distinct region of the MGMT CpG island critical for transcriptional regulation is preferentially methylated in glioblastoma cells and xenografts.

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that removes alkyl DNA adducts such as those induced by alkylating agents. Loss of MGMT expression through transcriptional silencing by hypermethylation of its CpG island (CGI) is found in diverse human cancers including glioblastomas. Glioblastomas that have MGMT methylation respond to temozolomide, an alkylating agent, resulting in improved survival. Consequently, assessment of MGMT methylation has become a therapy response and prognostic indicator. However, it is not clear whether the region of the MGMT CGI commonly analysed is the critical region involved in transcriptional control. We measured methylation levels at each CpG site for the entire MGMT CGI using bisulfite modification and pyrosequencing, and compared them with MGMT mRNA expression in glioblastoma cell lines, xenografts and normal brain tissues (41 samples). Two critical regions were identified (DMR1 and DMR2). DMR2 encompasses the commonly analysed region and was always methylated when DMR1 was methylated. A luciferase reporter assay showed that substitutions of several specific CpG sites within DMR2 significantly attenuated the promoter activity of the MGMT CGI. Our results indicate that several CpG sites within DMR2 play a critical role in the transcriptional control of MGMT, making DMR2 the optimal target for methylation testing. However, given the highly variable patterns of MGMT methylation associated with transcriptional silencing observed in this region among the tumours in this study, methylation levels need to be measured at a number of individual CpGs within DMR2 to confidently predict transcriptional silencing and thus sensitivity to alkylating agents.

Prognostic relevance of DNA copy number changes in colorectal cancer.

In a study of 109 colorectal cancers, DNA copy number aberrations were identified by comparative genomic hybridization using a DNA microarray covering the entire genome at an average interval of less than 1 Mbase. Four patterns were revealed by unsupervised clustering analysis, one of them associated with significantly better prognosis than the others. This group contained tumours with short, dispersed, and relatively few regions of copy number gain or loss. The good prognosis of this group was not attributable to the presence of tumours showing microsatellite instability (MSI-H). Supervised methods were employed to determine those genomic regions where copy number alterations correlate significantly with multiple indices of aggressive growth (lymphatic spread, recurrence, and early death). Multivariate analysis identified DNA copy number loss at 18q12.2, harbouring a single gene, BRUNOL4 that encodes the Bruno-like 4 splicing factor, as an independent prognostic indicator. The data show that the different patterns of DNA copy number alterations in primary tumours reveal prognostic information and can aid identification of novel prognosis-associated genes.

Primary effusion lymphoma: genomic profiling revealed amplification of SELPLG and CORO1C encoding for proteins important for cell migration.

Primary effusion lymphoma (PEL) is associated with Kaposi sarcoma herpesvirus (KSHV) but its pathogenesis is poorly understood. Many KSHV-associated products can deregulate cellular pathways commonly targeted in cancer. However, KSHV infection alone is insufficient for malignant transformation. PEL also lacks the chromosomal translocations seen in other lymphoma subtypes. We investigated 28 PELs and ten PEL cell lines by 1 Mb resolution array comparative genomic hybridization (CGH) and found frequent gains of 1q21-41 (47%), 4q28.3-35 (29%), 7q (58%), 8q (63%), 11 (32%), 12 (61%), 17q (29%), 19p (34%), and 20q (34%), and losses of 4q (32%), 11q25 (29%), and 14q32 (63%). Recurrent focal amplification was seen at several regions on chromosomes 7, 8, and 12. High-resolution chromosome-specific tile-path array CGH confirmed these findings, and identified selectin-P ligand (SELPLG) and coronin-1C (CORO1C) as the targets of a cryptic amplification at 12q24.11. Interphase FISH and quantitative PCR showed SELPLG/CORO1C amplification (>4 extra copies) and low levels of copy number gain (1-4 extra copies) in 23% of PELs, respectively. Immunohistochemistry revealed strong expression of both SELPLG and coronin-1C in the majority of PELs, irrespective of their gene dosage. SELPLG is critical for cell migration and chemotaxis, while CORO1C regulates actin-dependent processes, thus important for cell motility. Their overexpression in PEL is expected to play an important role in its pathogenesis.

Understanding the Role of Innate Immune Cells and Identifying Genes in Breast Cancer Microenvironment.

The innate immune system is the first line of defense against invading pathogens and has a major role in clearing transformed cells, besides its essential role in activating the adaptive immune system. Macrophages, dendritic cells, NK cells, and granulocytes are part of the innate immune system that accumulate in the tumor microenvironment such as breast cancer. These cells induce inflammation in situ by secreting cytokines and chemokines that promote tumor growth and progression, in addition to orchestrating the activities of other immune cells. In breast cancer microenvironment, innate immune cells are skewed towards immunosuppression that may lead to tumor evasion. However, the mechanisms by which immune cells could interact with breast cancer cells are complex and not fully understood. Therefore, the importance of the mammary tumor microenvironment in the development, growth, and progression of cancer is widely recognized. With the advances of using bioinformatics and analyzing data from gene banks, several genes involved in NK cells of breast cancer individuals have been identified. In this review, we discuss the activities of certain genes involved in the cross-talk among NK cells and breast cancer. Consequently, altering tumor immune microenvironment can make breast tumors more responsive to immunotherapy.

An Integrative Phenotype-Genotype Approach Using Phenotypic Characteristics from the UAE National Diabetes Study Identifies HSD17B12 as a Candidate Gene for Obesity and Type 2 Diabetes.

The United Arab Emirates National Diabetes and Lifestyle Study (UAEDIAB) has identified obesity, hypertension, obstructive sleep apnea, and dyslipidemia as common phenotypic characteristics correlated with diabetes mellitus status. As these phenotypes are usually linked with genetic variants, we hypothesized that these phenotypes share single nucleotide polymorphism (SNP)-clusters that can be used to identify causal genes for diabetes. Materials and We explored the National Human Genome Research Institute-European Bioinformatics Institute Catalog of Published Genome-Wide Association Studies (NHGRI-EBI GWAS) to list SNPs with documented association with the UAEDIAB-phenotypes as well as diabetes. The shared chromosomal regions affected by SNPs were identified, intersected, and searched for Enriched Ontology Clustering. The potential SNP-clusters were validated using targeted DNA next-generation sequencing (NGS) in two Emirati diabetic patients. RNA sequencing from human pancreatic islets was used to study the expression of identified genes in diabetic and non-diabetic donors. Eight chromosomal regions containing 46 SNPs were identified in at least four out of the five UAEDIAB-phenotypes. A list of 34 genes was shown to be affected by those SNPs. Targeted NGS from two Emirati patients confirmed that the identified genes have similar SNP-clusters. ASAH1, LRP4, FES, and HSD17B12 genes showed the highest SNPs rate among the identified genes. RNA-seq analysis revealed high expression levels of HSD17B12 in human islets and to be upregulated in type 2 diabetes (T2D) donors. Our integrative phenotype-genotype approach is a novel, simple, and powerful tool to identify clinically relevant potential biomarkers in diabetes. HSD17B12 is a novel candidate gene for pancreatic ß-cell function.

Toxicogenomic analysis of publicly available transcriptomic data can predict food, drugs, and chemical-induced asthma.

BACKGROUND: : With the increasing incidence of asthma, more attention is focused on the diverse and complex nutritional and environmental triggers of asthma exacerbations. Currently, there are no established risk assessment tools to evaluate asthma triggering potentials of most of the nutritional and environmental triggers encountered by asthmatic patients. PURPOSE:  The objective of this study is to devise a reliable workflow, capable of estimating the toxicogenomic effect of such factors on key player genes in asthma pathogenesis. METHODS: Gene expression extracted from publicly available datasets of asthmatic bronchial epithelium were subjected to a comprehensive analysis of differential gene expression to identify significant genes involved in asthma development and progression. The identified genes were subjected to Gene Set Enrichment Analysis using a total of 31,826 gene sets related to chemical, toxins, and drugs to identify common agents that share similar asthma-related targets genes and signaling pathways. RESULTS: Our analysis identified 225 differentially expressed genes between severe asthmatic and healthy bronchial epithelium. Gene Set Enrichment Analysis of the identified genes showed that they are involved in response to toxic substances and organic cyclic compounds and are targeted by 41 specific diets, plants products, and plants related toxins (eg adenine, arachidonic acid, baicalein, caffeic acid, corilagin, curcumin, ellagic acid, luteolin, microcystin-RR, phytoestrogens, protoporphyrin IX, purpurogallin, rottlerin, and salazinic acid). Moreover, the identified chemicals share interesting inflammation-related pathways like NF-κB. CONCLUSION: Our analysis was able to explain and predict the toxicity in terms of stimulating the differentially expressed genes between severe asthmatic and healthy epithelium. Such an approach can pave the way to generate a cost-effective and reliable source for asthma-specific toxigenic reports thus allowing the asthmatic patients, physicians, and medical researchers to be aware of the potential triggering factors with fatal consequences.

Comparative metabolomics of MCF-7 breast cancer cells using different extraction solvents assessed by mass spectroscopy.

Metabolic profiling of cancer cells can play a vital role in revealing the molecular bases of cancer development and progression. In this study, gas chromatography coupled with mass spectrometry (GC-MS) was employed for the determination of signatures found in ER+/PR+ breast cancer cells derived from MCF-7 using different extraction solvents including: A, formic acid in water; B, ammonium hydroxide in water; C, ethyl acetate; D, methanol: water (1:1, v/v); and E, acetonitrile: water (1:1, v/v). The greatest extraction rate and diversity of metabolites occurs with extraction solvents A and E. Extraction solvent D showed moderate extraction efficiency, whereas extraction solvent B and C showed inferior metabolite diversity. Metabolite set enrichment analysis (MSEA) results showed energy production pathways to be key in MCF-7 cell lines. This study showed that mass spectrometry could identify key metabolites associated with cancers. The highest enriched pathways were related to energy production as well as Warburg effect pathways, which may shed light on how energy metabolism has been hijacked to encourage tumour progression and eventually metastasis in breast cancer.

Association Trends Between Antihypertensive Drug Therapies and Diastolic Hypotension in Emirati Patients with Type 2 Diabetes: A Single-Center Retrospective Longitudinal Study.

INTRODUCTION: Diabetes mellitus (DM) is associated with multiple complications, including cardiovascular diseases. Previously, it was believed that the latter are mainly caused by hypertension and increased systolic blood pressure. However, recent studies have challenged this concept, by showing that diastolic dysfunction may also be involved in the cardiovascular events that are associated with DM. Pharmacologic management of hypertension in patients with type 2 DM appears to adversely influence diastolic function. METHODS: Four hundred and eight medical records of hypertensive and obese Emirati patients with type 2 DM were included in the present retrospective study. The main objectives of the present study were (1) to determine the prevalence of low diastolic blood pressure (DBP) and diastolic hypotension in this group of patients and (2) to investigate the associations, if any, between the use of various antihypertensive medications and low DBP and diastolic hypotension. RESULTS: The results of the present study showed that low DBP (< 70 mmHg) was experienced by 40% of the hypertensive type 2 DM patients, whereas diastolic hypotension (< 60 mmHg) was reported to occur in about 10% of the patients. Another important factor that has been significantly correlated with diastolic hypotension is age (p < 0.01). Association trends have been reported between low DBP and diastolic hypotension and several antihypertensive therapies, including (1) monotherapies such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), (2) dual therapies such as ACE inhibitors in combination with thiazide-like diuretics (THLDs) or beta blockers, and (3) triple therapy combinations of ACE inhibitors with THLDs and potassium-sparing diuretics. CONCLUSION: The use of antihypertensive medications, in particular ACE inhibitors and ARBs, appears to be a risk factor for the development of low DBP and diastolic hypotension in obese hypertensive Emirati patients with type 2 DM, whereas calcium channel blockers seem to be a safer option for this group of patients.

Efficacy of photochemical internalisation using disulfonated chlorin and porphyrin photosensitisers: An in vitro study in 2D and 3D prostate cancer models.

This study shows the therapeutic outcome of Photochemical Internalisation (PCI) in prostate cancer in vitro surpasses that of Photodynamic Therapy (PDT) and could improve prostate PDT in the clinic, whilst avoiding chemotherapeutics side effects. In addition, the study assesses the potential of PCI with two different photosensitisers (TPCS2a and TPPS2a) in prostate cancer cells (human PC3 and rat MatLyLu) using standard 2D monolayer culture and 3D biomimetic model. Photosensitisers were used alone for photodynamic therapy (PDT) or with the cytotoxin saporin (PCI). TPPS2a and TPCS2a were shown to be located in discrete cytoplasmic vesicles before light treatment and redistribute into the cytosol upon light excitation. PC3 cells exhibit a higher uptake than MatLyLu cells for both photosensitisers. In the 2D model, PCI resulted in greater cell death than PDT alone in both cell lines. In 3D model, morphological changes were also observed. Saporin-based toxicity was negligible in PC3 cells, but pronounced in MatLyLu cells (IC50 = 18 nM). In conclusion, the study showed that tumour features such as tumour cell growth rate or interaction with drugs determine therapeutic conditions for optimal photochemical treatment in metastatic prostate cancer.