Inflammation-related Processes Research Articles

Differential Profile of Plasma Circular RNAs in Type 1 Diabetes Mellitus.

BackgroundNo currently available biomarkers or treatment regimens fully meet therapeutic needs of type 1 diabetes mellitus (T1DM). Circular RNA (circRNA) is a recently identified class of stable noncoding RNA that have been documented as potential biomarkers for various diseases. Our objective was to identify and analyze plasma circRNAs altered in T1DM.MethodsWe used microarray to screen differentially expressed plasma circRNAs in patients with new onset T1DM (n=3) and age-/gender-matched healthy controls (n=3). Then, we selected six candidates with highest fold-change and validated them by quantitative real-time polymerase chain reaction in independent human cohort samples (n=12). Bioinformatic tools were adopted to predict putative microRNAs (miRNAs) sponged by these validated circRNAs and their downstream messenger RNAs (mRNAs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to gain further insights into T1DM pathogenesis.ResultsWe identified 68 differentially expressed circRNAs, with 61 and seven being up- and downregulated respectively. Four of the six selected candidates were successfully validated. Curations of their predicted interacting miRNAs revealed critical roles in inflammation and pathogenesis of autoimmune disorders. Functional relations were visualized by a circRNA-miRNA-mRNA network. GO and KEGG analyses identified multiple inflammation-related processes that could be potentially associated with T1DM pathogenesis, including cytokine-cytokine receptor interaction, inflammatory mediator regulation of transient receptor potential channels and leukocyte activation involved in immune response.ConclusionOur study report, for the first time, a profile of differentially expressed plasma circRNAs in new onset T1DM. Further in silico annotations and bioinformatics analyses supported future application of circRNAs as novel biomarkers of T1DM.

ApoL1 induces kidney inflammation through RIG-I/NF-κB activation

The genetic variations of the apolipoprotein L1 (APOL1) gene are associated with non-diabetic kidney diseases. However, very little is known about the role of ApoL1 in glomerular damage. Here, we aimed to identify the function and mechanism of ApoL1 in glomerular damage. The mice were randomly divided into two groups: one group was intraperitoneally injected with phosphate buffer saline (PBS), while the other group was intraperitoneally injected with recombinant ApoL1 every other day for 3 months. Hematoxylin and eosin (HE) and periodic acid Schiff (PAS) staining were used to demonstrate the effects of ApoL1 on kidney inflammation and injury. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses revealed that ApoL1-treated mice exhibited enhanced expression of various inflammation markers in the kidney and serum compared to the PBS-treated mice. Immunofluorescence staining revealed that ApoL1 accumulated in kidney podocytes. Treatment with ApoL1 dose-dependently increased the expression of inflammation markers and apoptotic markers. The abnormal gene expression associated with ApoL1-mediated podocyte inflammation was evaluated using microarray analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the upregulated genes were enriched in the inflammation-related processes, such as the RIG-I/NF-κB signaling pathway. Consistently, the knockdown of RIG-I significantly mitigated the ApoL1-induced upregulation of inflammatory and apoptotic markers in the human podocytes. Additionally, the ApoL1-induced glomerular damage was attenuated in AAV-shRIG-I mice. Therefore, the effects of ApoL1 on glomerular damage may be, at least partially, through inducing abnormal expression of inflammatory molecules, which may have important implications for treatment of kidney diseases.

Sample multiplexing for targeted pathway proteomics in aging mice

Pathway proteomics strategies measure protein expression changes in specific cellular processes that carry out related functions. Using targeted tandem mass tags-based sample multiplexing, hundreds of proteins can be quantified across 10 or more samples simultaneously. To facilitate these highly complex experiments, we introduce a strategy that provides complete control over targeted sample multiplexing experiments, termed Tomahto, and present its implementation on the Orbitrap Tribrid mass spectrometer platform. Importantly, this software monitors via the external desktop computer to the data stream and inserts optimized MS2 and MS3 scans in real time based on an application programming interface with the mass spectrometer. Hundreds of proteins of interest from diverse biological samples can be targeted and accurately quantified in a sensitive and high-throughput fashion. It achieves sensitivity comparable to, if not better than, deep fractionation and requires minimal total sample input (∼10 µg). As a proof-of-principle experiment, we selected four pathways important in metabolism- and inflammation-related processes (260 proteins/520 peptides) and measured their abundance across 90 samples (nine tissues from five old and five young mice) to explore effects of aging. Tissue-specific aging is presented here and we highlight the role of inflammation- and metabolism-related processes in white adipose tissue. We validated our approach through comparison with a global proteome survey across the tissues, work that we also provide as a general resource for the community.

Chronic Stress Contributes to Osteosarcopenic Adiposity via Inflammation and Immune Modulation: The Case for More Precise Nutritional Investigation.

Chronic stress and low-grade chronic inflammation (LGCI) are key underlying factors for many diseases, including bone and body composition impairments. Objectives of this narrative review were to examine the mechanisms by which chronic stress and LGCI may influence osteosarcopenic adiposity (OSA) syndrome, originally named as ostoesarcopenic obesity (OSO). We also examined the crucial nutrients presumed to be affected by or cause of stress and inflammation and compared/contrasted them to those of our prehistoric ancestors. The evidence shows that stress (particularly chronic) and its related inflammatory processes, contribute to osteoporosis, sarcopenia, and adiposity ultimately leading to OSA as a final and most deranged state of body composition, commencing at the mesenchymal cell lineage disturbance. The foods/nutrients consumed by modern humans, as well as their altered lifestyle, also contribute to stress, LGCI and subsequently to OSA. The processes can also go in opposite direction when stress and inflammation impact nutritional status, particularly some micronutrients’ levels. While nutritional management of body composition and LGCI have been studied, the nutrients (and their quantities) most affected by stressors and those which may act toward the alleviation of stressful state, ultimately leading to better body composition outcomes, need to be elucidated.

Antibacterial, Antioxidant and Anti-Inflammatory Potential of the Different Extracts of Holoptelia Integrifolia

Medicinal plants are play significant impact in the personal medicine for most of the people all over the world as an alternative live saving medicines and most of their medicinal properties are well known for anticancer activity. The different extracts of Holoptelea integrifolia (H.integrifolia) leaves, stem bark and fruits were studied as a potent natural source of antimicrobial, antioxidant and wound healing potential. This work was carried out to evaluate antimicrobial, antioxidant and anti-inflammatory activity of different extracts of H.integrifolia. The antimicrobial activity of the H.integrifolia ethanolic extract was studied against five fungal and bacterial strains by utilizing the agar well diffusion method and MIC. Among several strain, the ethanolic extract of fruit has shown higher antimicrobial inhibition zone as 9.25-16 mm compare to other two extracts of stem and leaves as 10- 13.25 mm and 6-10.2 mm respectively. The antioxidant activities for different extract were also determined by DPPH free radical assay, Hydroxyl Radical Scavenging and Nitric Oxide Radical Scavenging Activity method. The anti-inflammatory activity also estimated basedon formalin induced paw edema method on Wistar albino rats. The different extracts of leaves, stem bark and fruit parts of Holoptelea integrifolia were estimated for in vivo anti-inflammatory activity against the animal model of female Wistar albino rats. The results of anti-inflammatory activity revealed that the Ethanol extracts showed vital and dose-dependent anti-inflammatory effects. Our findings revealed that aerial parts of H.integrifolia contais potential antimicrobial, antioxidant and anti-inflammatory compounds, which expose the medicinal potential of the selected plant could be a significant drug candidates against microbial, oxidative and inflammation-related pathological processes as a future alternative medicine.

Antibacterial, Antioxidant and Anti-Inflammatory Potential of the Different Extracts of Holoptelia Integrifolia

Medicinal plants are play significant impact in the personal medicine for most of the people all over the world as an alternative live saving medicines and most of their medicinal properties are well known for anticancer activity. The different extracts of Holoptelea integrifolia (H.integrifolia) leaves, stem bark and fruits were studied as a potent natural source of antimicrobial, antioxidant and wound healing potential. This work was carried out to evaluate antimicrobial, antioxidant and anti-inflammatory activity of different extracts of H.integrifolia. The antimicrobial activity of the H.integrifolia ethanolic extract was studied against five fungal and bacterial strains by utilizing the agar well diffusion method and MIC. Among several strain, the ethanolic extract of fruit has shown higher antimicrobial inhibition zone as 9.25-16 mm compare to other two extracts of stem and leaves as 10- 13.25 mm and 6-10.2 mm respectively. The antioxidant activities for different extract were also determined by DPPH free radical assay, Hydroxyl Radical Scavenging and Nitric Oxide Radical Scavenging Activity method. The anti-inflammatory activity also estimated basedon formalin induced paw edema method on Wistar albino rats. The different extracts of leaves, stem bark and fruit parts of Holoptelea integrifolia were estimated for in vivo anti-inflammatory activity against the animal model of female Wistar albino rats. The results of anti-inflammatory activity revealed that the Ethanol extracts showed vital and dose-dependent anti-inflammatory effects. Our findings revealed that aerial parts of H.integrifolia contais potential antimicrobial, antioxidant and anti-inflammatory compounds, which expose the medicinal potential of the selected plant could be a significant drug candidates against microbial, oxidative and inflammation-related pathological processes as a future alternative medicine.

GENE-48. ANALYSIS OF HUMAN BRAIN TISSUE TRANSCRIPTOME TO IDENTIFY RISK GENES AND ALTERED MOLECULAR PATHWAYS IN GLIOMA-RELATED SEIZURES

Abstract OBJECTIVE Our goal is to identify new pathways perturbed in and which may lead to GRS. METHODS We collected brain transcriptome levels from healthy controls (n=5), patients with GRS (n=9), glioma without seizures (non-GRS, n=8), and idiopathic temporal lobe epilepsy (iTLE, n=7) using Illumina-based poly-A capture high-throughput RNA sequencing approach. Differential gene expression analysis was conducted to ascertain expression differences between the four groups. We identified molecular pathways enriched for differentially expressed genes (DEG) using Ingenuity Pathway Analysis. DEGs were defined as those with log2 fold change ≥ 2 and q-value < 0.01 when compared to GRS. RESULTS Principal component analysis revealed that diagnostic grouping was the main determinant of the transcriptome variance. We identified 212 DEGs in the GRS vs. non-GRS analysis. Among these, 108 genes were up-regulated and 104 genes were down-regulated. Among the genes that were down‐regulated, there was significant enrichment for those involved in acute phase response signaling and immune cell trafficking (e.g. H19, BMP5, CXCL8). Compared to iTLE samples, there were 1015 DEGs in the GRS samples. Among these 877 genes were up-regulated and 138 genes were down-regulated. There was significant enrichment for genes involved in cell-to-cell signaling among those that were either uniquely up‐regulated (e.g. NRK, RGS10, SLC4A4, and SELPLG) or down‐regulated in the GRS samples (e.g. SLC9A3 –Na+/H+ exchanger; SLC5A5-sodium-glucose co-transporter family). Further, two of the most down-regulated genes in samples with GRS, SCLC17A6- vesicular glutamate transporter 2 and FOSB, have previously been shown to be involved in glutamatergic transmission. CONCLUSIONS Our findings suggest that inflammation-related processes and alterations in cell-to cell signaling may underlie the pathogenesis of GRS. Our results also provide support for perturbations in glutamatergic transmission in GRS. Our findings require replication in larger human cohorts and functional experiments to explore the function of the genes perturbed in GRS.

Urinary Metabolomic and Proteomic Analyses in a Mouse Model of Prostatic Inflammation.

Lower urinary tract symptoms (LUTS) are common among aging men. Since prostatic inflammation is one of its etiologies, it is plausible that urinary metabolite and protein biomarkers could be identified and used to diagnose inflammation-induced LUTS. We characterized the urine metabolome and proteome in a mouse model of bacterial-induced prostatic inflammation. Mass Spectrometry (MS)-based multi-omics analysis was employed to discover urinary protein and metabolite-based biomarkers. The investigation of isobaric dimethylated leucine (DiLeu) labeling on metabolites allowed metabolomics and proteomics analysis on the same liquid chromatography (LC)-MS platform. In total, 143 amine-containing metabolites and 1058 urinary proteins were identified and quantified (data are available via ProteomeXchange with identifier PXD018023); among them, 14 metabolites and 168 proteins were significantly changed by prostatic inflammation. Five metabolic pathways and four inflammation-related biological processes were potentially disrupted. By comparing our findings with urinary biomarkers identified in a mouse model of genetic-induced prostate inflammation and with those previously found to be associated with LUTS in older men, we identified creatine, haptoglobin, immunoglobulin kappa constant and polymeric Ig receptor as conserved biomarkers for prostatic inflammation associated with LUTS. These data suggest that these putative biomarkers could be used to identify men in which prostate inflammation is present and contributing to LUTS.

Neutrophil to Lymphocyte ratio (NLR): A prognostic marker in melanoma patients receiving immunotherapy.

9573 Background: Cancer related inflammatory processes have been shown to have an important role in tumourigenesis, disease progression, and patient prognosis. An elevated neutrophil to lymphocyte ratio (NLR) is associated with a worse outcome in several malignancies. The relationship between NLR and immune checkpoint blockade is poorly understood. We sought to investigate the role of NLR in patients receiving immune checkpoint inhibitors for metastatic melanoma (MM). We aimed to do this by comparing outcomes of patients with MM with high ( > 3) and low ( < 3) NLRs receiving immunotherapy, and investigating whether NLR acts as a prognostic biomarker. Methods: We performed a retrospective review of electronic medical records and collected data on 40 patients with MM treated with immunotherapy from 2013 to 2018 in MMUH, Dublin. NLR was defined as absolute neutrophil count divided by absolute lymphocyte count. Continuous variables were expressed as a median. We examined NLR at baseline and at 6 weeks (+-2 weeks). We also examined percentage change in NLR. These parameters were tested for association with PFS and OS using the log rank test. Results: 40 patients received immune checkpoint inhibitors in the form of ipilimumab, nivolumab, and pembrolizumab. The median age was 61.2 ( 29.7 to 77.1). The median baseline NLR was 3.39 ( 1.05 to 26.03). The median NLR at 6 weeks (+-2 weeks) was 2.86 ( 0.83 to 19.9). The median change in NLR was -8.02% (- 80.99% to 409.38%). Median time to progression was 4.7 months (0.4 to 51.4 months). Overall survival was 12.9 months (0.4 to 67.7 months). When baseline NLR < 3 patients had a significantly longer PFS: 11.7 vs 2.8 months (p = 0.02). When NLR at approximately 6 weeks was < 3, patients also had significantly longer PFS: 10.8 vs 2.9 months (p = 0.04). When NLR decreased by > 20% from baseline, there was no significant difference in PFS (p = 0.82). When NLR < 3, patients had significantly longer OS: 18 months vs 8.2 months (p = 0.02). When NLR at approximately 6 weeks was < 3, patients had significantly longer OS: 20.3 months vs 7.4 months (p = 0.003). Conclusions: Baseline NLR < 3 and NLR < 3 approximately 6 weeks after initiation of treatment is associated with improved PFS and OS. Change in NLR after initiation of treatment is not significantly associated with improved outcomes, however our sample size was small. NLR may be used as a readily available and cheap prognostic marker in MM patients receiving immunotherapy.

Roscovitine, an experimental CDK5 inhibitor, causes delayed suppression of microglial, but not astroglial recruitment around intracerebral dopaminergic grafts

Inhibitors of cell cycle proteins are known to reduce glial activation and to be neuroprotective in a number of settings. In the context of intracerebral grafting, glial activation is documented to correlate with graft rejection. However, the effects of modification of glial reactivity following grafting in the CNS are poorly understood. Moreover, it is not completely clear if the glial cells themselves trigger the rejection process, or are they secondarily activated.The present study investigated the effect of microglial inhibition by the cyclin-dependant kinase 5 (CDK5) inhibitor roscovitine following intracerebral transplantation in the rodent model of Parkinson's disease. Single cell suspension of rat E14 ventral mesencephalic tissue was transplanted to the dopamine-depleted striatum of unilaterally 6-hydroxydopamine (6-OHDA) lesioned male Sprague-Dawley rats. Experimental animals received injections of roscovitine (20 mg/kg) or a vehicle solution three times following the procedure. Immunohistochemistry was carried out on Day 7 and Day 28 to quantitatively describe the glial reaction adjacent to grafts.The data confirm that systemic roscovitine treatment significantly reduced microglial recruitment adjacent to the grafts on Day 28, without exhibiting significant effects on astroglia. However, this was not found to correlate with elevated numbers of neurons in the grafts. Moreover, microglial reaction surrounding grafts was less pronounced compared to control animals, subjected to the mechanical influence only, even without roscovitine treatment.Our results are the first to show the effect of cell cycle inhibition in the context of neuronal transplantation. The findings suggest that microglial activation around intracerebral grafts can be modified pharmacologically. However, the results do not confirm direct neuroprotective effects of cell cycle inhibition after intracerebral transplantation. Reducing microglial recruitment around grafts could be beneficial by reducing inflammation-related degenerative processes. Sparing astrocytes in the same time provides transplanted cells with essential trophics and support. We consider microglial inhibition to be a possible approach for reducing later graft-related complications.

Pathway centrality in protein interaction networks identifies putative functional mediating pathways in pulmonary disease

Identification of functional pathways mediating molecular responses may lead to better understanding of disease processes and suggest new therapeutic approaches. We introduce a method to detect such mediating functions using topological properties of protein-protein interaction networks. We define the concept of pathway centrality, a measure of communication between disease genes and differentially expressed genes. Using pathway centrality, we identify mediating pathways in three pulmonary diseases (asthma; bronchopulmonary dysplasia (BPD); and chronic obstructive pulmonary disease (COPD)). We systematically evaluate the significance of all identified central pathways using genetic interactions. Mediating pathways shared by all three pulmonary disorders favor innate immune and inflammation-related processes, including toll-like receptor (TLR) signaling, PDGF- and angiotensin-regulated airway remodeling, the JAK-STAT signaling pathway, and interferon gamma. Disease-specific mediators, such as neurodevelopmental processes in BPD or adhesion molecules in COPD, are also highlighted. Some of our findings implicate pathways already in development as drug targets, while others may suggest new therapeutic approaches.

Helper T-cell signaling and inflammatory pathway lead to formation of calcium phosphate but not calcium oxalate stones on Randall's plaques.

To elucidate the difference in the lithogenesis of calcium oxalate and calcium phosphate stones. Renal papillary tissues were obtained from 23 idiopathic calcium oxalate and seven calcium phosphate stone patients who had undergone endoscopic lithotripsy. Samples were individually collected from two different regions in each patient: the papillary mucosa containing Randall's plaque and mucosa not containing Randall's plaque. A microarray analysis was carried out on those tissues to compare their gene expression patterns. Furthermore, a causal pathway analysis comparing their differences was carried out. Cluster analysis showed that gene expression profiles of calcium phosphate stone patients markedly differed from those of calcium oxalate stone patients. Disease and function analysis showed that Randall's plaque-containing tissues of calcium phosphate stone-forming patients had significantly higher movement and migration of mononuclear leukocytes, and lower tendency toward infection and lymph node formation than Randall's plaque-containing tissues of calcium oxalate stone formers. Additional pathway analysis showed increased immune cell signaling in calcium phosphate formers, such as the helper Tcell 1 and 2 pathways, which was confirmed by their messenger ribonucleic acid expression. The present results show the upregulation of helper T-cell signaling pathways in Randall's plaque-containing papillae in calcium phosphate, but not in calcium oxalate stone formers. Thus, helper T-cell immune responses and the related inflammatory processes seem to lead to the formation of calcium phosphate stones on Randall's plaques.

Comprehensive transcriptome analysis based on RNA sequencing identifies critical genes for lipopolysaccharide-induced epididymitis in a rat model.

Epididymitis is a commonly diagnosed disease associated with male infertility. However, little is known about the molecules that are involved in its development. This study was to identify critical genes associated with lipopolysaccharide-induced epididymitis and analyze the molecular mechanism of epididymitis through RNA sequencing. Experimental epididymitis models were generated by administering male Sprague–Dawley rats' lipopolysaccharide. A total of 1378 differentially expressed genes, including 531 upregulated and 847 downregulated genes, were identified in the epididymitis model rats compared with those in sham-operated rats by RNA sequencing. Functional enrichment analyses suggested that the upregulated genes were markedly enriched in inflammation-related biological processes, as well as in the tumor necrosis factor (TNF) signaling pathway, cytokine–cytokine receptor interactions, complement and coagulation cascades, and in the chemokine signaling pathway. Four downregulated genes (collagen type XXVIII alpha 1 chain [Col28α1], cyclin-dependent kinase-like 1 [Cdkl1], phosphoserine phosphatase [Psph], and fatty acid desaturase 2 [Fads2]) and ten upregulated genes (CCAAT/enhancer-binding protein beta [Cebpβ], C-X-C motif chemokine receptor 2 [Cxcr2], interleukin 11 [Il11], C-C motif chemokine ligand 20 [Ccl20], nuclear factor-kappa-B inhibitor alpha [Nfkbiα], claudin 4 [Cldn4], matrix metallopeptidase 9 [Mmp9], heat shock 70 kDa protein 8 [Hspa8], intercellular cell adhesion molecule-1 [Icam1], and Jun) were successfully confirmed by real-time polymerase chain reaction. Western blot demonstrated that CDKL1 was decreased, while MMP9 and NFKBIA were increased in the experimental model group compared with those in the sham-operated group. Our study sheds new light on the understanding of the early response of the epididymis during bacterial epididymitis.

2018 AHA Late-Breaking Basic Science Abstracts.

2018 AHA Late-Breaking Basic Science Abstracts.

Non-invasive Vagus Nerve Stimulation Protects Against Cerebral Ischemia/Reperfusion Injury and Promotes Microglial M2 Polarization Via Interleukin-17A Inhibition.

Microglia play an essential role during cerebral an ischemia/reperfusion (I/R)-related inflammatory process. Because the M2 phenotype of microglia exhibits anti-inflammation activity, it has become a promising target for anti-inflammatory therapy. Vagus nerve stimulation (VNS) reportedly has neuroprotective effects against cerebral I/R injuries via its anti-inflammatory action. The aim of this study was to investigate the ability of non-invasive VNS (nVNS) to alleviate cerebral I/R in mice by promoting microglial M2 polarization. Neurological scoring and cerebral infarct volume assessments were performed 72h after a middle cerebral artery occlusion (MCAO)-induced stroke. M2 phenotype microglia were identified by immunohistochemistry staining using Arg-1 and Iba-1 antibodies. The protein expressions of Arg-1, IL-17A, IL-10, Bax, and Bcl-2 were detected by Western blot. Apoptotic cells were detected using TUNEL staining. According to our results, nVNS decreased infarct volume, improved neurological outcomes, reduced apoptotic neurons (TUNEL+NeuN+ cells), and promoted microglial M2 polarization as indicated by elevated Arg-1 protein expression and increased Arg-1+ cells after MCAO. Moreover, nVNS attenuated the increased levels of IL-17A protein expression after MCAO. To test the possible involvement of IL-17A in nVNS-induced neuroprotection and microglial M2 polarization, 1-μg recombinant IL-17A (rIL-17A) was intranasally administered once daily for three consecutive days after reperfusion. We found that the intranasal administration of rIL-17A nullified the nVNS-induced promotion of microglial M2 polarization. Furthermore, rIL-17A administration abolished the neuroprotective effect of nVNS. In conclusion, our study identifies microglial M2 polarization as an important mechanism underlying the nVNS-mediated neuroprotection against cerebral I/R. This effect of nVNS could be attributed to the inhibition of IL-17A expression.

Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis.

Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF), it remains unclear if lung fibroblasts (FB) are the main therapeutic target.To resolve this question, we employed a comparative transcriptomic approach and analysed lung homogenates (LH) and FB derived from IPF patients treated with or without pirfenidone.In FB, pirfenidone therapy predominantly affected growth and cell division pathways, indicating a major cellular metabolic shift. In LH samples, pirfenidone treatment was mostly associated with inflammation-related processes. In FB and LH, regulated genes were over-represented in the Gene Ontology node "extracellular matrix". We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated IPF patients. Plasma levels of CEMIP were elevated in IPF patients compared to healthy controls and decreased after 7 months of pirfenidone treatment. CEMIP expression in FB was downregulated in a glioma-associated oncogene homologue-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration.Cumulatively, our approach indicates that pirfenidone exerts beneficial effects via its action on multiple pathways in both FB and other pulmonary cells, through its ability to control extracellular matrix architecture and inflammatory reactions.

The Association of Simultaneous Increase in Interleukin-6, C Reactive Protein, and Matrix Metalloproteinase-9 Serum Levels with Increasing Stages of Colorectal Cancer.

Background Tumor development and growth are driven in many cases by inflammatory cells, which can produce cytokines and other factors that can stimulate the development of the malignant process. The aim of this study was to evaluate interleukin-6 (IL-6), C-reactive protein (CRP), matrix metalloproteinase-9 (MMP-9), serum levels in patients with colorectal cancer (CRC), and their association with the stage of CRC. Methods IL-6, MMP-9, and CRP serum levels were measured in 75 patients with CRC just before surgical treatment, as well as in 20 healthy individuals as controls. Surgically obtained tissue material was subjected to pathological analysis. Results Significant increase in CRP and IL-6 serum concentration is associated with increasing stage of CRC (p <0.05), where MMP-9 serum level was significantly higher in stages III and IV compared to the stage II CRC. Significant correlation was found between IL-6 and MMP-9 serum levels (rho=0.478; p <0.001) as well as between IL-6 and CRP serum levels (rho=0.720; p <0.001) and between MMP-9 and CRP serum levels (rho=0.379; p <0.001). Serum levels of MMP-9 and CRP have been shown to be independent predictors of the CRC stage. Conclusion Combined quantification of IL-6, MMP-9, and CRP serum levels seems to be a reliable index of inflammation-related processes during colorectal carcinogenesis.

Updating the epidemiological transition model.

The main feature of the epidemiological transition is a shift in the recorded causes of death from infectious diseases to other morbid conditions. This paper outlines modifications made to Omran's original model and stages of transition, and suggests that without a focus on aetiology and morbidity, these have been basically descriptive rather than explanatory, and potentially misleading because infections have been confirmed as causes of various chronic diseases. Common infections and related immune responses or inflammatory processes contribute to the multifactorial aetiology of morbid conditions that together make a substantial contribution to overall mortality, and infectious causation is suspected for many others because of strong evidence of association. Investigation into possible infectious causes of conditions frequently recorded as the underlying cause of death can be integrated into a framework for comparative research on patterns of disease and mortality in support of public health and prevention. A theory of epidemiological transition aimed at understanding changes in disease patterns can encompass the role in different conditions and chronic diseases of infections contracted over the life course, and their contribution to disability, morbidity and mortality relative to other causes and determinants.

Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case–control pharmacokinetic study

IntroductionDiabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to...

Focus on the Involvement of the Nose and Paranasal Sinuses in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome): Nasal Cytology Reveals Infiltration of Eosinophils as a Very Common Feature

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis that predominantly affects small- to medium-sized vessels. It is characterized by a wide spectrum of extrapulmonary symptoms, including sinonasal and paranasal sinus abnormalities. These are the most common features of this disease, constituting diagnostic criteria for EGPA. However, the actual clinical features, cellular mechanisms and impact on patients’ quality of life (QoL) are still a matter of study. Methods: Thirty-nine EGPA patients underwent multidimensional rhinological evaluations, including rhinofibroscopy, nasal cytology, and QoL questionnaires. This was coupled with respiratory and rheumatological assessments. Results: Twenty-eight patients were diagnosed with chronic rhinosinusitis (CRS). Of these, 18 had nasal polyposis (NP). Chronic rhinitis was diagnosed in 10 patients. Of these, 3 had allergic rhinitis (AR) and seven had non-AR (NAR). Overall, only 1 patient (2.6%) was normal. Nasal cytology showed that hypereosinophilia was present in 17/28 patients with CRS, 4/7 patients with NAR and all patients with AR. SNOT-22 and SF-36 showed a severe impact of nasal symptoms on QoL. No differences in asthma control or rheumatological patterns for EGPA were observed among patients with or without NP. Conclusions: Even when the rheumatological assessment scored EGPA “under control” according to the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, sinonasal diseases and related nasal inflammatory processes were not controlled. Therefore, there is a need for clinical monitoring and targeted treatment to control the inflammatory processes and improve the QoL of EGPA patients.