Pathogenesis Of Chronic Disease Research Articles

The State of Microbiome Science at the Intersection of Infectious Diseases and Antimicrobial Resistance.

Along with the rise in modern chronic diseases, ranging from diabetes to asthma, there are challenges posed by increasing antibiotic resistance, which results in difficult-to-treat infections, as well as sepsis. An emerging and unifying theme in the pathogenesis of these diverse public health threats is changes in the microbial communities that inhabit multiple body sites. Although there is great promise in exploring the role of these microbial communities in chronic disease pathogenesis, the shorter timeframe of most infectious disease pathogenesis may allow early translation of our basic scientific understanding of microbial ecology and host-microbiota-pathogen interactions. Likely translation avenues include development of preventive strategies, diagnostics, and therapeutics. For example, as basic research related to microbial pathogenesis continues to progress, Clostridioides difficile infection is already being addressed clinically through at least 2 of these 3 avenues: targeted antibiotic stewardship and treatment of recurrent disease through fecal microbiota transplantation.

Liver homeostasis is maintained by midlobular zone 2 hepatocytes.

The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal zone 1 and pericentral zone 3 contracted in number, whereas cells from midlobular zone 2 expanded in number. Cells within zone 2, which are sheltered from common injuries, also contributed to regeneration after pericentral and periportal injuries. Repopulation from zone 2 was driven by the insulin-like growth factor binding protein 2-mechanistic target of rapamycin-cyclin D1 (IGFBP2-mTOR-CCND1) axis. Therefore, different regions of the lobule exhibit differences in their contribution to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration.

Zoning in on liver growth

Lineage Tracing For organ homeostasis or regrowth after injury or disease, one or more stem cell populations is needed to rebuild lost tissue. There is considerable debate about the source of new cells in the liver. Two groups now identify the source of new hepatocytes (see the Perspective by Andersson). Although the liver may seem to lack major variation across its structure, its lobule is organized into concentric zones where hepatocytes express different metabolic enzymes. Wei et al. sought to systematically define the source of new liver cells by comparing 14 fate-mapping mice that label different liver cell types. They found that different regions of the liver lobule exhibit differences in hepatocyte turnover, with zone 2 representing a primary source of new hepatocytes during homeostasis and regeneration. Similarly, He et al. designed a genetic approach to record cell proliferation in vivo with high spatial and temporal resolution to enable continuous recording of proliferative events of any specific cell type at the whole-cell population level. Using this method, they identified zone 2 as having the highest proliferative activity and contributing the most to liver regrowth. These findings have implications for the cellular basis of chronic disease pathogenesis, cancer development, and regenerative medicine strategies. Science , this issue p. [eabb1625][1], p. [eabc4346][2]; see also p. [887][3] [1]: /lookup/doi/10.1126/science.abb1625 [2]: /lookup/doi/10.1126/science.abc4346 [3]: /lookup/doi/10.1126/science.abg4864

Glycosylation Profiling as a Biomarker of Suboptimal Health Status for Chronic Disease Stratification.

WHO defines health as "a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity." We coined and defined suboptimal health status (SHS) as a subclinical, reversible stage of the pre-chronic disease. SHS is a physical state between health and disease, characterized by health complaints, general weakness, chronic fatigue, and low energy levels. We have developed an instrument to measure SHS, Suboptimal Health Status Questionnaire-25 (SHSQ-25), a self-reported survey assessing five health components that has been validated in various ethnical populations. Our studies suggest that SHS is associated with the major components of cardiovascular health and the early onset of metabolic diseases. Besides subjective measure of health (SHS), glycans are conceived as objective biomarkers of SHS. Glycans are complex and branching carbohydrate moieties attached to proteins, participating in inflammatory regulation and chronic disease pathogenesis. We have been investigating the role of glycans and SHS in multiple cardiometabolic diseases in different ethnical populations (African, Chinese, and Caucasian). Here we present case studies to prove that a combination of subjective health measure (SHS) with objective health measure (glycans) represents a window of opportunity to halt or reverse the progression of chronic diseases.

Evaluation of anti-inflammatory and immunoregulatory activities of Stimunex® and Stimunex D3® in human monocytes/macrophages stimulated with LPS or IL-4/IL-13

Macrophages exert an important role in maintaining and/or ameliorating the inflammatory response. They are involved in the activation of an immune response to pathogens, with a balance between the immunomodulatory role and tissue integrity maintenance, however, excessive macrophage activity promotes tissue injury and chronic disease pathogenesis. There is a high interest in evaluating the anti-inflammatory properties of new botanical preparations. Stimunex® and Stimunex D3® are two food supplements formulated as syrups, containing the extract of elderflower (Sambucus nigra, Caprifoliaceae), standardized in polyphenol (6%) and anthocyanins (4%), associated with wellmune WGP® β-glucan, with the addiction of vitamin D3 (in Stimunex D3® formulation). The aim of the work was the evaluation of Stimunex® and Stimunex D3® activity in human polarized-macrophages, in order to support their use as supplement for preventing and reducing the inflammatory processes.In primary human stimulated macrophages, both syrups were able to revert LPS- and IL-4/IL-13-mediated response, reducing the release of several pro-inflammatory cytokines. Results support that these standardized botanical preparations fortified with β-glucan, may have a potential use in the prevention and coadjuvant management of inflammatory process as respiratory recurrent infections and other similar conditions. Moreover, the addition of vitamin D3 revealed to be an advantage in Stimunex D3® for its important role in maintaining and enhancing the innate immune response.

Association of Dietary Inflammatory Index with cardiovascular disease in Kurdish adults: results of a prospective study on Ravansar non-communicable diseases

BackgroundVarious diets and dietary compounds, through their inflammatory properties, are involved in the pathogenesis of chronic diseases including Cardiovascular Diseases (CVDs). Dietary Inflammatory Index (DII) can evaluate the inflammatory properties of diet. The purpose of this study was to determine the association between DII and CVDs in participants of the Ravansar Non-Communicable Diseases (RaNCD) cohort study, Kermanshah, Iran.MaterialsThe present cross-sectional study was conducted using the recruitment phase data of the RaNCD cohort study on 6369 participants aged 35 to 65 years. The Food Frequency Questionnaire (FFQ) was used to assess diet. The DII scores were calculated using FFQ data. Participants with a history of myocardial infarction, stroke and coronary artery disease, and/or taking medications for the CVDs were considered as the CVDs patients.ResultsOf the 6369 studied participants, 9% (n = 579) had CVDs history. The mean DII score in this study was − 0.84 ± 1.6. Odds ratio (OR) of CVDs in women was 1.6 times higher than in men (CI 95% = 1.3–1.9), which this association was remained after adjusting for confounding variables (OR = 1.5, CI% = 1.2–1.9). The risk of CVDs in the fourth quartile of DII was 1.4 times higher than the first quartile of DII (OR: 1.4, CI 95% = 1.1–1.8). We found that higher adhere to DII was associated with risk of CVDs.ConclusionAccording to current documents, given the role of diet through inflammatory properties on the risk of CVDs, it is recommended to use DII as an appropriate index to measure the effect of diet on CVDs in Iranian population. In addition, a diet with lower DII may be healthier diet for cardiovascular health.

AB0492 INTESTINAL MICROBIOTA COMPOSITION OF PATIENT’S WITH BEHCET’S DISEASE: DIFFERENCES BETWEEN EYE, MUCOCUTANEOUS AND VASCULAR INVOLVEMENT (RHEUMA-BIOTA STUDY)

Background:Recently, it has been shown that changes in microbiota composition play a role in the etiology and pathogenesis of chronic diseases. Changes in oral and intestinal microbiota diversity and composition are suggested in Behcet disease (BD), however there are no study available about the potential gut microbiota changes among different clinical forms of BD.Objectives:The aim of this study was to evaluate the intestinal microbiota composition of patient with BD and healthy controls, and also compare BD patients regarding to their eye, mucocutaneous and vascular involvement.Methods:In this prospective cohort study,27 patients diagnosed with BD and 10 aged and sex matched healthy controls were included. Patients with a body mass index> 35, who have used antibiotics or probiotics in the last 4 weeks, patients with chronic gastrointestinal or other systemic diseases, and those with acute / severe gastrointestinal symptoms requiring medical treatment were excluded from the study. For the intestinal microbiota analysis, gene amplification, library formation, sequence analysis and bioinformatic evaluation of the results were performed with 16SrRNA next generation sequencing methods with Illumina MiSeq.Results:There was no difference between the BD group and the control group in terms of alpha (Chao-1 and Shannon) and beta (Bray-Curtis) microbiota diversity indices (p> 0.05).Actinomyces, Libanicoccus, Collinsella, Eggerthella, Enetrohabdus, Catenibacterium and Enterobacterwere significantly higher in BD group compared to the control group. In addition,Bacteriodes, Cricetibacter, Alistipes, Lachnospira, Dielma, Akkermansia, Sutterella, Anaerofilum, Ruminococcease-UCG007, Acetanaerobacterium; and Copropaacterwere lower than the control group. There was no difference between the uveitis, mucocutaneous and vascular involvement groups in terms of alpha (Chao-1 and Shannon) and beta (Bray-Curtis) microbiota diversity and wealth indices (p> 0.05) while we obtained a significant p value of the beta diversity between three groups in weighted UniFrac PCoA (p<0.05). When we compared 3 three different system involvement (Eye, Mucocutaneous and Vascular), The LEfSe provides us with cladograms of six-level (from kingdom to genus). We found difference for the generaLachnospiraceae NK4A136in uveitis group,Dialister, İntestinomonas and Marvinbryantiain mucocutaneous group andGemellain vascular involvement group.Conclusion:There was a significant difference in the composition of intestinal microbiota in Behçet’s disease compared to healthy adults. We found also found the different clinical forms of Behcet’s disease have some different gut microbiota composition. Especially in Behçet’s disease, it will be useful to evaluateCatenibacterium, Collinsella and Eggerthellaincrease,Bacteroides and Akkermansiadecrease in larger series. In addition, due to the increase in theEggerthella lentastrain observed both in the FMF and Behcet patient group, it is useful to make more detailed metagenomic analyzes regarding the role of this agent in the etiopathogenesis and course of rheumatic diseases.Disclosure of Interests:None declared

Abstract C033: Dietary advanced glycation end products (dAGEs) and breast cancer by race in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

Abstract INTRODUCTION Advanced glycation end-products (AGEs) are implicated in the pathogenesis of chronic diseases and cancer. AGEs are produced endogenously but can also be consumed in foods. High amounts of AGEs are found in animal products and processed foods, and AGE formation is accelerated during cooking at high temperatures. Existing disparities in dietary practices could result from limited access to healthy foods among many other factors, further contributing to racial health disparities. The objective of the study was to investigate the association between dAGE intake and breast cancer risk among different racial/ethnic groups of women using the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). METHODS The PLCO enrolled women aged 55 to 74 years into a randomized controlled trial examining various cancer screening modalities. In this prospective analysis, the study sample included only women enrolled in the intervention arm who were cancer-free at baseline and completed a baseline questionnaire and food frequency questionnaire (DQX) [non-Hispanic White (NHW): 25,096; non-Hispanic Black (NHB): 1,179 and Other race/ethnicity: 1,300]. dAGE values were assigned and quantified to foods in the DQX using a published AGE database. Descriptive analysis was used to obtain means and percentages while Cox proportional hazards model estimated the hazard ratios (HR) and 95% CIs of breast cancer by tertiles of dAGE intake with adjustment for multiple potential confounders. RESULTS After a median 11.5 years of follow-up, 1,599 women were diagnosed with breast cancer, including 1,472 NHW, 51 NHB, and 76 Other race/ethnicity. The average dAGE consumption among all the women was 6,106 KU/1000kcal per day (SD: 2691 KU/1000kcal per day) and was highest among NHB (6765 ± 3353 KU/1000kcal per day) compared to NHW (6101 ± 2648 KU/1000kcal per day) and Other race/ethnicity (5604 ± 2723 KU/1000kcal per day). There was an increased risk of breast cancer across the tertiles of dAGE intake (HRT2 VS T1:1.14, 95% CI: 1.00, 1.31 and HRT3 VS T1:1.20, 95% CI: 1.02, 1.42). In stratified analyses, increased risk of breast cancer was observed in all races but was significant only in NHW women (HRT2 VS T1: 1.15, 95% CI: 1.00, 1.32 and HRT3 VS T1: 1.22, 95% CI: 1.02, 1.45). For NHB the association for the highest tertile compared to the lowest tertile was HRT3 VS T1: 1.20, 95% CI: 0.48, 3.01, and for Other race/ethnicity the association was HRT3 VS T1: 1.70, 95% CI: 0.78, 3.73. CONCLUSION Among all women in the study, high intake of dAGE increased the risk of breast cancer. Overall the association appeared to be more prominent among NHW women, though small sample sizes resulted in imprecise estimates for other racial/ethnic groups. Citation Format: Omonefe O Omofuma, David P Turner, Lindsay L Peterson, Anwar T Merchant, Jiajia Zhang, Susan E Steck. Dietary advanced glycation end products (dAGEs) and breast cancer by race in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C033.

Nutrient modulation of DNA repair in lung cancer

Noncommunicable diseases associated with aging and inflammation is rising in recent decades, contributing global burden of disease globally. Among them are cardiovascular diseases, diabetes, and cancer. Our objective is to illustrate the molecular mechanisms behind the chemoprotective effects of major dietary carotenoids. We hypothesize that carotenoids play a role in modulating genome stability. Telomeres are essential for the stability of our genome, and oxidative stress caused by the reactive oxygen species poses a risk for telomere shortening, thereby contributing to the pathogenesis of chronic diseases, including lung cancer. Human telomeres are composed of 10–15 kilobases of TTAGGG repeats. Guanine is the most readily oxidized of the natural bases, and TTAGG repeats are preferred sites for conversion of Guanine to 8‐oxoG, which repaired by base excision repair through an enzyme called OGG1. In the current study, we investigated mRNA and protein expression of OGG1 and retinoic acid receptors (RARs) in human alveolar epithelial cells exposed to cigarette smoke. Cells pre‐treated with various doses of β‐carotene for 24 hours, and the following day exposed to smoke using a smoking chamber. We found out that while β‐carotene increased OGG1 expression at lower doses, it led to a dramatic decrease at higher concentrations suggesting that at higher doses β‐carotene exerted a pro‐oxidant effect. Previously it was reported that the expression of the RARβ, putative tumor suppressor gene, is reduced in lung cancer. In parallel to OGG1 inhibition, we observed decreased levels of RARβ. We are in the process of quantifying 8‐oxoG by HPLC‐MS/MS. We believe that these novel findings will shed light on the mechanism of action of β‐carotene at the molecular level.Support or Funding InformationUSDA‐NIFA Hatch Project

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target.

Multimorbidity is increasingly common and current healthcare strategies are not always aligned to treat this complex burden of disease. COPD, type-2 diabetes mellitus (T2D) and cardiovascular disease, especially atherosclerosis, occur more frequently together than expected, even when risk factors such as smoking, obesity, inactivity and poverty are considered. This supports the possibility of unifying mechanisms that contribute to the pathogenesis or progression of each condition.Neutrophilic inflammation is causally associated with COPD, and increasingly recognised in the pathogenesis of atherosclerosis and T2D, potentially forming an aetiological link between conditions. This link might reflect an overspill of inflammation from one affected organ into the systemic circulation, exposing all organs to an increased milieu of proinflammatory cytokines. Additionally, increasing evidence supports the involvement of other processes in chronic disease pathogenesis, such as cellular senescence or changes in cellular phenotypes.This review explores the current scientific evidence for inflammation, cellular ageing and cellular processes, such as reactive oxygen species production and phenotypic changes in the pathogenesis of COPD, T2D and atherosclerosis; highlighting common mechanisms shared across these diseases. We identify emerging therapeutic approaches that target these areas, but also where more work is still required to improve our understanding of the underlying cellular biology in a multimorbid disease setting.

Anti-glycation effect and the α-amylase, lipase, and α-glycosidase inhibition properties of a polyphenolic fraction derived from citrus wastes

The advanced glycation end products (AGEs) constitute a wide variety of substances synthesized from interactions between amino groups of proteins and reducing sugars, which excess induces pathogenesis of chronic diseases. Brazil is the major producer of citrus, a low-cost source of hesperidin, which is a polyphenol recognized for its capacity to inhibit AGEs formation. This is the first work to evaluate the effects of a polyphenolic fraction derived from citrus wastes on the antiglycation and on the inhibition properties of digestive enzymes on the possibility to process these wastes in high value-added products. At concentrations of 10, 15 and 20 mg/mL inhibition of AGEs was higher than 60%. The extracts were able to inhibit by 76% the activity of pancreatic lipase and by 98% the activity of α-glucosidase. For the α-amylase the inhibition capacity was lower than 50%. Strong correlation was obtained among anti-glycation with polyphenolic content and antioxidant capacity.

Histone Deacetylase 9: Its Role in the Pathogenesis of Diabetes and Other Chronic Diseases.

As a member of the class IIa histone deacetylases (HDACs), HDAC9 catalyzes the deacetylation of histones and transcription factors, commonly leading to the suppression of gene transcription. The activity of HDAC9 is regulated transcriptionally and post-translationally. HDAC9 is known to play an essential role in regulating myocyte and adipocyte differentiation and cardiac muscle development. Also, recent studies have suggested that HDAC9 is involved in the pathogenesis of chronic diseases, including cardiovascular diseases, osteoporosis, autoimmune disease, cancer, obesity, insulin resistance, and liver fibrosis. HDAC9 modulates the expression of genes related to the pathogenesis of chronic diseases by altering chromatin structure in their promotor region or reducing the transcriptional activity of their respective transcription factors. This review summarizes the current knowledge of the regulation of HDAC9 expression and activity. Also, the roles of HDAC9 in the pathogenesis of chronic diseases are discussed, along with potential underlying mechanisms.

Overexpression of pink1 or parkin in indirect flight muscles promotes mitochondrial proteostasis and extends lifespan in Drosophila melanogaster.

Dysfunctional mitochondria have been implicated in aging and age-related disorders such as Parkinson’s diseases (PD). We previously showed that pink1 and parkin, two familial PD genes, function in a linear pathway to maintain mitochondrial integrity and function. Studies of mammalian cell lines also suggest that these genes regulate mitochondrial autophagy(mitophagy). Overexpressing Parkin promotes proteostasis and function of aged muscles both in fruit flies and mice, and recent studies also indicated that mitochondrial ubiquitination are accumulated in aged muscles. However, the underlying mechanisms for pink1 and parkin mediated mitophagy on longevity is not fully understood. Here, we found that mitochondrial ubiquitination increased in indirect flight muscles (IFMs) in an age-dependent manner. Overexpression of pink1 or parkin in IFMs can abolish mitochondrial ubiquitination, restore ATP level and extend lifespan, while blocking autophagy via ATG1 knock-down suppress these effects in aged IFMs. Taken together, these results show that pink1/parkin promotes mitophagy of mitochondrial ubiquitination in aged muscles and extend lifespan in an Atg1-dependent manner. Our study provides physiological evidence that mitophagy of mitochondrial ubiquitination mediated by PINK1/ Parkin is crucial for muscle function and highlights the role of mitophagy in the pathogenesis of chronic diseases like PD.

A journey from microenvironment to macroenvironment: the role of metaflammation and epigenetic changes in cardiorenal disease.

Chronic non-communicable diseases have become a pandemic public problem in the 21st century, causing enormous burden on the economy, health and quality of life of societies. The role of a chronic inflammatory state in the pathogenesis of chronic disease has been more comprehensively recognized by recent findings. The new paradigm ‘metaflammation’ focuses on metabolism-induced (high fat or fructose-based diet or excessive calorie intake) chronic inflammation. There is a close correlation between the increased incidence of chronic kidney disease (CKD) and chronic heart failure with both increased inflammatory marker levels and western-type diet. In this review we describe the concept of metaflammation, its role in the development of CKD and chronic heart disease, the molecular and signalling pathways involved and the therapeutic consequences.

Dysregulated expression but redundant function of the long non-coding RNA HOTAIR in diabetic kidney disease.

Long non-coding RNAs (lncRNAs) are garnering increasing attention for their putative roles in the pathogenesis of chronic diseases, including diabetic kidney disease (DKD). However, much about in vivo lncRNA functionality in the adult organism remains unclear. To better understand lncRNA regulation and function in DKD, we explored the effects of the modular scaffold lncRNA HOTAIR (HOX antisense intergenic RNA), which approximates chromatin modifying complexes to their target sites on the genome. Experiments were performed in human kidney tissue, in mice with streptozotocin-induced diabetes, the db/db mouse model of type 2 diabetes, podocyte-specific Hotair knockout mice and conditionally immortalised mouse podocytes. HOTAIR was observed to be expressed by several kidney cell-types, including glomerular podocytes, in both human and mouse kidneys. However, knockout of Hotair from podocytes had almost no effect on kidney structure, function or ultrastructure. Glomerular HOTAIR expression was found to be increased in human DKD, in the kidneys of mice with streptozotocin-induced diabetes and in the kidneys of db/db mice. Likewise, exposure of cultured mouse podocytes to high glucose caused upregulation of Hotair expression, which occurred in a p65-dependent manner. Although HOTAIR expression was upregulated in DKD and in high glucose-exposed podocytes, its knockout did not alter the development of kidney damage in diabetic mice. Rather, in a bioinformatic analysis of human kidney tissue, HOTAIR expression closely paralleled the expression of its genic neighbour, HOXC11, which is important to developmental patterning but which has an uncertain role in the adult kidney. Many lncRNAs have been found to bind to the same chromatin modifying complexes. Thus, there is likely to exist sufficient redundancy in the system that the biological effects of dysregulated lncRNAs in kidney disease may often be inconsequential. The example of the archetypal scaffold lncRNA, HOTAIR, illustrates how lncRNA dysregulation may be a bystander in DKD without necessarily contributing to the pathogenesis of the condition. In the absence of in vivo validation, caution should be taken before ascribing major functional roles to single lncRNAs in the pathogenesis of chronic diseases.

Exosomes as Mediators of Chemical-Induced Toxicity.

This review provides information regarding how exosomes may contribute to environmental chemical-induced pathogenesis of chronic diseases. In connecting exosome biology to environmental toxicology and disease pathogenesis, we address vital questions regarding what constitutes exosomal cargo, how toxicants influence exosomal cargo, and how environmental stimuli influence exosomal physiological and pathological functions. Recent studies in the field demonstrate that exosomal cargo changes depending on external stimuli, which has consequences for the microenvironment of recipient cells. Based on recent findings, it is evident that exosomal cargo comprises various biological molecules including proteins, nucleic acids, and lipid molecules. Misfolded proteins and miRNA are examples of exosomal cargo molecules that can be altered by toxicants, ultimately changing the microenvironment of recipient cells in ways that are conducive to pathological processes. It will be crucial to map out the key signaling pathways that toxicants target to modulate exosomal cargo and their release.

ASSOCIATION OF VITAMIN D LEVELS WITH INCIDENT ALLCAUSE DEMENTIA IN LONGITUDINAL OBSERVATIONAL STUDIES: A SYSTEMATIC REVIEW AND META-ANALYSIS

The role of vitamin D is not only limited to bone health and pathogenesis of chronic diseases. Evidence now suggests that it is also involved in the development of various dementias and Alzheimer's disease (AD). To carry out a systematic review and meta-analysis to evaluate the association between vitamin D levels and increased risk of incident all-cause dementia in longitudinal studies. We conducted a systematic review and meta-analysis using the electronic bibliographic databases PubMed and Scopus. Prospective cohort studies. Community-dwelling older adults. Vitamin D serum concentrations were categorized in three groups: normal levels (>50 nmol/L), insufficient levels (25 - 49.9 nmol/L), and deficient levels (<25 nmol/L). We performed a meta-analysis using the general inverse variance method to calculate the pooled risk of AD and all-cause dementia according to vitamin D levels. Random-effects or fixed-effect model were used to calculate the pooled risk based on the heterogeneity analysis. Five studies were included in the meta-analysis. The pooled risk of all-cause dementia and AD was significantly higher in those with deficient serum vitamin D level compared to those with normal level (1.33, CI95% [1.15, 1.54], and 1.87, CI95% [1.03, 3.41], respectively). Those with insufficient level also had a higher pooled risk of all-cause dementia and AD, but the strength of association was less robust (1.14 CI95% [1.02, 1.27] and 1.25, CI95% [1.04 - 1.51], respectively). We found a gradient effect for the risk of all-cause dementia and AD according to the vitamin D level, with higher risk in those in the deficient levels group and intermediate risk in those with insufficient levels. Our findings were limited by the relatively small number of studies included in the meta-analysis and their geographic restriction.

Emerging Role of Immunosuppression in Diseases Induced by Micro- and Nano-Particles: Time to Revisit the Exclusive Inflammatory Scenario

Fibrosis, cancer, and autoimmunity developing upon particle exposure have been exclusively linked with uncontrolled inflammatory processes. The critical role of inflammation is now challenged by several contradictory observations indicating that the emergence of these chronic disorders may result from non-inflammatory events. A growing number of studies reveals that micro- and nano-particles can cause exaggerated and persistent immunosuppression characterized by the release of potent anti-inflammatory cytokines (IL-10 and TGF-β), and the recruitment of major regulatory immune cells (M2 macrophages, T and B regs, and MDSC). This persistent immunosuppressive environment is initially established to limit early inflammation but contributes later to fibrosis, cancer, and infection. Immunosuppression promotes fibroblast proliferation and matrix element synthesis and subverts innate and adaptive immune surveillance against tumor cells and microorganisms. This review details the contribution of immunosuppressive cells and their derived immunoregulatory mediators and delineates the mutual role of inflammatory vs. immunosuppressive mechanisms in the pathogenesis of chronic diseases induced by particles. The consideration of these new results explains how particle-related diseases can develop independently of chronic inflammation, enriches current bioassays predicting particle toxicity and suggests new clinical strategies for treating patients affected by particle-associated diseases.

IL-17A-associated IKK-\u03b1 signaling induced TSLP production in epithelial cells of COPD patients

Thymic stromal lymphopoietin (TSLP) is a cytokine expressed in the epithelium, involved in the pathogenesis of chronic disease. IL-17A regulates airway inflammation, oxidative stress, and reduction of steroid sensitivity in chronic obstructive pulmonary disease (COPD). TSLP and IL-17A were measured in induced sputum supernatants (ISs) from healthy controls (HC), healthy smokers (HS), and COPD patients by enzyme-linked immunosorbent assay. Human bronchial epithelial cell line (16HBE) and normal bronchial epithelial cells were stimulated with rhIL-17A or ISs from COPD patients to evaluate TSLP protein and mRNA expression. The effects of the depletion of IL-17A in ISs, an anticholinergic drug, and the silencing of inhibitor kappa kinase alpha (IKKα) on TSLP production were evaluated in 16HBE cells. Coimmunoprecipitation of acetyl-histone H3(Lys14)/IKKα was evaluated in 16HBE cells treated with rhIL-17A and in the presence of the drug. TSLP and IL-17A levels were higher in ISs from COPD patients and HS compared with HC. TSLP protein and mRNA increased in 16HBE cells and in normal bronchial epithelial cells stimulated with ISs from COPD patients compared with ISs from HC and untreated cells. IKKα silencing reduced TSLP production in 16HBE cells stimulated with rhIL-17A and ISs from COPD patients. RhIL-17A increased the IKKα/acetyl-histone H3 immunoprecipitation in 16HBE cells. The anticholinergic drug affects TSLP protein and mRNA levels in bronchial epithelial cells treated with rhIL-17A or with ISs from COPD patients, and IKKα mediated acetyl-histone H3(Lys14). IL-17A/IKKα signaling induced the mechanism of chromatin remodeling associated with acetyl-histone H3(Lys14) and TSLP production in bronchial epithelial cells. Anticholinergic drugs might target TSLP derived from epithelial cells during the treatment of COPD.

Basis of the general theory of pathology (Part 2. Pathogenesis of chronic diseases)

The authors believe that, despite of the endless variety of pathology, there is a single stereotyped pathogenetic mechanism for all chronic diseases. This mechanism doesn't dependent on a cause of an illness. If unnumbered etiological factors have a direct link to a damage of a certain number of cells (structures) of the target organ, then a disease, as a reaction to this damage, aims to restore the structure and function of the damaged organ. However a new pathogenetic mechanism arises in the course of a disease. This mechanism is based on energy deficiency. It arises due to violations of biorhythms of a remaining tissue. The violations of biorhythms in their turn are based on deviations from the law of «optimal construction». This mechanism destroys the remaining tissue that haven't been damaged by etiological factors. A "separation" of a disease from an etiologic factor occurs. A disease continues its course even without external damaging factors. Consequently a treatment of chronic diseases requires a fundamentally different approach than etiotropic therapy. Until now only an empirically obtained experience of non-specific treatment has been used. Therefore all existing therapy requires a fundamental revision.