Pathogenesis Of Chronic Disease Research Articles

ИССЛЕДОВАНИЕ СЕКРЕЦИИ ЭРИТРОПОЭТИНА У БОЛЬНЫХ ВИЧ-ИНФЕКЦИЕЙ С АНЕМИЕЙ ХРОНИЧЕСКИХ ЗАБОЛЕВАНИЙ, ЖЕЛЕЗОДЕФИЦИТНОЙ АНЕМИЙ И СОЧЕТАНИЕМ ДВУХ ТИПОВ АНЕМИЙ

Aim. To compare the secretion of erythropoietin in patients with infection caused by human immune deficiency virus (HIV infection) with anemia of chronic diseases (ACD), iron deficiency anemia (IDA), and their combination. Material and methods. 125 patients with HIV infection were examined: 101 with anemia (55 males, 46 women, 39.4±9.6 years), 24 - a control group of patients with HIV infection without anemia (13 males, 11 women, average age 37.6± 7.37 years). In all patients, the number of red blood cells, the concentration of hemoglobin, ferritin, C-reactive protein (CRP), transferrin saturation index (TSI) and erythropoietin were examined. All patients with anemia after determining TSI, CRP, ferritin based on Van Santen and Worwood criteria were divided into three groups depending on the type of anemia: group 1 - 36 patients with ACD (19 males, 17 women, average age 41.7 ± 11, 8 years, TSI 16.9[IQR, 10.2-23.1]%, ferritin 638.7[IQR, 326-861] μg/l, CRP 54.5 [IQR, 4.8-103.3] mg/l), group 2 – 30 patients with a combination of ACD/IDA (18 males, 12 women, average age 41.2±10 years, TSI 13.2[IQR, 9.8-14]%, ferritin 156.2 [IQR, 123-235] mcg/l, CRP 5.9 [IQR, 0.5-8.2] mg/l), group 3 – 35 patients with IDA (18 males, 17 women, average age 35.4 ±7.1 years, TSI 11.1[IQR, 4.7-13.7]%, ferritin 29[IQR, 4.2-38.9] µg/l, CRP 2.9[IQR, 0.4 -1.6] mg/l). For quantitative indicators, the median (Me), standard error of the mean (m), and interquartile range (IQR) were calculated. The significance of differences between several unrelated groups was determined using the Kruskal-Wallis test. Results. In the ACD group, a lower number of red blood cells was detected (3.3(2.7-3.8)×1012/l), compared to the group of patients with IDA (3.8(3.7-4.1)×1012/l ). Also, in the group of patients with ACD, the maximum concentration of erythropoietin was detected (28.5[11.2-28.5], U/ml), significantly higher than the concentration of this indicator in the ACD/IDA groups (14[8.1-16.3], U/ml), IDA (15.8[6.2-27.4], U/ml) and patients in the control group (6.3[4.9-7.8], U/ml). Conclusions. In the present study, ACD in isolated form or in combination with IDA was diagnosed in 65.3% of patients with HIV infection and anemic syndrome. In patients with ACD, an increased concentration of erythropoietin is combined with the lowest number of red blood cells in comparison with other groups of patients with anemia (p<0.05). The results obtained indicate a compensatory increase in erythropoietin secretion in response to suppressed erythropoiesis, or to reduced sensitivity of erythropoietin receptors. Further study of the importance of erythropoietin in the pathogenesis of chronic disease in patients with HIV infection is necessary, including to improve its treatment.

Exploring the Gut-Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders.

This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences cellular stress responses through Rac1 activation, Forkhead-type transcription factors inactivation, and mitochondria-mediated apoptosis, alongside modulatory effects of gut microbiota-derived metabolites and endotoxins. Employing an integrative approach, the review synthesizes findings from a broad array of studies, including molecular biology techniques and analyses of microbial metabolites' impacts on host cellular pathways. The results underscore a complex interplay between microbial metabolites, p66Shc activation, and mitochondrial dysfunction, highlighting the significance of the gut microbiome in influencing disease outcomes through oxidative stress pathways. Conclusively, the review posits that targeting the gut microbiota-p66Shc-mitochondrial axis could offer novel therapeutic strategies for mitigating the development and progression of metabolic diseases. This underscores the potential of dietary interventions and microbiota modulation in managing oxidative stress and inflammation, pivotal factors in chronic disease etiology.

(090) The Relationship Between C-Reactive Protein and Total Testosterone in Aging Men: Findings from the Baltimore Longitudinal Study of Aging

Abstract Introduction Elevated C-Reactive Protein (CRP) and testosterone deficiency are associated with advanced age and chronic inflammatory diseases, such as cancer, diabetes, and cardiovascular disease. Testosterone decreases inflammation through several mechanisms, and testosterone replacement therapy (TRT) has been shown to lower CRP levels in aging, hypogonadal men. While cross-sectional studies have shown an inverse relationship between CRP and total testosterone (TT) levels, mixed findings have been reported when individual components of metabolic syndrome are considered. We hypothesized that men with testosterone deficiency will have high levels of CRP. Objective We evaluated the relationship between CRP and TT levels in men from 2004-2018 using the Baltimore Longitudinal Study of Aging and specifically attempted to determine if low androgen status is associated with a high inflammatory profile independent of comorbidities. Methods Male participants with serum TT level measured during two separate visits >3 years apart were included in our cohort. CRP, High-Density Lipoprotein (HDL) and Triglyceride levels were collected via blood specimens. Comorbidity data were documented at each visit. Panel regression was used to analyze the relationship of a series of independent variables collected in pooled cross-sectional observations over time with a dependent variable for modeling. Results A total of 347 patients were included in this study (mean age = 69 ± 15, average follow up time = 6.7 ± 3.2 years). Participants had a median CRP level of 1.0 mg/dL and a median TT level of 446 ng/dL. On univariable analysis TT and HDL levels were associated with a decline in CRP, while BMI, congestive heart failure (CHF), Diabetes, and Triglycerides were associated with increased CRP. Age was not associated with CRP. On multivariable analysis, we found that increasing TT level was associated with a decline in CRP levels, independent of comorbidities (p = 0.018; Table 1). BMI was associated with a significant increase in CRP (p = 0.001, Table 1). Age, CHF, Diabetes, HDL, and Triglycerides were not significant predictors of CRP on multivariable analysis. Conclusions Lower levels of serum total testosterone are associated with an increased CRP in older men. Given the importance of CRP in pathogenesis of chronic disease, we highlight the potential benefits of restoring testosterone levels in older, hypogonadal men via TRT. Disclosure No.

Label-free electrochemical biosensor for direct detection of Oncostatin M (OSM) inflammatory bowel diseases (IBD) biomarker in human serum

Oncostatin M (OSM) is an interleukin-6 (IL-6) member family cytokine implicated in the pathogenesis of chronic diseases including inflammatory bowel disease (IBD). OSM is a novel diagnostic biomarker over-expressed in the serum of IBD patients. This paper reports on the first electrochemical OSM immunosensor, developed using a multistep fabrication process aimed at covalently immobilizing OSM antibodies on a mixed self-assembled monolayer coated gold working electrode. Cyclic voltammetry, atomic force microscopy (AFM), IR spectroscopy and optical characterizations were used to validate the sensor functionalization protocol. Electrochemical impedance spectroscopy (EIS) measurements were performed to assess the reliability of the immunosensor preparation and to verify the antibody-antigen complexes formation. The label-free immunosensor showed high sensitivity identifying OSM at clinically relevant concentrations (37–1000 pg mL−1) with low detection limit of 2.86 pg mL−1. Both sensitivity and selectivity of the proposed immunosensor were also demonstrated in human serum in the presence of interfering biomarkers, making it an innovative potential platform for the OSM biomarker detection in IBD patients’ serum.

Genome-wide study of Almaty region people for a long time living in areas of pesticide contamination

The purpose of this study is to analyze the associations of gene polymorphisms involved in the pathogenesis of chronic diseases that develop against the background of the toxic effects of pollutants in the environment. The study sample for the research was a cohort of people who had been exposed to pesticide pollution for a long time, taken from villages in the Almaty region, on the territory of which destroyed warehouses of pesticides prohibited for use were discovered. Analysis were performed using Genome-wide association study (GWAS) method. A total of 297,397 SNPs were analyzed, 6 of which were found to be significantly associated with the negative effects of chronic exposure to pesticides.

Determination of the phytochemical profile and anti-oxidant capacity of the roots of Beta vulgaris (Chenopodiaceae)

Introduction: Chronic inflammation due to oxidative stress plays an essential role in the pathogenesis of chronic diseases like cardiovascular diseases. Regular consumption of fruits/vegetables known as medicinal plants are considered as fundamental approach in treating non communicable diseases like hypertension. These is achieved through secondary metabolites contained in the above-mentioned plants.
 Objective: To determine the phytochemical profile and anti-oxidant capacity of the roots of Beta vulgaris (Chenopodiaceae).
 Methodology: Qualitative phytochemical analysis was carried out according to Harbone and Evans principles. Total polyphenol content was assessed according to Li et al, total flavonoid content was assessed according to Zhishen et al and total tannins content was measured according to Julkumen-Titto. Antioxidant capacity were performed in vitro using the DPPH tests (radical scavenging) according to Blois and Ferric Reducing Ability of Plasma (FRAP) according to Benzie and strain. All tests were performed in triplicates at 1500μg/mL. The type of antioxidant ability (primary or secondary) was assessed.
 Results: The phytochemical analysis of the raw root of Beta vulgaris revealed the presence of polyphenols, flavonoids, alkaloids and terpenes. Total polyphenol, flavonoids and tannins content was 18,56±1,0, 31,19±3,12 572,84±54 mg of catechin, quercetin and tannic acid equivalent/gram dry matter respectively. Antioxidant tests revealed radical scavenging activity with DPPH whose SC50 was 108.2
 μg/mL against 302.5 μg/mL for gallic acid and FRAP (chelating antioxidant) activity at 1089.14±99.23 mg catechin equivalent per gram of dry matter. The antioxidant ability was secondary (preventive).
 Conclusion: Beta vulgaris possess the three main group of secondary metabolites and secondary antioxidant activity.

The Role of the Microbiome in the Pathogenesis and Treatment of Ulcerative Colitis-A Literature Review.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the colon and rectum. UC's pathogenesis involves colonic epithelial cell abnormalities and mucosal barrier dysfunction, leading to recurrent mucosal inflammation. The purpose of the article is to show the complex interplay between ulcerative colitis and the microbiome. The literature search was conducted using the PubMed database. After a screening process of studies published before October 2023, a total of 136 articles were selected. It has been discovered that there is a fundamental correlation of a robust intestinal microbiota and the preservation of gastrointestinal health. Dysbiosis poses a grave risk to the host organism. It renders the host susceptible to infections and has been linked to the pathogenesis of chronic diseases, with particular relevance to conditions such as ulcerative colitis. Current therapeutic strategies for UC involve medications such as aminosalicylic acids, glucocorticoids, and immunosuppressive agents, although recent breakthroughs in monoclonal antibody therapies have significantly improved UC treatment. Furthermore, modulating the gut microbiome with specific compounds and probiotics holds potential for inflammation reduction, while fecal microbiota transplantation shows promise for alleviating UC symptoms. This review provides an overview of the gut microbiome's role in UC pathogenesis and treatment, emphasizing areas for further research.

The intestinal-level metabolic benefits of green tea catechins: Mechanistic insights from pre-clinical and clinical studies

BackgroundThe intestinal-level host-microbiota interaction has been implicated in the pathogenesis of chronic diseases. The current review is intended to provide a comprehensive insight into deciphering whether intestinal-level bioactivities mediate the overall metabolic health benefits of green tea catechins. PurposeWe have comprehensively discussed pre-clinical and clinical evidences of intestinal-level changes in metabolism, microbiota, and metabolome due to catechin-rich green tea treatments, ultimately limiting metabolic diseases. Exclusive emphasis has been given to purified catechins and green tea, and discussions on extraintestinal mechanisms of metabolic health benefits were avoided. MethodsA literature search for relevant pre-clinical and clinical studies was performed in various online databases (e.g., PubMed) using specific keywords (e.g., catechin, intestine, microbiota). Out of all the referred literature, ∼15% belonged to 2021-2023, ∼51% were from 2011-2020, and ∼32% from 2000-2010. ResultThe metabolic health benefits of green tea catechins are indeed influenced by the intestinal-level bioactivities, including reduction of mucosal inflammation and oxidative stress, attenuation of gut barrier dysfunction, decrease in intestinal lipid absorption and metabolism, favorable modulation of mucosal nuclear receptor signaling, alterations of the luminal global metabolome, and mitigation of the gut dysbiosis. The results from the recent clinical studies support the pre-clinical evidences. The challenges and pitfalls of the currently available knowledge on catechin bioactivities have been discussed, and constructive directions to harness the translational benefits of green tea through future interventions have been provided. ConclusionThe metabolism, metabolome, and microbiota at the intestinal epithelia play critical roles in catechin metabolism, pharmacokinetics, bioavailability, and bioactivities. Especially the reciprocal interaction between the catechins and the gut microbiota dictates the metabolic benefits of catechins.

Anti-Inflammatory and Antioxidant Activities of Lipophilic Fraction from Liriope platyphylla Seeds Using Network Pharmacology, Molecular Docking, and In Vitro Experiments.

Antioxidant and anti-inflammatory mechanisms counteract the pathogenesis of chronic diseases, such as diabetes, aging, and cancer. Therefore, enhancing antioxidant and anti-inflammatory functions may help manage these pathological conditions. This study aimed to assess the antioxidant and anti-inflammatory potentials of lipophilic fraction of Liriope platyphylla seeds (LLPS) using network pharmacology, molecular docking, and in vitro experiments. Here GC-MS analysis tentatively identified forty-three lipophilic compounds in LLPS. LLPS exhibited powerful antioxidant activity, according to the results from chemical-based antioxidant assays on DPPH, ABTS+, superoxide anion, hydrogen peroxide, nitric oxide, and hydroxyl radicals scavenging, lipid peroxidation, reducing antioxidant powers, and total antioxidant capacity. Additionally, LLPS enhanced cellular antioxidant capacity by inhibiting reactive oxygen species formation and elevating antioxidant enzyme levels, including catalase and heme oxygenase-1. Moreover, LLPS attenuated inflammatory response by reducing nitric oxide secretion and downregulating the expression of inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-1β in lipopolysaccharide-treated macrophages. Network pharmacology and molecular docking analyses showed that key compounds in LPPS, particularly phytosterols and fatty acid esters, exerted antioxidant and anti-inflammatory properties through regulating NFKB1, PTGS1, PTGS2, TLR4, PRKCA, PRKCD, KEAP1, NFE2L2, and NR1l2. Overall, these data suggest that LLPS may be a potential antioxidant and anti-inflammatory agent for developing functional foods.

The mechanisms and therapeutic potential of long noncoding RNA NEAT1 in fibrosis.

Fibrosis is the excess deposition of extracellular matrix involved in the pathogenesis of chronic diseases and finally leads to the disruption of tissue architecture and failure of organ function. Long noncoding RNAs (lncRNAs) are a class of RNAs with lengths greater than 200 nucleotides and do not code proteins, which regulate gene expression at multiple levels. Nuclear-enriched abundant transcript 1 (NEAT1) is a long noncoding RNA that is widely expressed in mammalian cells and known as essential architectural scaffold for the formation of paraspeckles. Recently, the accumulating studies demonstrated that lncRNA NEAT1 was remarkable upregulated in the development of fibrosis in different organs, such as liver fibrosis, renal fibrosis, cardiac fibrosis, and lung fibrosis. More importantly, knockdown of NEAT1 remarkably alleviated fibrosis in vitro and in vivo. In this review, we summarized current studies of NEAT1 in fibrosis and hopefully aid in a better understanding of the mechanisms of fibrosis and the potential of NEAT1 as novel therapeutic target for fibrosis.

Comparison of vitamin D levels in children with motor development delay and asthma

Background & Objective: Vitamin D plays an important role in musculoskeletal health and is also potentially involved in the pathogenesis of chronic diseases. In this study, we aimed to determine the vitamin D status of children aged 2-6 years with motor developmental delay and compare them with asthmatic children. Method: Serum 25-Hydroxy cholecalciferol 25 (OH) D vitamin levels of children were measured between June 2020 and September 2020. Vitamin D deficiency was defined as a serum 25 (OH) vitamin D level less than 20 ng/mL and insufficiency as levels between 20 and 30 ng/mL. The deficiency and insufficiency rates and mean 25 (OH) vitamin D levels between the two groups were compared. Results: The study population included 818 children (192 children with asthma, 368 children with motor development delay and 258 healthy controls). There was no statistically significant difference between groups in terms of age and gender (p=0.130 and p= 0.082, respectively). Vitamin D deficiency and insufficiency were detected in one thirds of children with motor developmental delay (33.7%; 35.6% respectively). The rate of vitamin D deficiency of children with motor development delay between 24 - 47 months of age was found to be significantly higher than control and asthma group (p=0.001 and p=0.034). Conclusions: Vitamin D deficiency and insufficiency were common between 2-6 years of age children with motor development delay. Acceleration of2 motor development between 24 - 47 months of age may be a cause of high incidence of D vitamin deficiency. Clinicians should check and optimize vitamin D status in children with motor development delay especially between 24 - 47 months of age.

In vitro and in silico perspectives on the activation of antioxidant responsive element by citrus-derived flavonoids.

Oxidative stress plays an essential role in the pathogenesis of chronic diseases. Disrupting the Keap1-Nrf2 pathway by binding Keap1 is identified as a potential strategy to prevent oxidative stress-related chronic diseases. Therefore, of special interest is the utilization of dietary antioxidations from citrus, including narirutin, naringenin, hesperetin, hesperidin, naringin, neohesperidin dihydrochalcone, neohesperidin, and nobiletin, has been exploited as a prospective way to treat or prevent several human pathologies as Keap1-Nrf2 inhibitors for modulation of antioxidant properties. To probe into the structural foundation of the molecular identification of citrus-derived antioxidations, we calculated the antioxidant responsive element activation ability of citrus-derived flavonoids after binding with Keap1. Also, the quantum chemistry properties and binding mode were performed theoretically with frontier molecular orbitals, molecular electrostatic potential analysis, molecular docking, and absorption, distribution, metabolism, excretion (ADME) calculation. Experimental findings combining computational assays revealed that the tested citrus-derived flavonoids can be grouped into strong agonists and weak agonists. The citrus-derived antioxidations were well housed in the bound zone of Keap1 via stable hydrogen bonding and hydrophobic interaction. Eventually, three of eight antioxidations were identified after ADME and physicochemical evaluations. The citrus-derived flavonoids were identified as potential dietary antioxidants of the Keap1-Nrf2 interaction, and can be used to improve oxidative stress-related chronic diseases.

The Roles of Lipid Metabolism in the Pathogenesis of Chronic Diseases in the Elderly.

Lipid metabolism plays crucial roles in cellular processes such as hormone synthesis, energy production, and fat storage. Older adults are at risk of the dysregulation of lipid metabolism, which is associated with progressive declines in the physiological function of various organs. With advancing age, digestion and absorption commonly change, thereby resulting in decreased nutrient uptake. However, in the elderly population, the accumulation of excess fat becomes more pronounced due to a decline in the body's capacity to utilize lipids effectively. This is characterized by enhanced adipocyte synthesis and reduced breakdown, along with diminished peripheral tissue utilization capacity. Excessive lipid accumulation in the body, which manifests as hyperlipidemia and accumulated visceral fat, is linked to several chronic lipid-related diseases, including cardiovascular disease, type 2 diabetes, obesity, and nonalcoholic fatty liver disease. This review provides a summary of the altered lipid metabolism during aging, including lipid digestion, absorption, anabolism, and catabolism, as well as their associations with age-related chronic diseases, which aids in developing nutritional interventions for older adults to prevent or alleviate age-related chronic diseases.

Protective effects of peptide KSPLY derived from Hericium erinaceus on H2O2-induced oxidative damage in HepG2 cells

Reactive oxygen species (ROS)-induced oxidative damage is strongly associated with the pathogenesis of chronic diseases, and natural antioxidant peptides have good abilities of scavenging ROS. The antioxidant activity of peptide Lys-Ser-Pro-Leu-Tyr (KSPLY) derived from Hericium erinaceus remains unclear. In the present study, the antioxidant effect and mechanism of KSPLY on H2O2-induced oxidative damage in HepG2 cells were investigated. The results indicated that KSPLY exhibited the antioxidant capacity in H2O2-induced HepG2 cells by enhancing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities. In comparison with the H2O2-treated damage group, the apoptosis rate, ROS level, and malondialdehyde (MDA) content of HepG2 cells treated with KSPLY were significantly decreased. The H. Erinaceus-derived peptide KSPLY pretreatment promoted the expression of detoxification and antioxidant enzymes via the Keap1/Nrf2 signal pathway, thereby inhibiting the generation of ROS and MDA. In conclusion, the H. erinaceus-derived peptide KSPLY effectively protected HepG2 cells against H2O2-induced oxidative damage, and it provided a theoretical basis for the further development of new natural antioxidants.

Effects of a lifestyle intervention on the biomarkers of oxidative stress in non-communicable diseases: A systematic review.

Oxidative stress plays a critical role in the pathogenesis of chronic diseases. Therefore, improvement of oxidative stress status through lifestyle intervention can play a vital role in preventing and treating chronic diseases. This systematic review aims to provide an overview of articles published in the last decade examining the association between lifestyle intervention and oxidative stress biomarkers in the context of non-communicable diseases. The electronic databases PubMed and Web of Science were searched for relevant studies, following the PRISMA (Preferred Reporting of Systematic Reviews and Meta-Analyses) guidelines. This systematic review focused on the four important oxidative stress biomarkers; glutathione (GSH), superoxide dismutase (SOD), catalase, and malondialdehyde. 671 articles were identified, of which nine met the inclusion criteria. A trend emerged, showing that lifestyle modifications that focus on diet and physical health can improve oxidative stress in the form of an increase in superoxide dismutase and CAT levels and a decrease in Malondialdehyde levels in participants with non-communicable diseases (NCDs), GSH levels were not affected. However, the results are difficult to compare because of the heterogeneity of the methods of the biomarkers studied. Our review indicates that oxidative stress can be influenced by lifestyle modifications and may be an effective tool for the prevention and management of non-communicable diseases. This review also elucidated the importance of analyzing multiple oxidative stress biomarkers to evaluate oxidative stress, it further highlights the need to conduct long-term lifestyle intervention studies on oxidative stress biomarkers to understand the connection between oxidative stress biomarkers, NCDs and Lifestyle intervention.

The epithelial barrier theory: Development and exacerbation of allergic and other chronic inflammatory diseases.

It is now longer than half a century, humans, animals, and nature of the world are under the influence of exposure to many newly introduced noxious substances. These exposures are nowadays pushing the borders to be considered as the causative or exacerbating factors for many chronic disorders including allergic, autoimmune/inflammatory, and metabolic diseases. The epithelial linings serve as the outermost body's primary physical, chemical, and immunological barriers against external stimuli. The "epithelial barrier theory" hypothesizes that these diseases are aggravated by an ongoing periepithelial inflammation triggered by exposure to a wide range of epithelial barrier-damaging insults that lead to "epithelitis" and the release of alarmins. A leaky epithelial barrier enables the microbiome's translocation from the periphery to interepithelial and even deeper subepithelial areas together with allergens, toxins, and pollutants. Thereafter, microbial dysbiosis, characterized by colonization of opportunistic pathogen bacteria and loss of the number and biodiversity of commensal bacteria take place. Local inflammation, impaired tissue regeneration, and remodeling characterize the disease. The infiltration of inflammatory cells to affected tissues shows an effort to expulse the tissue invading bacteria, allergens, toxins, and pollutants away from the deep tissues to the surface, representing the "expulsion response." Cells that migrate to other organs from the inflammatory foci may play roles in the exacerbation of various inflammatory diseases in distant organs. The purpose of this review is to highlight and appraise recent opinions and findings on epithelial physiology and its role in the pathogenesis of chronic diseases in view of the epithelial barrier theory.

Molecular mechanisms of environmental exposures and human disease.

A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome - the cumulative measure of environmental influences over the lifespan - and its integration into future environmental health research.

Spatially resolved transcriptomics reveals pro-inflammatory fibroblast involved in lymphocyte recruitment through CXCL8 and CXCL10.

The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP. Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis.

Targeting Tumor Necrosis Factor Alpha to Mitigate Lung Injury Induced by Mustard Vesicants and Radiation.

Pulmonary injury induced by mustard vesicants and radiation is characterized by DNA damage, oxidative stress, and inflammation. This is associated with increases in levels of inflammatory mediators, including tumor necrosis factor (TNF)α in the lung and upregulation of its receptor TNFR1. Dysregulated production of TNFα and TNFα signaling has been implicated in lung injury, oxidative and nitrosative stress, apoptosis, and necrosis, which contribute to tissue damage, chronic inflammation, airway hyperresponsiveness, and tissue remodeling. These findings suggest that targeting production of TNFα or TNFα activity may represent an efficacious approach to mitigating lung toxicity induced by both mustards and radiation. This review summarizes current knowledge on the role of TNFα in pathologies associated with exposure to mustard vesicants and radiation, with a focus on the therapeutic potential of TNFα-targeting agents in reducing acute injury and chronic disease pathogenesis.

S-38-9: DNA DAMAGE REPAIR AND DNA METHYLATION IN THE KIDNEY AND CKD

In recent years, the results of large clinical trials have suggested that transient treatment for lifestyle-related diseases has sustained effects on prevention for cardiovascular complication over a long period of time, which has been noted as “memory effect’’. One of the possible mechanisms of the memory effect is epigenetic changes. Epigenetic alterations have sustained effects on gene expressions, which contribute to the pathogenesis of chronic diseases, including kidney diseases. DNA damage repair is one of the chances to re-write the epigenetic marks, and continuous DNA damage may cause accumulation of epigenetic changes. We have demonstrated the importance of DNA damage repair in the kidney and its relations to kidney diseases through DNA methylation changes. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. In this talk, I would like to focus on DNA damage repair in podocytes and proximal tubular epithelial cells, and discuss the possibility as a prognostic marker and a therapeutic target. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.