Systemic Inflammatory Mediators Research Articles

Impact of Glycemic Control on Coronary Inflammation Evaluated by Computed Tomography Pericoronary Fat Attenuation Index in Patients with Acute Coronary Syndrome.

Coronary inflammation causes significantly increased risk of cardiovascular disease (CVD) in diabetic patients. This study investigated the relationship between coronary local inflammation, detected by pericoronary fat attenuation index (FAI), and different blood glucose control levels in low-risk acute coronary syndrome (ACS) patients with or without diabetes. A total of 309 patients with low-risk ACS were classified into three groups: non-diabetes, well-regulated diabetes, and poorly regulated diabetes. Pericoronary FAI around the proximal or left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA), were evaluated by coronary computed tomography angiography (CCTA), and systemic inflammatory variables and other biochemical indicators were detected by flow cytometry. Pericoronary FAI values around the proximal LAD, LCX, and RCA in poorly regulated diabetes were significantly higher than those in well-regulated diabetes and non-diabetes, whereas those in well-regulated diabetes were not statistically different from those in non-diabetes. Further, plasma glycated hemoglobin (HbA1c) level was positively correlated with the pericoronary FAI values in LAD, LCX, and RCA. However, no significantly increased systemic inflammatory mediators were found in diabetic patients with poor glycemic control. Diabetic patients with poor glycemic control may have higher coronary local inflammation as detected by pericoronary FAI surrounding the three major coronary arteries. NCT05590858.

#3658 PERITONEAL INFLAMMATION INDUCES SYSTEMIC ERYPTOSIS IN PERITONEAL DIALYSIS-ASSOCIATED PERITONITIS

Abstract Background and Aims Eryptosis is stress-induced RBC (Red Blood Cell) death mechanism. Our preliminary data show that there is a significative increased of eryptosis during peritoneal dialysis-associated peritonitis. Furthremore, there is an elevation of local and systemic inflammatory mediators. The aim of this study was to evaluate the relationship between systemic eryptosis levels in peritonitis and specific peritonitis biomarkers in peritonitis effluent (PDE), such as Peritoneal White Blood cell count (pWBC), peritoneal NGAL (pNGAL) and peritoneal cytokines levels. Method We enrolled 22 PD patients with peritonitis and 17 healthy subjects. PD-related peritonitis was defined according to the Guidelines of the International Society of Peritoneal Dialysis. At the time of diagnosis, blood samples were collected for eryptosis and peritoneal effluent were taken to evaluate pWBC, pNGAL and cytokines. All eryptotic measurements were made in freshly isolated RBCs. PS avidly binds AnnexinV, which is thus employed to identify eryptotic cells. Thus, PS exposure at RBC surface was estimated from FITC-AnnexinV binding using flow cytometric analyses. Results 13/22 patients were treated with continuous ambulatory PD (CAPD) and 9 with automated PD (APD). The median length of PD treatment was 28.1 months and the range was: minimum: 3 – maximum: 124.9 months. The percentage of AnnexinV-binding RBCs was significantly higher in PD patients with peritonitis than in CTR (PD patients with peritonitis: 7.7; IQR 4.3-14.2, versus CTR: 0.8; IQR 0.7-1.3; p<0.001) (Figure 1). WBC, NGAL and cytokines levels in PDE are reported in Table 2. We observed important correlation between eriptosis levels and peritoneal biomarkers (Figure 2). Conclusion In conclusion, we investigated a potential connection between systemic eryptosis and peritoneal biomarkers involved in peritonitis. The presented results revealed that upregulated inflammatory markers could be the cause of high levels of systemic eryptosis during PD-related peritonitis.

Systemic Inflammation, Endothelial Function, and Risk of Periodontitis in Overweight/Obese Adults.

The network interaction between systemic inflammatory mediators, endothelial cell adhesion function, and adiponectin as mediators of the association between metabolic diseases and periodontitis has not been evaluated. The objective of this study is to assess whether the interaction of baseline serum levels of TNF-α, hs-CRP, ICAM-1, VCAM-1, and adiponectin leads to periodontitis. Five hundred and ninety-seven overweight/obese (overweight: BMI 25 to <30 kg/m2; obese: >30 kg/m2) adults, aged 40-65 years, with complete 3-year follow-up data were included. Generalized structural equation models with negative binomial regression were used to estimate the regression coefficient (β) for the outcome number of teeth with probing pocket depth (PPD) ≥ 4 mm and bleeding on probing (BOP) at 3-year follow-up for a 1 standard deviation unit increase (Δ = +1SD) in each biomarker. After adjusting for multiple covariates, baseline ICAM-1 and VCAM-1 had significant direct effects on increased log-transformed number of teeth with PPD ≥ 4 mm and BOP (β: 0.16; 95% CI: 0.02-0.30; β: 0.15; 95% CI: 0.02-0.30, respectively). Baseline hs-CRP showed a significant indirect effect via ICAM-1 on the log-transformed number of teeth with PPD ≥ 4 mm and BOP (β: 4.84; 95% CI: 0.27-9.42). Thus, elevated serum ICAM-1 and VCAM-1 have a significant direct effect and increased hs-CRP has a significant indirect effect on the predicted level of periodontitis at the 3-year follow-up among overweight/obese Hispanic adults.

In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury.

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.

Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats.

Leptin is a proinflammatory adipokine that contributes to obesity-associated osteoarthritis (OA), especially in women. However, the extent to which leptin causes knee OA separate from the effect of increased body weight is not clear. We hypothesized that leptin is necessary to induce knee OA in obese female rats but not sufficient to induce knee OA in lean rats lacking systemic metabolic inflammation. The effect of obesity without leptin signaling was modeled by comparing female lean Zucker rats to pair fed obese Zucker rats, which possess mutant fa alleles of the leptin receptor gene. The effect of leptin without obesity was modeled in female F344BN F1 hybrid rats by systemically administering recombinant rat leptin versus saline for 23 weeks via osmotic pumps. Primary OA outcomes included cartilage histopathology and subchondral bone micro-computed tomography. Secondary outcomes included targeted cartilage proteomics, serum inflammation, and synovial fluid inflammation following an acute intra-articular challenge with interleukin-1β (IL-1β). Compared to lean Zucker rats, obese Zucker rats developed more severe tibial osteophytes and focal cartilage lesions in the medial tibial plateau, with modest changes in proximal tibial epiphysis trabecular bone structure. In contrast, exogenous leptin treatment, which increased plasma leptin sixfold without altering body weight, caused mild generalized cartilage fibrillation and reduced Safranin O staining compared to vehicle-treated animals. Leptin also significantly increased subchondral and trabecular bone volume and bone mineral density in the proximal tibia. Cartilage metabolic and antioxidant enzyme protein levels were substantially elevated with leptin deficiency and minimally suppressed with leptin treatment. In contrast, leptin treatment induced greater changes in systemic and local inflammatory mediators compared to leptin receptor deficiency, including reduced serum IL-6 and increased synovial fluid IL-1β. In conclusion, rat models that separately elevate leptin or body weight develop distinct OA-associated phenotypes, revealing how obesity increases OA pathology through both leptin-dependent and independent pathways. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The role of O3 exposure and physical activity status on redox state, inflammation, and pulmonary toxicity of young men: A cross-sectional study

The exposure to traffic-related air pollutants, such as NO2 and O3, are associated with detrimental health effects, becoming one of the greatest public health issues worldwide. Exercising in polluted environments could result in harmful outcomes for health and may blunt the physiological adaptations of exercise training. This study aimed to investigate the influence of physical activity and O3 exposure on redox status, an inflammatory marker, response to stress, and pulmonary toxicity of healthy young individuals. We performed a cross-sectional study with 100 individuals that, based on their exposure to O3 and physical fitness (PF) level, were distributed in four groups: Low PF + Low O3; Low PF + High O3; High PF + Low O3; High PF + High O3. We evaluated personal exposure to NO2 and O3, physical activity level, variables of oxidative stress (SOD, ROS, CAT, GSH, TBARS), pulmonary toxicity (CC16), and inflammatory mediators (IL-1β, IL-4, IL-6, IL-10, TNF-α, HSP70). Spearman correlation test to check the association among the variables was used and to compare groups we used one-way ANOVA followed by Bonferroni's post hoc and Kruskal Wallis test followed by Dunn's post hoc. O3 levels correlated with physical activity (r = 0.25; p = 0.01) but not with age or markers of body composition (p > 0.05). The individuals with high physical fitness that were less exposed to O3 presented higher CAT activity (p < 0.001), lower TBARS (p < 0.01) and IL-1β concentrations (p < 0.01), higher IL-6 (p < 0.05) and IL-10 concentrations (p < 0.05), lower IL-6:1L-10 ratio (p < 0.05), lower CC16 levels (p < 0.05), and higher HSP70 concentration (p < 0.05). Physical activity could result in higher exposure to O3 that could partially blunt some exercise adaptations, while high physical fitness improved the antioxidant defense system, systemic inflammatory mediators, and pulmonary toxicity.

Host-microbiome interactions in apical periodontitis: The endodontic microbiome in relation to circulatory immunologic markers.

To explore microbial differences in the endodontic infection of teeth with primary or secondary apical periodontitis (AP), with or without symptomatology. Additionally, to investigate if these differences are depicted in immunologic markers in blood. Twenty-nine teeth with primary or secondary AP were extracted and cryo-pulverized. Blood was drawn from the subjects at three different time-points before and three time-points after the extraction in a time period of four months. The V4 hypervariable region of the 16S rRNA gene was sequenced using Illumina MiSeq. The microbial profiles were ordinated using principal component analysis and tested for differences between groups with permutational multivariate analysis of variance using the Bray-Curtis distance. If significantly different, the microbial profiles were further analysed using the LDA effect size (LEfSe) biomarker discovery tool. A broad panel of inflammatory mediators in blood was examined longitudinally in all subjects during the six visits with mixed models. The Spearman correlation between these mediators and the zOTUs was calculated, and significant correlations (p < .05) were used as input for significant analysis of microarrays (SAM) using MeV. After subsampling, the 467 zOTUs were classified into 9 phyla and 99 genera or higher level taxa. The predominant genus in the entire sample set was Fusobacterium with a relative abundance of 12.3%, followed by Prevotella (9.9%), Actinomyces (7.7%) and Streptococcus (6.7%). The microbiomes of the endodontic infections were significantly associated with endodontic status (primary/secondary infection; p=.015) as well as with the presence or absence of pain (p=.011). There was also a difference in the concentration of inflammatory mediators, namely, C-reactive protein, Interleukin (IL)-8, IL-10, IL-12p70, RANKL and TNF-α, depending on the existence of pain. In addition, the presence of specific bacteria (zOTUs) was correlated, positively or negatively, with the expression of several circulating inflammatory markers. The microbial profiles and the concentration-time relationship of systemic inflammatory mediators of primary endodontic infection differed from those of secondary, and of symptomatic from those of asymptomatic cases. The fingerprint of associations between the immunological and microbiological profiles differed between asymptomatic and symptomatic patients.

TNF-Alpha Promotes an Inflammatory Mammary Microenvironment That Favors Macrophage and Epithelial Migration in a CCL2- and Mitochondrial-ROS-Dependent Manner.

The influence of an inflammatory microenvironment on tumorigenesis has been widely accepted. Systemic conditions that favor the onset of an inflammatory landscape predispose the progression of breast cancer. Under obesity conditions, the endocrine function of adipose tissue is one of the main determinants of the production of local and systemic inflammatory mediators. Although these mediators can stimulate tumorigenesis and recruit inflammatory cells, as macrophages, the mechanism involved remains poorly understood. In the present work, we describe that the TNFα treatment of mammary preadipocytes from human normal patients blocks adipose differentiation and promotes the generation of pro-inflammatory soluble factors. The latter stimulate the mobilization of THP-1 monocytes and MCF-7 epithelial cancer cells in an MCP1/CCL2- and mitochondrial-ROS-dependent manner. Together, these results reaffirm the contribution of an inflammatory microenvironment and mtROS in the progression of breast cancer.

Porphyromonas gingivalis regulates atherosclerosis through an immune pathway.

Atherosclerosis (AS) is a chronic inflammatory disease, involving a pathological process of endothelial dysfunction, lipid deposition, plaque rupture, and arterial occlusion, and is one of the leading causes of death in the world population. The progression of AS is closely associated with several inflammatory diseases, among which periodontitis has been shown to increase the risk of AS. Porphyromonas gingivalis (P. gingivalis), presenting in large numbers in subgingival plaque biofilms, is the "dominant flora" in periodontitis, and its multiple virulence factors are important in stimulating host immunity. Therefore, it is significant to elucidate the potential mechanism and association between P. gingivalis and AS to prevent and treat AS. By summarizing the existing studies, we found that P. gingivalis promotes the progression of AS through multiple immune pathways. P. gingivalis can escape host immune clearance and, in various forms, circulate with blood and lymph and colonize arterial vessel walls, directly inducing local inflammation in blood vessels. It also induces the production of systemic inflammatory mediators and autoimmune antibodies, disrupts the serum lipid profile, and thus promotes the progression of AS. In this paper, we summarize the recent evidence (including clinical studies and animal studies) on the correlation between P. gingivalis and AS, and describe the specific immune mechanisms by which P. gingivalis promotes AS progression from three aspects (immune escape, blood circulation, and lymphatic circulation), providing new insights into the prevention and treatment of AS by suppressing periodontal pathogenic bacteria.

Recent Advances in the Management of Hepatorenal Syndrome: A US Perspective

Acute kidney injury (AKI) is a common complication among decompensated patients with cirrhosis and is associated with significant mortality. 1 Garcia-Tsao G. Parikh C.R. Viola A. Acute kidney injury in cirrhosis. Hepatology. 2008; 48: 2064-2077 Crossref PubMed Scopus (441) Google Scholar In this setting, the most common phenotypes of AKI are hypovolemic/prerenal, acute tubular injury/necrosis, and hepatorenal syndrome (HRS). In this article, the most recent terminology put forth by the International Club of Ascites is used, HRS-AKI, which replaces the prior term HRS type 1. 2 Angeli P. Gines P. Wong F. et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015; 64: 531-537 Crossref PubMed Google Scholar HRS-AKI is a devastating complication of advanced cirrhosis occurring in approximately 17% of AKI cases 1 Garcia-Tsao G. Parikh C.R. Viola A. Acute kidney injury in cirrhosis. Hepatology. 2008; 48: 2064-2077 Crossref PubMed Scopus (441) Google Scholar and is associated with a high 90-day mortality rate of 45% to 51%. 3 Wong F. Pappas S.C. Curry M.P. et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med. 2021; 384: 818-828 Crossref PubMed Scopus (86) Google Scholar ,4 Sanyal A.J. Boyer T.D. Frederick R.T. et al. Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies. Aliment Pharmacol Ther. 2017; 45: 1390-1402 Crossref PubMed Scopus (54) Google Scholar The pathophysiology of HRS-AKI is complex. 5 Biggins S.W. Angeli P. Garcia-Tsao G. et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021; 74: 1014-1048 Crossref PubMed Scopus (110) Google Scholar Because of portal hypertension, blood pools in the splanchnic circulation, leading to decreased effective arterial blood volume. As a result, endogenous vasoconstricting systems are activated, leading to sodium and water retention and decreased kidney perfusion. Overlapping with this process there also is increased gut permeability, bacterial translocation, and up-regulation of systemic inflammatory mediators, a secondary cascade that contributes further to impaired kidney perfusion and concomitantly leads to the functional kidney injury seen in HRS-AKI. These dynamic pathophysiologic changes could be potentiated further by infections, acute-on-chronic liver failure (ACLF), or variceal bleeding.

Effects of Vitamin D on Cardiovascular Risk and Oxidative Stress.

Vitamin D has been primarily studied as an important factor influencing bone and calcium metabolism. Metabolites of vitamin D are essential for whole-body calcium homeostasis, maintaining serum calcium levels within a narrow range by regulating this process in the bones and gut. Nevertheless, its deficiency is also related to increased risk of type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), and cardiovascular disease (CVD)-with increased visceral adipose tissue and body mass index (BMI), as well as the frequently associated hypercholesterolemia. It has been reported that vitamin D levels are inversely related to cardiovascular (CV) risk in men and women. However, the effects of vitamin D on distinct outcomes in women and the dose of supplementation needed to improve clinical endpoints have not been established. 25-Hydroxyvitamin D [25(OH)D] reduces systemic inflammatory mediators in CVD and favors the release of anti-inflammatory cytokines from the immune system. In addition, 25(OH)D can be primarily converted into calcitriol (1,25-dihydroxycholecalciferol [1,25(OH)2D]) in the kidneys through the action of the 1-α-hydroxylase enzyme. Calcitriol, through the downregulation mechanism of renin expression, renin-angiotensin-aldosterone system (RAAS) activity, and its interaction with the vitamin D receptor, can bring CV benefits. The calcitriol form also lowers parathyroid hormone (PTH) levels by indirectly causing a reduction in aldosterone and mineralocorticoid synthesis. Elevated plasma aldosterone is related to endothelial dysfunction and CVD in hypovitaminosis D status. Vitamin D supplementation may benefit certain risk groups, as it improves metabolic variables, reducing oxidative stress and CV outcomes. More studies are needed to define interventions with vitamin D in men and women.

Altered early immune response after fracture and traumatic brain injury.

Clinical and preclinical data suggest accelerated bone fracture healing in subjects with an additional traumatic brain injury (TBI). Mechanistically, altered metabolism and neuro-endocrine regulations have been shown to influence bone formation after combined fracture and TBI, thereby increasing the bone content in the fracture callus. However, the early inflammatory response towards fracture and TBI has not been investigated in detail so far. This is of great importance, since the early inflammatory phase of fracture healing is known to be essential for the initiation of downstream regenerative processes for adequate fracture repair. Therefore, we analyzed systemic and local inflammatory mediators and immune cells in mice which were exposed to fracture only or fracture + TBI 6h and 24h after injury. We found a dysregulated systemic immune response and significantly fewer neutrophils and mast cells locally in the fracture hematoma. Further, local CXCL10 expression was significantly decreased in the animals with combined trauma, which correlated significantly with the reduced mast cell numbers. Since mast cells and mast cell-derived CXCL10 have been shown to increase osteoclastogenesis, the reduced mast cell numbers might contribute to higher bone content in the fracture callus of fracture + TBI mice due to decreased callus remodeling.

Lipoxins are correlated with inflammatory milieu in low-risk pregnancies

Endogenous lipoxins play a role in eliminating reactive oxygen species, inhibiting neutrophil chemotaxis, and decreasing both NF-κB and TNF- α. This mediator of systemic inflammation, inducible with aspirin, is not well described in literature regarding pro-inflammatory adverse pregnancy conditions. Our goal was to study lipoxins related to inflammatory milieu in healthy pregnancies. This longitudinal cohort study recruited participants defined as low risk for pre-eclampsia per the United States Preventative Services Task Force (USPSTF) major criteria. Participants attended study visits each trimester. Serum samples were obtained at two time points: 11-16 and 28-32 weeks’ gestation. Lipoxin (LXA4) and C-reactive protein (CRP) in maternal plasma were quantified using Cayman Lipoxin A4 ELISA kits (Ann Arbor, MI) and hsCRP protein enzyme immunoassay test kit (Foster City, CA), respectively. We utilized t-tests, paired t-test, and simple linear regression where appropriate. 56 participants were included. LXA4 was highest in the first trimester and decreased mid-trimester. There was no correlation between LXA4 concentration and maternal age, BMI, or parity at either pregnancy time point. A statistically significant inverse linear relationship between LXA4 and CRP was present in the first trimester (P=0.04) and third trimester (P=0.0004) (Figures 1 & 2). Plasma LXA4 concentration decreased between enrollment and the third trimester (termed Delta LXA4). Delta LXA4 and Delta CRP were compared, but this association was not statistically significant (P=0.91). Lipoxins were not related to BMI or age in this low-risk cohort. The marked inverse relationship between CRP and LXA4 suggests either reduced production or increased utilization in pro-inflammatory environments which may be a therapeutic target for aspirin prophylaxis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Excess body weight significantly affects systemic and tumor inflammatory status and correlates to poor prognosis parameters in patients with breast cancer

IntroductionObesity is a pro-inflammatory disease critical for developing breast cancer (BC), which impacts the profiles of systemic inflammatory mediators and determinants of different disease clinical outcomes remains little explored. MethodsA total of 195 patients diagnosed with breast cancer were included. Aiming to exclude chemotherapy interference on circulating mediators, samples were collected at diagnosis, out of the treatment period. Patients were classified as normal weight (BMI up to 24.9 kg/m2) or overweight (BMI ≥25.0 kg/m2). Serum levels of IL-4, IL-12, hydroperoxides, and nitric oxide metabolites (NOx) were measured. Also, tumor expression of inducible nitric oxide synthase (iNOS), TGF-β1, CD4+, and CD8+ lymphocytes were evaluated. ResultsIL-4 levels were significantly increased in the overweight BC group (p = 0.0329), including patients with luminal B subtype (p = 0.0443), presence of lymph node metastases (p = 0.0115) and age of diagnosis below 50 years, (p = 0.0488). IL-12 levels were significantly increased in overweight BC patients with lymph node metastases (p = 0.0115). Hydroperoxides were increased in overweight BC patients (p = 0.0437), including those with tumors smaller than 2 cm (p = 0.05). NOx levels were also increased in overweight BC patients, including those with luminal B disorders (p = 0.0443), high-grade tumors (p = 0.0351) and lymph node metastases (p = 0.0155). The expression of iNOS (p < 0.001) and TCD4+ lymphocytes (p = 0.0378) was significantly investigated in tumor biopsies from overweight BC women. ConclusionsThese data provide a picture of the influence of excess body weight on inflammatory mediators' systemic and tumoral profiles, especially in patients displaying poor outcome BC.

Endotheliopathy and systemic inflammation: reversibility of cause-and-effect relationship in the pathological functional system (review of literature)

The review considers the involvement of the endothelium and endothelial glycocalyx in the systemic inflammatory response. The role of the endothelium in the inflammation is ambivalent and depends on the nature of the inflammatory process. The physiological response of endothelial cells to local inflammation is necessary to successful eliminate the pathogen and restore the tissue homeostasis. In systemic inflammation, the endothelium is the most «suffering» structure of the body. However, endothelial cells can be a source of systemic inflammatory mediators, supporting the pathological inflammatory process. The problem of generalization of inflammation is discussed where endotheliopathy develops and closes the vicious circle, being both a consequence of systemic inflammation and the cause of its prolongation and intensification. In the pathogenesis of a new coronavirus infection the relationship between endotheliopathy and systemic inflammation was most clearly manifested. Preceding endothelial dysfunction causes a severe course of COVID-19 with a «cytokine storm» and coagulopathy that can lead to the death. SARS-CoV-2 infection induces long-term endothelial dysfunction, which is recorded even after the virus elimination. The early detection of blood level of endothelial glycocalyx damage markers (i. e. syndecan-1, glycosaminoglycans like heparan sulfate and hyaluronic acid) may seem to be an effective approach to the prevention of severe forms of COVID-19. Endothelial-protective drugs can reduce the risk of severe new coronavirus infection and eliminate the manifestations of long-COVID.

Abstract A011: Effect of IL-23 knockdown on obesity driven CRC in high-fat diet fed Apcmin/+ mice

Abstract Colorectal cancer (CRC) is the 3rd common cancer in the United States with an estimated 151,030 new cases and 52,580 deaths in 2022. Several studies suggest that western-style diet-induced obesity contributes to CRC promotion via systemic inflammatory mediators. Recently, we have reported significant elevation of circulating IL-23 levels in obese human subjects (BMI&amp;gt;30). Also, TCGA gene expression data indicated IL-23A over expression in colonic tumors (CT) that correlated with tumor stage, patient obesity, nodal metastasis, and poor survival rates. Importantly, we have shown that IL-23 knockdown in Apc min/+ mice led to significant suppression of the intestinal tumors strongly supporting our hypothesis that pro-inflammatory cytokine IL-23 could be a possible link between obesity and CRC. Here we explored the contribution of IL-23 in obesity induce CRC in vivo using high-fat diet (HFD) fed Apc min/+ mouse model. For this study, Apc min/+ and IL-23 KO (IL-23A p19-/- mice; MMMRC) were cross-bred to generate Apc min/+ mice with IL-23 normal (IL-23+/+) or KO (IL-23-/-) genotypes. Six-week old Apc min/+ mice (N≥15/gender) were grouped by IL-23 genotypes and fed HFD (60 Kcal) until termination. Mice were euthanized at 20 weeks age, intestines were harvested and evaluated for tumors incidence and multiplicity. In Apc min/+ mice, IL-23 deletion had significant suppressive effect on HFD driven CT and small intestinal tumors (SIT). IL-23-/- Apc min/+ male mice had 50% less CT (0.81+0.25 vs 1.61±0.27; p&amp;lt;0.05) while female mice had 40% less CT (0.40±0.16 vs 0.94±0.21; p=0.05) compared to the IL-23+/+ Apc min/+ control mice. Similarly, CT incidence was also suppressed by 36% and 48% in male and female IL-23-/- Apc min/+ mice respectively compared to control mice. SIT multiplicity was also inhibited by 48% in male (15.00±1.13 vs 28.54±1.11; p&amp;lt;0.0001) and by 41% in female (14.83±1.35 vs 25.18±1.71; p&amp;lt;0.0005) IL23-/- Apc min/+ compared to control mice. Tumor data was complemented by significant reduction in markers of proliferation, immune evasion, circulating proinflammatory cytokine and chemokines (IL-1, IL- 17, IL-23, IL-10, CCL-3, CCL-2, CCL-5, IFNγ, TNFα, etc.) in IL-23 KO compared to control mice. Our data clearly indicates that IL-23 is a promising target for CRC prevention in high-risk obese individuals and warrants further investigation. (Supported in part by P30CA225520 and Kerley-Cade Endowed Chair). Citation Format: Venkateshwar Madka, Srikanth Chiliveru, Yuting Zhang, Nicole Stratton, Anh Bao, Nandini Kumar, Chinthalapally V. Rao. Effect of IL-23 knockdown on obesity driven CRC in high-fat diet fed Apcmin/+ mice [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A011.

A review on use of computational biology in testing of skeletal muscle function in COPD patients

Computer biology and bioinformatics are interdisciplinary fields that develop and apply computational methods to analyse large amounts of biological data, such as genetic sequences, cell populations, or protein samples, in order to make new predictions or find novel biology. Analytical approaches, mathematical modelling, and simulation are among the computational methods employed.Chronic Obstructive Pulmonary Disease (COPD) is a lung inflammatory disease that causes persistent airflow restriction. These individuals frequently have extensive systemic consequences, such as skeletal muscle dysfunction, which severely restrict their life expectancy. Despite extensive research, the molecular basis of muscle deterioration in COPD remains a matter of contention. We used a network biology approach to investigate the link between the molecular and physiological responses of muscles to training and systemic inflammatory mediators in this study. Failure to coordinately activate expression of various tissue remodelling and bioenergetics pathways is a distinctive feature of COPD diseased muscles, according to our model. Our findings also point to a relationship between this phenomena and aberrant expression of a number of histone modifiers, which we discovered associated with oxygen utilisation. These findings highlighted the intriguing hypothesis that cell hypoxia is a crucial contributor in COPD patients' skeletal muscle.

Intravenous injection of adipose-derived mesenchymal stromal cells benefits gait and inflammation in a spontaneous osteoarthritis model.

Osteoarthritis (OA) is a leading cause of morbidity among aging populations, yet symptom and/or disease-modification remains elusive. Adipose-derived mesenchymal stromal cells (adMSCs) have demonstrated immunomodulatory and anti-inflammatory properties that may alleviate clinical signs and interrupt disease onset and progression. Indeed, multiple manuscripts have evaluated intra-articular administration of adMSCs as a therapeutic; however, comparatively few evaluations of systemic delivery methods have been published. Therefore, the aim of this study was to evaluate the short-term impact of intravenous (IV) delivery of allogeneic adMSCs in an established model of spontaneous OA, the Hartley guinea pig. Animals with moderate OA received once weekly injections of 2 × 106 adMSCs or vehicle control for 4 weeks in peripheral veins; harvest occurred 2 weeks after the final injection. Systemic administration of adMSCs resulted in no adverse effects and was efficacious in reducing clinical signs of OA (as assessed by computer-aided gait analysis) compared to control injected animals. Further, there were significant decreases in key inflammatory mediators (including monocyte chemoattractant protein-1, tumor necrosis factor, and prostaglandin E2 ) both systemically (liver, kidney, and serum) and locally in the knee (joint tissues and synovial fluid) in animals treated with IV adMSCs relative to controls (as per enzyme-linked immunosorbent assay and/or immunohistochemistry, dictated by tissue sample). Thus, systemic administration of adMSCs by IV injection significantly improved gait parameters and reduced both systemic and intra-articular inflammatory mediators in animals with OA. These findings demonstrate the potential utility of alternative delivery approaches for cellular therapy of OA, particularly for patients with multiple affected joints.

The Plausible Relationship Between Periodontitis and Glaucoma.

Periodontitis has been associated with several medical conditions. For some of these medical conditions, periodontitis has been hypothesized to share important pathogenic mechanisms with other systemic conditions affecting the body. Recently, advances in technology have led to the identification of novel inflammatory mediators implicated in some chronic medical conditions associated with periodontitis. The potential identification of these systemic inflammatory mediators in periodontitis would offer additional support to the potential periodontal-systemic disease association. In recent years, the term oral foci of infection has attained an upturn in terms of systemic morbidities, while finite scrutinization indicates the implication of chronic oral inflammation in the pathogenesis of eye diseases. Initially, there is a singularity for the mechanistic understanding of the reported link between periodontal diseases and ocular comorbidities. There is a limited number of scientific evidence in the literature that suggests a relationship between glaucoma and periodontitis, and they share a common pathway/link based on inflammatory markers. Based on a molecular biological technique, it was believed by researchers and clinicians that eye diseases were a result of oral infections. Furthermore, this review will try to focus on the concept of oral dysbiosis in the progression of inflammatory eye diseases such as diabetic retinopathy, scleritis, uveitis, glaucoma, and age-related macular degeneration (AMD).

Understanding the Role of Inflammation in Secondary Osteoarthritis

Osteoarthritis (OA) is the most seen form of arthritis, affecting a population of about 3.3 to 3.6% worldwide. In the ranking, it is the 11th most incapacitating disease worldwide, and in about a 43million people, it causes mild to severe disability. Estimated that 80% of the population In the United States over 65 years old have radiographic evidence of OA, although only 60-70% of this subset has symptoms. There were about 1 million hospitalizations for OA in 2011, with a cumulative cost of nearly $15 billion. This makes A the second most expensive disease seen in the United States [1, 2]. Secondary OA can affect older adults, and it could also affect younger people, usually those under 35 years of age.&#x0D; Secondary OA has been regarded more as a mechanically-driven disease than an inflammatory disease. However, low-grade inflammation plays some part in cartilage degeneration and repair at many stages of arthropathy. In the past years, many published scientific papers on both animal models and human studies have indicated an increased role for both synovial inflammations and the activation of the membrane attack complexes of the complement system in the pathogenesis of secondary OA. There is also increasing evidence that significant risk factors for secondary OA have been linked with changes in systemic and local (at the articular cartilage chondrocyte level) cytokines and inflammatory mediators.&#x0D; However, it remains controversial whether or not the inflammatory mediators are primary or secondary regulators of the damage to the cartilage or defective repair mechanisms present in secondary Osteoarthritis because the pathways for signaling involved in inflammatory and biomechanical stress are very much similar. So, these pathways could also induce and increase the expression of cytokine and chemokine genes.&#x0D; Although research on the inflammatory mediators associated with Osteoarthritis has been done and much knowledge has been gained in the last decade, more studies are needed to define better the mechanisms by which these factors tip the balance between homeostasis and activation to promote cell death and matrix destruction. In response to stress and inflammatory insults, osteoarthritis chondrocytes produce a variety of matrix-degrading enzymes, including metalloproteinases and aggrecans. The expression of most of these enzymes of degradation is dysregulated in chondrocytes of patients with Osteoarthritis, and their increased activities and aberrant expression are the main contributors to cartilage degradation during osteoarthritis development and progression [3]. This student project aims to understand the role of inflammation in secondary Osteoarthritis.