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For the most part, a pathologist's work consists of other than tumor samples. Inflammatory and degenerative diseases are classified according to etiology and character into groups differing significantly in their treatment and prognosis. In these diseases, histopathologic analysis continues to be one of the most important tools for their classification and assessment of the degree of severity. Even a negative finding assists in directing further investigations and follow-up. The development of new analysis methods along with new marker substances has helped to find even novel disease groups such as IgG4-associated inflammatory diseases.

The vascular blood-brain barrier is a highly regulated interface between the blood and brain. Its primary function is to protect central neurons while signaling the presence of systemic inflammation and infection to the brain to enable a protective sickness behavior response. With increasing degrees and duration of systemic inflammation, the vascular blood-brain barrier becomes more permeable to solutes, undergoes an increase in lymphocyte trafficking, and is infiltrated by innate immune cells; endothelial cell damage may occasionally occur. Perturbation of neuronal function results in the clinical features of encephalopathy. Here, the molecular and cellular anatomy of the vascular blood-brain barrier is reviewed, first in a healthy context and second in a systemic inflammatory context. Distinct from the molecular and cellular mediators of the blood-brain barrier's response to inflammation, several moderators influence the direction and magnitude at genetic, system, cellular and molecular levels. These include sex, genetic background, age, pre-existing brain pathology, systemic comorbidity, and gut dysbiosis. Further progress is required to define and measure mediators and moderators of the blood-brain barrier's response to systemic inflammation in order to explain the heterogeneity observed in animal and human studies., (© 2021. The Author(s).)

Background:Higher-grade inflammatory infiltrate is a promising marker for better prognosis in colorectal cancer (CRC). However, the knowledge on the interrelationships between different inflammatory cells and classifications is fragmentary.Methods:We analysed the densities of eight types of inflammatory cells in a prospectively recruited group of 117 CRC patients and determined their interrelationships and contributions to Klintrup-Mäkinen (K-M) score of overall peritumoural inflammation. We characterised the inflammatory infiltrate in relation to stage and recurrences in 24-month follow-up.Results:There were high positive correlations between the inflammatory cell densities, with the exception of mast cells and CD1a+ immature dendritic cells. High K-M score associated with high peri- and intratumoural densities of CD3+, CD8+, CD68+, CD83+, and FoxP3+ cells and neutrophils. Advanced stage associated with low K-M score, as well as low CD3+, CD8+, CD83+, and FoxP3+ cell counts, of which low K-M score, low CD3+ T-cell count, and low FoxP3+ T-cell count were linked to higher recurrence rate.Conclusion:The density of CRC inflammatory infiltrate declines as stage advances. Especially, low K-M score and low T-cell counts predict higher recurrence rate. The high positive correlations between the individual inflammatory markers support the value of overall inflammatory reaction scoring. [ABSTRACT FROM AUTHOR]

Background:Inflammation contributes to the pathogenesis of colorectal cancer (CRC), and cytokine levels are altered during colorectal carcinogenesis.Methods:The serum levels of 13 cytokines and their relation to clinical and pathological parameters, and systemic inflammatory response (mGPS, CRP and neutrophil-lymphocyte ratio), were analysed from a prospective series of 148 CRC patients and 86 healthy age- and sex-matched controls.Results:CRC patients had higher serum platelet-derived growth factor, interleukin (IL)-6, IL-7, and IL-8 levels and lower monocyte chemotactic protein-1 (MCP-1) levels than the controls. A logistic regression model for discriminating the patients from the controls - including the five most predictive cytokines (high IL-8, high IL-6, low MCP-1, low IL-1ra, and low IP-10) - yielded an area under curve value of 0.890 in receiver operating characteristics analysis. Serum cytokines showed distinct correlation with other markers of systemic inflammatory response, and advanced CRCs were associated with higher levels of IL-8, IL-1ra, and IL-6. A metastasised disease was accompanied by an orientation towards Th2 cytokine milieu.Conclusion:CRC is associated with extensive alterations in serum cytokine environment, highlighting the importance of studying relative cytokine level alterations. Serum cytokine profile shows promise in separating CRC patients from healthy controls but its clinical value is yet to be confirmed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Our aim was to perform a cross-sectional study to estimate the prevalence of elevated pancreatic enzymes in patients with inflammatory bowel disease and to correlate the enzyme activities with clinical, endoscopic. and histological findings. METHODS: Two hundred thirty-seven patients diagnosed with inflammatory bowel disease (IBD), including a sub-group with known hepatobiliary disease, were studied cross-sectionally. Serum and urinary pancreatic enzymes were prospectively sampled and compared lo endoscopic and histological findings obtained previously. RESULTS: Hyperamylasemia was found in 11% and hyperlipasemia in 1% of the total study group. The corresponding prevalences in patients with Crohn's disease were 17% and 9%. those in ulcerative colitis 9% and 7%, and those in indeterminate colitis 10% and 5%, respectively. High levels of serum amylase and pancreatic isoamylase were associated with extensive colonic disease (p < 0.05) and high histological activity (p < 0.05). Amylase, but not lipase, was significantly elevated in patients with primary sclerosing cholangitis. Smokers showed higher urinary amylase levels than non- and ex-smokers. The use of medication bad no influence on the enzyme levels. CONCLUSIONS: Pancreatic enzymes are elevated in a significant proportion of patients with IBD, and the enzyme increase is associated with a more extensive and active disease, and in some cases with primary sclerosing cholangitis. [ABSTRACT FROM AUTHOR]

Perioperative neurocognitive disorder (PND) is a common disorder following anesthesia and surgery, especially in the elderly. The complex cellular and molecular processes are involved in PND, but the underlying pathogenesis of which remains inconclusive due to conflicting data. A growing body of evidence has been shown that perioperative systemic inflammation plays important roles in the development of PND. We reviewed the relevant literature retrieved by a search in the PubMed database (on July 20, 2023). The search terms used were "delirium", "post operative cognitive dysfunction", "perioperative neurocognitive disorder", "inflammation" and "systemic", alone and in combination. All articles identified were English-language, full-text papers. The ones cited in the review are those that make a substantial contribution to the knowledge about systemic inflammation and PNDs. The aim of this review is to bring together the latest evidence for the understanding of how perioperative systemic inflammation mediates neuroinflammation and brain injury, how the inflammation is regulated and how we can translate these findings into prevention and/or treatment for PND. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood–brain barrier's (BBB´s) and blood–cerebrospinal fluid barrier´s (BCSFB´s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate functional alterations to neurodegenerative processes. The present work aims to explain these processes and the pathophysiological interactions involved in CNS damage in the absence of microbes or inflammatory cells. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to investigate the prognostic impact of tumor-infiltrating lymphocytes (TILs) in a panel of 264 sporadic breast cancers by quantifying TIL levels according to Salgado and correlate this with type I and II nuclear receptor expression. Breast cancer cases with a TIL Salgado score of >15% showed a significantly decreased overall survival and peritumoral inflammation (according to Klintrup) determined the prognostic value of ER, PR, and PPARγ in BC. Therefore, the present study demonstrates significant relations between TIL levels, nuclear receptor expression and prognosis in breast cancer. The prognostic impact of tumor-infiltrating lymphocytes (TILs) is intensively investigated in breast cancer (BC). It is already known that triple-negative breast cancer (TNBC), the most aggressive type of BC, has the highest percentage of TILs. In addition, there is an influence of steroid hormone receptor expression (type I nuclear receptors) on TIL subpopulations in breast cancer tissue. The link between type II nuclear receptors and the level of TILs is unclear. Therefore, the aim of this study was to quantify TILs in a panel of 264 sporadic breast cancers and investigate the correlation of TIL levels with type I and II nuclear receptors expression. TIL levels were significantly increased in the subgroup of TNBC. By contrast, they decreased in estrogen (ER)- or progesterone receptor (PR)-positive cases. Moreover, TIL levels were correlated with type II nuclear receptors, including PPARγ, with a significant inverse correlation of the nuclear form (r = −0.727, p < 0.001) and a weak positive correlation of the cytoplasmic form (r = 0.202, p < 0.002). Surprisingly, BC cases with a TIL Salgado score of >15% showed a significantly decreased overall survival. In addition, peritumoral inflammation was also quantified in BC tissue samples. In our cohort, although the level of peritumoral inflammation was not correlated with OS, it determined the prognostic value of ER, PR, and PPARγ in BC. Altogether, the present study provides a differentiated overview of the relations between nuclear receptor expression, TIL levels, peritumoral inflammation, and prognosis in BC. [ABSTRACT FROM AUTHOR]

BACKGROUND: Inflammatory cytokines play roles in the pathogenesis of celiac disease. To introduce new diagnostic markers in patients with celiac disease for easy, fast, low cost, and non-invasive diagnosis, we evaluated the peripheral blood expression levels of interleukin-15 (IL-15), interleukin-17A (IL-17A), interleukin23A (IL-23A), granzyme B (GzmB), T-box transcription factor 21 (TBX21), and tumor necrosis factor alpha-induced protein 3 (TNFAIP3) of patients compared with the healthy controls, which were extracted from public databases organized in a protein-protein interaction network, in this group. METHODS: Peripheral blood mononuclear cells were collected from 30 patients with celiac disease and 30 healthy subjects. Total RNA was extracted, and mRNA expression levels of targeted genes were investigated by the quantitative realtime polymerase chain reaction (PCR) method. SPSS software was used for statistical analysis. Receiver operating characteristic (ROC) curve analysis was performed to characterize the diagnostic ability of the studied genes. RESULTS: The expression of IL-15, IL-17A, IL-23A, GzmB, TBX21, and TNFAIP3 genes in peripheral blood mononuclear cells of patients with celiac disease showed a significant increase compared with the control group. Among them, TNFAIP3, IL23A, and GzmB have better resolution and diagnostic value in differentiating patients with celiac disease from healthy controls. CONCLUSION: Our results suggest that TNFAIP3, IL23A, and GzmB could be useful and sensible markers in differentiating patients with celiac disease from healthy controls. However, the diagnostic relevance of other genes recognized by pathway analysis needs to be further investigated. [ABSTRACT FROM AUTHOR]

Introduction: H. pylori are gram-negative, microaerophilic helical-shaped bacteria with multiple flagella and commonly exist in the stomach. This infection may cause significant mucosal inflammation and damage, leading to ulcers in the stomach. It can also affect organ systems external to the gastrointestinal tract. To assess cardiovascular risk factors and to predict cardiovascular disorders, we are evaluating and comparing lipid profile and inflammatory marker between H. pylori-positive and negative patients. Objective: To evaluate and compare lipid profile (TC; TG; LDL; HDL) and inflammatory marker (hs-CRP) in dyspeptic patients with and without H. pylori infection. Methods: Comparative cross-sectional study was conducted from September 2020 to January 2021 at Debre Markos Referral Hospital, Debre Markos Health Center, and Hidassie Health Center, Ethiopia. Each of 50 H. pylori-positive and negative dyspeptic patients were studied. The data were checked for completeness and analyzed by SPSS version 25.0 Software. A p-value < 0.05 was considered statistically significant. Results: Serum mean high-density lipoprotein (HDL) values were 37.54 ± 7.98 mg/dL and 43.12 ± 7.86 mg/dL (p < 0.05) for H. pylori-positive and negative dyspeptic patients, respectively, and median serum high sensitive C reactive protein (hs-CRP) levels were 6.29 mg/L (1.66– 41.34) and 3.35 mg/L (0.39– 10.01) (p < 0.05) for H. pylori-positive and negative dyspeptic patients, respectively. Conclusion: H. pylori infection significantly alters serum high-density lipoprotein (HDL) and high sensitive C reactive protein (hs-CRP) levels in dyspeptic patients, as a result, increase the potential risk of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

As a complex multicellular structure of the vascular system at the central nervous system (CNS), the blood-brain barrier (BBB) separates the CNS from the system circulation and regulates the influx and efflux of substances to maintain the steady-state environment of the CNS. Lipopolysaccharide (LPS), the cell wall component of Gram-negative bacteria, can damage the barrier function of BBB and further promote the occurrence and development of sepsis-associated encephalopathy (SAE). Here, we conduct a literature review of the direct and indirect damage mechanisms of LPS to BBB and the relationship between these processes and SAE. We believe that after LPS destroys BBB, a large number of inflammatory factors and neurotoxins will enter and damage the brain tissue, which will activate brain immune cells to mediate inflammatory response and in turn further destroys BBB. This vicious circle will ultimately lead to the progression of SAE. Finally, we present a succinct overview of the treatment of SAE by restoring the BBB barrier function and summarize novel opportunities in controlling the progression of SAE by targeting the BBB. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening organ dysfunction triggered by a dysregulated host immune response attempting to eliminate the infection. After hospital discharge, half of the sepsis survivors recover, one-third of the patients die the following year, and one-sixth have a long-term cognitive impairment, including memory dysfunction, anxiety, depression, and post-traumatic stress disorder. The infection triggers the host immune response, and both can cause vascular endothelial damage, interrupting tight junctions proteins; consequently, the blood-brain barrier (BBB) breaks down, allowing and facilitating the entry of peripheral immune cells into the brain, which triggers or exacerbates the activation of glial cells and neuroinflammation. The focus of this review is to identify biochemical abnormalities induced by sepsis, which is associated with BBB dysfunction; provide evidence of biomarkers involved in the tight junction disruption and BBB damage, and draw attention to the role of the BBB as a bridge between systemic infection and brain inflammation. [ABSTRACT FROM AUTHOR]

Inflammation has been linked with cancer, but whether it is part of the problem or part of the solution remains to be a matter of debate in breast cancer. Our group and others have demonstrated that inflammation aggravates cancer progression; however, some claim that inflammation may support immune cell infiltration and suppress cancer. We defined the gene set variation analysis of the Molecular Signatures Database Hallmark inflammatory response gene set as the inflammatory pathway score and analyzed 3632 tumors in total from 4 breast cancer cohorts (METABRIC, TCGA, GSE25066, and GSE21094). In the whole breast cancer cohort, high-score tumors were associated with aggressive clinical characteristics, such as worse disease specific survival, higher Nottingham histological grade, and younger age. Inflammatory score was significantly higher in triple-negative (TNBC) as well as basal and normal subtypes compared with the other subtypes, which suggest that the detrimental effect of high level of inflammation may be because it includes a more aggressive subtype. On the contrary, high score within TNBC was significantly associated with better survival. TNBC with high score enriched not only IFN-α, IFN-γ response, IL-2/STAT5 signaling, Allograft rejection, Complement, p53 pathway, Reactive Oxygen, and Apoptosis but also TNF-α signaling, IL6-JAK-STAT signaling, TGF-β signaling, Coagulation, Angiogenesis, EMT, KRAS signaling, and PI3K-AKT-MTOR signaling gene sets. High score was associated with mainly favorable anticancerous immune cell infiltration as well as Leukocyte fraction, TIL regional fraction, Lymphocyte infiltration, IFN-γ response, TGF-β response, and cytolytic activity scores. Although the inflammatory pathway score was not associated with neoadjuvant treatment response, it associated with expressions of immune checkpoint molecules. In conclusion, inflammation was associated with worse outcome in the whole breast cancer cohort, but with better outcome in TNBC, which was associated with favorable anticancerous immune response and immune cell infiltrations. [ABSTRACT FROM AUTHOR]

Background: Inflammation plays an important albeit dual role in carcinogenesis. Survival studies have highlighted the prognostic significance of peritumorous inflammation. Currently, the theoretical background allows inflammation, epithelial mesenchymal transition (EMT) and the closely associated stem cell differentiation in colorectal carcinoma (CRC) to be linked. However, there is scarce direct morphological evidence. Purpose and methods: The aim of our study was to investigate the role of inflammation in cancer growth and invasion by analyzing the association between inflammation and known morphological prognostic features of colorectal cancer, EMT, stemness and mismatch repair (MMR) protein expression. The study was designed as a retrospective morphological and immunohistochemical assessment of 553 consecutive cases of surgically treated primary CRC. Results: There were statistically significant associations between high-grade inflammation and lower pT (p = 0.002), absence of lymph node metastases (p < 0.001) and less frequent lymphatic (p = 0.003), venous (p = 0.017), arterial (p = 0.012), perineural (p = 0.001) and intraneural (p = 0.01) invasion. In contrast, Crohn's like reaction (CLR) by density of lymphoid follicles in the invasive front lacked significant differences in regard to pT, pN, tumor invasion into surrounding structures (blood or lymphatic vessels, nerves), grade or necrosis (all p > 0.05). The expression of E-cadherin, CD44 and MMR proteins yielded no statistically significant associations with peritumorous inflammation by Klintrup-Mäkinen score or the density of lymphoid follicles. Nevertheless, E-cadherin levels were significantly associated with the density of eosinophils (p = 0.007). Conclusion: High-grade peritumorous inflammation is associated with beneficial morphologic CRC features, including less frequent manifestations of invasion, and is not secondary to tissue damage and necrosis. CLR is not associated with cancer spread by pTN; this finding indirectly suggests an independent role of CLR in carcinogenesis. Further, inflammation by Klintrup-Mäkinen grade and CLR is not dependent on epithelial-mesenchymal transition and stem cell differentiation. Our study highlights the complex associations between inflammation, tumor morphology, EMT, stemness and MMR protein expression in human CRC tissues. [ABSTRACT FROM AUTHOR]

Aim: Identification of the important processes and the related genes that are dis-regulated in the celiac disease (CD) was the aim of this study. Background: Celiac disease is an autoimmune disorder which is characterized by immune reaction response mostly to wheat gluten. The gluten-free diet is the best-known treatment of the patients. Methods: Significant differentially expressed proteins (DEPs) related to the CD are extracted from a published proteomics study and are included in protein-protein interaction PPI) network analysis by Cytoscape software and its applications. The central proteins and related processes are identified and discussed. Results: Among 53 queried genes, 51 individuals were recognized by the database, and after network construction, 48 ones included in the network, and three genes remained as isolated nodes. Following 50 neighbors, the network was analyzed, and eight central genes were identified as dis-regulated elements. Related processes and the role of the central genes in celiac are discussed in detail. Conclusion: CAT, ENO1, PCK2, ACO2, ALDOOB, GALM, ADA, and ACTBADA as critical genes and Antioxidant activity, carbohydrate metabolism, inflammation, cell growth processes are highlighted as the dis-regulated individuals in CD. [ABSTRACT FROM AUTHOR]

Background: Extra-gastric manifestation of Helicobacter pylori infection involves systemic inflammation, which results in the production of several cytokines. Only a few clinical trials have investigated the effect of H. pylori eradication therapy on lipid metabolism in the infected patients with chronic gastritis. We aimed to evaluate the effect of H. pylori eradication therapy on lipid metabolism in a Japanese population with chronic gastritis. Methods: One hundred and sixty-three patients with H. pylori-associated chronic gastritis were enrolled in this study between June 2015 and March 2017. They underwent H. pylori eradication therapy; the effects of the therapy were assessed by the urea breath test performed at least 4 weeks after the therapy. After confirming H. pylori eradication, the health screening examination was repeated between May 2016 and August 2018. The clinical parameters were compared before and after the administration of the eradication therapy. Results: The mean age of the enrolled patients was 56.7 years, and the mean follow-up duration was 514.7 days. Weight, body mass index, and obesity index were significantly increased post-eradication therapy compared to those pre-eradication therapy. White blood cell and platelet counts were significantly decreased, and high density lipoprotein cholesterol (HDL) level was significantly increased (P = 0.001), while low density lipoprotein cholesterol (LDL), total cholesterol, and triglycerides levels were not altered significantly. Hence, the LDL/HDL ratio was significantly decreased. Conclusions: This study reported that H. pylori eradication therapy increase the HDL levels in the infected patients with chronic gastritis. Hence, the LDL/HDL ratio, which is used to evaluate the risk of atherosclerosis, was significantly decreased post-eradication therapy compared to that pre-eradication therapy. [ABSTRACT FROM AUTHOR]

Oxymatrine (OMT) plays a significant role in chemical agents induced intestinal injury. However, its functional role in L-arginine (Arg) induced acute pancreatitis (AP) following intestinal injury and the corresponding molecular mechanism are unclear to our knowledge. We investigate OMT function in Arg induced AP following intestinal injury in vivo and vitro. OMT (4 mg/ml) decreased Arg (from 100 to 600 µM) induced IEC-6 cells growth in dose-dependent manner and inhibited Arg induced the increase of pAKT, bcl2, and the decrease of Bax. Meanwhile, OMT inhibited Arg (600 µM) induced the increase of pro-inflammatory cytokines TNF-a, IL-6, IL-1β, and NFkBp65 and the decrease of anti-inflammatory cytokine IL-10 expression. Moreover, the change of tight junction proteins claudins 1-4 expression induced by Arg was also reversed by OMT. Consistent with the results in vitro, OMT (50 mg/kg) inhibited Arg (250 mg/100 g) induced AP following intestinal injury in vivo. In detail, OMT resisted Arg induced inflammatory histology of both pancreas and intestine and inhibited Arg induced the change of pAKT, Bax, bcl2, TNF-a, IL-6, IL-1β, IL-10, NFkBp65, claudin 1-4 expression. Moreover, OMT inhibited Arg induced NFkBp65 and ICAM-1 expression in vivo by IHC. Oxymatrine improves Arg-induced acute pancreatitis following intestinal injury via inhibiting AKT/NFkB and claudins signaling. [ABSTRACT FROM AUTHOR]

Toll like receptor (TLR) signaling is involved in activating innate and adaptive immune responses and plays a critical role in inflammation‐induced diseases such as colorectal cancer (CRC). Dysregulation of this signaling pathway can result in disturbance of epithelial layer hemostasis, chronic inflammatory, excessive repair responses, and development of CRC. There is now substantial evidence for the benefit of targeting of this pathway in cancer treatment, and several agents have been approved, such as BCG (Bacillus Calmette Guérin), MPL (monophosphoryl lipid A) and imiquimod. This review summarizes the current knowledge about the different functions of TLRs on tumor cells and their application in cancer therapy with particular emphasis on recent preclinical and clinical research in treatment of CRC. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia resulting in atherosclerosis is associated with an increased risk of ischemic heart disease and colorectal cancer (CRC). However, the roles of apoliprotein (Apo) E (Apoe) and low-density lipoprotein (Ldl) receptor (Ldlr) in colorectal carcinogenesis have not yet been investigated. In this study, we examined the susceptibility of Apoe-deficient and Ldlr-deficient mice, which are genetic animal models of atherosclerosis to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. In Experiment 1, male Apoe-deficient (n = 20) and wild type (WT) mice (C57BL/6J, n = 21) were treated with a single intraperitoneal (i.p.) injection of AOM (10 mg/kg body weight) and then given 1.5% DSS in drinking water for seven days. They were maintained up to week 20 and sacrificed for the histopathological examination of colorectal tumors. The mRNA expression of cyclooxygenase (Cox)-2, inducible nitric oxide synthase (Nos2), tumor necrosis factor (Tnf )-a interleukin (Il)-1b, and Il-6 was assayed in the colorectal mucosa. In Experiment 2, male Ldlr-deficient (n = 14) and WT mice (C57BL/6J, n = 10) were given a single i.p. injection of AOM (10 mg/kg body weight) and then given 2% DSS in drinking water for seven days. They were sacrificed at week 20 to evaluate their colorectum histopathologically. In Experiment 1, the multiplicity of CRCs was significantly higher in the Apoe-deficient mice (2.75 ± 1.48) than in the WT mice (0.62 - 0.67). The serum lipoprotein levels in the Apoe-deficient mice were also significantly higher than in the WT mice. In Experiment 2, the incidence (29%) and multiplicity (0.50 ± 0.94) of CRCs in the Ldlr mice were significantly lower than in the WT mice (80% incidence and 3.10 ± 2.38 multiplicity). The mRNA expression of two inducible enzymes and certain pro-inflammatory cytokines in the colorectum of each genotype was greater than in the respective WT mice. The values in the Apoe-deficient mice were much greater than in the Ldlr mice. These findings suggest that Apoe-deficient mice showed increased susceptibility to inflammation-associated colorectal carcinogenesis due to their high reactivity to inflammatory stimuli. [ABSTRACT FROM AUTHOR]

Adenosine, an immunomodulatory biomolecule, is produced by the ecto-enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5'-nucleotidase) by dephosphorylation of extracellular ATP. CD73 is expressed by many cell types during injury, infection and during steady-state conditions. Besides host cells, many bacteria also have CD39-CD73-like machinery, which helps the pathogen subvert the host inflammatory response. The major function for adenosine is anti-inflammatory, and most recent research has focused on adenosine's control of inflammatory mechanisms underlying various autoimmune diseases (e.g., colitis, arthritis). Although adenosine generated through CD73 provides a feedback to control tissue damage mediated by a host immune response, it can also contribute to immunosuppression. Thus, inflammation can be a double-edged sword: it may harm the host but eventually helps by killing the invading pathogen. The role of adenosine in dampening inflammation has been an area of active research, but the relevance of the CD39/CD73-axis and adenosine receptor signaling in host defense against infection has received less attention. Here, we review our recent knowledge regarding CD73 expression during murine Salmonellosis and Helicobacter-induced gastric infection and its role in disease pathogenesis and bacterial persistence. We also explored a possible role for the CD73/adenosine pathway in regulating innate host defense function during infection. [ABSTRACT FROM AUTHOR]

The antibacterial and anti-inflammatory activities, and protective effects of extracts (flavonoid glycosides) of Polygonum capitatum were investigated to detect the evidence for the utilization of the herb in the clinical therapy of gastritis caused by H. pylori. A mouse gastritis model was established using H. pylori. According to treating methods, model mice were random assigned into a model group (MG group), a triple antibiotics group (TG group, clarithromycin, omeprazole and amoxicillin), low/middle/high concentrations of flavonoid glycosides groups (LF, MF and HF groups) and low/middle/high concentrations of flavonoid glycosides and amoxicillin groups (LFA, MFA and HFA groups). A group with pathogen-free mice was regarded as a control group (CG group). The eradicate rates of H. pylori were 100%, 93%, 89% in TG, MFA and HF groups. The serum levels of IFN-gamma and gastrin were higher in a MG group than those from all other groups (P < 0.05). The serum levels of IFN-gamma and gastrin were reduced significantly in LF, MF and HF groups (P < 0.05) while little changes were observed in LFA, MFA and HFA groups. In contrast, the serum levels of IL-4 were lower and higher in MG and CG groups compared with other groups (P<0.05). The serum levels of IL-4 were increased significantly in LF, MF and HF groups (P < 0.05) while little changes were found in LFA, MFA and HFA groups. According to pathological scores, flavonoid glycosides therapy showed better protection for gastric injuries than the combination of flavonoid glycoside and amoxicillin (P < 0.05). The results suggested that flavonoid glycoside has repairing functions for gastric injuries. The results suggest that the plant can treat gastritis and protect against gastric injuries. The flavonoid glycosides from Polygonum capitatum should be developed as a potential drug for the therapy of gastritis caused by H. pylori. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase 2 regulates acid-base homeostasis, and recent findings have indicated a correlation between cellular control of acid-base status and the innate defense of the kidney. Mice deficient in carbonic anhydrase 2 (Car2-/- mice) have metabolic acidosis, impaired urine acidification, and are deficient in normal intercalated cells. The objective of the present study was to evaluate the biological consequences of carbonic anhydrase 2 deficiency in a murine model of pyelonephritis. Infection susceptibility and transcription of bacterial response components in Car2-/- mice were compared with wild-type littermate controls. Car2-/- mice had increased kidney bacterial burdens along with decreased renal bacterial clearance after inoculation compared with wild-type mice. Standardization of the urine pH and serum HCO3- levels did not substantially alter kidney infection susceptibility between wild-type and Car2-/- mice; thus, factors other than acid-base status are responsible. Car2-/- mice had significantly increased neutrophil-gelatinase-associated lipocalin mRNA and protein and expression at baseline and a marked decreased ability to upregulate key bacterial response genes during pyelonephritis. Our findings provide in vivo evidence that supports a role for carbonic anhydrase 2 and intercalated cells in promoting renal bacterial clearance. Decreased carbonic anhydrase expression results in increased antimicrobial peptide production by cells other than renal intercalated cells, which is not sufficient to prevent infection after a bacterial challenge. [ABSTRACT FROM AUTHOR]

Helicobacter pylori is one of the most common infections in the world. Despite inciting inflammation, immunological clearance of the pathogen is often incomplete. CD4+ CD25hi forkhead box protein 3 (FoxP3+) regulatory T cells ( Tregs) are potent suppressors of different types of immune responses and have been implicated in limiting inflammatory responses to H. pylori. Investigating the influence of H. pylori on Treg function and proliferation, we found that H. pylori-stimulated dendritic cells ( DCs) induced proliferation in Tregs and impaired their suppressive capability. This effect was mediated by interleukin ( IL)-1β produced by H. pylori-stimulated DCs. These data correlated with in-vivo observations in which H. pylori+ gastric mucosa contained more Tregs in active cell division than uninfected stomachs. Inciting local proliferation of Tregs and inhibiting their suppressive function may represent a mechanism for the chronic gastritis and carcinogenesis attributable to H. pylori. [ABSTRACT FROM AUTHOR]

Chronic inflammatory disorders such as inflammatory bowel diseases (IBDs) affect bone metabolism and are frequently associated with the presence of osteopenia, osteoporosis, and increased risk of fractures. Although several mechanisms may contribute to skeletal abnormalities in IBD patients, inflammation and inflammatory mediators such as TNF, IL-1β, and IL-6 may be the most critical. It is not clear whether the changes in bone metabolism leading to decreased mineral density are the result of decreased bone formation, increased bone resorption, or both, with varying results reported in experimental models of IBD and in pediatric and adult IBD patients. New data, including our own, challenge the conventional views, and contributes to the unraveling of an increasingly complex network of interactions leading to the inflammation-associated bone loss. Since nutritional interventions (dietary calcium and vitamin D supplementation) are of limited efficacy in IBD patients, understanding the pathophysiology of osteopenia and osteoporosis in Crohn's disease and ulcerative colitis is critical for the correct choice of available treatments or the development of new targeted therapies. In this review, we discuss current concepts explaining the effects of inflammation, inflammatory mediators and their signaling effectors on calcium and phosphate homeostasis, osteoblast and osteoclast function, and the potential limitations of vitamin D used as an immunomodulator and anabolic hormone in IBD. [ABSTRACT FROM AUTHOR]

Endoscopic evaluation and mucosal biopsy analysis have assumed important roles in the clinical management of patients with symptoms related to the gastrointestinal tract. Several common inflammatory diseases, including eosinophilic esophagitis, Barrett's esophagus, Helicobacter pylori infection, celiac disease, lymphocytic colitis, collagenous colitis, and inflammatory bowel disease, may display a patchy or discontinuous distribution and, thus, multiple mucosal samples may be required to obtain diagnostic tissue in some cases. Not surprisingly, clinicians and pathologists are increasingly challenged to determine the optimum number of procedures and tissue samples necessary to detect, or exclude, the presence of inflammatory disorders of the gastrointestinal tract. Unfortunately, clinical practice varies widely with respect to tissue sample procurement in the evaluation of these disorders, particularly when the endoscopic appearance of the gastrointestinal mucosa is normal or shows only minimal changes. Guidelines concerning the appropriate number of tissue samples are well established for some diseases, such as Barrett's esophagus and chronic gastritis, but are not clear in other instances. The purpose of this review is to discuss the available literature pertaining to appropriate endoscopic sampling in the assessment of medical diseases of the gastrointestinal tract, and to develop recommendations regarding the clinical evaluation of common gastrointestinal disorders.Am J Gastroenterol 2009; 104: 774–783; doi:10.1038/ajg.2008.108; published online 10 February 2009 [ABSTRACT FROM AUTHOR]

Since its discovery, Helicobacter pylori has been implicated in the pathogenesis of several diseases, both digestive and extradigestive. Interestingly, the majority of the extradigestive-related literature is focused on two vascular manifestations: stroke and ischemic heart disease. Potential mechanisms for the establishment of a H. pylori-induced ischemic heart disease have been proposed with regard to chronic inflammation, molecular mimicry, oxidative modifications, endothelial dysfunction, direct effect of the microorganism on atherosclerotic plaques as well as changes regarding traditional or novel risk factors for ischemic heart disease or even platelet- H. pylori interactions. A positive link between H. pylori infection and ischemic heart disease has been suggested by a series of studies focusing on epidemiologic evidence, dyslipidemic alterations, upregulation of inflammatory markers or homocysteine levels, induction of hypercoagulability, oxidation of low-density lipoprotein, causation of impaired endothelial function, detection of H. pylori DNA in atherosclerotic plaques, and participation of certain antigens and antibodies in a cross-reactivity model. There are studies, however, which investigated the relationship between H. pylori and ischemic heart disease with regard to the same parameters and failed to confirm the suggested positive association. Further studies in the direction of interaction between H. pylori and the host's genotype as well as a quest for evidence towards novel risk factors for ischemic heart disease such as oxidative stress, vascular remodeling, vascular calcification, or vasomotor activity, may reveal a field of great interest, thus contributing to the determination of new potential mechanisms. [ABSTRACT FROM AUTHOR]

Lymphocytic gastritis (LG) is associated with helicobacter pylori (Hp) and celiac disease (CD). We aimed to clarify the relationship between Hp infection and CD by defining a unique histopathology profile of LG in these two diseases. Forty patients who underwent upper endoscopy were divided into four groups: eight controls, ten active CD patients without Hp, twelve CD negative with Hp, and ten active CD with Hp infection. Antral samples were assessed by immunohistochemical staining for CD20, CD3, CD4, CD8, CD57, CNA42, and Ki67 for lymphoid aggregates, intraepithelial lymphocytes (IELs) number, density of lamina propria (LP) lymphocytes, and inflammatory glandular involvement. Only IELs positive for CD3 and CD8 were increased significantly in CD patients with or without Hp infection. Hp did not contribute to the number of CD8 IELs. In complicated cases with Hp and suspicious for CD, the number of CD8+ IELs hints toward a CD rather than Hp infection. [ABSTRACT FROM AUTHOR]

Background: Inflammatory alterations of the gastric mucosa are commonly caused by Helicobacter pylori (Hp) infection in patients with symptomatic gallstone disease. However, the additional pathogenetic role of an impaired gallbladder function leading to an increased alkaline duodenogastric reflux is controversially discussed. Aim: To investigate the relation of gallbladder function and Hp infection to gastric mucosa inflammation in patients with symptomatic gallstones prior to cholecystectomy. Patients: Seventy-three patients with symptomatic gallstones were studied by endoscopy and Hp testing. Methods: Gastritis classification was performed according to the updated Sydney System and gallbladder function was determined by total lipid concentration of gallbladder bile collected during mainly laparoscopic cholecystectomy. Results: Fifteen patients revealed no, 39 patients mild, and 19 moderate to marked gastritis. No significant differences for bile salts, phospholipids, cholesterol, or total lipids in gallbladder bile were found between these three groups of patients. However, while only 1 out of 54 (<2%) patients with mild or no gastritis was found histologically positive for Hp, this infection could be detected in 14 (74%) out of 19 patients with moderate to marked gastritis. Conclusion: Moderate to marked gastric mucosa inflammation in gallstone patients is mainly caused by Hp infection, whereas gallbladder function is not related to the degree of gastritis. Thus, an increased alkaline duodenogastric reflux in gallstone patients seems to be of limited pathophysiological relevance. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The importance of examining the status of gastric inflammation has been acknowledged; the new classification by the updated Sydney system (USS) allows us to evaluate the quantitative status of gastric inflammation. However, this system is based on the histological classification derived from biopsy specimens. Therefore, more convenient, objective and practical biomarkers are recommended. Aim: We undertook a systematic review to find out potential biomarkers by summarizing the relationship between biomarkers and grades of inflammation. Methods: By a primary search via Medline up to December 2004, we extracted a total of 6,526 papers that described biomarkers for human gastric inflammation. All papers were screened by title and abstract. The authors then retrieved 435 citations for complete review; ultimately 231 were appropriate for inclusion criteria. These papers were subclassified into several categories and summarized by each author. Results: In addition to standard markers such as pepsinogens, we confirmed the close relationship between the levels of several biomarkers including gastrin, interleukin-8, HLA class II molecules, reactive oxygen species, and the histological grades. Conclusions: This review provides valuable information describing the clinical implication of these biomarkers for evaluating the static conditions or dynamic alterations of human gastric inflammation. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract The objective of this systematic review was to determine whether periodontal disease is associated with an increased risk for coronary heart disease (CHD) and preterm and/or low birth weight deliveries (PLBW). A literature search was performed to identify cross-sectional, case-control, and cohort studies as well as clinical trials addressing different aspects of periodontal disease (clinical, microbial, immunological) and clinical outcomes of CHD or PLBW. The periodontitis–CHD association was evaluated in eight cohort, four case-control- and four cross-sectional studies. Meta-analysis was not performed due to the extensive heterogeneity of the studies, particularly with regard to periodontitis measures, which varied from full mouth probing assessments to questionnaires. Percentage-wise, 50% of the cohort studies (4/8), 75% of the case-control studies (3/4) and 50% of the cross-sectional studies (2/4) reported a significant association between clinical measures of periodontitis and CHD (excess risk ranged from 0 to 3.3-fold). The periodontitis–PLBW association was evaluated in one cohort and two case-control studies. The cohort study as well as one of the two case-control studies reported a significant association between periodontitis and PLBW (odds ratios 4.4–7.9). From two additional case-control studies microbiological data could be extracted. Bacteroides forsythus was found to be associated with PLBW in both studies. In conclusion, the evidence linking periodontitis with an increased risk for CHD and PLBW is limited. There is a clear need for new, well designed observational and intervention studies to confirm the thus far observed associations, explore the validity of the associations in diverse populations, establish whether they are causal in nature and determine potential benefits of periodontal intervention in reducing the risk for these conditions. [ABSTRACT FROM AUTHOR]

More than a century ago, inflammation and infection were considered to have atherogenic effects. During last century, however, this hypothesis was completely abandoned, and the old idea that coronary heart disease (CHD) possibly has an infectious etiology has only re-emerged in recent years. Both viral and bacterial pathogens have been proposed to be associated with the inflammatory changes found in atherosclerosis. Herpes group viruses, especially cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV1), have been associated with both atherosclerosis and restenosis. Helicobacter pylori and dental infections have also been linked to CHD, but the evidence is strongest for a respiratory tract bacterium, Chlamydia pneumoniae. The association was originally found in seroepidemiological studies, but the presence of organisms in atherosclerotic lesions, the first animal studies and preliminary successful intervention trials with antibiotics suggest that C. pneumoniae may have a pathogenetic role in the disease. The causal relationship has not yet been proven, but ongoing large intervention trials and research on pathogenetic mechanisms may lead to the use of antimicrobial agents in the treatment of CHD in the future. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is one of the most lethal forms of cancer, characterized by its aggressiveness and metastatic potential. Despite significant improvements in PC treatment and management, the complexity of the molecular pathways underlying its development has severely limited the available therapeutic opportunities. Toll-like receptors (TLRs) play a pivotal role in inflammation and immune response, as they are involved in pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Activation of TLRs initiates a signaling cascade, which in turn, leads to the transcription of several genes involved in inflammation and anti-microbial defense. TLRs are also deregulated in several cancers and can be used as prognostic markers and potential targets for cancer-targeted therapy. In this review we discuss the current knowledge about the role of TLRs in PC progression, focusing on the available TLRs-targeting compounds and their possible use in PC therapy. [ABSTRACT FROM AUTHOR]

Hemolysis is a physiological condition in which red blood cells (RBCs) lyse, releasing their contents into the extracellular environment. Hemolysis can be a manifestation of several diseases and conditions, such as sickle cell disease, hemorrhagic stroke, and trauma. Heme and hemoglobin are among the unique contents of RBCs that are released into the environment. Although these contents can cause oxidative stress, especially when oxidized in the extracellular environment, they can also initiate a proinflammatory response because they bind to receptors such as the Toll-like receptor (TLR) family. This review seeks to clarify the mechanism by which TLRs initiate a proinflammatory response to heme, hemoglobin, and their oxidized derivatives, as well as the possibility of using soluble TLRs (sTLRs) as therapeutic agents. Furthermore, this review explores the possibility of using sTLRs in hemorrhagic disorders in which mitigating inflammation is essential for clinical outcomes, including hemorrhagic stroke and its subtypes, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). [ABSTRACT FROM AUTHOR]

Simple Summary: Esophageal adenocarcinoma has a poor 5-year survival rate and is among the highest mortality cancers. Changes in the esophageal microbiome have been associated with cancer pathogenesis; however, the molecular mechanism remains obscure. This review article critically analyzes the molecular mechanisms through which microbiota may mediate the development and progression of esophageal adenocarcinoma and its precursors-gastroesophageal reflux disease and Barrett's esophagus. It summarizes changes in esophageal microbiome composition in normal and pathologic states and subsequently discusses the role of altered microbiota in disease progression. The potential role of esophageal microbiota in protecting against the development of esophageal adenocarcinoma is also discussed. By doing so, this article highlights specific directions for future research developing microbiome-mediated therapeutics for esophageal adenocarcinoma. Esophageal adenocarcinoma (EAC) is associated with poor overall five-year survival. The incidence of esophageal cancer is on the rise, especially in Western societies, and the pathophysiologic mechanisms by which EAC develops are of extreme interest. Several studies have proposed that the esophageal microbiome may play an important role in the pathophysiology of EAC, as well as its precursors—gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE). Gastrointestinal microbiomes altered by inflammatory states have been shown to mediate tumorigenesis directly and are now being considered as novel targets for both cancer treatment and prevention. Elucidating molecular mechanisms through which the esophageal microbiome potentiates the development of GERD, BE, and EAC will provide a foundation on which new therapeutic targets can be developed. This review summarizes current findings that elucidate the molecular mechanisms by which microbiota promote the pathogenesis of GERD, BE, and EAC, revealing potential directions for additional research on the microbiome-mediated pathophysiology of EAC. [ABSTRACT FROM AUTHOR]

Abstract Helicobacter pylori is a recently rediscovered Gram-negative bacteria that causes peptic ulcer disease, gastric lymphoma and gastric carcinoma. Helicobacter pylori achieves its pathogenetic role by triggering an intense leucocyte infiltration of the gastric submucosa which is mediated by proinflammatory cytokines. This pathogenetic mechanism is common to many other diseases and, therefore, Helicobacter pylori seroprevalence has also been investigated in other diseases. It is now known that H. pylori seropositivity is associated with an increasing number of cardiovascular, respiratory, extra-gastroduodenal digestive, neurological, skin, autoimmune, growth and miscellaneous disorders. Although the precise role for H. pylori is unknown in these diseases, it is of tremendous interest to most clinicians and scientists as H. pylori is amenable to eradication therapy using simple and reliable drug regimens. The conditions associated with H. pylori seropositivity are highlighted in this concise article. [ABSTRACT FROM AUTHOR]

Background: Studies of eradication of Helicobacter pylori and subsequent resolution of H. pylori-related gastritis, have focused mainly on medium and long-term change following eradication therapies. Results from those studies have shown that both acute and chronic inflammatory changes found in gastric mucosa eventually return to normal. However, the early events in the stomach, particularly the effects on bacterial density and acute inflammatory markers of anti-H. pylori treatment, are largely unknown. The objective of this study was therefore to examine changes in the number of H. pylori, and the severity of gastric mucosal inflammation in the gastric biopsy specimens of patients before (0 h group, n = 14) and 12 h (12 h group, n = 14) after initiating anti-H. pylori treatment. Methods: Biopsies were assessed, either quantitatively or semi-quantitatively, for the presence of H. pylori, neutrophils, mast cells, intraepithelial lymphocytes and the expression of histocompatibility leucocyte antigen (HLA)-DR by gastric epithelium and the results were compared between groups. Results: Median H. pylori scores were 5 (range 2–5) and 0 (range 0–2) in biopsies from untreated and 12 h post-treatment groups, respectively (P < 0.001). In most 12 h post-treatment biopsies, H. pylori organisms could not be identified. There was a significant reduction in HLA-DR expression by gastric epithelium (median 3.5 with range 2–4 at 0 h group vs median 2 with range 0–4, P < 0.05), but there was no significant difference in the number of intraepithelial lymphocytes, CD3+ cells, mast cells or the distribution and density of neutrophils (all P > 0.05). Furthermore, the severity of gastritis as scored with the Sydney system was similar in both untreated and treated groups. Conclusions: The results of this study indicate that elimination of H. pylori organisms and resolution of some inflammatory markers occurs as early as 12 h following a single dose of omeprazole 40 mg, amoxycillin 1.0 g and metronidazole 400 mg, which suggests that rational therapeutic strategies with shorter duration using the currently available drugs may be possible. [ABSTRACT FROM AUTHOR]

Regnström J, Jovinge S, Båvenholm P, Ericssond C-G, de Faire U, Hamsten A, Hellenius M-L, Nilsson J, Tornvall P (Karolinska Hospital and Danderyd Hospital, Stockholm, Sweden). Helicobacter pylori seropositivity is not associated with inflammatory parameters, lipid concentrations and coronary artery disease. J Intern Med 1998; 243: 109–13. ObjectivesTo determine the prevalence of chronic infection with Helicobacter pylori (HP) in patients with established coronary artery disease (CAD) and in healthy controls. Furthermore, to investigate whether HP infection is associated with inflammatory parameters, lipid concentrations and degree and progression of CAD. DesignA case–control study combined with a prospective angiographic study. SettingStockholm Metropolitan Area, Sweden. Patients and methodsA material consisting of 92 young men aged 40.9 ± 3.2 (mean ± SD) years, with previous myocardial infarction and documented coronary atherosclerosis, and 95 healthy sex-matched controls, aged 43.2 ± 3.0 (mean ± SD) years, with similar socio-economic status and ethnic background was analysed for the prevalence of HP seropositivity, plasma concentrations of the inflammatory parameters fibrinogen, tumour necrosis factor alpha and orosomucoid, and serum concentrations of lipids. The impact of HP seropositivity on degree and progression of CAD, as assessed by quantitative coronary angiography, was also determined. ResultsThe study population of mainly Scandinavian origin had a low prevalence of HP seropositivity in comparison with previously published European populations. No significant increase in HP seropositivity was found in patients compared with controls (42.2 vs. 32.6%). Furthermore, HP infection was not associated with increased levels of inflammatory parameters, lipid concentrations or with degree of angiographically determined CAD at baseline, or progression of CAD and clinical events over 5 years. ConclusionsHP infection is not associated with inflammatory parameters and lipid concentrations and could not be confirmed as a risk factor for CAD. [ABSTRACT FROM AUTHOR]

Purpose of Review: Allergen is an umbrella term for irritants of diverse origin. Along with other offenders such as pathogens, mutagens, xenobiotics, and pollutants, allergens can be grouped as inflammatory agents. Danger-associated molecular patterns (DAMPs) are altered metabolism products of necrotic or stressed cells, which are deemed as alarm signals by the innate immune system. Like inflammation, DAMPs play a role in correcting the altered physiological state, but in excess, they can be lethal due to their signal transduction roles. In a vicious loop, inflammatory agents are DAMP generators and DAMPs create a pro-inflammatory state. Only a handful of DAMPs such as uric acid, mtDNA, extracellular ATP, HSPs, amyloid β, S100, HMGB1, and ECM proteins have been studied till now. A large number of DAMPs are still obscure, in need to be unveiled. The identification and functional characterization of those DAMPs in inflammation pathways can be insightful.Recent Findings: As inflammation and immune activation have been implicated in almost all pathologies, studies on them have been intensified in recent times. Consequently, the pathologic mechanisms of various DAMPs have emerged. Following PRR ligation, the activation of inflammasome, MAPK, and NF-kB is some of the common pathways.Summary: The limited number of recognized DAMPs are only a fraction of the vast array of other DAMPs. In fact, any misplaced or abnormal level of metabolite can be a DAMP. Sophisticated analysis studies can reveal the full profile of the DAMPs. Lowering the level of DAMPs is useful therapeutic intervention but certainly not as effective as avoiding the DAMP generators, i.e., the inflammatory agents. So, rather than mitigating DAMPs, efforts should be focused on the elimination of inflammatory agents. [ABSTRACT FROM AUTHOR]

Age is one of the biggest risk factors for ovarian cancer. Older women have higher rates of diagnosis and death associated with the disease. In mouse models, it was shown that aged mice had greater tumor burden than their younger counterparts when intraperitoneally injected with ovarian tumor cells. While very few papers have been published looking at the direct link between ovarian cancer metastasis and age, there is a wealth of information on how age affects metastatic microenvironments. Mesothelial cells, the peritoneal extracellular matrix (ECM), fibroblasts, adipocytes and immune cells all exhibit distinct changes with age. The aged peritoneum hosts a higher number of senescent cells than its younger counterpart, in both the mesothelium and the stroma. These senescent cells promote an inflammatory profile and overexpress Matrix Metalloproteinases (MMPs), which remodel the ECM. The aged ECM is also modified by dysregulated collagen and laminin synthesis, increases in age-related crosslinking and increasing ovarian cancer invasion into the matrix. These changes contribute to a vastly different microenvironment in young and aged models for circulating ovarian cancer cells, creating a more welcoming “soil”. [ABSTRACT FROM AUTHOR]