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In recent years, the incidence rate of chronic liver diseases continues to rise, such as chronic hepatitis B, nonalcoholic fatty liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma, and the age of onset gradually becomes younger. At present, the role of many CC chemokines in chronic liver diseases has been confirmed. This article summarizes the research advances in CC chemokines and their receptors that affect chronic liver diseases in recent years and explore their potential application in chronic liver diseases, so as to provide new ideas for the prevention and treatment of chronic liver diseases. [ABSTRACT FROM AUTHOR]

This paper is concerned with a cross-diffusion tumor invasion model with double-taxis effect. We first investigate the global existence of classical solutions of this model in two-dimensional space. The essential difficulty lies in the second-level taxis effect of immune cells on tumor cells, where chemotactic factor (tumor cells) exhibit their own taxis behavior, the double-taxis effect makes us have to use more detailed analysis and calculation, and some new estimation techniques are used. Subsequently, we also investigate the stability of some equilibria. For small proliferation coefficient, we prove the global asymptotic stability or local asymptotic stability of a semitrivial equilibrium point. While, for the other equilibria, the stability analysis is complicated even for some special cases, and both the double chemotactic coefficients will affect the stability of the solution. [ABSTRACT FROM AUTHOR]

Introduction: The microbial community plays a crucial role in the pathological microenvironment. However, the structure of the microbial community within endometriotic lesions and its impact on the microenvironment is still limited. Methods: All 55 tissue samples, including ovarian ectopic (OEMs) and normal (NE) endometrium, were subjected to 16S rRNA sequencing, metabolomic and proteomic analysis. Results: We found the abundance of Tuzzerella is significantly lower in OEMs compared to NE tissue (p < 0.01). We selected samples from these two groups that exhibited the most pronounced difference in Tuzzerella abundance for further metabolomic and proteomic analysis. Our findings indicated that endometriotic lesions were associated with a decrease in l-Glutamine levels. However, proteomic analysis revealed a significant upregulation of proteins related to the complement pathway, including C3, C7, C1S, CLU, and A2M. Subsequent metabolic and protein correlation predictions demonstrated a negative regulation between l-Glutamine and C7. In vitro experiments further confirmed that high concentrations of Glutamine significantly inhibit C7 protein expression. Additionally, immune cell infiltration analysis, multiplex immunofluorescence, and multifactorial testing demonstrated a positive correlation between C7 expression and the infiltration of regulatory T cells (Tregs) in ectopic lesions, while l-Glutamine was found to negatively regulate the expression of chemotactic factors for Tregs. Conclusion: In this study, we found a clear multi-omics pathway alteration, "Tuzzerella (microbe)—l-Glutamine (metabolite)—C7 (protein)," which affects the infiltration of Tregs in endometriotic lesions. Our findings provide insights into endometriosis classification and personalized treatment strategies based on microbial structures. [ABSTRACT FROM AUTHOR]

Objective To explore the correlation of serum Chemerin level with disease activity and the ratio of T helper 17/regulatory T cells (Th17/Treg) in patients with rheumatoid arthritis (RA). Methods A total of 180 patients with RA who were admitted to our hospital were regarded as the observation group. According to the DAS28 score, the observation group was divided into the high activity group (60 cases), the moderate activity group (60 cases) and the low activity group (60 cases). Another 180 healthy people who underwent physical examination in our hospital during the same period were regarded as the control group. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum levels of Chemerin, interleukin-9 (IL-9), interleukin-10 (IL-10) and interleukin-17 (IL-17). Flow cytometry was used to detect the Th17/Treg ratio. Spearman correlation analysis was applied to analyze the correlation between serum Chemerin level and DAS28 score. Pearson correlation analysis was used to analyze the correlation between serum Chemerin level and Th17, Treg cell percentage and Th17/Treg ratio. Results The results of this study showed that the serum level of Chemerin was higher in the observation group than that in the control group (P＜0.05). The serum Chemerin level was positively correlated with DAS28 score (P＜0.05). Serum Chemerin levels and DAS28 scores decreased in turn in the high, moderate and low activity groups (P＜0.05). The percentage of Th17 cells and the ratio of Th17/Treg were higher in the observation group than those in the control group, and the percentage of Treg cells was lower in the observation group than that in the control group (P＜ 0.05). The level of IL-10 was lower in the observation group than that in the control group, while levels of IL-17 and IL-9 were higher in the observation group than those in the control group (P＜0.05). The results of Pearson correlation analysis showed that serum Chemerin level was positively correlated with the percentage of Th17 cells and the ratio of Th17/Treg, and negatively correlated with the percentage of Treg cells (P＜0.05). Conclusion Serum Chemerin level is elevated in patients with RA, which is closely related to disease activity and Th17/Treg ratio. [ABSTRACT FROM AUTHOR]

Objectives: Previous observational studies have indicated correlations between various inflammatory cytokines and functional outcomes following ischemic stroke (IS); however, the causality remains unclear. We aimed to further evaluate the causal association between 41 circulating inflammatory cytokines and functional outcomes following IS. Methods: Two‐sample bidirectional Mendelian randomization (MR) analysis was used in this study. The genetic variation of 41 circulating inflammatory cytokines were derived from genome‐wide association study (GWAS) data of European ancestry (n = 8293). The corresponding genetic association of functional outcomes following IS were derived from European ancestry GWAS data (n = 6021). Results: Inverse variance weighted (IVW) analysis showed that genetically predicted increased levels of regulation and activation in normal T‐cell expression and secretion factor (RANTES/CCL5) and eosinophilic chemotactic factor (EOTAXIN/CCL11) were positively correlated with the increased adverse functional outcomes (modified Rankin Scale [mRS≥3] following IS (OR: 1.40, 95% CI: 1.002–1.96, p = 0.049; OR: 1.33, 95% CI: 1.15–1.54, p = 0.0001). Interleukin 18 (IL‐18) level might be the downstream consequence of adverse functional outcomes following IS (β: −0.09, p = 0.039). Other inflammatory cytokines and functional outcomes following IS did not appear to be causally related. Conclusions: This study suggests a causality between inflammation and adverse functional outcomes following IS. RANTES (CCL5) and EOTAXIN (CCL11) may be the upstream factors of adverse functional outcomes following IS, while IL‐18 may be the downstream effect of adverse functional outcomes following IS. Whether these cytokines can be used to predict or improve adverse functional outcomes after IS requires further researches. [ABSTRACT FROM AUTHOR]

SLC7A11 has significant translational value in cancer treatment. However, there are few studies on whether SLC7A11 affects the immune status of lung adenocarcinoma (LUAD). Information on SLC7A11 expression and its impact on prognosis was obtained from the cancer genome atlas and gene expression omnibus databases. The differentially expressed genes (DEGs) were analysed by GO and KEGG. GSEA enrichment analysis was performed in the SLC7A11-high and SLC7A11-low groups. The relationship between SLC7A11 and tumour immunity, immune checkpoints, and immune cell infiltration was studied using R language. We analysed the correlation between SLC7A11 and chemotactic factors (CFs) and chemokine receptors using the TISIDB database. SLC7A11 is overexpressed in many tumours, including LUAD. The 5-year overall survival of patients in the SLC7A11-high group was lower than in the SLC7A11-low group. KEGG analysis found that the DEGs were enriched in ferroptosis signaling pathways. GSEA analysis found that the survival-related signaling pathways were enriched in the SLC7A11-low group. The SLC7A11-low group had higher immune scores and immune checkpoint expression. SLC7A11 was negatively correlated with many immune cells (CD8+ T cells, immature dendritic cells), CFs, chemokine receptors (such as CCL17/19/22/23, CXCL9/10/11/14, CCR4/6, CX3CR1, CXCR3) and MHCs (major histocompatibility complex). SLC7A11 may regulate tumour immunity and could be a potential therapeutic target for LUAD. [ABSTRACT FROM AUTHOR]

Macrophages play a pivotal role in the process of healing burns. One of the major risks in the course of burn healing, in the absence of regenerating epidermis, is infections, which greatly contribute to morbidity and mortality in such patients. Therefore, it is widely agreed that accelerating the recruitment of macrophages into burns may contribute to faster regeneration of the epidermis, thus decreasing the risk of infections. This review describes a unique method for the rapid recruitment of macrophages into burns and the activation of these macrophages to mediate accelerated regrowth of the epidermis and healing of burns. The method is based on the application of bio-degradable "α-gal" nanoparticles to burns. These nanoparticles present multiple α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R), which bind the abundant natural anti-Gal antibody that constitutes ~1% of immunoglobulins in humans. Anti-Gal/α-gal nanoparticle interaction activates the complement system, resulting in localized production of the complement cleavage peptides C5a and C3a, which are highly effective chemotactic factors for monocyte-derived macrophages. The macrophages recruited into the α-gal nanoparticle-treated burns are activated following interaction between the Fc portion of anti-Gal coating the nanoparticles and the multiple Fc receptors on macrophage cell membranes. The activated macrophages secrete a variety of cytokines/growth factors that accelerate the regrowth of the epidermis and regeneration of the injured skin, thereby cutting the healing time by half. Studies on the healing of thermal injuries in the skin of anti-Gal-producing mice demonstrated a much faster recruitment of macrophages into burns treated with α-gal nanoparticles than in control burns treated with saline and healing of the burns within 6 days, whereas healing of control burns took ~12 days. α-Gal nanoparticles are non-toxic and do not cause chronic granulomas. These findings suggest that α-gal nanoparticles treatment may harness anti-Gal for inducing similar accelerated burn healing effects also in humans. [ABSTRACT FROM AUTHOR]

Background: This study targeted at developing a robust, prognostic signature based on super-enhancer-related genes (SERGs) to reveal survival prognosis and immune microenvironment of breast cancer. Methods: RNA-sequencing data of breast cancer were retrieved from The Cancer Genome Atlas (TCGA), 1069 patients of which were randomly assigned into training or testing set in 1:1 ratio. SERGs were downloaded from Super-Enhancer Database (SEdb). After which, a SERGs signature was established based on the training set, with its prognostic value further validated in the testing set. Subsequently, we identified the potential function enrichment and tumor immune infiltration of the model. Moreover, in vitro experiments were completed to further explore the biological functions of ZIC2 gene (one of the risk genes in the prognostic model) in breast cancer. Results: A risk score system of prognostic value was constructed with 6 SERGs (ZIC2, NFE2, FOXJ1, KLF15, POU3F2 and SPIB) to find patients in high-risk group with significantly worse prognosis in both training and testing sets. In addition, a multivariate regression was established via integrating the 6 genes with age and N stage, indicating well performance by calibration, time-dependent receiver operating characteristic (ROC) analysis and decision curve analysis (DCA). Further analysis demonstrated that tumor-associated pathological processes and pathways were significantly enriched in the high-risk group. In general, the novel SERGs signature could be applied to screen breast cancer with immunosuppressive microenvironment for the risk score was negatively correlated with ESTIMATE score, tumor-infiltration lymphocytes (such as CD4 + and CD8 + T cell), immune checkpoints and chemotactic factors. Furthermore, down-regulation of ZIC2 gene expression inhibited the cell viability, cellular migration and cell cycle of breast cancer cells. Conclusions: The novel SERGs signature could predict the prognosis of breast cancer; and SERGs might serve as potential therapeutic targets for breast cancer. [ABSTRACT FROM AUTHOR]

In this paper, we define an intraguild predation model of one-resource and two-predator, in which the mesopredator catched by a top predator, feeds on a resource that grows according to a logistic growth law; for both the meso and the top predator, Holling type II functional responses are considered. Predators and prey diffuse into a connected bounded region in R². Two scenarios are considered: 1. As a defense mechanism, the resource attracts the top predator that feeds on the mesopredator; 2. The top predator in search of food moves towards areas where the mesopredator population is increasing. Some general properties of the solutions of the model are proved. In addition, the results of the numerical simulations carried out to analyze the effect on the spatial distribution of the populations of the indirect defense mechanism of the first scenario are shown. This is contrasted with the results of the model simulations corresponding to the second scenario, in which the diffusion of the top predator is regulated by a tendency to move towards the mesopredator gradient. [ABSTRACT FROM AUTHOR]

Summary: Leukotriene B4 (LTB4) was recognized as an arachidonate‐derived chemotactic factor for inflammatory cells and an important drug target even before the molecular identification of its receptors. We cloned the high‐ and low‐affinity LTB4 receptors, BLT1 and BLT2, respectively, and examined their functions by generating and studying gene‐targeted mice. BLT1 is involved in the pathogenesis of various inflammatory and immune diseases, including asthma, psoriasis, contact dermatitis, allergic conjunctivitis, age‐related macular degeneration, and immune complex‐mediated glomerulonephritis. Meanwhile, BLT2 is a high‐affinity receptor for 12‐hydroxyheptadecatrienoic acid, which is involved in the maintenance of dermal and intestinal barrier function, and the acceleration of skin and corneal wound healing. Thus, BLT1 antagonists and BLT2 agonists are promising candidates in the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Atrophic rhinitis is a chronic debilitating nasal disease which may be primary, or secondary to various underlying etiologies. Several methods of treatment have been previously adopted with minimal success rate. In order to achieve effective and long-standing method of treatment for this challenging pathology, this method should work mainly on reversal of the pathologic changes in nasal microanatomy. Objective: Review article investigating the use of platelet-rich plasma in treatment of atrophic rhinitis. Methods: We scoured scholarly journals and databases including PubMed, Google Scholar, and Science Direct for reports on Treatment of atrophic rhinitis, Platelet-rich plasma and new biological modality between November 1990 and April 2023. However, only the latest or most comprehensive study was considered. The authors also assessed the usefulness of references drawn from similar books. As a result, non-English documents have been overlooked due to a lack of resources to translate them. It was commonly recognized that scientific research did not include things like unpublished publications, oral presentations, conference abstracts, or dissertations. Conclusion: Platelet Rich Plasma (PRP) is a plasma fraction with a very high platelet content that also contains phagocytic cells, a significant amount of fibrinogen, a number of chemotactic factors and cytokines that may be used to control tissue inflammatory response, as well as growth factors that can help with tissue healing and regeneration. It is now considered the best treatment for treating atrophic rhinitis as a result. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BRCA) is the most common malignancy with high morbidity and mortality in women, and transcription factor (TF) is closely related to the occurrence and development of BRCA. This study was designed to identify a prognostic gene signature based on TF family to reveal immune characteristics and prognostic survival of BRCA. Methods: In this study, RNA-sequence with corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and GSE42568. Prognostic differentially expressed transcription factor family genes (TFDEGs) were screened to construct a risk score model, after which BRCA patients were stratified into low-risk and high-risk groups based on their corresponding risk scores. Kaplan–Meier (KM) analysis was applied to evaluate the prognostic implication of risk score model, and a nomogram model was developed and validated with the TCGA and GSE20685. Furthermore, the GSEA revealed pathological processes and signaling pathways enriched in the low-risk and high-risk groups. Finally, analyses regarding levels of immune infiltration, immune checkpoints and chemotactic factors were all completed to investigate the correlation between the risk score and tumor immune microenvironment (TIME). Results: A prognostic 9-gene signature based on TFDEGs was selected to establish a risk score model. According to KM analyses, high-risk group witnessed a significantly worse overall survival (OS) than low-risk group in both TCGA-BRCA and GSE20685. Furthermore, the nomogram model proved great possibility in predicting the OS of BRCA patients. As indicted in GSEA analysis, tumor-associated pathological processes and pathways were relatively enriched in high-risk group, and the risk score was negatively correlated with ESTIMATE score, infiltration levels of CD4+ and CD8+T cells, as well as expression levels of immune checkpoints and chemotactic factors. Conclusions: The prognostic model based on TFDEGs could distinguish as a novel biomarker for predicting prognosis of BRCA patients; in addition, it may also be utilized to identify potential benefit population from immunotherapy in different TIME and predict potential drug targets. [ABSTRACT FROM AUTHOR]

Tumor microparticles (T-MPs) are considered as a tumor vaccine candidate. Although some studies have analyzed the mechanism of T-MPs as tumor vaccine, we still lack understanding of how T-MPs stimulate a strong anti-tumor immune response. Here, we show that T-MPs induce macrophages to release a key chemotactic factor CCL2, which attracts monocytes to the vaccine injection site and enhances endocytosis of antigen. Monocytes subsequently enter the draining lymph node, and differentiate into monocyte-derived DCs (moDCs), which present tumor antigens to T lymphocytes and deliver a potent anti-tumor immune response. Mechanically, T-MPs activate the cGAS-STING signaling through DNA fragments, and then induce monocytes to upregulate the expression of IRF4, which is a key factor for monocyte differentiation into moDCs. More importantly, monocytes that have endocytosed T-MPs acquire the ability to treat tumors. Collectively, this work might provide novel vaccination strategy for the development of tumor vaccines and facilitate the application of T-MPs for clinic oncotherapy. [ABSTRACT FROM AUTHOR]

Summary: Neutrophils or polymorphonuclear neutrophils (PMNs) are an important component of innate host defense. These phagocytic leukocytes are recruited to infected tissues and kill invading microbes. There are several general characteristics of neutrophils that make them highly effective as antimicrobial cells. First, there is tremendous daily production and turnover of granulocytes in healthy adults—typically 1011 per day. The vast majority (~95%) of these cells are neutrophils. In addition, neutrophils are mobilized rapidly in response to chemotactic factors and are among the first leukocytes recruited to infected tissues. Most notably, neutrophils contain and/or produce an abundance of antimicrobial molecules. Many of these antimicrobial molecules are toxic to host cells and can destroy host tissues. Thus, neutrophil activation and turnover are highly regulated processes. To that end, aged neutrophils undergo apoptosis constitutively, a process that contains antimicrobial function and proinflammatory capacity. Importantly, apoptosis facilitates nonphlogistic turnover of neutrophils and removal by macrophages. This homeostatic process is altered by interaction with microbes and their products, as well as host proinflammatory molecules. Microbial pathogens can delay neutrophil apoptosis, accelerate apoptosis following phagocytosis, or cause neutrophil cytolysis. Here, we review these processes and provide perspective on recent studies that have potential to impact this paradigm. [ABSTRACT FROM AUTHOR]

Introduction: Cancer is a disease caused by abnormal growth and uncontrolled cells. Moringa leaf extract can prevent or destroy tumors and cancer cells because it contains benzyl isothiocyanate. Many scientific studies have shown that these chemicals have anti-cancer and chemoprotective capabilities. IL-8 is a chemotactic factor expressed in endothelial cells. This study aims to know the potential of Moringa leaf extract as anti-angiogenesis of oral cancer by IL-8 expression in rats induced by benzo(a)pyrene. Material and methods: This research was an experimental laboratory with a post-test only control group design divided into four groups, control group (K) and a treatment group was given Moringa extract with a dose of 20mg/kg/BW, 40mg/kg/BW, 80mg/kg/BW. Immunohistochemical analysis was used to determine IL-8 expression. Result: ANOVA data analysis revealed that group treatment with 40mg/kg/BW has the lowest number of IL-8 expression in endothelial cells of rats induced by benzo(a)pyrene. Conclusion: Moringa oleifera extract with a dose of 40 mg/kg/BW is the best dose that can inhibit angiogenesis of oral cancer cells in male rats (Rattus norvegicus) induced benzo(a)pyrene. [ABSTRACT FROM AUTHOR]

The development of cholestatic liver injury (CLI) involves inflammation, but the dominant pathway mediating the chemotaxis is not yet established. This work explored key signaling pathway mediating chemotaxis in CLI and the role of Kupffer cells in the inflammatory liver injury. Probe inhibitors T-5224 (100 mg/kg) for AP-1 and C188–9 (100 mg/kg) for STAT3 were used to validate key inflammatory pathways in alpha-naphthylisothiocyanate (ANIT, 100 mg/kg)-induced CLI. Two doses of GdCl 3 (10 mg/kg and 40 mg/kg) were used to delete Kupffer cells and explore their role in CLI. Serum and liver samples were collected for biochemical and mechanism analysis. The liver injury in ANIT-treated mice were significantly increased supported by biochemical and histopathological changes, and neutrophils gathering around the necrotic loci. Inhibitor treatments down-regulated liver injury biomarkers except the level of total bile acid. The chemokine Ccl2 increased by 170-fold and to a less degree Cxcl2 by 45-fold after the ANIT treatment. p-c-Jun and p-STAT3 were activated in the group A but inhibited by the inhibitors in western blot analysis. The immunofluorescence results showed AP-1 not STAT3 responded to inhibitors in ANIT-induced CLI. With or without GdCl 3 , there was no significant difference in liver injury among the CLI groups. In necrotic loci in CLI, CXCL2 colocalized with hepatocyte biomarker Albumin, not with the F4/80 in Kupffer cells. Conclusively, AP-1 played a more critical role in the inflammation cascade than STAT3 in ANIT-induced CLI. Hepatocytes, not the Kupffer cells released chemotactic factors mediating the chemotaxis in CLI. [Display omitted] • AP-1 inhibitor T-5224 and STAT3 inhibitor C188-9 deleted cholestatic liver injury respectively. • Activation of AP-1 correlated more to cholestatic liver injury than STAT3. • Chemokines mediating the chemotaxis in cholestatic liver injury was released by hepatocytes not the Kupffer cells. • Kupffer cells in cholestatic liver injury were neither protective nor disruptive. [ABSTRACT FROM AUTHOR]

Objectives: To assess the prevalence of leukocyte cell-derived chemotactic 2 (LECT2), its organ involvement, and its clinical association in autopsies from an ethnically biased population.Methods: The tissues from all autopsies of individuals diagnosed with amyloidosis were reassessed and typed for amyloid light chain (AL) amyloidosis, amyloid A (AA) amyloidosis, transthyretin amyloidosis (ATTR), and leukocyte chemotactic factor 2 amyloidosis (ALECT2) by immunohistochemistry. Organ involvement was described and correlated with its clinical associations.Results: Of 782 autopsies, 27 (3.5%) had a confirmed diagnosis of amyloidosis. Of these, 14 (52%) corresponded to ALECT2, 5 (19%) to AL amyloidosis, 2 (7%) to ATTR amyloidosis, 1 (4%) to AA amyloidosis, and 5 (21%) as undetermined-type amyloidosis. The LECT2 amyloid deposits were found in the kidneys, liver, spleen, and adrenal glands in most individuals. Except for the kidneys, there were no clinical signs suggestive of amyloid deposition in most of the affected organs. LECT2 amyloidosis was not associated with the cause of death in any case. No cases had heart or brain involvement. Potential subclinical effects of amyloid deposition in organs such as adrenal glands and spleen require further study.Conclusions: This autopsy study confirms the high prevalence of LECT2 amyloidosis in the Mexican population, with frequent amyloid deposition in the kidneys, liver, spleen, and adrenal glands. [ABSTRACT FROM AUTHOR]

Bacteria or viral outbreaks can cause tilapia hemorrhage, ensuring considerable volume of hemoglobin (Hb) into the tissue. However, the hemoglobin toxicity on tissue and high doses also effect on tissue this phenomena is still under consideration. Therefore, current study exploited Nile tilapia kidney (NTK) cells to deeply expose the toxic effect of Hb on NTK cells. Toxicity of Hb on NTK cells was determined in terms of cells growth, expression of iron metabolism and inflammation-related genes, consequently examined antioxidant-related enzymes genes expression, intracellular iron and reactive oxygen species (ROS) contents, and apoptosis-related genes expression. The results showed that Hb and heme significantly inhibited NTK cells growth and up-regulated iron metabolism-related genes expression in different degrees. The Hb and heme activated the expression of pro-inflammatory cytokines (TNF-α, tumor necrosis factor-α; IL-1β, interleukin 1β; IL-6, interleukin 6), the anti-inflammatory factor (IL-10, interleukin 10) and the chemotactic factors (IL-4, interleukin 4; IL-8, interleukin 8) through NF-κB pathway, meanwhile activated the expression of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Moreover, the Hb significantly increased intracellular iron and ROS contents while the expression of apoptosis-related genes was significantly activated by both Hb and heme. Current investigation suggested that high oxidative activity of Hb could activate iron metabolism- and inflammation-related genes expression, and increase intracellular iron and ROS levels, lead to up-regulated the expression of apoptosis genes in NTK cells. • Hb promoted the expression of inflammation-related genes. • Hb activated the expression of genes related to iron metabolism. • Hb enhanced the expression of antioxidant-related genes. • Hb increased intracellular iron and ROS contents. • Hb activated the expression of apoptosis-related genes. [ABSTRACT FROM AUTHOR]

Chronic endometritis (CE) is a chronic and persistent inflammation condition of endometrium, mainly caused by pathogen infection. It is potentially associated with infertility and poor reproductive outcomes. Although the pregnancy outcomes of some CE patients have been greatly improved after antibiotic treatment at present, the persistent CE is still a thorny problem in other patients, because the etiology of persistent CE is still unknown and the treatment effect is poor. More and more studies have suggested that the immune status of the endometrium in CE patients has changed, which is involved in the pathological process contributing to the reduced endometrial receptivity and adverse pregnancy outcomes. The changes of endometrial immune state in CE patients are mainly manifested as the number alterations of both innate immunocytes represented by uterine natural killer cells (uNK cells) and macrophages and adaptive immunocytes represented by B cells and CD4+T cells, the dysregulated proportion of CD4+T immune cell subsets and abnormal expression of cytokines and chemokines. In this artile, we reviewed the research progresses of endometrial immune state changes of CE, so as to gain further insights into the pathological characteristics and the internal mechanism that possibly affects the pregnancy outcomes of women with CE from the immune perspective. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the levels of YKL-40 during and after coronary artery bypass grafting surgery (CABG) and to establish possible connections between YKL-40 and markers of oxidative stress, inflammation, and myocardial injury. Patients undergoing elective CABG utilizing cardiopulmonary bypass (CPB) were recruited into the study. Blood samples were collected at the onset of anesthesia, during surgery and post-operatively. Levels of YKL-40, 8-isoprostane, interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1) and troponin T (TnT) were measured by immunoassay. YKL-40 levels increased significantly 24 h after CPB. Positive correlation was seen between post-operative TnT and YKL-40 levels (r = 0.457, p = 0.016) and, interestingly, baseline YKL-40 predicted post-operative TnT increase (r = 0.374, p = 0.050). There was also a clear association between YKL-40 and the chemotactic factors MCP-1 (r = 0.440, p = 0.028) and IL-8 (r = 0.484, p = 0.011) linking YKL-40 to cardiac inflammation and fibrosis following CABG. The present results show, for the first time, that YKL-40 is associated with myocardial injury and leukocyte-activating factors following coronary artery bypass surgery. YKL-40 may be a factor and/or biomarker of myocardial inflammation and injury and subsequent fibrosis following heart surgery. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cell-2 (TREM2) is a transmembrane receptor which is specifically expressed on myeloid cells. To date, TREM2 has been confirmed as a key factor in many pathologies, such as Alzheimer's disease, obesity-related metabolic syndrome, fatty liver and atherosclerosis. However, the role of TREM2 in tumors remains poorly understood. TREM2 is highly expressed in more than 200 primary and metastatic tumors, a feature that makes TREM2 a potential clinical target for tumor immunotherapy. The tumor microenvironment (TME) is the "soil" which tumors survive on and exhibits immunosuppressive characteristics. During the development of a tumor, TME will secrete various chemotactic factors to recruit myeloid cells. It is clear now that cancer progression and metastasis depend on the interactions between cancer cells and myeloid cell infiltration in TME. As an important receptor involved in inflammatory suppression signaling pathways, TREM2 may play an important role in immune escape by the tumor. Recently, several studies have illustrated that TREM2 expressed on tumor infiltrated myeloid cells acts as a crucial regulator of the antitumor immune response. In this review, we systematically summarize recent publications about the latest advances in knowledge of TREM2 in cancer, especially focusing on its role in tumor associated myeloid cells and tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is the most common type of degenerative arthritis and affects the entire joint, causing pain, joint inflammation, and cartilage damage. Various risk factors are implicated in causing OA, and in recent years, a lot of research and interest have been directed toward chronic low-grade inflammation in OA. Monocyte chemoattractant protein-1 (MCP-1; also called CCL2) acts through C-C chemokine receptor type 2 (CCR2) in monocytes and is a chemotactic factor of monocytes that plays an important role in the initiation of inflammation. The targeting of CCL2-CCR2 is being studied as part of various topics including the treatment of OA.Methods: In this study, we evaluated the potential therapeutic effects the sCCR2 E3 gene may exert on OA. The effects of sCCR2 E3 were investigated in animal experiments consisting of intra-articular injection of sCCR2 E3 in a monosodium iodoacetate (MIA)-induced OA rat model. The effects after intra-articular injection of sCCR2 E3 (fusion protein encoding 20 amino acids of the E3 domain of the CCL2 receptor) in a monosodium iodoacetate-induced OA rat model were compared to those in rats treated with empty vector (mock treatment) and full-length sCCR2.Results: Pain improved with expression of the sCCR2 gene. Improved bone resorption upon sCCR2 E3 gene activation was confirmed via bone analyses using micro-computed tomography. Histologic analyses showed that the sCCR2 E3 gene exerted protective effects against cartilage damage and anti-inflammatory effects on joints and the intestine.Conclusions: These results show that sCCR2 E3 therapy is effective in reducing pain severity, inhibiting cartilage destruction, and suppressing intestinal damage and inflammation. Thus, sCCR2 E3 may be a potential therapy for OA. [ABSTRACT FROM AUTHOR]

Alveolar organoids (AOs), derived from human pluripotent stem cells (hPSCs) exhibit lung-specific functions. Therefore, the application of AOs in pulmonary disease modeling is a promising tool for understanding disease pathogenesis. However, the lack of immune cells in organoids limits the use of human AOs as models of inflammatory diseases. In this study, we generated AOs containing a functional macrophage derived from hPSCs based on human fetal lung development using biomimetic strategies. We optimized culture conditions to maintain the iMACs (induced hPSC-derived macrophages) AOs for up to 14 days. In lipopolysaccharide (LPS)-induced inflammatory conditions, IL-1β, MCP-1 and TNF-α levels were significantly increased in iMAC-AOs, which were not detected in AOs. In addition, chemotactic factor IL-8, which is produced by mononuclear phagocytic cells, was induced by LPS treatment in iMACs-AOs. iMACs-AOs can be used to understand pulmonary infectious diseases and is a useful tool in identifying the mechanism of action of therapeutic drugs in humans. Our study highlights the importance of immune cell presentation in AOs for modeling inflammatory pulmonary diseases. [ABSTRACT FROM AUTHOR]

The rapid clearance of apoptotic cells (ACs), known as efferocytosis, prompts the inhibition of inflammatory responses and autoimmunity and maintains homeostatic cell turnover by controlling the release of intracellular contents. The fast clearance of ACs requires professional and nonprofessional phagocytic cells that can accurately and promptly recognize ACs and migrate towards them. Cells undergoing apoptosis alarm their presence by releasing special soluble chemotactic factors, such as lactoferrin, that act as "Find me," "Keep out," or "Stay away" signals to recruit phagocytic cells, such as macrophages or prevent granulocyte migration. Efferocytosis effectively serves to prevent damage‐associated molecular pattern release and secondary necrosis and inhibit inflammation/autoimmunity at the very first step. Since less attention has been given to the cross‐talk and balance of "Find me" and "Keep out" signals released from ACs in efferocytosis, we set out to investigate the current knowledge of the roles of "Find me" and "Keep out" signals in the efferocytosis process. [ABSTRACT FROM AUTHOR]

Oxidized low-density lipoprotein (ox-LDL) is the most harmful form of cholesterol associated with vascular atherosclerosis and hepatic injury, mainly due to inflammatory cell infiltration and subsequent severe tissue injury. Lox-1 is the central ox-LDL receptor expressed in endothelial and immune cells, its activation regulating inflammatory cytokines and chemotactic factor secretion. Recently, a Lox-1 truncated protein isoform lacking the ox-LDL binding domain named LOXIN has been described. We have previously shown that LOXIN overexpression blocked Lox-1-mediated ox-LDL internalization in human endothelial progenitor cells in vitro. However, the functional role of LOXIN in targeting inflammation or tissue injury in vivo remains unknown. In this study, we investigate whether LOXIN modulated the expression of Lox-1 and reduced the inflammatory response in a high-fat-diet mice model. Results indicate that human LOXIN blocks Lox-1 mediated uptake of ox-LDL in H4-II-E-C3 cells. Furthermore, in vivo experiments showed that overexpression of LOXIN reduced both fatty streak lesions in the aorta and inflammation and fibrosis in the liver. These findings were associated with the down-regulation of Lox-1 in endothelial cells. Then, LOXIN prevents hepatic and aortic tissue damage in vivo associated with reduced Lox-1 expression in endothelial cells. We encourage future research to understand better the underlying molecular mechanisms and potential therapeutic use of LOXIN. [ABSTRACT FROM AUTHOR]

Phytochemical study of the MeOH extract of Cucumis prophetarum fruits (family Cucurbitaceae) by using different chromatographic techniques led to the isolation of three metabolites; spinasterol (1), cucurbitacin B (2), and 2-O-β-D-glucopyranosylcucurbitacin E (3). Their chemical structures were created on the basis of physical, chemical, spectroscopic data 1D (1H and 13C NMR), and 2D NMR (HSQC and HMBC), as well as similarity with literature data. Cucurbitacin B (Cu-B) (2) was found to be the major constituent. Potential protective activities of MeOH extract, CHCl3, and EtOAc fractions and Cu-B were evaluated against carrageenan-induced prostatic inflammation in rats. Acute toxicity was assessed by evaluating LD50. Pretreatment with CHCl3 fraction and Cu-B ameliorated the rise in the prostate index and obviously protected against histopathological changes. Further, MeOH, extract, CHCl3, and EtOAc fractions as well as Cu-B significantly protected against oxidative stress in prostatic tissues. The anti-inflammatory activities of the extract, fractions and Cu-B were confirmed by ameliorating the rise in prostatic content of the inflammatory mediators TNF-α, IL-1β, COX-2, and iNOS induced by carrageenan. In addition, the rise in the chemotactic factors were myeloperoxidase (MPO), F4-80, and monocyte chemoattractant protein-1 (MCP-1) was significantly hampered. In conclusion, three known compounds (1–3) were isolated from Cucumis prophetarum fruits. Cu-B (2) was the major identified compound. Particularly, CHCl3 fraction and isolated Cu-B exhibited potent anti-inflammatory activity against carrageenan-induced prostatitis. The anti-inflammatory activity can be attributed, at least partly, to inhibition of neutrophil and macrophage infiltration into prostatic tissues. [ABSTRACT FROM AUTHOR]

IL-21/IL-21R was documented to participate in the regulation of multiple infection and inflammation. During Chlamydia muridarum (C. muridarum) respiratory infection, our previous study had revealed that the absence of this signal induced enhanced resistance to infection with higher protective Th1/Th17 immune responses. Here, we use the murine model of C. muridarum respiratory infection and IL-21R deficient mice to further identify a novel role of IL-21/IL-21R in neutrophilic inflammation. Resistant IL-21R-/- mice showed impaired neutrophil recruitment to the site of infection. In the absence of IL-21/IL-21R, pulmonary neutrophils also exhibited reduced activation status, including lower CD64 expression, MPO activity, and neutrophil-produced protein production. These results correlated well with the decrease of neutrophil-related chemokines (KC and MIP-2), inflammatory cytokines (IL-6, IL-1β, and TNF-α), and TLR/MyD88 pathway mediators (TLR2, TLR4, and MyD88) in infected lungs of IL-21R-/- mice than normal mice. Complementarily, decreased pulmonary neutrophil infiltration, activity, and levels of neutrophilic chemotactic factors and TLR/MyD88 signal in infected lungs can be corrected by rIL-21 administration. These results revealed that IL-21/IL-21R may aggravate the neutrophil inflammation through regulating TLR/MyD88 signal pathway during chlamydial respiratory infection. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is characterized by pulmonary diffusion abnormalities that may progress to multiple-organ failure in severe cases. There are limited effective treatments for ALI, which makes the search for new therapeutic avenues critically important. Macrophages play a pivotal role in the pathogenesis of ALI. The degree of macrophage polarization is closely related to the severity and prognosis of ALI, and S100A9 promotes M1 polarization of macrophages. The present study assessed the effects of S100A9-gene deficiency on macrophage polarization and acute lung injury. Our cohort study showed that plasma S100A8/A9 levels had significant diagnostic value for pediatric pneumonia and primarily correlated with monocyte-macrophages and neutrophils. We established a lipopolysaccharide (LPS)-induced mouse model of acute lung injury and demonstrated that knockout of the S100A9 gene mitigated inflammation by suppressing the secretion of pro-inflammatory cytokines, reducing the number of inflammatory cells in the bronchoalveolar lavage fluid, and inhibiting cell apoptosis, which ameliorated acute lung injury in mice. The in vitro and in vivo mechanistic studies demonstrated that S100A9-gene deficiency inhibited macrophage M1 polarization and reduced the levels of pulmonary macrophage chemotactic factors and inflammatory cytokines by suppressing the TLR4/MyD88/NF-κB signaling pathway and reversing the expression of the NLRP3 pyroptosis pathway, which reduced cell death. In conclusion, S100A9-gene deficiency alleviated LPS-induced acute lung injury by inhibiting macrophage M1 polarization and pyroptosis via the TLR4/MyD88/NFκB pathway, which suggests a potential therapeutic strategy for the treatment of ALI. [Display omitted] • S100A8/A9 exhibits excellent diagnostic efficiency in distinguishing CAP caused by different pathogens in children. • S100A9-/- alleviates the infiltration of inflammatory cells in lung tissue of acute lung injury in mice. • S100A9-/- attenuates inflammation by inhibiting M1 macrophage polarization and pyroptosis via the TLR4/MyD88/NFκB signaling axis. [ABSTRACT FROM AUTHOR]

Leukocyte cell‐derived chemotaxin‐2 (LECT2 or LECT‐2), also called chondromodulin II (ChM‐II or CHM2) plays a versatile role in various tissues. It was first identified as a chemotactic factor to promote the migration of neutrophils. It was also reported as a hepatokine to regulate glucose metabolism, obesity, and nonalcoholic fatty liver disease. As a secreted factor, LECT2 binds to several cell surface receptors CD209a, Tie1, and Met to regulate inflammatory reaction, fibrogenesis, vascular invasion, and tumor metastasis in various cell types. As an intracellular molecule, it is associated with LECT2‐mediated amyloidosis, in which LECT2 misfolding results in insoluble fibrils in multiple tissues such as the kidney, liver, and lung. Recently, LECT2 was found to be associated with the development of rheumatoid arthritis and osteoarthritis, involving the dysregulation of osteoclasts, mesenchymal stem cells, osteoblasts, chondrocytes, and endothelial cells in the bone microenvironment. LECT2 is implicated in the development of cancers, such as hepatocellular carcinoma via MET‐mediated PTP1B/Raf1/ERK signaling pathways and is proposed as a biomarker. The mechanisms by which LECT2 regulates diverse pathogenic conditions in various tissues remain to be fully elucidated. Further research to understand the role of LECT2 in a tissue tropism‐dependent manner would facilitate the development of LECT2 as a biomarker for diagnosis and therapeutic target. [ABSTRACT FROM AUTHOR]

Amyloidosis is a well‐known disease with various types and subtypes. One of the most recently identified types is leukocyte chemotactic factor 2 amyloidosis (LECT 2), which was found to be common in certain ethnic backgrounds. It is suggested that the diagnosis of this type is vital to prevent any therapy‐related complications when it is erroneously diagnosed as AL amyloidosis. The clinical presentation is usually slowly progressive kidney disease and mild hepatic impairment. We report a case of LECT2 amyloidosis, which presented with severe painless cholestasis and hepatic encephalopathy alongside progressive kidney disease. [ABSTRACT FROM AUTHOR]

Eotaxin at 10 nM significantly enhanced basophil histamine release triggered by anti-IgE antibody and C5a (Figure 1A); release was similarly enhanced in highly pure (purity: ~90%) basophils (Figure 1B). Keywords: allergy; basophils; eotaxin (CCL11); histamine; leukotriene C4 EN allergy basophils eotaxin (CCL11) histamine leukotriene C4 3549 3552 4 11/01/21 20211101 NES 211101 ACKNOWLEDGEMENTS The authors thank Drs Kei Onuma, Ryo Hatano (Juntendo University) and Hiroshi Kawasaki (JCHO Yugawara Hospital) for kindly providing us with anti-CCR3 hybridoma, Ms Sayaka Igarashi for helpful advice on the experimental procedures, Dr Hirokazu Sakasegawa for his critical reading of this manuscript, and Ms Yasuko Asada for her excellent secretarial work. [Extracted from the article]

Background and aim Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by destruction of pancreatic islet ßcells, leading to absolute insulin deficiency. The D vitamins are a group of sterols that have a hormone-like function, which bind to vitamin D receptor. Vitamin D (25(OH) D) deficiency is involved in the induction of autoimmune destruction of ß-cells and onset of T1DM. The majority of circulating 25(OH) D is bound to vitamin D-binding protein (VDBP), which protects it from biodegradation, limits its access to target tissues, and helps its reabsorption from the kidneys. VDBP also binds fatty acids, activates macrophages, enhances the chemotactic activity of C5, and associates with immune cell surfaces. The aim of our work was to evaluate the levels of 25(OH) D and VDBP and their relation to each other in T1DM and comparing 25(OH) D level with some variables in children with T1DM. Patients and methods In this simple comparative study, 60 children with T1DM and 35 normal children were enrolled, and for them, we measured serum 25-hydroxyvitamin D, serum VDBP, and glycosylated hemoglobin (HbA1c). Results 25(OH) D level was significantly lower in T1DM group than control (20.73 ± 5.69 and 41.16 ± 3.61 ng/ml, respectively) (t = 8.3 and P < 0.0001). Moreover, VDBP level was significantly lower in T1DM group than control group (203.96 ± 32.52 and 238.32 ± 34.82 µg/ml, respectively) (t = 4.7 and P < 0.0001). 25(OH)D level in T1DM had a significant positive correlation with age at onset of the disease (r=0.77) and a significant negative correlation with HbA1c % (r=-0.74) and no correlation with VDBP levels or disease duration. Conclusion 25(OH)D and VDBP levels in T1DM were significantly lower than normal children. 25(OH)D level had no correlation with VDBP levels, a positive correlation with age at onset of the disease, a negative correlation with HbA1c %, and no correlation with disease duration. [ABSTRACT FROM AUTHOR]

Problem: Immune responses of fetal membranes involve the production of chemoattractant mediators causing infiltration of maternal and fetal leukocytes, intrauterine inflammation and potentially the disruption of maternal‐fetal tolerance. Prolactin (PRL) has deep immunoregulatory effects in the fetal‐maternal interface. We aimed to test the in vitro PRL effect upon chemotactic capacities of human fetal membranes. Method of Study: Fetal membranes and umbilical cord blood were collected from healthy non‐laboring caesarean deliveries at term. Fetal membranes were cultured in Transwell® frames to mimic the barrier function between choriodecidual and amniotic sides. Tissues were treated with PRL, Lipopolysaccharide (LPS), or both simultaneously. Then, RANTES, MCP‐1, MIP‐1α, IP‐10, and PECAM‐1 were quantified in a conditioned medium by choriodecidual or amniotic sides. The chemotaxis of subsets of migrating mononuclear cells from umbilical cord blood was evaluated in a Boyden Chamber in response to the conditioned medium by both sides. Results: Lipopolysaccharide stimulates the production of RANTES, MCP‐1, MIP‐1α, and PECAM‐1 in choriodecidua, while MIP‐1α and PECAM‐1 only increase in amnion. PRL decrease RANTES, MCP‐1, and MIP‐1 only in choriodecidua, but PECAM‐1 was decreased mainly in amnion. The leukocyte migration was regulated significantly in response to the conditioned medium by the amnion, increase in the conditioned medium after LPS treatment, contrary with, the leukocyte migration decreased in a significant manner in response to conditioned medium after PRL and LPS‐PRL co‐treatment. Finally, T cells were the most responsive subset of cells. Conclusions: Prolactin modified in a tissue‐specific manner the chemotactic factor and the leukocyte migration differentially in fetal membranes. [ABSTRACT FROM AUTHOR]

Problem: Polycystic ovary syndrome (PCOS) is a common hormonal disorder that has a huge impact on the human infertility. Increased levels of various circulating inflammatory cytokines have been observed in PCOS patients, which can contribute to the pathogenesis of PCOS. Monocyte chemoattractant protein‐1 (MCP‐1), a secretory chemokine, is a potent chemotactic factor that recruits monocytes/macrophages to inflammatory foci. Several previous studies comparing the circulating MCP‐1 levels between non‐PCOS and PCOS patients have yielded contradictory results. Therefore, the aim of this meta‐analysis was to investigate whether circulating MCP‐1 levels vary between non‐PCOS and PCOS patients. Methods: Research articles published before November 11, 2020, were screened to identify eligible studies. Heterogeneity, sensitivity, and publication bias were analyzed using STATA software. Standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated by the STATA software using a random‐effects model. Results: 11 studies were included in this meta‐analysis involving 897 individuals: 368 non‐PCOS patient and 529 PCOS patients. Our pooled meta‐analysis results show that circulating MCP‐1 levels were significantly higher in PCOS patients than in non‐PCOS patients (SMD = 0.84, 95% CI = [0.37, 1.31], Z = 3.50, p < 0.01). However, due to the limited number of studies included in this meta‐analysis, subgroup analysis determined that circulating MCP‐1 levels were not significantly varied between obese non‐PCOS and obese PCOS patients (SMD = 0.42, 95% CI = [−0.65, 1.49], Z = 0.77, p = 0.442) as well as between non‐PCOS and PCOS patients without obesity (SMD = 2.04, 95% CI = [−0.84, 4.93], Z = 1.39, p = 0.166). In addition, circulating MCP‐1 levels were also not significantly different between obese and non‐obese PCOS patients (SMD = −0.04, 95% CI = [−0.68, 0.60], Z = 0.11, p = 0.909). Conclusion: Our findings reveal that circulating MCP‐1 levels are upregulated in women with PCOS and are associated with an increased risk of PCOS. [ABSTRACT FROM AUTHOR]

Erythema elevatum diutinum (EED) is a rare chronic cutaneous leucocytoclastic vasculitis with diffuse fibrosis, and its pathomechanism remains unclear.1,2 The published literature reported that chemotaxis towards interleukin-8 (IL-8) of neutrophils increased in patients with EED.3 IL-8 is a known neutrophil chemotaxis factor; recently, it has been suggested to be associated with fibrotic ailments, and elevated IL-8 levels in serum and skin have been reported in systemic sclerosis.4,5 Damaged endothelial cells release various chemotactic factors, including IL-8, which recruit inflammatory cells to exacerbate tissue damage, leading to scarring.6 Therefore, IL-8 is assumed to be involved in vasculitis and fibrosis of EED. The serum IL-8 levels were higher in the case with severe systemic symptoms of vasculitis; however, our case showed elevated levels of 19.5 pg/mL despite only skin symptoms. From differences in the number and distribution of IL-8-positive cells between EED and other vasculitis, IL-8 might trigger vasculitis leading to fibrosis in EED. [Extracted from the article]

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and β-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated β-catenin and the Wnt/β-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients. [ABSTRACT FROM AUTHOR]

Drug-induced allergy (DIA), an unexpectedly triggered side effect of drugs used for therapeutic purposes, is a serious clinical issue that needs to be resolved because it interrupts the treatment of the primary disease. Since conventional allergy testing is insufficient to accurately predict the occurrence of DIA or to determine the drugs causing it, the development of diagnostic and predictive tools for allergic reactions is important. We demonstrated a novel method, termed high-sensitive allergy test (HiSAT), for the rapid diagnosis of allergy (within 1 hr; with true-positive diagnosis rates of 89% and 9% for patients with and without allergy-like symptoms, respectively). HiSAT analyzes the cell kinetics as an index against chemotactic factors in a patient's serum, as different from the diagnosis using conventional methods. Once allergy has occurred, HiSAT can be used to determine the causative medicine using culture supernatants incubated with the subject's lymphocytes and the test allergen. This test is more efficient (60%) than the lymphocyte transformation test (20%). Furthermore, in HiSAT, cell mobility significantly increases in a dose-dependent manner against supernatant incubated with lymphocytes from a subject with pollinosis collected at a time when the subject is without allergic symptoms and the antigen. The result demonstraed that HiSAT might be a promising method to rapidly diagnose DIA or to determine with high accuracy the antigen causing allergy. [ABSTRACT FROM AUTHOR]

Calcium sensing receptor (CaSR), a class C GPCR, regulates essential secretory pathways, involving communication between endocytic and secretory Rab GTPases, via still to be fully defined molecular mechanisms. To address how communication between endocytic and secretory vesicles occurs, we hypothesized that CaSR activates endocytic Rab11A-dependent effector pathways acting upstream of Rab27B-regulated secretion. We found that Rab11A is critical to promote Rab27B-dependent secretion of chemotactic and inflammatory factors, including IL-8, CCL2/MCP-1, and IL1-β, in response to CaSR stimulation. It also attenuates secretion of IL-6. The process is mediated by endosomal PI3-kinases, Vps34 and PI3KC2α, which promote Rab27B activation. Rab11A interacts with and activates MADD, a guanine exchange factor for Rab3, and Rab27A/B. Mechanistically, CaSR drives Rab11A-dependent coupling of recycling endosomes to secretory-vesicles via endosomal PI3K-mediated activation of a MADD/Rab27B pathway. [Display omitted] • CaSR promotes communication between endocytic and secretory Rab GTPases. • CaSR activates an endocytic Rab11A-MADD-GEF-Rab27B secretory cascade. • Endosomal PI3-kinases are involved in the activation of Rab27B by CaSR. [ABSTRACT FROM AUTHOR]

During neuronal development, neuronal cells read extracellular stimuli from the micro/nano-environment within which they exist, retrieving essential directionality and wiring information. Here, focal adhesions (FAs -protein clusters anchoring integrins to cytoskeleton) act as sensors, by integrating signals from both the extracellular matrix environment and chemotactic factors, contributing to the final neuronal pathfinding and migration. In the processes that orchestrate neuronal development, the important function of ubiquitin E3A ligase (UBE3A) is emerging. UBE3A has crucial functions in the brain and changes in its expression levels lead to neurodevelopmental disorders: the lack of UBE3A leads to Angelman syndrome (AS, OMIN 105830), while its increase causes autisms (Dup15q-autism). By using nano/micro-structured anisotropic substrates we previously showed that UBE3A-deficient neurons have deficits in contact guidance (Tonazzini et al, Mol Autism 2019). Here, we investigate the adhesion and migration dynamics of UBE3A-silenced SH-SY5Y neuroblastoma cells in vitro by exploiting nano/micro-grooved substrates. We analyze the molecular processes regulating the development of FAs by transfection with EGFP-vector encoding for paxillin, a protein of FA clusters, and by live-cell total-internal-reflection-fluorescence microscopy. We show that UBE3A-silenced SH-SY5Y cells have impaired FA morphological development and pathway activation, which lead to a delayed adhesion and also explain the defective contact guidance in response to directional topographical stimuli. However, UBE3A-silenced SH-SY5Y cells show an overall normal migration behavior, in terms of speed and ability to follow the GRs directional stimulus. Only the collective cell migration upon cell gaps was slightly delayed for UBE3Ash SHs. Overall, the deficits of UBE3Ash SHS-SY5Y cells in FA maturation/sensing and in collective migration may have patho-physiological implications, in AS condition, considering the much more complex stimuli that neurons find in vivo during the neurodevelopment. [ABSTRACT FROM AUTHOR]

Objective: To study the influence of butyphthalide combined with urinary kallikrein in acute cerebral infarction (ACI) treatment on neuro-cytokines and indicators of vascular endothelial function, observe the curative effect and adverse effects, and discuss its safety and feasibility. Method: 110 ACI patients were chosen as the objects, and classified into observation group (55 cases) and control group (55 cases) according to the method of random number table. Butyphthalide injection combined with urinary kallikrein was adopted for the observation group based on conventional treatment, while cinepazide maleate injection combined with alprostadil injection was applied for the control group based on conventional treatment. The following indicators of both groups were compared before and after treatment: neurotrophic factor (NTF), nerve growth factor (NGF), neuron specific enolase (NSE); content of CXC chemotactic factor ligand 16 (CXCL16), soluble CD ligand (CD40L), Fibulin-5 and high mobility group box B1 (HMGB1); the content of indicators of vascular endothelial function including plasma endothelin −1 (ET-1) and no therapeutic effects and adverse effects were recorded. Results: NSE of both groups after treatment decreased obviously, and the content of NTF and NGF increased obviously. NSE content of observation group was lower than that of control group. NTF content and NGF content of observation group were higher than those of control group. The differences had statistical significance (p < 0.05). The levels of CXCL16, CD40L, Fibulin-5 and HMGB1 declined obviously, compared with pre-treatment, and the levels of observation groups were significantly lower than those of control grip. The differences had statistical significance (p < 0.05). ET-1 level rose significantly after treatment, and NO level declined obviously after treatment. ET-1 level of observation group was significantly higher than that of control group, and NO level of observation group was significantly lower than that of control group. The difference had statistical significance (p < 0.05). Clinical effect of observation group was significantly higher than that of control group. The difference had statistical significance (p < 0.05). The comparison difference of both groups in the occurrence rate of adverse effects had no statistical significance (p > 0.05). Conclusion: The application of butyphthalide combined with urinary kallikrein in ACI treatment can effectively inhibit secretion and release of neuro-cytokines, and improve patients' vascular endothelial function, with significant treatment effect and high safety. Therefore, it deserves to be promoted clinically. [ABSTRACT FROM AUTHOR]

Background: Myeloid-derived suppressor cells (MDSC) are categorized as granulocytic (G-MDSCs) and monocytic (M-MDSCs) and their expansion play a role in cancer progression. Recruitment to the cancer site depends upon the presence of a chemoattractant. We aimed to investigate the presence of MDSC subtypes and of interleukin-8 (CXCL-8) in the peripheral blood in lung cancer subtypes including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients. Materials and Methods: Peripheral blood samples of 26 NSCLC patients, 18 SCLC patients, and 8 healthy control donors (HDs) were harvested and the surface expression of CD14, CD15, CD11b, and HLA-DR on MDSCs was measured using flow cytometry. The level of serum CXCL8 was measured by the ELISA method. Results: The frequency of circulating M-MDSCs was significantly higher in patients with NSCLC than in SCLC and HDs. In contrast, there was no statistical difference concerning the frequency of circulating G-MDSCs between the three groups. The concentration of CXCL-8 was significantly higher in the NSCLC and SCLC patients than in HD control with no significant difference between NSCLC and SCLC groups. There was no correlation between serum CXCL8 and G-MDSC levels. Conclusion: Our data confirm a higher frequency of circulating M-MDSCs, but not G-MDSCs, in the blood of those suffering from NSCLC but not for SCLC cases. Measuring MDSC subtypes and serum chemotactic factors may have implications for the differential diagnosis of NSCLC. [ABSTRACT FROM AUTHOR]

Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite stable (MSS) phenotype. In the current study, a combination of fruquintinib plus anti–PD-1 for MSS CRC therapy was investigated. First, a case of advanced MSS CRC was reported. After failure of multiline therapy, the patient finally achieved rapid response after receiving fruquintinib plus anti–PD-1 treatment. Then the effect of fruquintinib plus anti–PD-1 was verified using a murine syngeneic model of CT26 cells (MSS). The results showed that cotreatment significantly inhibited tumor growth and promote survival time for tumor-bearing mice compared with the single drug alone. In addition, fruquintinib/anti–PD-1 cotreatment decreased angiogenesis, enhanced normalization of the vascular structure, and alleviated tumor hypoxia. Moreover, the combination therapy reprogrammed the immune microenvironment by enhancing chemotactic factor release, increasing CD8+ T cell infiltration and activation, decreasing ration of regulatory T cells, and promoting M1/M2 ratio of macrophage. Finally, the enhanced antitumor effect of fruquintinib/anti–PD-1 cotreatment was significantly reversed in CD8 knockout mice compared with that in the wild-type mice. Our study indicated that combination of fruquintinib and anti–PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses. [ABSTRACT FROM AUTHOR]

• CDDP/PEM enhanced anti-tumor effects of anti-PD-1 antibody against MPM in mice. • CDDP/PEM decreased intratumoral myeloid-derived suppressor cells (MDSCs). • CDDP/PEM reduced VEGF in MPM cells, which is a chemotactic factor for MDSCs. The combination of anti-PD-1/PD-L1 antibody with chemotherapy has been approved for the first-line therapy of lung cancer. However, the effects against malignant mesothelioma (MPM) and the immunological mechanisms by which chemotherapy enhances the effect of targeting PD-1/PD-L1 in MPM are poorly understood. We utilized syngeneic mouse models of MPM and lung cancer and assessed the therapeutic effects of anti-PD-1 antibody and its combination with cisplatin (CDDP) and pemetrexed (PEM). An immunological analysis of tumor-infiltrating cells was performed with immunohistochemistry. We observed significant therapeutic effects of anti-PD-1 antibody against MPM. Although the effect was associated with CD8+ and CD4+ T cells in tumors, the number of Foxp3+ cells was not reduced but rather increased. Consequently, combination with CDDP/PEM significantly enhanced the antitumor effects of anti-PD-1 antibody by decreasing numbers of intratumoral myeloid-derived suppressor cells (MDSCs) and vessels probably through suppression of VEGF expression by CDDP + PEM. The combination of anti-PD-1 antibody with CDDP + PEM may be a promising therapy for MPM via inhibiting the accumulation of MDSCs and vessels in tumors. [ABSTRACT FROM AUTHOR]

Soft tissue is composed of cells surrounded by an extracellular matrix that is made up of a diverse array of intricately organized proteins. These distinct components work in concert to maintain homeostasis and respond to tissue damage. During tissue repair, extracellular matrix proteins and their degradation products are known to influence physiological processes such as angiogenesis and inflammation. In this study we developed a discovery platform using a decellularized extracellular matrix biomaterial to identify new chemotrophic factors derived from the extracellular matrix. An in vitro culture of RAW.264 macrophage cells with the biomaterial ovine forestomach matrix led to the identification of a novel ~12 kDa chemotactic factor, termed 'MayDay', derived from the N-terminal 31–188 sequence of decorin. The recombinant MayDay protein was shown to be a chemotactic agent for mesenchymal stromal cells in vitro and in vivo. We hypothesize that the macrophage-induced cleavage of decorin, via MMP-12, leads to the release of the chemotactic molecule MayDay, that in turn recruits cells to the site of damaged tissue. [ABSTRACT FROM AUTHOR]

Netrin is a remarkably conserved midline landmark, serving as a chemotactic factor that organizes the bilateral neural architecture in the post-gastrula bilaterian embryos. Netrin signal also guides cell migration in many other neural and non-neural organogenesis events in later developmental stages but has never been found to participate in gastrulation – the earliest cell migration in metazoan embryogenesis. Here, we found that the netrin signaling molecules and their receptors are expressed during gastrulation of the leech Helobdella. Intriguingly, Hau-netrin-1 was expressed in the N lineage, which gives rise in part to the ventral midline of ectoderm, at the onset of gastrulation. We demonstrated that the N lineage is required for the entrance of mesoderm into the germinal band and that misexpression of Hau-netrin-1 in early gastrulation prevented mesoderm from entering the germinal band. Together, these results suggested that Hau-netrin-1 secreted by the N lineage guides mesoderm migration during germinal band assembly. Furthermore, ectopic expression of Hau-netrin-1 after the completion of germinal band assembly disrupted the epibolic migration of the germinal bands in a later stage of gastrulation. Thus, Hau-netrin-1 is likely involved in two distinct events in sequential stages of leech gastrulation: the assembly of germinal bands in early gastrulation and their epibolic migration in mid-gastrulation. Given that the leech netrin is expressed in the precursor cells of the ventral midline during gastrulation, we propose that a heterochronic change from the midline netrin expression had taken place in the evolution of a novel mode of gastrulation in the directly developing leech embryos. Image 1 • Netrin and netrin receptors are expressed during leech gastrulation. • Leech netrins are expressed in cell lineages contributing to future midline. • Netrin guides mesoderm migration during leech gastrulation. • Netrin may contribute to the evolution of a new mode of gastrulation. [ABSTRACT FROM AUTHOR]

Background: Lymphocytes circulate between peripheral lymphoid tissues via blood and lymphatic systems, and chemokine-induced migration is important in trafficking lymphocytes to distant sites. The small GTPase Rap1 is important in mediating lymphocyte motility, and Rap1-GEFs are involved in chemokine-mediated Rap1 activation. Here, we describe the roles and mechanisms of Rap1-GEFs in lymphocyte trafficking. Results: In this study, we show that RA-GEF-1 and 2 (also known as Rapgef2 and 6) are key guanine nucleotide exchange factors (GEF) for Rap1 in lymphocyte trafficking. Mice harboring T cell-specific knockouts of Rapgef2/6 demonstrate defective homing and egress of T cells. Sphingosine-1-phosphate (S1P) as well as chemokines activates Rap1 in a RA-GEF-1/2-dependent manner, and their deficiency in T cells impairs Mst1 phosphorylation, cell polarization, and chemotaxis toward S1P gradient. On the other hand, B cell-specific knockouts of Rapgef2/6 impair chemokine-dependent retention of B cells in the bone marrow and passively facilitate egress. Phospholipase D2-dependent production of phosphatidic acid by these chemotactic factors determines spatial distribution of Rap1-GTP subsequent to membrane localization of RA-GEFs and induces the development of front membrane. On the other hand, basal de-phosphorylation of RA-GEFs is necessary for chemotactic factor-dependent increase in GEF activity for Rap1. Conclusions: We demonstrate here that subcellular distribution and activation of RA-GEFs are key factors for a directional movement of lymphocytes and that phosphatidic acid is critical for membrane translocation of RA-GEFs with chemokine stimulation. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the association between gene methylation and leukocytopenia from the perspective of gene regulation. A total of 30 patients confirmed as having post-infection leukocytopenia at People's Hospital of Xinjiang Uygur Autonomous Region between January 2016 and June 2017 were successively recruited as the leukocytopenia group; 30 patients with post-infection leukocytosis were enrolled as the leukocytosis group. In addition, 30 healthy volunteers who received a health examination at the hospital during the same period were included as the normal control group. In each group, four individuals were randomly selected for whole genome methylation screening. After selection of key methylation sites, the remaining samples in each group were used for verification using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The levels of serum complement factors C3 and C5 in the leukocytopenia group were significantly lower than those in the other two groups (P<0.05). According to whole-genome DNA methylation detection, 66 and 27 methylation loci may be associated with leukocytopenia and leukocytosis, respectively. Most of these abnormal loci are located on chromosomes 2, 6, 7, 1, 17 and 11. The rates of WW domain containing E3 ubiquitin protein ligase 2 gene methylation at cytosine-phosphate-guanine (CpG)_1, CpG_5/6 and CpG_7 in the leukocytopenia group were higher than in the other two groups (P<0.05); the rate of AKT2 CpG_1 methylation was higher in the leukocytopenia group than in the other two groups (P<0.05); the rate of calcium-binding atopy-related autoantigen 1 gene CpG_2 methylation was higher in the leukocytosis group than in the normal control group (P<0.05); and the rate of NAD PH oxidase 5 gene CpG_3 methylation was higher in the leukocytosis group than in the normal control group (P<0.05). Chemotactic factor secretion and cell migration abnormalities, ubiquitination modification disorders and reduced oxidative burst may participate in infection-complicated leukocytopenia. The results of this study shed new light on the molecular biological mechanisms of infection-complicated leukocytopenia and provide novel avenues for diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Leukocyte chemotactic factor 2 (ALECT2) amyloidosis is one of the recently described types of amyloidosis. In this study, we reported the first large case series of renal ALECT2 amyloidosis in Chinese patients. Methods: We studied the prevalence, clinical characteristics, renal pathology, outcome and genetic features among seven patients diagnosed with renal ALECT2 amyloidosis at Peking University First Hospital of China from 2000 to 2018. Results: Seven patients were diagnosed with ALECT2 amyloidosis, representing 1.9% of the renal biopsy-proven amyloidosis cases. The mean age at diagnosis was 68 years without gender preference. The patients mainly manifested with varying impaired kidney function with a mean estimated glomerular filtration rate of 42.7 mL/min/1.73 m2 (range 8.0–80.5) and proteinuria at 3.9 g/24 h (range 0.4–11.3). There were four ALECT2 amyloidosis patients with concurrent membranous nephropathy (MN), who presented a higher proteinuria (6.4 ± 4.0 g/24 h vs. 2.0 ± 1.8 g/24 h) and higher frequency of nephrotic syndrome (50% vs. 0) than patients with isolated ALECT2 amyloidosis. Renal biopsy showed strongly congophilic amyloid deposits distributed mainly in the renal cortical interstitium, as well as the glomerular mesangium, the inner layer of glomerular basement membrane (GBM), and vascular walls. Two patients with concurrent ALECT2 amyloidosis and MN showed mild amyloid deposits, which have not been identified as ALECT2 amyloidosis by IHC and LMD/MS methods. All patients were corroborated by immunoelectron microscopy to exhibit the specific location of LECT2 in the amyloid fibrils. Genetic analysis revealed no mutations but homozygosity for the G allele encoding valine at position 40 in the mature protein in all patients. Except for one patient who died 8 years later after he was diagnosed with ALECT2 amyloidosis, the others presented with relatively stable renal function during the mean follow-up period of 12.5 months. Conclusions: ALECT2 amyloidosis was the third most common type of renal amyloidosis in Chinese patients from a single centre. The majority of ALECT2 amyloidosis patients were of Han ethnicity, with a high rate of concurrent MN. The recognition and accurate diagnosis of renal ALECT2 amyloidosis should be considered in Chinese patients. [ABSTRACT FROM AUTHOR]

This prospective one-year follow-up study was conducted from 835 visits in 178 rheumatoid arthritis (RA) patients. Tender-/swollen-joint count, Health Assessment Questionnaire Disability Index (HAQ-DI), Disease Activity Score 28-ESR (DAS28-ESR), DAS28-CRP, Simplified Disease Activity Index (SDAI) and DAS28-monocyte chemotactic protein-1 (DAS28-MCP-1) scores were obtained every 3 months. Radiographs of hands and feet were acquired at baseline and one year. We evaluated the correlation and accuracy of activity scores in predicting remission, HAQ-DI changes and radiographic changes. DAS28-MCP-1 correlated strongly with DAS28-ESR, DAS28-CRP and SDAI scores (0.830, 0.899 and 0.931, respectively, with all P < 0.001). Score changes of DAS28-MCP-1 were comparable to those of DAS28-ESR, DAS28-CRP and SDAI in predicting changes in HAQ-DI and bone erosion. DAS28-MCP-1 (<2.2) was better than DAS28-ESR (<2.6) in indicating modified American Rheumatism Association remission and 2011 American College of Rheumatology/European League Against Rheumatism remission (75.61% vs. 36.99% and 81.71% vs. 49.13%, respectively) with odds ratios of 5.28 and 4.62 (both P < 0.001), respectively. We compared DAS28-MCP-1 with SDAI (≦3.3) in indicating remission with odds ratios of 2.63 (P = 0.002) and 0.98, respectively (and DAS28-MCP-1 with DAS28-CRP < 2.5: 1.33 and 0.92). Therefore, DAS28-MCP-1 is useful as an alternative in assessing RA activity. [ABSTRACT FROM AUTHOR]

Sperm migration towards an oocyte in the female reproductive tract is an important step for successful fertilization. Although several sperm-chemotactic factors have been identified in mammals, it is unclear whether these chemoattractants contribute to sperm migration towards an oocyte that is the final destination for sperm. Furthermore, chemoattractants for bovine sperm are still undiscovered even though the follicular fluid attracts sperm in cattle. Here, we demonstrated that a single bovine cumulus-oocyte complex (COC) had the ability to attract sperm, suggesting that the COC secreted sperm chemoattractants. We identified stromal cell-derived factor 1 (SDF1), which was expressed in COCs, and its receptor CXCR4 in sperm, as a candidate. Our results showed that bovine sperm preferentially migrated to the area with a high SDF1 concentration and occasionally showed turn movements by asymmetric flagellar bends during the migration. We also demonstrated that increasing the intracellular Ca2+ concentration via Ca2+ channels was related to SDF1-induced sperm chemotaxis. Finally, a CXCR4 inhibitor significantly suppressed the in vitro bovine sperm migration towards a COC. Taken together, we propose that SDF1 is a chemotactic factor for bovine sperm to regulate their migration towards an oocyte via the CXCR4 receptor. [ABSTRACT FROM AUTHOR]