Role Of Inflammatory Pathways Research Articles

Role of Inflammatory Pathways in the Development of Rosacea

Role of Inflammatory Pathways in the Development of Rosacea

Bivariate genome-wide association study of circulating fibrinogen and C-reactive protein levels

BackgroundFibrinogen and C-reactive protein (CRP) play an important role in inflammatory pathways and share multiple genetic loci reported in previously published genome-wide association studies (GWAS), highlighting their common genetic background. Leveraging the shared biology may identify further loci pleiotropically associated with both fibrinogen and CRP. ObjectivesTo identify novel genetic variants that are pleiotropic and associated with both fibrinogen and CRP, by integrating both phenotypes in a bivariate GWAS by using a multitrait GWAS. MethodsWe performed a bivariate GWAS to identify further pleiotropic genetic loci, using summary statistics of previously published GWAS on fibrinogen (n = 120 246) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, consisting of European ancestry samples and CRP (n = 363 228) from UK Biobank, including 5 different population groups. The main analysis was performed using metaUSAT and N-GWAMA. We conducted replication for novel CRP associations to test the robustness of the findings using an independent GWAS for CRP (n = 148 164). We also performed colocalization analysis to compare the associations in identified loci for the 2 traits and Genotype-Tissue Expression data. ResultsWe identified 87 pleiotropic loci that overlapped between metaUSAT and N-GWAMA, including 23 previously known for either fibrinogen or CRP, 58 novel loci for fibrinogen, and 6 novel loci for both fibrinogen and CRP. Overall, there were 30 pleiotropic and novel loci for both traits, and 7 of these showed evidence of colocalization, located in or near ZZZ3, NR1I2, RP11-72L22.1, MICU1, ARL14EP, SOCS2, and PGM5. Among these 30 loci, 13 replicated for CRP in an independent CRP GWAS. ConclusionBivariate GWAS identified additional associated loci for fibrinogen and CRP. This analysis suggests fibrinogen and CRP share a common genetic architecture with many pleiotropic loci.

USP18 reduces the inflammatory response of LPS-induced SA-AKI by inhibiting the PI3K-AKT-NF-κB pathway and regulate apoptosis of cells

Background Sepsis-associated acute kidney injury (SA-AKI) is marked by systemic inflammation and organ dysfunction. Ubiquitin-specific protease 18 (USP18) is a regulator in immune responses and apoptosis. Objectives To explore USP18's role in inflammatory pathways and apoptosis in SA-AKI, particularly its interactions with the PI3K-AKT-NF-κB pathway. Design A combination of animal experiments and cellular models was employed to investigate the expression and regulatory functions of USP18 in both in vivo and in vitro settings. Methods We established SA-AKI models in mice and HK-2 cells using LPS. Gene expression was analyzed via RNA-seq, and Cr, BUN, and inflammatory factors were measured using biochemical assays and ELISA. Kidney pathology was assessed with HE staining, mRNA levels with qRT-PCR, protein expression with Western blots, and cell apoptosis with flow cytometry. Results In SA-AKI mice model and HK-2 cell lines, upregulated USP18 was linked to increased activity in the PI3K-AKT-NF-κB pathway and heightened inflammation. Conversely, USP18 downregulation decreased early cell apoptosis and raised levels of inflammatory proteins. Elevated USP18 levels were also found in SA-AKI patients’ blood and urine. Conclusion USP18 enhances in vitro and in vivo responses by modulating inflammation and apoptosis through the PI3K-AKT-NF-κB pathway, presenting a potential target for SA-AKI therapy.

Abstract 5588: Protein Arginine Methyltransferase 2 is involved in the control of inflammatory processes in acute myeloid leukemia

Abstract A direct link between chronic inflammation and development of Acute Myeloid Leukemia (AML) has been highlighted in the past few years, demonstrating an interconnection between marked inflammatory phenotype and aberrant myeloproliferation in AML patients. Treating AML patients exhibiting a higher inflammatory signature with anti-inflammatory molecules resulted in significant increase of overall survival. Protein Arginine Methyltransferases (PRMTs) are epigenetic factors known to regulate gene expression through methylation of histone tails. It has been previously reported that PRMT1, 4, and 5 inhibition exhibit anti-proliferative effects on AML models. In this study, we investigated the role of another PRMT, called PRMT2, in the development of AML through its regulatory roles in inflammatory pathways. We first determined from an AML cohort (The Leucegene project, IRIC, Montréal, QC, Canada) that patients with a low PRMT2 expression display an enrichment of proinflammatory pathways compared to patients with a high PRMT2 expression. Therefore, we hypothesized that PRMT2 could be a key regulator of inflammatory processes in AML. We thus used a PRMT2 knockout mouse model (Prmt2 KO) and a PRMT2 knockout human AML cell line to validate our hypothesis. Although we demonstrated no difference in the bone marrow progenitors or mature cell populations of Prmt2 KO mice compared to control, we observed that Prmt2 KO Bone-Marrow Derived Macrophages (BMDMs) are more sensitive to LPS stimulation and express higher levels of pro-inflammatory cytokines, supporting our previous findings for a role of PRMT2 in the negative regulation of inflammatory processes. PRMT2 depleted human AML cells displayed an increased pro-inflammatory signature due to overactivation of STAT3, which is caused by an enhanced activation of the NFkB signaling pathway, leading to an overproduction of IL6. Together, these findings demonstrate that PRMT2 is a key regulator of the control of inflammation in AML. Recognition of PRMT2 as a biomarker of inflammation in AML would help to adapt treatment possibly through the synergistic use of anti-inflammatory molecules with other cytotoxic drugs. Citation Format: Camille Sauter, Thomas Morin, Fabien Guidez, John Simonet, Cyril Fournier, Céline Row, Denis Masnikov, Baptiste Pernon, Anne Largeot, Aziza Aznague, Yann Herault, Guy Sauvageau, Marc Maynadie, Mary Callanan, Jean-Noël Bastie, Romain Aucagne, Laurent Levadny Delva. Protein Arginine Methyltransferase 2 is involved in the control of inflammatory processes in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5588.

Abstract 4398: TET2 accelerates clonal hematopoiesis in an age-dependent manner

Abstract Aging is a process of systemic deterioration and the most significant risk factor for cancers. Clonal hematopoiesis (CH) commonly occurs with aging and links to higher mortality, leukemia risk, and cardiovascular diseases. Age-related CH involves the abnormal clonal expansion of hematopoietic stem cells (HSCs) bearing somatic mutations in genes frequently mutated in leukemia, including genes encoding epigenetic regulators, such as the DNA demethylase TET2. While such mutations are known to alter the HSC epigenome, the mechanisms through which these mutations drive HSC self-renewal, myeloid transformation, and inflammatory response remain elusive. In this study, we hypothesize that aging and CH mutations cooperatively reshape the HSC transcriptomic landscape and enhancing HSC competitive advantage that facilitates clonal expansion. Recently, TET2-mutant CH in humans has been strongly associated with epigenetic age acceleration. Using single-cell multi-omic analyses and flow-cytometric phenotyping, we demonstrated, for the first time, that HSC aging processes at transcriptomic, epigenomic, and cellular levels are accelerated by Tet2 deficiency in mice, in an age-dependent manner. Tet2-deficient HSCs increase the HSC aging scores at an older age of greater than or equal to 16 months, but not at a young or mid-age, based on gene expression and chromatin accessibility at a single-cell resolution. This age acceleration was further validated by epigenetic clock analysis of DNA methylation mapping. Moreover, we found that Tet2 deficiency drives a significant expansion of HSCs, a cellular hallmark of HSC aging, in an age-dependent manner. Specifically, we observed increased expression of S100a6, Cdk6, Egr1 in Tet2-deficient HSCs from older mice, suggesting that Tet2 deficiency hijacks the HSC expansion strategy during HSC aging by enhanced self-renewal. We also observed that the differentially expressed genes between Tet2-deficient older HSCs and control older HSCs are associated with open chromatin accessibility. Many of these genes are enriched in the targets of specific transcription factors (TFs), such as Egr1, Creb1, Stat family and Hoxb8. These target genes play critical roles in inflammatory pathways and HSC functions. In conclusion, our findings reveal that Tet2 deficiency significantly contributes to the acceleration of HSC aging, and hijacks the HSC expansion strategy (e.g., self-renewal) during HSC aging, which exacerbates age-related clonal hematopoiesis. By elucidating the transcriptomic and epigenomic alterations in Tet2-deficient HSCs, our study provides novel insights into how age and somatic mutations collaborate to promote the pathogenesis of age-related hematological diseases. These discoveries not only enhance our understanding of HSC aging mechanisms but also offer potential biomarkers for early detection and targets for therapeutic intervention in age-associated clonal disorders. Citation Format: Shilpita Karmakar, Yang Liu, Efthymios Motakis, Kaustav Sengupta, Travis Roeder, Kristina Mujica, Jennifer Trowbridge, Hideyuki Oguro, Sheng Li. TET2 accelerates clonal hematopoiesis in an age-dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4398.

Evaluation of the Expression of Infection-Related Long Noncoding RNAs among COVID-19 Patients: A Case-Control Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a worldwide pandemic, activates signaling cascades and leads to innate immune responses and secretion of multiple chemokines and cytokines. Long noncoding RNAs (lncRNAs) have a crucial role in inflammatory pathways. Through our search on the PubMed database, we discovered that existing research has primarily focused on examining the regulatory impacts of five lncRNAs in the context of viral infections. However, their role in regulating other conditions, including SARS-CoV-2, has not been explored. Therefore, this study aimed to investigate the expression pattern of lncRNAs in the peripheral blood mononuclear cells (PBMC) and their potential roles in SARS-CoV-2 infection. Potentially significant competing endogenous RNA (ceRNA) networks of these five lncRNAs were found using online in-silico techniques. Ethylenediaminetetraacetic acid (EDTA) blood samples of the control group consisted of 45 healthy people, and a total of 53 COVID-19-infected patients in case group, with a written informed consent, was collected. PBMCs were extracted, and then, the RNA extraction and complementary DNA (cDNA) synthesis was performed. The expression of five lncRNAs (lnc ISR, lnc ATV, lnc PAAN, lnc SG20, and lnc HEAL) was assessed by real-time PCR. In order to evaluate the biomarker roles of genes, receiver operating characteristic (ROC) curve was drawn. Twenty-four (53.3%) and 29 (54.7%) of healthy and COVID-19-infected participants were male, respectively. The most prevalent symptoms were as follows: cough, general weakness, contusion, headache, and sore throat. The results showed that three lncRNAs, including lnc ISR, lnc ATV, and lnc HEAL, were expressed dramatically higher in the case group compared to healthy controls. According to ROC curve analysis, lnc ATV has a higher AUC and is a better biomarker to differentiate COVID-19 patients from the healthy controls. Then, using bioinformatics methods, the ceRNA network of these lncRNAs enabled the identification of mRNAs and miRNAs with crucial functions in COVID-19. The considerable higher expression of ISR, ATV, and HEAL lncRNAs and the significant area under curve (AUC) in ROC curve demonstrate that these RNAs probably have a potential role in controlling the host innate immune responses and regulate the viral replication of SARS-CoV-2. However, these assumptions need further in vitro and in vivo investigations to be confirmed.

Chronic hepatitis B infection biochemical, virological and tissue treatment response in correlation with platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in Egyptian patients infected with chronic hepatitis B virus

Abstract Background Hepatitis B virus (HBV) is considered one of the most significant public health challenges due to its chronicity and complications that happen after several years of infection. The main event in HBV effect is its recognition as a foreign antigen which activates the immunity to target and destroy infected cells, hence HBV is not a cytotoxic virus. This destruction happens intermittently through the course of chronic infection leading to inflammation and necrosis of the liver tissue. The repetition of these periods of liver injury yields liver fibrosis and hepatocellular carcinoma. For disease prognostication, assessment of treatment of treatment indications and management in HBV chronic infected patients, assessment of liver fibrosis and cirrhosis status is crucial. Liver biopsy is an accurate but invasive method, while transient elastography and different serum biomarkers are considered non-invasive modalities. The platelet-lymphocyte ratio (PLR) is a novel inflammatory marker, which can be used for predicting inflammation and mortality in many diseases. While NLR has been recommended as a new marker for systemic inflammation as Lymphomononuclear cells play a fundamental role in inflammatory pathways during the development of cirrhosis. PLR values were considerably lower in chronic Hepatitis B (CHB) patients with significant liver fibrosis and it is suggested that combining noninvasive parameters such as PLR and NLR may help identifying patients at high risk of developing advanced and progressive disease. Aim To correlate hepatitis B viral replication, liver biochemical tests and liver fibrosis to platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) and follow up treatment response of HBV with PLR and NLR. Patients and methods This prospective study was conducted on 60 patients with HBV eligible for antiviral treatment with NAs, agreeable to regular follow-up, recruited from Ain Shams University Virology Center in Cairo during the period from January 2022 to January 2023 after informed consents were taken from the patients and agreement for follow up. All patients were investigated by laboratory tests (CBC, AST, ALT, Total bilirubin, serum albumin, INR, serum creatinine, alpha fetoprotein, HBsAg, HBV DNA PCR, HBeAg), Pelviabdominal ultrasound and Fibroscan followed by calculation of PLR and NLR before and six months after initiating treatment. Results Our study shows a negative and a statistically significant correlation between PLR and Fibroscan in patients before treatment (P value <0.001) and 6 months after treatment initiation (P value <0.001) Also PLR statistically correlated in a positive way to HBV DNA in patients before treatment (P value <0.001). While there was no statistically significant correlation between NLR and neither the Fibroscan nor HBV DNA PCR in both study periods. Conclusions PLR partially correlates with HBV DNA PCR but strongly correlated with fibrosis stage in fibroscan with an inverse correlation and can be used as a marker of fibrosis. While NLR neither reflects HBV DNA nor fibrosis stage in fibroscan and cannot be used as a marker of fibrosis

Multiscale molecular dynamics simulations predict arachidonic acid binding sites in human ASIC1a and ASIC3 transmembrane domains.

Acid-sensing ion channels (ASICs) play important roles in inflammatory pathways by conducting ions across the neuronal membrane in response to proton binding under acidic conditions. Recent studies have shown that ASICs can be modulated by arachidonic acid (AA), and, in the case of the ASIC3 subtype, even activated by AA at physiological pH. However, the mechanism by which these fatty acids act on the channel is still unknown. Here, we have used multiscale molecular dynamics simulations to predict a putative, general binding region of AA to models of the human ASIC protein. We have identified, in agreement with recent studies, residues in the outer leaflet transmembrane region which interact with AA. In addition, despite their similar modulation, we observe subtle differences in the AA interaction pattern between human ASIC1a and human ASIC3, which can be reversed by mutating three key residues at the outer leaflet portion of TM1. We further probed interactions with these residues in hASIC3 using atomistic simulations and identified possible AA coordinating interactions; salt bridge interactions of AA with R65hASIC3 and R68hASIC3 and AA tail interactions with the Y58hASIC3 aromatic ring. We have shown that longer fatty acid tails with more double bonds have increased relative occupancy in this region of the channel, a finding supported by recent functional studies. We further proposed that the modulatory effect of AA on ASIC does not result from changes in local membrane curvature. Rather, we speculate that it may occur through structural changes to the ion channel upon AA binding.

Investigation of different genomic variants in familial Mediterranean fever cases with monoallelic MEFV mutation.

Familial Mediterranean Fever (FMF) is an inflammatory disease characterised by periodic fever and concurrent episodes of serous membrane inflammation. FMF is considered to be inherited in autosomal recessive manner and biallelic mutations in the MEFV gene are associated with the disease. However, approximately 20-25% of patients only have a single mutation in MEFV gene, which creates confusion in differential diagnosis of many patients. This study aimed to reveal rare variants that may act in conjunction with the single pathogenic MEFV variant in the pathogenesis of FMF. We performed whole exome sequencing in 17 individuals from 5 different families who were diagnosed according to the clinical criteria, responded positively to colchicine treatment, but had no biallelic MEFV mutation. A disease-causing variant or a common affected cellular pathway that was shared in all index cases was not detected. When cases were examined individually, two de novo variants were identified in the BIRC2 and BCL10 genes, both of which play a role in inflammatory pathways. Functional studies are needed to confirm the physiopathological relationship of these genes with FMF. This study is one of the most extensive aetiological researches in FMF cases with monoallelic MEFV mutation. We have shown that genotype-phenotype correlation in these cases may not be established by rare genetic variants and discussed underlying causes. Clinical criteria with emphasis on colchicine response and family history should be the main tool and genetic results should only be used for support in FMF diagnosis.

In-silico docking, synthesis, structure analysis, DFT calculations, energy frameworks, and pharmacological intervention of [1,3,4]-thiadiazoles analogous as XO inhibitor and on multiple molecular inflammatory targets COX and LOX

Xanthine oxidase (XO) is an interesting target for the synergic treatment of several diseases such as gout, hypertension, type 2 diabetes, and kidney disease. Associated complication includes hyperuricemia, which is considered one of the most common metabolic lifestyle disorders worldwide. Overproduction and insufficient excretion of uric acid during purine metabolism results in the formation of uric acid crystals in kidneys, joints, and other tissues. Allopurinol and Febuxostat, a clinically available drug used to reduce XO activity and serum uric acid level, are demonstrated to produce adverse effects including gastrointestinal distress, hypersensitivity, and skin rash, raising safety concerns. Exploring newer and novel XO inhibitors with minimum or no side effects is the aim of the current study. [1,3,4]-Thaidiazole analogs (7a-j) scaffold plays an important role in the design of efficient and potent inhibitors. In the present work, (7a-j) were evaluated for their ability to inhibit XO and found that among the series compound (7i) is selected as the best compound for inhibition of XO. Further, cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX), enzymes that generate biologically active lipid molecules termed eicosanoids, are considered inflammatory and play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types, the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new novel [1,3,4]-thiadiazole analogous (7a-j) and tested them against XO, COX, and LOX. To gain insight into the activity of XO, COX, and LOX inhibition, molecular docking studies were carried out for XO, COX, and LOX enzymes utilizing the newly synthesized compounds (7a-j), and the results inferred that among the synthesized series of [1,3,4]-thiadiazoles (7a-j), the compound (7i) showed extremely good result in both In silico and evaluation studies of XO, COX, and LOX, which is in agreement with the experimental results. Furthermore, density functional theory (DFT) was applied to calculate HOMO-LUMO, energy gap, and other parameters under the hybrid exchange-correlation functional (B3LYP) with the triple split valence basis set (6-311G).

Therapeutic Effects of Azithromycin on Spinal Cord Injury in Male Wistar Rats: A Role for Inflammatory Pathways.

Inflammatory responses, including macrophages/microglia imbalance, are associated with spinal cord injury (SCI) complications. Accumulating evidence also suggests an anti-inflammatory property of azithromycin (AZM). Male Wistar rats were subjected to T9 vertebra laminectomy. SCI was induced by spinal cord compression at this level with an aneurysmal clip for 60 seconds. They were divided into three groups: the sham-operated group and two SCI treatment (normal saline as a vehicle control vs. AZM at 180 mg/kg/d intraperitoneally for 3 days postsurgery; first dose: 30 minutes after surgery) groups. Locomotor scaling and behavioral tests for neuropathic pain were evaluated and compared through a 28-day period. At the end of the study, tissue samples were taken to assess neuroinflammatory changes and neural demyelination using ELISA and histopathologic examinations, respectively. In addition, the proportion of M1/M2 macrophage polarization was assessed by using flow cytometry. Post-SCI AZM treatment (180 mg/kg/d for 3 days) significantly improved locomotion (p < 0.01) and decreased sensitivity to mechanical (p < 0.01) and thermal allodynia (p < 0.001). Moreover, there was a significant tumor necrosis factor-α (TNF-α) decline (p < 0.01) and interleukin-10 (IL-10) elevation (p < 0.01) in the spinal cord tissue of the AZM-treated group compared with the control groups 28 days post-SCI. AZM significantly improved neuroinflammation as evidenced by reduction of the M1 expression, elevation of M2 macrophages, and reduction of the M1/M2 ratio in both the dorsal root ganglion and the spinal cord tissue after SCI compared with controls (p < 0.01). AZM treatment can be considered a therapeutic agent for SCI, as it could reduce neuroinflammation and SCI sensory/locomotor complications.

An Insight into Anti-Inflammatory Activities and Inflammation Related Diseases of Anthocyanins: A Review of Both In Vivo and In Vitro Investigations.

Anthocyanin is a type of flavonoid pigment widely present in fruits and vegetables. It can not only be used as natural pigment, but also has a variety of health functions, for instance, anti-oxidant, anti-inflammatory, anti-tumor, and neuroprotective activities. Persistent proinflammatory status is a major factor in the development, progression, and complications of chronic diseases. Not surprisingly, there are thus many food ingredients that can potentially affect inflammation related diseases and many studies have shown that anthocyanins play an important role in inflammatory pathways. In this paper, the inflammation related diseases (such as, obesity, diabetes, cardiovascular disease, and cancer) of anthocyanins are introduced, and the anti-inflammatory effect of anthocyanins is emphatically introduced. Moreover, the anti-inflammatory mechanism of anthocyanins is elaborated from the aspects of NF-κB, toll like receptor, MAPKs, NO, and ROS and the main efficacy of anthocyanins in inflammation and related diseases is determined. In conclusion, this review aims to get a clear insight into the role of anthocyanins in inflammation related diseases.

The association of NLRP3 p.Q705K and CARD8 p.C10X genetic polymorphisms with rheumatoid arthritis: A review of the literature

Many genetic factors are involved in the pathogenesis of rheumatoid arthritis (RA). This study is aimed to summarize the literature regarding the relationship between variation in the genes encoding NLRP3/CARD8 and RA, using a candidate polymorphism approach. Several investigations have been conducted on the association of the genetic alterations of the NLRP3 p.Q705K and CARD8 p.C10X with the inflammatory diseases. Although there are variable results, the role of inflammatory pathways and genes involved is undeniable. The genetic context of the NLRP3 p.Q705K and CARD8 p.C10X gene variants in the pathogenesis of RA is still unclear to confirm that these variations show a pivotal role in the pathophysiology of RA. More comprehensive studies in this area seem to be needed.

Poly(ADP‑ribose) polymerase‑1 inhibitor ameliorates dextran sulfate sodium‑induced colitis in mice by regulating the balance of Th17/Treg cells and inhibiting the NF‑κB signaling pathway

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a critical role in inflammatory pathways. The PARP-1 inhibitor, 5-aminoisoquinolinone (5-AIQ), has been demonstrated to exert significant pharmacological effects. The present study aimed to further examine the potential mechanisms of 5-AIQ in a mouse model of dextran sodium sulfate (DSS)-induced colitis. Colitis conditions were assessed by changes in weight, disease activity index, colon length, histopathology and pro-inflammatory mediators. The colonic expression of PARP/NF-κB and STAT3 pathway components was measured by western blot analysis. Flow cytometry was used to analyze the proportion of T helper 17 cells (Th17) and regulatory T cells (Tregs) in the spleen. Western blot analysis and reverse transcription-quantitative PCR were employed to determine the expression of the transcription factors retinoic acid-related orphan receptor and forkhead box protein P3. The results demonstrated that 5-AIQ reduced tissue damage and the inflammatory response in mice with experimental colitis. Moreover, 5-AIQ increased the proportion of Treg cells and decreased the percentage of Th17 cells in the spleen. Furthermore, following 5-AIQ treatment, the main components of the PARP/NF-κB and STAT3 pathways were downregulated. Collectively, these results demonstrate that the PARP-1 inhibitor, 5-AIQ, may suppress intestinal inflammation and protect the colonic mucosa by modulating Treg/Th17 immune balance and inhibiting PARP-1/NF-κB and STAT3 signaling pathways in mice with experimental colitis.

P38γ Activation and BGP (Biliary Glycoprotein) Induction in Primates at Risk for Inflammatory Bowel Disease and Colorectal Cancer-A Comparative Study with Humans.

Colorectal cancer (CRC) is a common cause of cancer-related deaths largely due to CRC liver metastasis (CRLM). Identification of targetable mechanisms continues and includes investigations into the role of inflammatory pathways. Of interest, MAPK is aberrantly expressed in CRC patients, yet the activation status is not defined. The present study assessed p38γ activation in CRC patients, cancer cells, and tissues of cotton top tamarin (CTT) and common marmoset (CM). The primate world is an overlooked resource as colitis-CRC-prone CTT are usually inure to liver metastasis while CM develop colitis but not CRC. The results demonstrate that p38γ protein and phosphorylation levels are significantly increased in CRC patients compared to normal subjects and CTT. Furthermore, p38γ phosphorylation is significantly elevated in human CRC cells and hepatoblastoma cells but not in CM colon. Additionally, carcinoembryonic antigen (CEA) and biliary glycoprotein (BGP) are induced in the CRC patients that showed p38γ phosphorylation. Inhibition of p38 MAPK in CRC cells showed a significant decline in cell growth with no effect on apoptosis or BGP level. Overall, p38γ is activated in CRC tumorigenesis and likely involves CEA antigens during CRLM in humans but not in the CTT or CM, that rarely develop CRLM.

&lt;p&gt;Human Secretary Phospholipase A2 Mutations and Their Clinical Implications&lt;/p&gt;

Phospholipases A2 (PLA2s) belong to a superfamily of enzymes responsible for hydrolysis of the sn-2 fatty acids of membrane phospholipids to release arachidonic acid. PLA2s are the rate limiting enzyme for the downstream synthesis of prostaglandins and leukotrienes that are the main mediators of inflammation. The extracellular forms of this enzyme are also called the secretary phospholipase A2 (sPLA2) and are distributed extensively in most of the tissues in the human body. Their integral role in inflammatory pathways has been the primary reason for the extensive research on this molecule. The catalytic mechanism of sPLA2 is initiated by a histidine/aspartic acid/calcium complex within the active site. Though they are known to have certain housekeeping functions, certain mutations of sPLA2 are known to be implicated in causation of certain pathologies leading to diseases such as atherosclerosis, cardiovascular diseases, benign fleck retina, neurodegeneration, and asthma. We present an overview of human sPLA2 and a comprehensive compilation of the mutations that result in various disease phenotypes. The study not only helps to have a holistic understanding of human sPLA2 mutations and their clinical implications, but is also a useful platform to initiate research pertaining to structure–function relationship of the mutations to develop effective therapies for management of these diseases.

Inflammatory Pathways in Psychiatric Disorders: The case of Schizophrenia and Depression.

A better understanding of the key molecules/pathways underlying the pathophysiology of depression and schizophrenia may contribute to novel therapeutic strategies. In this review, we have discussed the recent developments on the role of inflammatory pathways in the pathogenesis of depression and schizophrenia. Inflammation is an innate immune response that can be triggered by various factors, including pathogens, stress and injury. Under normal conditions, the inflammatory responses quiet after pathogen clearance and tissue repair. However, abnormal long-term or chronic inflammation can lead to damaging effects. Accumulating evidence suggest that dysregulated inflammation is linked to the pathogenesis of neuropsychiatric disorders. In this review, we have discussed the roles of complement system, infiltration of peripheral immune cells into the central nervous system (CNS), the gut-brain axis, and the kynurenine pathway in depression and schizophrenia. There is a large body of compelling evidence on the role of inflammatory pathways in depression and schizophrenia. Although most of these findings show their roles in the pathophysiology of the above disorders, additional studies are warranted to investigate the therapeutic potential of various immune signaling targets discussed in this article.

The Role of Inflammation and Inflammasome in Myeloproliferative Disease.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are rare hematological conditions known as myeloproliferative neoplasms (MPNs). They are characterized for being BCR-ABL negative malignancies and affected patients often present with symptoms which can significantly impact their quality of life. MPNs are characterized by a clonal proliferation of an abnormal hematopoietic stem/progenitor cell. In MPNs; cells of all myeloid lineages; including those involved in the immune and inflammatory response; may belong to the malignant clone thus leading to an altered immune response and an overexpression of cytokines and inflammatory receptors; further worsening chronic inflammation. Many of these cytokines; in particular, IL-1β and IL-18; are released in active form by activating the inflammasome complexes which in turn mediate the inflammatory process. Despite this; little is known about the functional effects of stem cell-driven inflammasome signaling in MPN pathogenesis. In this review we focused on the role of inflammatory pathway and inflammasome in MPN diseases. A better understanding of the inflammatory-state-driving MPNs and of the role of the inflammasome may provide new insights on possible therapeutic strategies

Pathophysiology of Intracranial Aneurysms: COX-2 Expression, Iron Deposition in Aneurysm Wall, and Correlation With Magnetic Resonance Imaging.

The pathophysiology of development, growth, and rupture of intracranial aneurysms (IAs) is only partly understood. Cyclooxygenase 2 (COX-2) converts arachidonic acid to prostaglandin H2, which, in turn, is isomerized to prostaglandin E2. In the human body, COX-2 plays an essential role in inflammatory pathways. This explorative study aimed to investigate COX-2 expression in the wall of IAs and its correlation to image features in clinical (1.0T, 1.5T, and 3.0T) magnetic resonance imaging (MRI) and ultra-high-field 7T MRI. The study group comprised 40 patients with partly thrombosed saccular IAs. The cohort included 17 ruptured- and 24 unruptured IAs, which had all been treated microsurgically. Formaldehyde-fixed paraffin-embedded samples were immunohistochemically stained with a monoclonal antibody against COX-2 (Dako, Santa Clara, CA; Clone: CX-294). We correlated Perls Prussian blue staining, MRI, and clinical data with immunohistochemistry, analyzed using the Trainable Weka Segmentation algorithm. Aneurysm dome size ranged between 2 and 67 mm. The proportion of COX-2 positive cells ranged between 3.54% to 85.09%. An upregulated COX-2 expression correlated with increasing IA dome size (P=0.047). Furthermore, there was a tendency of higher COX-2 expression in most ruptured IAs (P=0.064). At all field strengths, MRI shows wall hypointensities due to iron deposition correlating with COX-2 expression (P=0.022). Iron deposition and COX-2 expression in IAs walls correlate with signal hypointensity in MRI, which might, therefore, serve as a biomarker for IA instability. Furthermore, as COX-2 was also expressed in small unruptured IAs, it could be a potential target for specific medical treatment.

Risk factors related to liver injury in non-Intensive Care Unit admitted patients infected with COVID-19: A retrospective study of 102 patients.

Background:COVID-19 targets the liver and there is no available data about liver injury due to mild to moderate form of COVID-19. In this study, we evaluated the risk factors associated with liver injury in NON-ICU admitted COVID-19 patients.Methods:in this retrospective study, 102 eligible adult participants admitted in the ward were included. The patients with previous history of liver disease were excluded. The patients with AST or ALT or bilirubin more than normal ranges were allocated in liver injury group and patients with normal ranges of them were categorized in non-liver injury. Characteristics and laboratory data were analyzed between these two groups.Results:The mean age of the population was 55.13± 17.02 years old. The most common symptom was fever (45.8%). The most frequent co-morbidity was hypertension (25%). 65 patients had liver injury (63.72%). CRP were significantly higher in liver injury group (P=0.01). Univariate analysis reported ALKP, and CRP was associated significantly with liver injury (P=0.04, OR= 1.003, Cl 95%= 1.000-1.007; P=0.03, OR= 1.009, Cl 95%= 1.000- 1.017, respectively). No independent factor was detected in multivariate analysis. Based on the Spearman’s rank correlation coefficients CRP correlated significantly with AST (r=0.22, P=0.00). Moreover, neutrophil and CRP, correlated with ALT (r=0.01, P=0.90; r=0.23, P=0.02, respectively).Conclusion:No independent factor was detected to predict liver injury chance due to COVID-19. However, CRP had a significant association with it. It appears that the role of inflammatory pathways in liver damage was due to COVID-19.