scholarly journals A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis

2018 ◽  
Vol 27 (13) ◽  
pp. 2383-2391 ◽  
Author(s):  
Michael J Jurynec ◽  
Allen D Sawitzke ◽  
Timothy C Beals ◽  
Michael J Redd ◽  
Jeff Stevens ◽  
...  
Keyword(s):  
Immune Response ◽  
Early Onset ◽  
Kinase Domain ◽  
Interacting Protein ◽  
Disease Occurrence ◽  
Functional Analyses ◽  
Bacterial Peptidoglycan ◽  
First Time ◽  
Significant Amino Acid

Abstract Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of receptor interacting protein kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-κB pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated that the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-κB pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.

scholarly journals Arginase Activity in Eisenia andrei Coelomocytes: Function in the Earthworm Innate Response

2021 ◽  
Vol 22 (7) ◽  
pp. 3687
Author(s):  
Joanna Homa ◽  
Alina Klosowska ◽  
Magdalena Chadzinska
Keyword(s):  
Immune Response ◽  
Wound Healing ◽  
Arginase Activity ◽  
Eisenia Andrei ◽  
Heavy Metals Ions ◽  
First Time ◽  
Important Marker

Arginase is the manganese metalloenzyme catalyzing the conversion of l-arginine to l-ornithine and urea. In vertebrates, arginase is involved in the immune response, tissue regeneration, and wound healing and is an important marker of alternative anti-inflammatory polarization of macrophages. In invertebrates, data concerning the role of arginase in these processes are very limited. Therefore, in the present study, we focused on the changes in arginase activity in the coelomocytes of Eisenia andrei. We studied the effects of lipopolysaccharide (LPS), hydrogen peroxide (H2O2), heavy metals ions (e.g., Mn2+), parasite infection, wound healing, and short-term fasting (5 days) on arginase activity. For the first time in earthworms, we described arginase activity in the coelomocytes and found that it can be up-regulated upon in vitro stimulation with LPS and H2O2 and in the presence of Mn2+ ions. Moreover, arginase activity was also up-regulated in animals in vivo infected with nematodes or experiencing segment amputation, but not in fasting earthworms. Furthermore, we confirmed that the activity of coelomocyte arginase can be suppressed by l-norvaline. Our studies strongly suggest that similarly to the vertebrates, also in the earthworms, coelomocyte arginase is an important element of the immune response and wound healing processes.

scholarly journals Significant and conflicting correlation of IL-9 with Prevotella and Bacteroides in human colorectal cancer

2020 ◽  
Author(s):  
E Niccolai ◽  
E Russo ◽  
S Baldi ◽  
F Ricci ◽  
G Nannini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Multinomial Regression ◽  
Tnf Α ◽  
Ifn Γ ◽  
Inflammatory Profile ◽  
Infiltrating Lymphocytes ◽  
First Time

ABSTRACTBackgroundColorectal cancer (CRC) is a widespread disease that represents an example of chronic inflammation-associated tumor. In fact, the immune system, besides protecting the host from developing tumors, can support the CRC progression. In this scenario, the gut microbiota (GM) is essential to modulate immune responses and a dysbiotic condition can favor chronic/abnormal immune activation that support the tumor growth. GM can elicit the production of cytokines, influencing the immunostimulatory or immunosuppressive reactions, such as the tendency to mount Th1, Th17, Tregs or Th9 responses that play different roles towards colon cancer. Paradigmatic is the role of IL-9 that can both promote tumor progression in hematological malignancies and inhibit tumorigenesis in solid cancers. Therefore, to investigate the microbiota-immunity axis in CRC patients is crucial to well understand the cancer development with positive relapses in prevention and treatment.AimThe cellular and molecular characterization of the immune response and the evaluation of GM composition in healthy and tumor mucosa, focusing on the correlation between cytokines’ profile and GM signature.MethodsWe collected tumoral (CRC) and healthy (CRC-S) mucosa samples of 45 CRC patients. For each sample, we characterized the Tissue Infiltrating Lymphocytes (TIL)’s subset profile and the GM composition. In addition, in 14 CRC patients, we evaluated the CRC and CRC-S molecular inflammatory response (26 cytokines/chemokines) and we correlated this profile with GM composition using the Dirichlet Multinomial Regression.ResultsThe analysis of T cells subsets distribution showed that CRC samples displayed higher percentages of Th17, Th2, Tregs, Tc17, Tc1/Tc17, and Tcreg, compared to CRC-S. Notably, also the number of Th9 was higher, even if not significantly, in CRC tissue compared to healthy one. In addition, we found that MIP-1α, IL-1β, IL-2, IP-10, IL-6, IL-8, IL-17A, IFN-γ, TNF-α, MCP-1, IL-1α, P-selectin and IL-9 were significantly increased in CRC compared to CRC-S. Moreover, the GM analysis revealed that CRC samples had significantly higher levels of Fusobacteria, Proteobacteria, Fusobacterium, Ruminococcus2 (Lachnospiraceae family) and Ruminococcus (Ruminococcaceae family) than CRC-S. Finally, we found that the abundance of Prevotella spp in CRC samples was negatively correlated with IL-17A and positively with IL-9. In addition, the abundance of Bacteroides and Escherichia/Shigella species in CRC samples showed a negative association with IL-9 and IP-10 respectively.ConclusionsOur data show a clear dissimilarity of inflammatory profile and GM composition between the tumor and the adjacent healthy tissue, displaying the generation of a peculiar CRC microenvironment. Interestingly, relating the tissue cytokine profile with the GM composition, we confirmed the presence of a bidirectional crosstalk between the immune response and the host’s commensal microorganisms; in detail, we documented for the first time that Prevotella spp. and Bacteroides spp. are correlated (positively and negatively, respectively) with the IL-9, whose role in CRC development is still debated.

scholarly journals Three-Dimensional Structures of the A, B, and CCapsids of Rhesus Monkey Rhadinovirus: Insights into GammaherpesvirusCapsid Assembly, Maturation, and DNAPackaging

2003 ◽  
Vol 77 (24) ◽  
pp. 13182-13193 ◽  
Author(s):  
Xue-Kui Yu ◽  
Christine M. O'Connor ◽  
Ivo Atanasov ◽  
Blossom Damania ◽  
Dean H. Kedes ◽  
...  
Keyword(s):  
Rhesus Monkey ◽  
Three Dimensional ◽  
Model System ◽  
Electron Cryomicroscopy ◽  
Interacting Protein ◽  
Structural Differences ◽  
Dimensional Reconstruction ◽  
Capsid Maturation ◽  
First Time

ABSTRACT Rhesus monkey rhadinovirus (RRV) exhibits high levels of sequence homology to human gammaherpesviruses, such as Kaposi's sarcoma-associated herpesvirus, and grows to high titers in cell cultures, making it a good model system for studying gammaherpesvirus capsid structure and assembly. We have purified RRV A, B, and C capsids, thus for the first time allowing direct structure comparisons by electron cryomicroscopy and three-dimensional reconstruction. The results show that the shells of these capsids are identical and are each composed of 12 pentons, 150 hexons, and 320 triplexes. Structural differences were apparent inside the shells and through the penton channels. The A capsid is empty, and its penton channels are open. The B capsid contains a scaffolding core, and its penton channels are closed. The C capsid contains a DNA genome, which is closely packaged into regularly spaced density shells (25Å apart), and its penton channels are open. The different statuses of the penton channels suggest a functional role of the channels during capsid maturation, and the overall structural similarities of RRV capsids to alphaherpesvirus capsids suggest a common assembly and maturation pathway. The RRV A capsid reconstruction at a 15-Å resolution, the best achieved for gammaherpesvirus particles, reveals overall structural similarities to alpha- and betaherpesvirus capsids. However, the outer regions of the capsid, including densities attributed to the Ta triplex and the small capsomer-interacting protein (SCIP or ORF65), exhibit prominent differences from their structural counterparts in alphaherpesviruses. This structural disparity suggests that SCIP and the triplex, together with tegument and envelope proteins, confer structural and potentially functional specificities to alpha-, beta-, and gammaherpesviruses.

scholarly journals Serpina3c Deficiency Induced Necroptosis Promotes Non-Alcoholic Steatohepatitis Through β-Catenin/Foxo1/TLR4 Signaling

2021 ◽  
Author(s):  
Linglin Qian ◽  
Jing-jing Ji ◽  
Yu Jiang ◽  
Jia-Qi Guo ◽  
Ya Wu ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Kinase Domain ◽  
Protective Role ◽  
Tlr4 Expression ◽  
Double Knockout ◽  
Interacting Protein ◽  
Hepatocyte Death ◽  
Precise Role

Abstract Background: Hepatocyte death and liver inflammation have been recognized as central characteristics of nonalcoholic steatohepatitis (NASH); however, the underlying molecular mechanism remains elusive. The aim of this study is to determine the precise role of serpina3c in the progression of NASH.Methods: Male Apoe-/-/serpina3c-/- double knockout (DKO) and Apoe-/- mice were fed a high-fat diet (HFD) for 12 weeks to induce NASH. Several markers of steatosis and inflammation were evaluated. In vitro cell models induced by palmitic acid (PA) treatment were used to evaluate the beneficial effect of serpina3c on necroptosis and the underlying molecular mechanism.Results: Compared with Apoe-/- mice, DKO mice exhibited a significantly exacerbated NASH phenotype that included hepatic steatosis, inflammation, fibrosis and liver damage, and increased hepatic triglyceride contents. We also indicated that the expression of the receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like (MLKL) was increased in DKO mice. Our results found that serpina3c knockdown promoted necroptosis and lipid droplet formation under conditions of lipotoxicity in vitro. However, these phenomena were reversed by the overexpression of serpina3c. Mechanistically, downregulation of serpina3c expression promoted Foxo1 and β-catenin expression, and Foxo1 and β-catenin colocalized in the nucleus under conditions of lipotoxicity, consequently upregulating the expression of Toll-like receptor4 (TLR4). However, disruption of the Foxo1-β/catenin by Foxo1 and β-catenin inhibitors decreased TLR4 expression and ameliorated hepatic necroptosis in vitro.Conclusion: Serpina3c plays a protective role against the progression of NASH by inhibiting necroptosis. Serpina3c, a Wnt/β-catenin inhibitor, inhibits necroptosis via β-catenin/Foxo1 by inhibiting TLR4 expression.

scholarly journals The Role of HSP90α in Methamphetamine/Hyperthermia-Induced Necroptosis in Rat Striatal Neurons

2021 ◽  
Vol 12 ◽  
Author(s):  
Lv-shuang Liao ◽  
Shuang Lu ◽  
Wei-tao Yan ◽  
Shu-chao Wang ◽  
Li-min Guo ◽  
...  
Keyword(s):  
Psychiatric Symptoms ◽  
Core Body Temperature ◽  
Primary Cultures ◽  
Specific Inhibitor ◽  
Heat Shock Protein 90 ◽  
Kinase Domain ◽  
Striatal Neurons ◽  
Interacting Protein

Methamphetamine (METH) is one of the most widely abused synthetic drugs in the world. The users generally present hyperthermia (HT) and psychiatric symptoms. However, the mechanisms involved in METH/HT-induced neurotoxicity remain elusive. Here, we investigated the role of heat shock protein 90 alpha (HSP90α) in METH/HT (39.5°C)-induced necroptosis in rat striatal neurons and an in vivo rat model. METH treatment increased core body temperature and up-regulated LDH activity and the molecular expression of canonical necroptotic factors in the striatum of rats. METH and HT can induce necroptosis in primary cultures of striatal neurons. The expression of HSP90α increased following METH/HT injuries. The specific inhibitor of HSP90α, geldanamycin (GA), and HSP90α shRNA attenuated the METH/HT-induced upregulation of receptor-interacting protein 3 (RIP3), phosphorylated RIP3, mixed lineage kinase domain-like protein (MLKL), and phosphorylated MLKL. The inhibition of HSP90α protected the primary cultures of striatal neurons from METH/HT-induced necroptosis. In conclusion, HSP90α plays an important role in METH/HT-induced neuronal necroptosis and the HSP90α-RIP3 pathway is a promising therapeutic target for METH/HT-induced neurotoxicity in the striatum.

scholarly journals Metataxonomic Review To Elucidate The Role of The Microbiome In Celiac Disease Across The Gastrointestinal Tract.

2021 ◽  
Author(s):  
Juliana Arcila ◽  
Viviana Loria-Kohen ◽  
Ana Ramírez de Molina ◽  
Enrique Carrillo de Santa Pau ◽  
Laura Judith Judith Zambrano
Keyword(s):  
Immune Response ◽  
Celiac Disease ◽  
Gastrointestinal Tract ◽  
High Throughput Sequencing ◽  
Short Chain Fatty Acids ◽  
Taxonomic Composition ◽  
Rrna Gene ◽  
Immunogenic Peptides ◽  
First Time

Abstract Background: Dysbiosis of the microbiome has been related to the Celiac disease (CeD) progress, an autoimmune disease characterised by gluten intolerance developed in genetically susceptible individuals under certain environmental factors. The microbiome contributes to CeD pathophysiology modulating the immune response by the action of short-chain fatty acids (SCFA), affecting gut barrier integrity allowing the entrance of gluten derived proteins, and degrading immunogenic peptides of gluten through endoprolyl peptidase enzymes. Results: We reviewed state of the art in taxonomic composition for CeD and compiled the larger dataset of 16S prokaryotic ribosomal RNA (rRNA) gene high-throughput sequencing for consensus profiling. We present for the first time an integrative analysis of metataxonomic data from CeD patients, including samples from different body sites (saliva, pharynx, duodenum, and stool). We found the presence of coordinated changes through the gastrointestinal tract characterised by an increase in Actinobacteria species in the upper tract (pharynx and duodenum), and an increase in Proteobacteria in the lower tract (duodenum and stool), as well as site-specific changes evidencing a dysbiosis in CeD patients' microbiota. Moreover, we described the effect of adherence to a gluten-free diet (GFD) evidenced by an increase in beneficial bacteria and a decrease in some Betaproteobacteriales but not fully restoring CeD-related dysbiosis. Conclusions: We illustrate that the gut microbiota acts as an enhancer of immune response in CeD through the production of lipopolysaccharides and other bacterial components that activate the immune response and by decrease SCFA producers bacteria. Furthermore, microbial changes observed through the gastrointestinal tract of CeD patients may help manage the disease and follow-up GFD treatment.

scholarly journals Metataxonomic review to elucidate the role of the microbiome in Celiac disease across the gastrointestinal tract

2021 ◽  
Author(s):  
Juliana Estefania Arcila Galvis ◽  
Viviana Loria-Kohen ◽  
Ana Ramirez de Molina ◽  
Enrique Castillo de Santa Pau ◽  
Laura Judith Marcos-Zambrano
Keyword(s):  
Immune Response ◽  
Celiac Disease ◽  
Gastrointestinal Tract ◽  
High Throughput Sequencing ◽  
Short Chain Fatty Acids ◽  
Taxonomic Composition ◽  
Rrna Gene ◽  
Immunogenic Peptides ◽  
First Time

Dysbiosis of the microbiome has been related to the Celiac disease (CeD) progress, an autoimmune disease characterised by gluten intolerance developed in genetically susceptible individuals under certain environmental factors. The microbiome contributes to CeD pathophysiology modulating the immune response by the action of short-chain fatty acids (SCFA), affecting gut barrier integrity allowing the entrance of gluten derived proteins, and degrading immunogenic peptides of gluten through endoprolyl peptidase enzymes. We reviewed state of the art in taxonomic composition for CeD and compiled the larger dataset of 16S prokaryotic ribosomal RNA (rRNA) gene high-throughput sequencing for consensus profiling. We present for the first time an integrative analysis of metataxonomic data from CeD patients, including samples from different body sites (saliva, pharynx, duodenum, and stool). We found the presence of coordinated changes through the gastrointestinal tract characterised by an increase in Actinobacteria species in the upper tract (pharynx and duodenum), and an increase in Proteobacteria in the lower tract (duodenum and stool), as well as site-specific changes evidencing a dysbiosis in CeD patients' microbiota. Moreover, we described the effect of adherence to a gluten-free diet (GFD) evidenced by an increase in beneficial bacteria and a decrease in some Betaproteobacteriales but not fully restoring CeD-related dysbiosis. We illustrate that the gut microbiota acts as an enhancer of immune response in CeD through the production of lipopolysaccharides and other bacterial components that activate the immune response and by decrease SCFA producers bacteria. Furthermore, microbial changes observed through the gastrointestinal tract of CeD patients may help manage the disease and follow-up GFD treatment.

scholarly journals The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update

2021 ◽  
Vol 22 (13) ◽  
pp. 6678
Author(s):  
Robert Eckenstaler ◽  
Ralf A. Benndorf
Keyword(s):  
Early Onset ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Functional Analyses ◽  
Urate Reabsorption ◽  
Shed Light

Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout.

Psychological Resilience Provides No Independent Protection From Suicidal Risk

Crisis ◽  
2016 ◽  
Vol 37 (2) ◽  
pp. 130-139 ◽  
Author(s):  
Danica W. Y. Liu ◽  
A. Kate Fairweather-Schmidt ◽  
Richard Burns ◽  
Rachel M. Roberts ◽  
Kaarin J. Anstey
Keyword(s):  
Risk Factors ◽  
Well Being ◽  
Current Status ◽  
Psychological Resilience ◽  
Cross Sectional ◽  
Life Project ◽  
Resilience Factors ◽  
First Time

Abstract. Background: Little is known about the role of resilience in the likelihood of suicidal ideation (SI) over time. Aims: We examined the association between resilience and SI in a young-adult cohort over 4 years. Our objectives were to determine whether resilience was associated with SI at follow-up or, conversely, whether SI was associated with lowered resilience at follow-up. Method: Participants were selected from the Personality and Total Health (PATH) Through Life Project from Canberra and Queanbeyan, Australia, aged 28–32 years at the first time point and 32–36 at the second. Multinomial, linear, and binary regression analyses explored the association between resilience and SI over two time points. Models were adjusted for suicidality risk factors. Results: While unadjusted analyses identified associations between resilience and SI, these effects were fully explained by the inclusion of other suicidality risk factors. Conclusion: Despite strong cross-sectional associations, resilience and SI appear to be unrelated in a longitudinal context, once risk/resilience factors are controlled for. As independent indicators of psychological well-being, suicidality and resilience are essential if current status is to be captured. However, the addition of other factors (e.g., support, mastery) makes this association tenuous. Consequently, resilience per se may not be protective of SI.

Vitamin A: dietologist’s position

2020 ◽  
pp. 49-57
Author(s):  
S. V. Orlova ◽  
E. A. Nikitina ◽  
L. I. Karushina ◽  
Yu. A. Pigaryova ◽  
O. E. Pronina
Keyword(s):  
Immune Response ◽  
Urinary Tract ◽  
Gastrointestinal Tract ◽  
Vitamin A ◽  
Developed Countries ◽  
Therapeutic Practice ◽  
The Past ◽  
Increased Risk ◽  
Mucous Membranes

Vitamin A (retinol) is one of the key elements for regulating the immune response and controls the division and differentiation of epithelial cells of the mucous membranes of the bronchopulmonary system, gastrointestinal tract, urinary tract, eyes, etc. Its significance in the context of the COVID‑19 pandemic is difficult to overestimate. However, a number of studies conducted in the past have associated the additional intake of vitamin A with an increased risk of developing cancer, as a result of which vitamin A was practically excluded from therapeutic practice in developed countries. Our review highlights the role of vitamin A in maintaining human health and the latest data on its effect on the development mechanisms of somatic pathology.

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