Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.
- MeSH
- Azoxymethane toxicity MeSH
- Chronic Disease MeSH
- Indoles pharmacology therapeutic use MeSH
- Colitis drug therapy chemically induced metabolism pathology MeSH
- Colorectal Neoplasms * drug therapy metabolism pathology MeSH
- Disease Models, Animal * MeSH
- Molecular Mimicry MeSH
- Mice, Inbred C57BL * MeSH
- Mice MeSH
- Colitis-Associated Neoplasms pathology drug therapy metabolism MeSH
- Dextran Sulfate toxicity MeSH
- Inflammation drug therapy metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. OBJECTIVES: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime. METHODS: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis. RESULTS: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up. CONCLUSION: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.
- MeSH
- Aspirin * administration & dosage therapeutic use adverse effects MeSH
- Double-Blind Method MeSH
- Extracellular Vesicles * metabolism drug effects MeSH
- Platelet Aggregation Inhibitors * administration & dosage adverse effects therapeutic use MeSH
- Factor Xa Inhibitors * administration & dosage adverse effects therapeutic use MeSH
- Cardiovascular Diseases * blood prevention & control drug therapy MeSH
- Drug Therapy, Combination * MeSH
- Middle Aged MeSH
- Humans MeSH
- Inflammation Mediators blood MeSH
- Prospective Studies MeSH
- Proteomics methods MeSH
- Rivaroxaban * administration & dosage MeSH
- Aged MeSH
- Thrombosis blood prevention & control drug therapy MeSH
- Treatment Outcome MeSH
- Inflammation blood MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
The soil microbiota exhibits an important function in the ecosystem, and its response to climate change is of paramount importance for sustainable agroecosystems. The macronutrients, micronutrients, and additional constituents vital for the growth of plants are cycled biogeochemically under the regulation of the soil microbiome. Identifying and forecasting the effect of climate change on soil microbiomes and ecosystem services is the need of the hour to address one of the biggest global challenges of the present time. The impact of climate change on the structure and function of the soil microbiota is a major concern, explained by one or more sustainability factors around resilience, reluctance, and rework. However, the past research has revealed that microbial interventions have the potential to regenerate soils and improve crop resilience to climate change factors. The methods used therein include using soil microbes' innate capacity for carbon sequestration, rhizomediation, bio-fertilization, enzyme-mediated breakdown, phyto-stimulation, biocontrol of plant pathogens, antibiosis, inducing the antioxidative defense pathways, induced systemic resistance response (ISR), and releasing volatile organic compounds (VOCs) in the host plant. Microbial phytohormones have a major role in altering root shape in response to exposure to drought, salt, severe temperatures, and heavy metal toxicity and also have an impact on the metabolism of endogenous growth regulators in plant tissue. However, shelf life due to the short lifespan and storage time of microbial formulations is still a major challenge, and efforts should be made to evaluate their effectiveness in crop growth based on climate change. This review focuses on the influence of climate change on soil physico-chemical status, climate change adaptation by the soil microbiome, and its future implications.
Systémová forma juvenilní idiopatické artritidy (sJIA) je charakterizována systémovým zánětem, který se projevuje rekurentní horečkou, kožní vyrážkou, hepatosplenomegalií, lymfadenopatií, serozitidou, artritidou a elevací laboratorních zánětlivých parametrů. Život ohrožující komplikací může být syndrom aktivace makrofágů (macrophage activation syndrome, MAS). Zejména na začátku nemoci se v patogenezi sJIA uplatňuje dysregulace vrozené imunitní odpovědi s nadprodukcí interleukinu 1 (IL-1). Při léčbě blokátory IL-1 je prokázáno významné zlepšení průběhu i prognózy sJIA, a to zejména v případě včasného zahájení léčby. Anakinra, antagonista receptoru pro interleukin 1, je účinným lékem u pacientů se sJIA, což ukazuje i naše kazuistika.
Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation, which manifests itself with recurrent fever, skin rash, hepatosplenomegaly, lymphadenopathy, serositis, arthritis and elevated inflammatory markers. Macrophage activation syndrome (MAS) can be a life-threatening complication of this disease. Especially at disease onset, the dysregulation in the innate immune response with overproduction of interleukin 1 (IL-1) plays a key role in the pathogenesis of sJIA. Anti-IL-1 therapy significantly improves treatment outcomes and prognosis, particularly when initiated early. Anakinra, an interleukin-1 receptor antagonist, is an effective treatment option for patients with sJIA.
Background: Activation of cannabinoid receptor 1 (CB1R) in the nervous system modulates the processing of acute and chronic pain. CB1R activity is regulated by desensitization and internalization. SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1) inhibits the internalization of CB1R. This causes increased and prolonged association of the desensitized receptor with G protein-coupled receptor kinase 3 (GRK3) and beta-arrestin on the cell membrane and results in decreased activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Genetic deletion of SGIP1 in mice leads to altered CB1R-related functions, such as decreased anxiety-like behaviors, modified cannabinoid tetrad behaviors, reduced acute nociception, and increased sensitivity to analgesics. In this work, we asked if deletion of SGIP1 affects chronic nociception and analgesic effect of Δ9-tetrahydrocannabinol (THC) and WIN 55,212-2 (WIN) in mice. Methods: We measured tactile responses of hind paws to increasing pressure in wild-type and SGIP1 knock-out mice. Inflammation in the paw was induced by local injection of carrageenan. To determine the mechanical sensitivity, the paw withdrawal threshold (PWT) was measured using an electronic von Frey instrument with the progression of the applied force. Results: The responses to mechanical stimuli varied depending on the sex, genotype, and treatment. SGIP1 knock-out male mice exhibited lower PWT than wild-type males. On the contrary, the female mice exhibited comparable PWT. Following THC or WIN treatment in male mice, SGIP1 knock-out males exhibited PWT lower than wild-type males. THC treatment in SGIP1 knock-out females resulted in PWT higher than after THC treatment of wild-type females. However, SGIP1 knock-out and wild-type female mice exhibited similar PWT after WIN treatment. Conclusions: We provide evidence that SGIP1, possibly by interacting with CB1R, is involved in processing the responses to chronic pain. The absence of SGIP1 results in enhanced sensitivity to mechanical stimuli in males, but not females. The antinociceptive effect of THC is superior to that of WIN in SGIP1 knock-out mice in the carrageenan-induced model of chronic pain.
- MeSH
- Benzoxazines * pharmacology MeSH
- Hyperalgesia * genetics MeSH
- Morpholines pharmacology MeSH
- Mice, Inbred C57BL MeSH
- Mice, Knockout * MeSH
- Mice MeSH
- Naphthalenes MeSH
- Nociception drug effects MeSH
- Receptor, Cannabinoid, CB1 * genetics metabolism MeSH
- Dronabinol * pharmacology MeSH
- Inflammation * MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Atherosclerosis is a chronic inflammatory disease of the blood vessels caused by elevated levels of lipoproteins. The hyperlipoproteinemia triggers a series of cellular changes, particularly the activation of the macrophages, which play a crucial role in the development and progression of atherosclerosis. The presence of free cholesterol (FC) in lipoproteins may contribute to macrophage stimulation. However, the mechanisms linking the accumulation of FC in macrophages to their pro-inflammatory activation remain poorly understood. Our research found a positive correlation between the number of pro-inflammatory macrophages (CD14 + CD16 + CD36high) in visceral adipose tissue and the levels of LDL-C and cholesterol remnant particles in 56 healthy people. In contrast, the proportion of anti-inflammatory, alternatively activated macrophages (CD14 + CD16-CD163+) correlated negatively with HDL-C. Additionally, our in vitro study demonstrated that macrophages accumulating FC promoted a pro-inflammatory response, activating the TNF-α and chemokine CCL3 genes. Furthermore, the accumulation of FC in macrophages alters the surface receptors on macrophages (CD206 and CD16) and increases cellular granularity. Notably, the CD36 surface receptor and the ACAT and CD36 genes did not show a response. These results suggest a link between excessive FC accumulation and systemic inflammation to underlie the development of atherosclerosis.
- MeSH
- Macrophage Activation MeSH
- CD36 Antigens metabolism MeSH
- Atherosclerosis metabolism MeSH
- Antigens, CD metabolism MeSH
- Cholesterol * metabolism MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Macrophages * metabolism immunology drug effects MeSH
- Intra-Abdominal Fat metabolism MeSH
- Tumor Necrosis Factor-alpha metabolism genetics MeSH
- Inflammation * metabolism MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Nonobese diabetic (NOD) mice are a widely used animal model to study mechanisms leading to autoimmune diabetes. A gluten-free diet reduces and delays the incidence of diabetes in NOD mice, but the underlying mechanisms remain largely unknown. In this study, we performed single-cell transcriptomic and flow cytometry analysis of T cells and innate lymphocytes in the spleen and pancreatic lymph nodes of NOD mice fed a gluten-free or standard diet. We observed that the gluten-free diet did not induce a substantial alteration in the abundance or phenotype of any lymphocyte subset that would directly explain its protective effect against diabetes. However, the gluten-free diet induced subtle changes in the differentiation of subsets with previously proposed protective roles in diabetes development, such as Tregs, activated γδT cells, and NKT cells. Globally, the gluten-free diet paradoxically promoted activation and effector differentiation across multiple subpopulations and induced genes regulated by IL-2, IL-7, and IL-15. In contrast, the standard diet induced type I interferon-responsive genes. Overall, the gluten-free diet might prevent diabetes in NOD mice by inducing small-scale changes in multiple cell types rather than acting on a specific lymphocyte subset.
- MeSH
- Lymphocyte Activation immunology MeSH
- Diet, Gluten-Free * MeSH
- Cell Differentiation MeSH
- Diabetes Mellitus, Type 1 * immunology MeSH
- Mice, Inbred NOD MeSH
- Mice MeSH
- T-Lymphocyte Subsets * immunology MeSH
- Transcriptome MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Tooth Bleaching methods MeSH
- Adult MeSH
- Humans MeSH
- Root Resorption * surgery MeSH
- Dental Prosthesis Retention methods MeSH
- Incisor surgery MeSH
- Root Canal Therapy methods MeSH
- Inflammation complications MeSH
- Crowns MeSH
- Dental Prosthesis Repair methods MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
Dlouhotrvající subklinický zánět je prokazatelně jedním z faktorů, které ovlivňují progresi aterosklerózy a vedou k destabilizaci aterosklerotických plátů s rizikem komplikací pod obrazem akutního koronárního syndromu. Kromě farmakologického ovlivnění tradičních rizikových faktorů aterosklerózy, jako je dyslipidemie, přináší kontrola prozánětlivého stavu podobné benefity ústící v pokles rizika kardiovaskulárních příhod, což lze monitorovat např. koncentrací vysoce senzitivního C-reaktivního proteinu. Možnosti cíleného ovlivnění subklinického zánětu medikamenty jsou prozatím velmi limitované, lze ovšem využít dostupná léčiva z plejády hypolipidemik, která vedle samotného hypolipidemického účinku umožňují kontrolu prozánětlivého stavu, což ústí v další redukci kardiovaskulárního rizika.
Long-term subclinical inflammation is one of the factors that influence the progression of atherosclerosis and lead to the destabilization of atherosclerotic plaques with increased risk of complications such as acute coronary syndrome. Control of the pro-inflammatory state brings similar benefits as pharmacological management of traditional risk factors of atherosclerosis resulting in lower risk of cardiovascular events. Decreased inflammatory state can be monitored, for example, by the concentration of highly sensitive C-reactive protein. The possibilities of targeted influence of subclinical inflammation are currently limited, but it is possible to use available substances with hypolipidemic effect, which are able to decrease the pro-inflammatory state resulting in a further reduction of cardiovascular risk.
Antiphospholipid syndrome (APS) is a systemic autoimmune condition characterized by the persistent presence of antiphospholipid antibodies (aPL), and is commonly associated with thrombosis and pregnancy-related complications. To date, relatively little is known about the potential of NK cells in mediating the pathological effects of APS. While the role of NK cells in controlling immune responses and maintaining tissue homeostasis is relatively clear, the fact that they are also linked to various autoimmune conditions is now being highlighted. Given the impact of NK cells on immune regulation, vascular function, and pregnancy outcomes, the unifying message of a critical role for NK cells in APS emerges. As innate immune cells, NK cells might be activated in an antibody dependent manner and exert antibody-dependent cellular cytotoxicity (ADCC). In this process, NK cells recognize and bind to the Fc portion of antibodies that have attached to target cells. With their immunoregulatory properties in the uterus, NK cells play a crucial role in facilitating endometrial tissue remodeling, supporting vascular function, and contributing to placental formation, all of which are essential for a successful pregnancy. In APS, the presence of aPL may disrupt the delicate balance of NK cell-mediated immune regulation leading to alterations in cell activation, cytokine production, and cytotoxic functions. Given the multifactorial nature of NK cells in peripheral blood and uterus, the review provides insight into the potential underlying mechanisms through which NK cells may contribute to thrombosis and pregnancy complications in APS.
- MeSH
- Antibodies, Antiphospholipid immunology MeSH
- Antiphospholipid Syndrome * immunology metabolism MeSH
- Antibody-Dependent Cell Cytotoxicity MeSH
- Killer Cells, Natural * immunology metabolism MeSH
- Pregnancy Complications immunology MeSH
- Humans MeSH
- Pregnancy MeSH
- Thrombosis immunology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
