Model Of Chronic Inflammation Research Articles

Hyperglycemia Alters the CD27:CD70 Axis of Human Immune Cells

Abstract Introduction/Objective The exact mechanism that inflammation plays in the pathogenesis from obesity to Type 2 diabetes is unclear, however, activated immune cells and pro-inflammatory cytokines have been found in the adipose tissue of Type 2 diabetics, implicating their role in the disease process. While the CD27-CD70 axis is being explored in other models of chronic inflammation, such as rheumatoid arthritis and colitis, the role played in Type 2 diabetes remains unknown. Objective Evaluate whether hyperglycemia alters immune cells phenotype and effector function, specifically of the CD27:CD70 axis on human immune cells. Methods/Case Report Human peripheral blood from donors was divided into three groups. n=40 total those that have a healthy blood glucose value and are without any co-morbidities (normoglycemic), patients identified as having pre-diabetes per their hemoglobin A1c (HgbA1c) value (5.6-6.5%), and patients with diabetes, having an elevated blood glucose and HgbA1c value (> 6.5%). The blood was then stained with monoclonal antibodies towards cell surface markers associated with inflammation, including CD27/CD70 and analyzed via flow cytometry. Previous data using cell cultures of human PBMC-derived T cells and autologous dendritic cells exposed to varing concentrations of glucose to simulate hyperglycemia and pre-diabetes was compared to this data. Results (if a Case Study enter NA) 1) T cells directly analyzed from pre-diabetic and hyperglycemia individuals down-regulate their CD27 expression. CD70 is up-regulated on immune cells directly analyzed from pre-diabetic individual when compared to immune cells from normoglycemic individuals. In accordance with the above resutls, CD4 T cells have an activated effector phenotype after co-culture with glucose stimulated dendritic cells. This includes down-regulation of CD27 on T cells and up-regulation of CD70 on dendritic cells. Conclusion Our data shows that certain markers of inflammation are up-regulated on the surface of immune cells from pre-diabetic and/or diabetic patients. Specifically, we demonstrate novel evidence that the CD27-CD70 axis is activated in diabetes or hyperglycemic conditions. These molecules may offer a potential target for therapeutics. Alternatively, our findings would allow a further way to characterize where a patient with an elevated blood glucose value is on the spectrum between pre-diabetes and full-blown diabetes.

Quantification of Grapiprant and Its Stability Testing under Changing Environmental Conditions.

Grapiprant is a new analgesic and anti-inflammatory drug belonging to the piprant class, approved in 2016 by the FDA Veterinary Medicine Center for the treatment of pain and inflammation associated with osteoarthritis in dogs. It acts as a highly selective antagonist of the EP4 receptor, one of the four prostaglandin E2 (PGE2) receptor subtypes. It has been shown to have anti-inflammatory effects in rat models of acute and chronic inflammation and clinical studies in people with osteoarthritis. The current state of knowledge suggests the possibility of using it in oncological therapy. The manuscript presents the development of conditions for the identification and quantitative determination of grapiprant by thin-layer chromatography with densitometric detection. The optimal separation of the substance occurs using silica gel 60F254 chromatographic plates and the mobile phase containing ethyl acetate-toluene-butylamine. Validation (according to ICH requirements) showed that the developed method is characterized by straightness of results in a wide concentration range with the limit of detection of 146.65 µg/mL. The %RSD values of the precision and accuracy confirm the sensitivity and reliability of the developed procedure. Next, the method was used for quantification of grapiprant in a pharmaceutical preparation, and for stability studies under various environmental conditions. Additionally, the mass studies were carried out on the stressed samples using the UPLC-MS/MS method. The degradation products were primarily characterized by comparing their mass fragmentation profiles with those of the drug. The results indicated a potential degradation pathway for grapiprant.

TNF overexpression and dexamethasone treatment impair chondrogenesis and bone growth in an additive manner

Children with chronic inflammation are often treated with glucocorticoids (GCs) and many of them experience growth retardation. It is poorly understood how GCs interact with inflammatory cytokines causing growth failure as earlier experimental studies have been performed in healthy animals. To address this gap of knowledge, we used a transgenic mouse model where human TNF is overexpressed (huTNFTg) leading to chronic polyarthritis starting from the first week of age. Our results showed that femur bone length and growth plate height were significantly decreased in huTNFTg mice compared to wild type animals. In the growth plates of huTNFTg mice, increased apoptosis, suppressed Indian hedgehog, decreased hypertrophy, and disorganized chondrocyte columns were observed. Interestingly, the GC dexamethasone further impaired bone growth, accelerated chondrocyte apoptosis and reduced the number of chondrocyte columns in huTNFTg mice. We conclude that TNF and dexamethasone separately suppress chondrogenesis and bone growth when studied in an animal model of chronic inflammation. Our data give a possible mechanistic explanation to the commonly observed growth retardation in children with chronic inflammatory diseases treated with GCs.

Chronic lipopolysaccharide impairs motivation when delivered to the ventricles, but not when delivered peripherally in male rats

Increased neuroinflammation relative to controls is observed in major depression. Moreover, depressive disorders are significantly elevated in conditions which increase neuroinflammation (e.g., brain injury, Parkinson's disease, Alzheimer's disease). To better understand the relationship between neuroinflammation and depression, additional research is needed. The current set of studies made use of the progressive ratio (PR) task in male rats, a stable measure of motivation which can be evaluated daily and thus is ideally suited for examining a potential role for chronic neuroinflammation in depressive-like behavior. Lipopolysaccharide (LPS) was used to induce an inflammatory response. Experiment 1 confirmed prior acute LPS administration experiments for sensitivity of the PR task, with a large effect at 2 mg/kg, a partial effect at 1 mg/kg, and no effect at 0.5 mg/kg. Experiment 2 evaluated a dose-response of continuous s.c. LPS infusion but found no significant elevation in brain cytokines after 14 days at any doses of 0.1, 0.5, 1, or 2 mg/kg/week. Experiment 3 assessed motivation during continuous s.c. infusion of a large 5 mg/kg/week LPS dose and found no significant impairments in motivation, but transient decreases in rates of lever pressing (i.e., only motoric deficits). Experiment 4 measured motivation during continuous ICV infusion of 10.5 μg/kg/week LPS and found significantly decreased motivation without changes to rates of lever pressing (i.e., only motivational deficits). Together these results suggest that the PR task is efficient for evaluating models of chronic inflammation, and that the adaptive response to chronic LPS exposure, even when delivered centrally, may necessitate alternative strategies for generating long-term neuroinflammation.

Topical Calendula officinalis L. inhibits inflammatory pain through antioxidant, anti-inflammatory and peripheral opioid mechanisms

ObjectiveThe present study evaluated the antinociceptive activity of Calendula officinalis L. (Ca) cream on inflammatory hypernociception. MethodsCreams with different Ca concentrations were tested for their ability to ameliorate pain-related behavior and edema in rats using formalin test, carrageenan (Cg)-induced acute inflammation model, bradykinin (BK)-induced acute inflammation model, and complete Freund’s adjuvant (CFA)-induced chronic inflammation model. Using the formalin test, we also examined the implication of peripheral opioid receptors in the antinociceptive mechanisms of Ca cream, by means of Q-naloxone, a peripherally acting nonselective opioid antagonist. Furthermore, the effects of Ca cream compared with diclofenac on BK-induced edema were examined when the kininase II in tissue was preserved or inhibited by captopril. The local production of redox biomarkers in formalin model, tumor necrosis factor-α (TNF-α) in Cg model and histopathological changes in CFA model were also evaluated. ResultsA single application of Ca cream at a dose of 10% or 30% (w/w) decreased the formalin-induced licking/biting behavior during both phases of this test in a Q-naloxone-sensitive manner. This effect was associated with the reduction of oxidative stress in the injured paw and the edema associated with the later phase of formalin-induced pain. A single application of Ca cream (10% or 30%) reduced paw edema and thermal hypernociception in Cg-induced acute inflammation, corresponding with a local decrease in TNF-α. Ca cream also inhibited BK-induced spontaneous nociceptive behavior and paw inflammation in both paradigms studied. Repeated applications of Ca cream also decreased CFA-induced chronic inflammation, mechanical hypernociception and histopathological changes in the paw. ConclusionThese results reveal the topical antinociceptive and antiedematogenic effects of Ca cream. A modulatory action on peripheral opioid receptors associated with its antioxidant mechanism may be involved, at least in part, in its analgesic effects. These findings may have an impact on the clinical management of painful inflammatory diseases.

An In Vivo Mouse Model for Chronic Inflammation-Induced Immune Suppression: A "Factory" for Myeloid-Derived Suppressor Cells (MDSCs).

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells known to play a role in perpetuating a wide range of pathologies, such as chronic infections, autoimmune diseases, and cancer. MDSCs were first identified in mice by the markers CD11b+ Gr1+ , and later, based on their morphology, they were classified into two subsets: polymorphonuclear MDSCs, identified by the markers CD11b+ Ly6G+ Ly6CLow , and monocytic MDSCs, detected as being CD11b+ Ly6G- Ly6CHi . MDSCs are studied as immunosuppressive cells in various diseases characterized by chronic inflammation and are associated with disease causes/triggers such as pathogens, autoantigens, and cancer. Therefore, different diseases may diversely affect MDSC metabolism, migration, and differentiation, thus influencing the generated MDSC functional features and ensuing suppressive environment. In order to study MDSCs in a pathology-free environment, we established and calibrated a highly reproducible mouse model that results in the development of chronic inflammation, which is the major cause of MDSC accumulation and immune suppression. The model presented can be used to study MDSC phenotypes, functional diversity, and plasticity. It also permits study of MDSC migration from the bone marrow to peripheral lymphatic and non-lymphatic organs and MDSC crosstalk with extrinsic factors, both in vivo and ex vivo. Furthermore, this model can serve as a platform to assess the effects of anti-MDSC modalities. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Repetitive M.tb immunizations for the induction of chronic inflammation Alternate Protocol 1: Creating a lower grade of inflammation by changing the site of immunization Alternate Protocol 2: In vivo evaluation of immune status Support Protocol 1: Preparation of reconstituted M.tb aliquots and M.tb-IFA emulsions for each of the three injections Support Protocol 2: Preparation of an ovalbumin lentiviral expression vector Support Protocol 3: Fluorescence titering assay for the lentiviral expression vector Support Protocol 4: Spleen excision, tissue dissociation, and preparation of a single-cell suspension Support Protocol 5: Labeling of splenocytes with CFSE proliferation dye.

Anti-inflammatory and arthritic activity of zaltoprofen compared to piroxicam in murine models.

Zaltoprofen, a unique propionic acid group of NSAIDs, works by blocking the enhancing effects of bradykinin along with the COX-2 enzyme. Therefore, it is of interest to evaluate the acute and chronic anti-inflammatory (arthritic) potential of zaltoprofen versus piroxicam in Murine models. A total of 48 Wister rats (200-250 g) of either sex (24 in each model) were used in the present study. The anti-inflammatory and arthritic potential of zaltoprofen was evaluated and compared by Carrageenan-induced acute inflammation and formalin-induced chronic inflammation. There was a significant inhibition of paw volume (P<0.001) on different time scales with two different doses of the test compound (Zaltoprofen 10 & 20 mg/kg) in the acute inflammation model compared to the negative control (NaCl 10 ml/kg). However, in the chronic inflammation model, zaltoprofen 10 mg/kg and 20 mg/kg doses of the test compound showed a significant reduction in chronic inflammation, comparable to the negative control (NaCl 10 ml/kg), although the potency was lower than the positive control (piroxicam 10 mg/kg) (P 0.05). Thus, zaltoprofen shows significant anti-inflammatory and arthritic effects in both acute and chronic models by inhibiting various inflammatory mediators.

CTLA-4-Ig internalizes CD80 in fibroblast-like synoviocytes from chronic inflammatory arthritis mouse model

CD80 interact with CD28 and CTLA-4 on antigen-presenting cells, and function in the co-stimulatory signaling that regulates T cell activity. CTLA-4-Ig is used to treat RA by blocking co-stimulatory signaling. Chronic inflammatory arthritis was induced in D1BC mice using low-dose arthritogenic antigens and treated with CTLA-4-Ig. We performed histopathology of the joints and lymph nodes, serological examination for rheumatoid factors, and flow cytometric analysis of isolated synovial cells, including CD45− FLSs and CD45+ synovial macrophages. CTLA-4-Ig treatment ameliorated the chronic inflammatory polyarthritis. There was a decrease in the number of infiltrating lymphoid cells in the joints as well as in the levels of RF-IgG associated with a decrease in the number of B cells in the lymph nodes; more than 15% of CD45− FLSs expressed CD80, and a small number of them expressed PD-L1, indicating the presence of PD-L1/CD80 cis-heterodimers in these cells. CTLA-4-Ig internalized CD80, but not PD-L1, in isolated synovial cells. Gene ontology analysis revealed that CTLA-4-Ig internalization did not significantly alter the expression of inflammation-related genes. The therapeutic effect of CTLA-4-Ig appears to extend beyond the lymph nodes into the inflamed synovial compartment through the synergistic inactivation of T cells by the CD80 and PD-L1 axes.

Tumor necrosis factor-alpha, prostaglandin-E2 and interleukin-1β targeted anti-arthritic potential of fluvoxamine: drug repurposing.

Fluvoxamine, a selective serotonin re uptake inhibitor, is used to treat depression. The aim of present study was to evaluate fluvoxamine in acute (egg albumin-induced inflammation) and chronic inflammatory rat models (formaldehyde and complete Freund's adjuvant (CFA)-induced arthritis). Fluvoxamine showed highly significant (p<0.001) protective effect at dose of 50 mg/kg orally with percentage suppression 21.3% as compared to disease control group in acute model. Likewise, formaldehyde-induced arthritic experiment confirmed the significant (p<0.001) anti-arthritic behavior, showed by fluvoxamine (50 mg/kg orally) throughout the study. Moreover, In CFA-induced model, the higher dose (fluvoxamine 50 mg/kg) exhibited highly significant (p<0.001) decrease in paw thickness and arthritic score with significant increase in weight of animals from 123.8± 1.934 g to 130.2± 1.655 g, significantly decreased the level of RF and CRP to level of 12.0±0.707 and 11.40±0.50 respectively and restoration of SOD, CAT (69.8±1.5, 72.0±1.4 respectively). Furthermore, the level of TNF-α, PGE2, and IL-1β (147.0±2.0, 406.8±2.5, and 93.8±1.3 respectively) in arthritic animals was reduced to significant (p<0.001) level (53.8±1.3, 205±3.6, and 42.0±1.4 respectively) after treatment with fluvoxamine. Furthermore, molecular docking of fluvoxamine against TNF-α, PGE2, and IL-1β protein targets showed good binding energies which hereby from computational studies proves our compound anti-inflammatory potential. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies reveled that fluvoxamine has very good pharmacokinetic profile with no specific hepatic toxicity and good absorption level. In addition, the skin sensitization test in vitro human cell line activation test (h-CLAT) and KeratinoSens have revealed that isolated flavone is not skin sensitive with confidence score of 59.6% and 91.6%. The current findings validated the anti-arthritic potential of fluvoxamine but it should be recommended for clinical investigation in future research.

Anti-inflammatory activity and metabolites profiling of aqueous stem bark extract of Ficus vogelii (Moraceae) in rats

IntroductionFicus vogelii is a terrestrial tree, used in Cameroonian pharmacopeia to treat various inflammatory diseases such as rheumatism. Accordingly, the present work aimed at evaluating anti-inflammatory potential of Ficus vogelii aqueous extract and identified phytochemicals of interest. MethodsThe characterization of the phytochemicals was carried out by HPLC-ESI-MSn. The anti-inflammatory potential of the aqueous extract of Ficus vogelii (100, 200, 400 and 600 mg/kg) was investigated using acute inflammatory models induced by chemicals, and chronic inflammatory models induced by formalin and Complete Freund Adjuvant (CFA) in rats. ResultsFicus vogelii significantly (p < 0.001) inhibited carrageenan-induced rat paw edema with maximum inhibitions of 75.86% (0.5 h), 82.41% (3 h) and 90.18% (6 h) at 100 mg/kg. This extract significantly (p < 0.001) reduced paw edema induced by histamine (54.10%), serotonin (54.06%), dextran (38.90%) and arachidonic acid (56.95%) respectively up to 1 h. Similarly, the extract significantly (p < 0.001) inhibited edema formation on the left paws of rats from day 2 up to 7 days post formalin injection, and significantly (p < 0.001) decreased paw edema of CFA-treated rats with the highest effect of 67.85% and 77.07% obtained on day 13 and day 21. Furthermore, the extract showed an antioxidant potential by improving the tissue levels of malondialdehyde, nitrites, superoxide dismutase and catalase. Phytochemicals analysis showed several compounds with isocitric acid (19%), trihydroxy-octadecenoic acid (18%), followed by dihydroxybenzoic acid, chlorogenic acid and vicenin-2 (8–9%). Oxylipins represented approximately 25% of the extract, thus being some of the compounds responsible for the observed activity. ConclusionThese results suggest that Ficus vogelii have anti-inflammatory effects on acute and chronic inflammation conditions.

Senescence-Independent Anti-Inflammatory Activity of the Senolytic Drugs Dasatinib, Navitoclax, and Venetoclax in Zebrafish Models of Chronic Inflammation.

Telomere shortening is the main molecular mechanism of aging, but not the only one. The adaptive immune system also ages, and older organisms tend to develop a chronic pro-inflammatory status with low-grade inflammation characterized by chronic activation of the innate immune system, called inflammaging. One of the main stimuli that fuels inflammaging is a high nutrient intake, triggering a metabolic inflammation process called metainflammation. In this study, we report the anti-inflammatory activity of several senolytic drugs in the context of chronic inflammation, by using two different zebrafish models: (i) a chronic skin inflammation model with a hypomorphic mutation in spint1a, the gene encoding the serine protease inhibitor, kunitz-type, 1a (also known as hai1a) and (ii) a non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) model with inflammation induced by a high-fat diet. Our results show that, although these models do not manifest premature aging, the senolytic drugs dasatinib, navitoclax, and venetoclax have an anti-inflammatory effect that results in the amelioration of chronic inflammation.

Novel model for chronic intestinal inflammation in chickens: (2) Immunologic mechanism behind the inflammatory response

Intestinal inflammation in poultry is a complex response that involves immune and intestinal cells which is still not fully understood. Thus, to better understand the mechanisms that drive the chronic intestinal inflammation in fowl we conducted an experiment applying a previously established nutritional model of low-grade chronic intestinal inflammation to evaluate cytokine and chemokine profiles in the chicken intestine. For this, we placed 90 one-day chickens into two treatments: (1) a control group (CNT) fed a corn-soybean diet, and (2) a group fed a diet high in non-starch polysaccharides (NSP). At days 14, 22, 28 and 36 of age, 6 birds from each treatment were euthanized, jejunal and ileal samples were collected for histological examination and cytokine measurements. The cytokines interferon-alpha (IFN-α), IFN-γ, interleukin-16 (IL-16), IL-10, IL-21, IL-6, macrophage-colony stimulating factor (M-CSF), chemokine C–C motif ligand 20 (CCL20), CCL4, CCL5 and vascular endothelial growth factor (VEGF) were quantified in the intestinal tissue. Histologically, both jejunum and ileum of broilers fed NSP diet showed marked infiltration of mononuclear immune cells into the villi. Further, these birds exhibited a significant (P < 0.05) increase in CCL20 concentration in the jejunum at 14d, but a dramatic reduction of M-CSF at 14 and 21d. Later at 28d and 36d, birds fed the NSP diet exhibited increased IL-16 concentration in the jejunum. Since M-CSF is a monocyte stimulatory cytokine and CCL20 a chemokine of T-cells, the reduced M-CSF and increased production of CCL20 may indicate the involvement of the adaptive immune response, specifically driven by T-cells, occurring around the third week of age in the NSP model. Lastly, as a result of the mononuclear cell infiltration and activation of T-cells, IL-16, a pro-inflammatory T-cell cytokine, increased. Therefore, the current work indicates the importance of adaptive immune cells, especially T-cells, in the chronic intestinal inflammation in broiler chicken.

Carrier-free curcumin nanoassemblies for enhancing therapy effects in inflammation related disease

Hyperinflammation can lead to tissue injury, organ failure, and even fatalities by overproducing proinflammatory cytokines. The long-term safety and outstanding anti-inflammatory ability of natural products have attracted much attention, but the low solubility and bioavailability limit their application. In this study, PGDE was conjugated with aromatic hydroxy groups of curcumin, resveratrol, and quercetin to prepare polyphenolic nano-assemblies. The nano-assemblies showed a comparable capacity for scavenging DPPH and ABTS free radicals with curcumin. The modification not only decreased the cytotoxicity of curcumin but also the anti-inflammation activity was preserved successfully. In vivo tests, NCAs were preferentially located at the inflammatory sites and performed effective therapeutic effects on acute and chronic inflammation models including sepsis, IBD, and liver fibrosis models. The anti-inflammatory activities were primarily realized by suppressing the overproduction of TNF-α, IL-6 and IL-β cytokines, and down-regulating the ROS-related NOX-1 and NOX-4. Additionally, NCAs inhibited the activation of the TGF-α/Smad pathway and decreased the production of α-SMA to alleviate collagen deposition in fibrosis mice. This study described a simple method for preparing nano-assemblies of insoluble polyphenols via the carrier-free self-assembly method, which improved the therapeutic effect on inflammatory diseases and broadened the application field of insoluble natural active polyphenols.

In vivo and in silico anti-inflammatory properties of the sesquiterpene valencene

Valencene (VLN) is a sesquiterpene found in juices and essential oils of citrus species such as Cyperus rotundus. Considering the evidence that this species has anti-inflammatory effects, the present study aims to evaluate the anti-inflammatory activity of VLN in vivo and in silico. Swiss mice (n = 6) were orally treated according to their treatment groups as follows: VLN (10, 100 or 300 mg/kg), negative control (0.9% saline), and positive controls (indomethacin 25 mg/kg or promethazine 6 mg/kg). The anti-inflammatory activity was evaluated in murine models of acute and chronic inflammation. The inhibition of acute inflammation was evaluated in models of paw edema induced by different inflammatory agents (carrageenan, dextran, histamine, and arachidonic acid (AA)) and carrageenan-induced pleurisy and peritonitis. The modulation of chronic inflammation was evaluated in a granuloma model induced cotton pellets implantation. The interaction with inflammatory targets was evaluated in silico using molecular docking analysis. The administration of VLN to challenged mice significantly inhibited paw edema formation with no significant difference between the administered doses. The compound also reduced albumin extravasation, leukocyte recruitment, and the production of myeloperoxidase (MPO), IL-1β, and TNF-α in both pleural and peritoneal lavages. According to the mathematical-statistical model observed in silico analysis, this compound has favorable energy to interact with the cyclooxygenase enzyme (COX-2) and the histamine 1 (H1) receptor. Finally, animals treated with the sesquiterpene showed a reduction in both granuloma weight and concentration of total proteins in a chronic inflammation model. Given these findings, it is concluded that NLV presents promising pharmacological activity in murine models of acute and chronic inflammation.

Progesterone Suppresses Uterine Contraction by Reducing Odontogenic Porphyromonas gingivalis Induced Chronic Inflammation in Mice.

Preterm birth is one of the most significant obstetric complications. Inflammation reportedly promotes uterine contraction and weakening of the fetal membrane, which induces preterm birth. Previous studies using animal models of lipopolysaccharide-induced acute inflammation have shown that progesterone (P4) promotes uterine quiescence. However, this effect is not fully understood in chronic inflammation. This study aimed to investigate the effects of P4 on uterine contractility and inflammation of the fetal membrane in mice infected with Porphyromonas gingivalis (P.g.), a major periodontal pathogen as a model of preterm birth caused by chronic inflammation. Mice were injected with 1 mg of P4 from day 15.5 to 17.5. P4 prolonged the mean gestation period of P.g mice from 18.3 to 20.4 days, and no reduction in the gestation period was observed. P4 treatment suppressed spontaneous uterine contractility and decreased oxytocin sensitivity. In addition, the expression of inflammatory cytokines in the fetal membrane was significantly reduced. Thus, P4 prevented preterm birth by suppressing enhanced uterine contractility induced by chronic inflammation in this model. This result describes the effects of P4 in a chronic inflammation model, which may lead to a better understanding of the efficacy of P4 in preventing preterm birth in humans.

Periodontitis y enfermedad cardiovascular: Una actualización

Periodontitis is an inflammatory disorder, initiated by the presence of bacterial plaque, which affects both the periodontal ligament and the bone that surrounds the teeth. These ailments include cardiovascular disease, gastrointestinal and colorectal cancer, diabetes and insulin and Alzheimer's disease, as well as respiratory tract disease and adverse events of pregnancy. In recent decades, several lines of evidence have supported the existence of a relationship between periodontitis and systemic health. Periodontitis acts within the same chronic inflammatory model seen in cardiovascular disease, it is now evident that cardiac disorders are worsened by periodontitis, both experimentally and in humans. For all these reasons, it is highly plausible that the prevention of periodontal lamina alteration has an impact on the progression of cardiovascular alterations. In this review, we have provided an updated account of the current understanding of periodontitis and cardiovascular disease.

Anti-inflammatory properties of the extract of maruna virgin (Tanacetum parthenium L.) on the model of chronic inflammation modeled by the Freund’ adjuvant in rats

Еhe aim of the study was to investigate the effectiveness of a thick extract of feverfew (Tanacetum parthenium L.) herb in chronic inflammation (adjuvant arthritis) in rats.&#x0D; The anti-inflammatory properties of the water-alcohol thick extract of feverfew (Tanacetum parthenium L.) herb (ETP) were studied in the model of adjuvant arthritis (ADA) (0.1 ml of Freund's adjuvant (PAF), once subcutaneously at the base of the tail of white nonlinear male rats (body weight 200–220 g). After 7 days, the introduction of PAF was repeated (subcutaneously in the right hind paw of rats). The animals were divided into 4 groups of 9 rats each, in the intact group – 6 animals. Distilled water (1 ml/100 g) was administered to positive control animals (PCs) on the background of pathology. An aqueous solution of ETP (50 mg/kg) and diclofenac sodium (1% starch suspension, 8 mg/kg) were administered from day 1 of the experiment and for four weeks daily intragastrically once daily. The volume of the affected foot (V) was measured using a LE7500 plethysmometer (PANLAB, Italy) in dynamics – at 1, 5, 10, 15, 20, 25 and 30 days after administration of a permissive dose of PAF. The intensity of inflammation in rats was assessed by peripheral blood parameters, biochemical indicators - markers of the inflammatory process. Statistical analysis of data was performed using the standard software package «Statistica v. 6.0». Differences between groups were considered statistically significant at p &lt;0.05.&#x0D; The course of ADA was characterized by the development of systemic inflammation, as evidenced by an increase in the number of leukocytes, increased erythrocyte sedimentation rate (ESR) and the content of C-reactive protein (CRP). A statistically significant increase in the level of LF and sialic acids indicates membrane-destructive processes in connective tissue. Against the background of ETP significantly decreased the level of the main indicator of inflammation CRP 2 times, the content of markers of destruction of joint tissue – sialic acid and LF decreased by 1.9 times relative to PC animals, indicating a positive effect on local and systemic manifestations of inflammation in ADA. The effectiveness of ETP was not inferior to diclofenac sodium (DS).&#x0D; Based on the data obtained, it can be concluded that the studied ETP at a dose of 50 mg/kg in the ADA model in rats has a pronounced anti-inflammatory effect and is not inferior to diclofenac sodium, which makes it promising further research as an effective anti-inflammatory agent.

Influence of gut microbiota on the development of insulin resistance

Insulin resistance (IR) is an important problem of humanity, which leads to development of many metabolic disorders. Сurrently the pathogenic mechanism of the development of IR is not completely investigated. Nevertheless, there are some hypotheses explaining the development of this condition. These include such hypotheses as the hypothesis of thrifty genotype, thrifty phenotype, hormonal, stress, good and bad calories, chronic metabolic inflammation, microbiotic and integrated model suggested by Professor Rainer Straub. In this article, the microbiotic theory will be considered in detail, explaining the mechanism of the development of peripheral tissue insensitivity to insulin in dysbiosis due to amplification of transmission by proinflammatory molecules from the intestine to the bloodstream and activation of systemic inflammation, disruption of the “gut-brain-periphery” mechanism and impaired receptor interactions of active intestinal metabolites of the gut microbiota (GM) at the level of cells of metabolic organs. The value of this theory is that its factors affect all links in the pathogenesis of the development of IR, reflected in the integrated model of Professor Straub. In this review the influence of GM and metabolic processes of human body on the development of IR will be considered in detail, data from clinical studies about the influence of GM (its composition, active metabolites, individual bacterial strains) on the development of IR and the role of chronic metabolic inflammation in this process will also be presented. In addition, attention will be paid to bidirectional effects of GM and metformin, as well as to data from clinical studies on changes in GM in healthy people and people with IR under the influence of metformin and how GM affects the pharmacokinetics of this drug. The possibility of IR correction through the use of dietary fiber will also be considered.

Ultrasound Neuromodulation of the Spleen Has Time-Dependent Anti-Inflammatory Effect in a Pneumonia Model.

Interfaces between the nervous and immune systems have been shown essential for the coordination and regulation of immune responses. Non-invasive ultrasound stimulation targeted to the spleen has recently been shown capable of activating one such interface, the splenic cholinergic anti-inflammatory pathway (CAP). Over the past decade, CAP and other neuroimmune pathways have been activated using implanted nerve stimulators and tested to prevent cytokine release and inflammation. However, CAP studies have typically been performed in models of severe, systemic (e.g., endotoxemia) or chronic inflammation (e.g., collagen-induced arthritis or DSS-induced colitis). Herein, we examined the effects of activation of the splenic CAP with ultrasound in a model of local bacterial infection by lung instillation of 105 CFU of Streptococcus pneumoniae. We demonstrate a time-dependent effect of CAP activation on the cytokine response assay during infection progression. CAP activation-induced cytokine suppression is absent at intermediate times post-infection (16 hours following inoculation), but present during the early (4 hours) and later phases (48 hours). These results indicate that cytokine inhibition associated with splenic CAP activation is not observed at all timepoints following bacterial infection and highlights the importance of further studying neuroimmune interfaces within the context of different immune system and inflammatory states.

Mitochondrial complex I dysfunction alters the balance of soluble and membrane-bound TNF during chronic experimental colitis

Inflammatory bowel disease (IBD) is a complex, chronic, relapsing and heterogeneous disease induced by environmental, genomic, microbial and immunological factors. MCJ is a mitochondrial protein that regulates the metabolic status of macrophages and their response to translocated bacteria. Previously, an acute murine model of DSS-induced colitis showed increased disease severity due to MCJ deficiency. Unexpectedly, we now show that MCJ-deficient mice have augmented tumor necrosis factor α converting enzyme (TACE) activity in the context of chronic inflammation. This adaptative change likely affects the balance between soluble and transmembrane TNF and supports the association of the soluble form and a milder phenotype. Interestingly, the general shifts in microbial composition previously observed during acute inflammation were absent in the chronic model of inflammation in MCJ-deficient mice. However, the lack of the mitochondrial protein resulted in increased alpha diversity and the reduction in critical microbial members associated with inflammation, such as Ruminococcus gnavus, which could be associated with TACE activity. These results provide evidence of the dynamic metabolic adaptation of the colon tissue to chronic inflammatory changes mediated by the control of mitochondrial function.