Inflammatory Processes In Mice Research Articles

A Lipopolysaccharide Mouse Model Mirrors Neuroinflammatory Transcriptional Signatures of Human AD, and the Glucagon-Like Peptide-1 Receptor Agonist Semaglutide Attenuates Neuroinflammation in this Model (P1-6.007)

<h3>Objective:</h3> We aimed to investigate the molecular effects of semaglutide on lipopolysaccharide (LPS) induced hippocampal neuroinflammation in mice and further to compare human gene expression signatures in Alzheimer’s disease (AD) brain tissue with those induced by LPS. <h3>Background:</h3> Neuroinflammation is part of the pathophysiology in AD. AD neuroimaging studies highlight increased inflammation, while genome wide association studies indicate that many AD-associated genes are expressed in glial cells. The glucagon-like peptide-1 receptor agonist semaglutide is currently being investigated in two phase 3a randomized, placebo-controlled trials in people with early Alzheimer’s disease (evoke/evoke+). <h3>Design/Methods:</h3> Mice were treated daily with subcutaneous semaglutide (30nmol/kg) or vehicle for 28 days, and LPS or vehicle was administered on days 15–17. RNA-sequencing and immunohistochemistry were performed to assess transcriptional and morphological changes in the hippocampus at Day 19 and Day 28 (Day 2 and 11 post-LPS, respectively). RNA-sequencing analyses included differentially expressed gene analysis, weighted gene co-regulated network analysis, pathway analysis and gene set enrichment analysis on published human AD datasets. <h3>Results:</h3> Semaglutide treatment significantly decreased the area of ionized calcium binding adaptor molecule 1 (Iba1) positive microglia (quantitative assessment) and attenuated co-expressed inflammatory genes vs vehicle in LPS-treated mice (p&lt;0.01) on Day 28. Pathway analysis was consistent with an overall dampening of inflammatory processes in mice treated with LPS and semaglutide. The mouse LPS model mirrored the transcriptional signatures identified in people with AD in data of human hippocampal subtype transcriptional signatures, suggesting that semaglutide could potentially alleviate homologous inflammatory molecular processes in humans. <h3>Conclusions:</h3> In an LPS-induced neuroinflammation mouse model, semaglutide reduced hippocampal neuroinflammation as measured by transcriptional changes and microglial area (Iba1). This could represent a novel mechanism whereby semaglutide may affect neuronal integrity and function, and thereby AD pathophysiology. <b>Disclosure:</b> Dr. Ludwig has nothing to disclose. Dr. Rausch has nothing to disclose. Dr. Secher has received personal compensation for serving as an employee of Novo Nordisk. An immediate family member of Dr. Secher has received personal compensation for serving as an employee of Novo Nordisk. Dr. Secher has stock in Novo Nordisk. Dr. Bentsen has received personal compensation for serving as an employee of Novo Nordisk. An immediate family member of Dr. Bentsen has stock in Novo Nordisk. Dr. Hansen has received personal compensation for serving as an employee of Neumirna Therapeutics. Dr. Hansen has received intellectual property interests from a discovery or technology relating to health care. Dr. Bjerregaard has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Niss has nothing to disclose. Kristoffer L Egerod has nothing to disclose. Dr. Hansen has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Hansen has stock in Novo Nordisk A/S. Dr. Dalgaard has received personal compensation for serving as an employee of Novo Nordisk. Dr. Merkestein has received personal compensation for serving as an employee of Novo Nordisk A/S. Dorte Holst has nothing to disclose. Charles Pyke has nothing to disclose. Mrs. Wichern has received personal compensation for serving as an employee of Gubra ApS. Dr. Polex-Wolf has received personal compensation for serving as an employee of Novo Nordisk A/S. Tune H Pers has nothing to disclose. Lotte B Knudsen has nothing to disclose.

A lipopolysaccharide mouse model mirrors neuroinflammatory transcriptional signatures of human Alzheimer’s disease, and the Glucagon‐Like Peptide‐1 receptor agonist semaglutide attenuates neuroinflammation in this model

AbstractBackgroundNeuroinflammation is part of the pathophysiology in Alzheimer’s disease (AD). AD neuroimaging studies highlight increased inflammation, while genome wide association studies indicate that many AD‐associated genes are expressed in glial cells. The hormone and neuropeptide Glucagon‐Like Peptide‐1 (GLP‐1) was originally developed for treatment of type 2 diabetes but has equally important effects in weight loss control and provides cardiovascular benefits. The potential for applying a licensed therapeutic option with a well‐established safety profile is currently being investigated in two phase 3a randomized, placebo‐controlled trials with semaglutide in people with early Alzheimer’s disease (evoke/evoke+). Here, we investigate the molecular effects of semaglutide on lipopolysaccharide (LPS) induced hippocampal neuroinflammation in mice and compare the identified pathways with human gene signatures in AD brain tissue.MethodMice were treated daily subcutaneously with semaglutide (30nmol/kg) or vehicle for 28 days, and LPS or vehicle was administered on days 15‐17. RNA‐sequencing and immunohistochemistry was performed to assess transcriptional and morphological changes in the hippocampus at Day 19 and Day 28 (Day 2 and 11 post‐LPS, respectively). RNA‐sequencing analyses included differentially expressed gene analysis, weighted gene co‐regulated network analysis, pathway analysis and gene set enrichment analysis on published human AD datasets.ResultSemaglutide treatment significantly decreased the area of ionized calcium binding adaptor molecule 1 (Iba1) positive microglia (quantitative assessment) and attenuated co‐expressed inflammatory genes in LPS/semaglutide‐treated mice (p&lt;0.01 vs LPS+vehicle treated mice) on Day 28. Pathway analysis was consistent with an overall dampening of inflammatory processes in mice treated with LPS and semaglutide. The mouse LPS model mirrored the transcriptional signatures identified in people with AD in data of human hippocampal subtype transcriptional signatures, suggesting that semaglutide could potentially alleviate homologous inflammatory molecular processes in humans. A single nucleus RNA‐sequencing study in mice is ongoing to further elucidate the molecular effects of semaglutide on neuroinflammation and will be presented at the conference.ConclusionIn an LPS‐induced neuroinflammation mouse model, subcutaneously semaglutide reduced hippocampal neuroinflammation as measured by transcriptional changes and microglial area (Iba1). This could be a novel mechanism through which semaglutide, may affect neuronal integrity and function relevant for AD pathophysiology.

Bovine-derived α-lactalbumin exhibits cardiovascular protection against aging by ameliorating the inflammatory process in mice

Cardiovascular aging is the most important factor leading to cardiovascular disease (CVD), and the incidence and severity of cardiovascular events increase with age. Cardiovascular disease is one of the leading causes of death in the aging population. Therefore, it is extremely urgent to develop and explore effective drugs or bioactive molecules to prevent cardiovascular aging and related diseases. In the current work, the effect of bovine α-lactalbumin (α-lactalbumin is one of the major bioactive protein molecules in milk) on cardiovascular aging was investigated in vitro and in vivo. First, a cellular model of cardiovascular aging was established using H2O2-induced in vitro cellular models. It was found that α-lactalbumin could alleviate cardiovascular senescence by assessing Sa-β-gal and senescence-related markers (such as p16/p21/p53) in in vitro cellular models. Bovine α-lactalbumin attenuated aging-related inflammation and oxidative stress. Furthermore, aged mice were used as an in vivo cardiovascular aging model. We explored the effect of α-lactalbumin on cardiovascular aging and found that cardiovascular aging was significantly attenuated by evaluating Sa-β-gal staining and aging-related marker molecules. Mechanistically, we found that α-lactalbumin may alleviate cardiovascular aging by regulating the expression of Sirt1 (Sirtuin 1). In summary, in the current work, we systematically explored the potential biological activity of α-lactalbumin against cardiovascular aging and found that α-lactalbumin has good anti-aging potential in vitro and in vivo, suggesting that α-lactalbumin could be used as an antiaging functional food in the future.

Brazilian Organic Honey from Atlantic Rainforest Decreases Inflammatory Process in Mice.

Honey is an ancient food in the human diet, and the chemical composition of some types of honey has been associated with several beneficial biological effects. Among them, honey has been highlighted to improve health and control inflammatory processes. However, there is no study elucidating the mechanism of action of honey produced organically. Here, we separated organic honey (OH) samples from the Brazilian Atlantic Rainforest into eight different profiles (OH-1 to OH-8) and evaluated, in vitro and in vivo, their anti-inflammatory potential. To determine cell viability, RAW 264.7 macrophages were treated with several concentrations of OH-1 up to OH-8, and anti-inflammatory activity was assessed through NF-κB activation and TNF-α levels. All types of the studied honey up to a concentration of 4% (w/v) did not interfere with macrophage viability and decreased NF-kB activation and TNF-α levels in macrophage culture in vitro. OH-7 was selected as the most promising anti-inflammatory and used in subsequent assays. Mice pretreated orally with OH-7 showed a decrease in neutrophil migration and TNF-α level. Thus, these types of Brazilian organic honey show promising anti-inflammatory potential, particularly the OH-7 variety. Brazilian organic honey may lead to the development of new products and/or be incorporated into food for use in veterinary medicine and human health as well.

5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction.

Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.

Regulatory T cells and anti-inflammatory cytokine profile of mice fed a high-fat diet after single-bulb garlic (&lt;i&gt;Allium sativum&lt;/i&gt; L.) oil treatment

Purpose: To analyze the effects of a single-bulb garlic (Allium sativum) oil (SGO) on the activation of regulatory T cells and anti-inflammatory cytokines IL-10 and TGF-β in mice fed a high-fat diet (HFD).Methods: The study was conducted with 24 BALB/c male mice divided into six groups consisting of four mice each, i.e., control group (non-HFD, no treatment), HFD group without treatment, HFD administered with simvastatin, and three HFD groups administered SGO doses of 12.5, 25.0 and 50.0 mg/kg, respectively, and continuously treated (with SGO) for 45 days. The relative number of regulatory T cells, IL-10 and TGF-β were measured using flow cytometry.Results: HFD decreased the expression of regulatory T cells, and the production of IL-10 and TGF-β compared to the control group (p < 0.05). SGO (50 mg/kg) significantly enhanced the activation of regulatory T cells and production of TGF-β in mice fed high-fat diet compared to simvastatin group (p < 0.05). The dose of 25 mg/kg SGO significantly increased the level of IL-10 in mice fed a HFD (p < 0.05).Conclusion: These results suggest that SGO inhibits inflammatory processes in mice fed a HFD, by enhancing regulatory T cells and the anti-inflammatory cytokine IL-10 and TGF-β. Thus, SGO a promising food supplements and/or therapeutic agent for management of inflammation disorders caused by a HFD.Keywords: Anti-inflammatory agent, Allium sativum, High-fat diet, Interleukin-10, Regulatory T cells, Transforming Growth Factor-β

TNF-Induced Vaso-Occlusive and Inflammatory Processes in Mice with Sickle Cell Anemia Are Abrogated By the Platelet Activation Inhibitor, Prasugrel

Background: Vaso-occlusive processes in sickle cell anemia (SCA) are triggered by inflammatory molecules, along with pancellular activation and the recruitment and adhesion of leukocytes to the endothelium. Interactions between platelets, neutrophils, and erythrocytes are observed in the SCA circulation, but the exact role of platelets in the initiation and propagation of vaso-occlusion is not well understood. Aim: We, herein, evaluated the effects of the inhibition of platelet activation on TNF-α (TNF)-triggered vaso-occlusive processes in the microcirculation of mice with SCA, using prasugrel, a platelet ADP P2Y12 receptor inhibitor. Methods: Chimeric male control (CON) and SCA (SCA) mice received prasugrel (1 mg/kg, by gavage) or vehicle (saline) in a single administration, 1h prior to TNF (0.5 μg/g, i.p). In some experiments, 1 mg/kg prasugrel was administered chronically for 5x per week for 4 weeks. Following i.v. injection of anti-CD41 PE, anti-CD45 PeCy-5 and anti-Ly6G Alexa 488 antibodies for labeling platelets, leukocytes (in general) and neutrophils respectively, the cremaster muscle was exposed and the microcirculation was observed by conventional and confocal intravital microscopy. Results: While the acute administration of prasugrel to CON and SCA mice did not alter the quantity of platelets in the microcirculation (data not shown), it significantly reduced the adhesion of platelets to the vascular wall in both CON animals (12±1.6 vs 5.7±1.4 % adhered of total platelets, n=3; p<0.05) and SCA mice after TNF (36.2±7.1 vs 4.8±2.5 % platelets adhered for w/out and with prasugrel, respectively; n=3; p<0.0001) (see Figure). Furthermore, prasugrel significantly reduced the number of platelet/neutrophil aggregates in TNF-treated CON (2.7±0.4 vs 0.53±0.3 aggregates adhered 100 µm−1, p<0.001 n=3) and SCA mice (3.1±0.7 vs 0.76±0.3 aggregates adhered 100 µm−1, p<0.01 n=3), and also platelet/non-neutrophil leukocytes in CON (1.3±0.7 vs 0.2±0.1 aggregates adhered 100 µm−1, p<0.01 n=3) and SCA mice (2.0±0.3 vs 0.2±0.1 aggregates adhered 100 µm−1, p<0.001 n=3). Alterations in platelet adhesion to the vascular wall and platelet-leukocyte aggregate formation were accompanied by reductions in the recruitment of leukocytes to the venule walls, after prasugrel administration. Prasugrel significantly decreased the rolling, adhesion and extravasation of leukocytes in both CON (4.9±2.7 vs 1.14±0.5 min−1; 9.2±0.8 vs 2.7±0.5 100 µm−1; 1.9±0.3 vs 0.4±0.1 100x50 µm-2; for w/out and with prasugrel, respectively; n=3; p<0.001) and SCA mice (36.0±3.0 vs 3.0±0.6 min−1; 16.6±1.5 vs 6.4±1.2 100 µm−1; 6.9±0.8 vs 1.7±0.4 100x50 µm-2; for w/out and with prasugrel, respectively; n=3; p<0.0001). Acute prasugrel treatment also increased blood flow velocity after TNF stimulation in CON mice (37±10 vs 110±35 mm3/s, p<0.01, n=3) and substantially augmented flow in SCA mice (13±2 vs 94±12 mm3/s, p<0.0001, n=3), approaching flow velocities similar to those observed in control animals that had not received TNF (Data not shown). The survival of SCA animals treated with a single dose of prasugrel increased by 1.3 hours compared to the SCA animals that received the vehicle (n=3, p<0.05). Complimentary experiments demonstrated a similar effect of the chronic administration of prasugrel, which significantly reduced leukocyte recruitment to the vascular wall after TNF in both CON and SCA mice (data not shown, P<0.05). Conclusions: Our findings show that the inhibition of platelet activation by prasugrel, while significantly decreasing the adhesion of platelets to venules walls and the formation of heterocellular aggregates, was able to almost abolish the recruitment of leukocytes to the microcirculation of SCA mice after an inflammatory stimulus. This reduction in platelet and leukocyte vascular recruitment was associated with major improvements in blood flow and in the survival of animals with SCA. Thus, our data suggest that platelet activation and the consequent adhesion of platelets to the vascular wall is a fundamental step in the initiation of the vaso-occlusive process in response to inflammatory stimuli. Our findings support further investigations into the use of drugs that inhibit platelet activation (including prasugrel itself) as a therapeutic approach for SCA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hydroalcoholic extract of Brazilian green propolis modulates inflammatory process in mice submitted to a low protein diet

The occurrence of inflammation and protein malnutrition is an aggravating risk factor for morbidity and mortality in the clinical setting. The green propolis, a natural product made by Apis mellifera bees from Baccharis dracunculifolia resin, has therapeutic potential to modulate chronic inflammation. However, its effect on inflammation in an impaired nutritional status is not known. The aim of this study was to characterize the effects of the administration of the hydroalcoholic extract of the green propolis in the chronic inflammatory process of mice submitted to a low-protein diet. For this, we used the subcutaneous implantation of sponge disks as an inflammatory model and the animals were distributed in the following groups: standard protein diet (12% protein content), control treatment; standard protein diet, propolis treatment; low-protein diet (3% protein content), control treatment; low-protein diet, propolis treatment. Propolis was given daily at a dose of 500 mg/kg (p.o.) during a period of 7 or 15 days. Our main findings show that animals fed with standard protein diet and treated with propolis had low levels of red blood cells, hemoglobin, and hematocrit, with the subsequent reestablishment of these levels, in addition to monocyte count elevation and higher TNF levels after one week of treatment. In the low-protein diet group, the propolis treatment provided a significant recovery in weight and maintenance of total serum protein levels at the end of two weeks of treatment. Histological analysis showed propolis reduced the inflammatory infiltrate in the sponges of both standard and low-protein diet groups. In addition, the propolis extract presented antiangiogenic effect in both groups. Therefore, our data suggests that the hydroalcoholic extract of the green propolis promotes weight recovery and avoid the reduction of protein levels, in addition to inhibit inflammation and angiogenesis in animals fed with a low-protein diet.

Baicalin modulates the Treg/Teff balance to alleviate uveitis by activating the aryl hydrocarbon receptor

Autoimmune uveitis is a sight-threatening ocular inflammatory disorder. Immunological inflammation is regarded as the key to pathogenesis in autoimmune uveitis. Baicalin, the major bioactive component of Scutellaria baicalensis, possesses immunomodulatory properties. However, the role of baicalin in uveitis and its underlying mechanisms remain unclear. In the current study, we found that baicalin treatment obviously inhibited the intraocular inflammatory process in mice with experimental autoimmune uveitis, along with clear declines in infiltrated inflammatory cells and inflammatory cytokine transcription in the retina and draining lymph nodes. Furthermore, baicalin treatment increased the frequency and number of regulatory T cells and decreased the frequency and number of effector T cells (Th1 and Th17 cells) in the draining lymph nodes of mice with experimental autoimmune uveitis. In vitro, baicalin treatment suppressed interphotoreceptor retinoid binding protein-specific CD4+ T cell proliferation and converted CD4+ T cell differentiation. Furthermore, the expression of aryl hydrocarbon receptor was activated by baicalin treatment. Baicalin-mediated modulation of CD4+ T cell differentiation was partially abrogated by the suppression of aryl hydrocarbon receptor. These findings suggest that baicalin modulates the Treg/Teff balance and CD4+ T cell proliferation to ameliorate experimental autoimmune uveitis by activating the aryl hydrocarbon receptor.

Trichomonas vaginalis exosome-like vesicles modify the cytokine profile and reduce inflammation in parasite-infected mice.

Trichomonas vaginalis (Tv) is a flagellated parasite commonly spread through sexual transmission. This protozoan initiates a severe inflammatory process, inducing nitric oxide, interleukin-6 (IL-6), IL-8, IL-10, IL-17 and IL-22 production by host immune cells. The parasites elicit these responses by releasing surface lipophosphoglycan, small extracellular vesicles (exosomes) and other factors. Tv exosomes are similar to mammalian exosomes and have been implicated in the modulation of IL-8 secretion by epithelial cells. Here, we report that exosome-like vesicles from T.vaginalis (Tv-ELVs) induced a more than 15-fold increase in IL-10 expression in RAW264.7 macrophages but only a two fold increase in IL-6 and TNF-α expression levels measured by RT-PCR. Because Tv-ELVs modulated the macrophage response, we also explored the effect of Tv-ELVs in a murine model of infection. Pretreatment with Tv-ELVs significantly increased IL-10 production as measured in vaginal washes by days 8 and 16 post-infection. Remarkably, Tv-ELVs-pretreated mice exhibited a decrease in IL-17 production and a significant decrease in vulvar inflammation. In addition, IL-6 and IL-13 were decreased during infection. Our results suggest that Tv-ELVs have an immunomodulatory role on the cytokine profile induced by the parasite and promote a decrease in the inflammatory process in mice infected with T.vaginalis.

Light-emitting diodes at 940 nm attenuate colitis-induced inflammatory process in mice

Inflammatory bowel disease (IBD) presents intense inflammatory infiltrate, crypt abscesses, ulceration and even loss of function. Despite the clinical relevance of IBD, its current therapy remains poorly effective. Infrared wavelength phototherapy shows therapeutic potential on inflammation. Our goal was to evaluate whether light-emitting diodes (LED) at 940nm are capable of mitigating the colitis-induced inflammatory process in mice. Forty male Swiss mice were assigned into five groups: control; control treated with LED therapy; colitis without treatment; colitis treated with LED therapy; colitis treated with Prednisolone. Experimental colitis was induced by acetic acid 7.5% (pH2.5) rectal administration. LED therapy was performed with light characterized by wavelength of 940nm, 45nm bandwidth, intensity of 4.05J/cm2, total power of 270mW and total dose of 64.8J for 4min in a single application. Colitis-induced intestinal transit delay was inhibited by LED therapy. Colitis caused an increase of colon dimensions (length, diameter, total area) and colon weight (edema), which were inhibited by LED therapy. LED therapy also decreased colitis-induced tissue gross lesion, myeloperoxidase activity, microscopic tissue damage score and the presence of inflammatory infiltrate in all intestinal layers. Furthermore, LED therapy inhibited colitis-induced IL-1β, TNF-α, and IL-6 production. We conclude LED therapy at 940nm inhibited experimental colitis-induced colon inflammation in mice, therefore, rendering it a promising therapeutic approach that deserves further investigation.

Loss of Metabotropic Glutamate Receptor 5 Function on Peripheral Benzodiazepine Receptor in Mice Prenatally Exposed to LPS

Parental microglial induced neuroinflammation, triggered by bacterial- or viral infections, can induce neuropsychiatric disorders like schizophrenia and autism to offspring in animal models. Recent investigations suggest that microglia, the resident immune cells of the brain, provides a link between neurotransmission, immune cell activation, brain inflammation and neuronal dysfunction seen with the offspring. Relatively little is known about how reduction of brain inflammation and restoration of glial function are associated with diminution of brain degeneration and behavioral deficits in offspring. Increased mGluR5 expression and the long-lasting excitotoxic effects of the neurotoxin during brain development are associated with the glial dysfunctions. We investigated the relationship of mGluR5 and PBR and how they regulate glial function and inflammatory processes in mice prenatally exposed to LPS (120μg/kg, between gestational days 15 and 17), an inflammatory model of a psychiatric disorder. Using PET imaging, we showed that pharmacological activation of mGluR5 during 5 weeks reduced expression of classic inflammation marker PBR in many brain areas and that this molecular association was not present in LPS-exposed offspring. The post-mortem analysis revealed that the down regulation of PBR was mediated through activation of mGluR5 in astrocytes. In addition, we demonstrated that this interaction is defective in a mouse model of the psychiatric deficit offering a novel insight of mGluR5 involvement to brain related disorders and PBR related imaging studies. In conclusion, mGluR5 driven glutamatergic activity regulates astrocytic functions associated with PBR (cholesterol transport, neurosteroidogenesis, glial phenotype) during maturation and could be associated with neuropsychiatric disorders in offspring.

Goishi tea consumption inhibits airway hyperresponsiveness in BALB/c mice

BackgroundAirway hyperresponsiveness (AHR) is one of the important traits that characterize bronchial asthma. Goishi tea is a post-heating fermented tea that has been reported to have higher free radical scavenging activity. In this study, we evaluated the prophylactic effects of Goishi tea on AHR in BALB/c mice.ResultsThe number of inflammatory cells in BAL fluid was considerably reduced in Goishi tea/Der f and Gallic acid/Der f groups as compared with Tap water/Der f group. Regarding inflammatory cells in BAL, a significant reduction of eosinophils and neutrophils was observed in Goishi tea-treated mice (p < 0.01), as well as in the Gallic acid/Der f group (p < 0.05), as compared with Tap water/Der f group. In asthmatic mice (Tap water/Der f group), the intensity of airway resistance increased simultaneously with the increase in acetylcholine concentration in a dose-dependant way. AHR was significantly inhibited in Goishi tea/Der f and Gallic acid/Der f (p < 0.01) groups as compared with the Tap water/Der f group. Regarding serum specific-IgG1, significantly lower levels of this antibody were observed in Goishi tea/Der f and Gallic acid/Der f groups as compared with the Tap water/Der f group (p < 0.05). In addition, adiponectin level was significantly higher in the Goishi tea group as compared with the Tap water treated mice (p < 0.01).ConclusionsThe results suggest that Goishi tea consumption exerted an inhibitory effect on eosinophilic and neutrophilic infiltration in the lung, attenuated the increase in airway resistance and increased the production of adiponectin; thus reducing Der f induced allergic inflammatory process in mice.

Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice

Resveratrol is a natural polyphenolic stilbene derivative found in a variety of edible fruits, including nuts, berries, and grape skin. Although resveratrol has been suggested to improve thermogenesis in the brown adipose tissues of obese animals, there have been no reports on the anti-adipogenic and anti-inflammatory effects of resveratrol in the white adipose tissues of obese animals. The primary aim of this study was to investigate whether resveratrol attenuates high-fat diet (HFD)-induced adipogenesis and inflammation in the epididymal fat tissues of mice and to explore the underlying mechanisms involved in this attenuation. In comparison with HFD-fed mice, mice fed with a 0.4% resveratrol-supplemented diet (RSD) showed significantly lower body weight gain (−48%), visceral fat-pad weights (−58%), and plasma levels of triglyceride, FFA, total cholesterol, glucose, tumor necrosis factor (TNF) α, and monocyte chemoattractant protein-1 (MCP1). Resveratrol significantly reversed the HFD-induced up-regulation of galanin-mediated signaling molecules (GalR1/2, PKCδ, Cyc-D, E2F1, and p-ERK) and key adipogenic genes (PPARγ2, C/EBPα, SREBP-1c, FAS, LPL, aP2, and leptin) in the epididymal adipose tissues of mice. Furthermore, resveratrol significantly attenuated the HFD-induced up-regulation of pro-inflammatory cytokines (TNFα, IFNα, IFNβ, and IL-6) and their upstream signaling molecules (TLR2/4, MyD88, Tirap, TRIF, TRAF6, IRF5, p-IRF3, and NF-κB) in the adipose tissues of mice. The results of this study suggest that resveratrol inhibits visceral adipogenesis by suppressing the galanin-mediated adipogenesis signaling cascade. It may also attenuate cytokine production in the adipose tissue by repressing the TLR2- and TLR4-mediated pro-inflammatory signaling cascades in HFD-fed mice.

Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice

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Protective effect of bioactive ceramics on liver injury: regulation of pro-inflammatory cytokins expression

A bioactive ceramics has been reported to regulate the expression of inflammatory cytokines in macrophage cells activated by lipopolysaccharides (LPS). In present study, we investigated the anti-inflammatory effect of bioactive ceramics using liver injury model in mouse. Mice were divided into three groups: Normal group, LPS group (LPS and no ceramics treatment), Ceramics group (LPS and ceramics treatment). LPS administration induced the increase of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in mouse. The losses of cytoplasm of hepatocytes due to LPS caused the increase of AST and ALT in mouse plasma. In Ceramics group, however, the concentration of AST and ALT were much lower than LPS group until 6 weeks. And the losses of cytoplasm were rarely seen in Ceramics group. RT-PCR results showed that the decrease of proinflammatory cytokines such as IL-1beta and IL-6 was observed in Ceramics group. Moreover, TGF-beta1 and VEGF expression was increased in Ceramics group. Bioactive ceramics effectively protected endotoxin-induced liver injury by attenuation of inflammatory processes in mice.

Analgesic effects of capsazepine and resiniferatoxin on bone cancer pain in mice

In the present paper, we describe the analgesic effects induced by the transient receptor potential vanilloid type 1 (TRPV1) antagonist, capsazepine, and the TRPV1 agonist, resiniferatoxin, on the thermal hyperalgesia induced by the presence of a tibial osteosarcoma or an inflammatory process in mice. The administration of capsazepine abolished the osteosarcoma-induced hyperalgesia at a dose range (3–10 mg/kg; s.c.) ineffective to inhibit the hyperalgesia elicited by the intraplantar administration of complete Freund's adjuvant (CFA). In contrast, the administration of resiniferatoxin (0.01–0.1 mg/kg; s.c.) inhibited both the osteosarcoma- and the CFA-induced hyperalgesia. Remarkably, a single dose of resiniferatoxin abolished the osteosarcoma-induced hyperalgesia for several days and completely prevented the instauration of thermal hyperalgesia when administered at the initial stages of osteosarcoma development. The potential of drugs acting through TRPV1 for the management of some types of bone cancer pain is proposed.

Evidence for activation of the tissue kallikrein-kinin system in nociceptive transmission and inflammatory responses of mice using a specific enzyme inhibitor.

The pharmacological activity of phenylacetyl-Phe-Ser-Arg-N-(2, 4-dinitrophenyl)-ethylenediamine (TKI), a tissue kallikrein specific inhibitor, was assessed using models of nociception and inflammation in mice. Injection of TKI (13.6 - 136 micromol kg(-1), i.p. or 41 - 410 micromol kg(-1), s.c.) produced a dose-related inhibition of the acetic acid-induced writhes (by 37 to 85% or 34 to 80%, respectively). The antinociceptive activity of TKI (41 micromol kg(-1), i.p.) was maximal after 30 min injection and lasted for 120 min. The effect was unaltered by pretreatment with naloxone (8.2 micromol kg(-1), s.c.) or bilateral adrenalectomy. TKI (41 and 136 micromol kg(-1), i.p.) produced a dose-related decrease of the late phase of formalin-induced nociception by 79 and 98%, respectively. At 136 micromol kg(-1), i.p., TKI also shortened the duration of paw licking in the early phase by 69%. TKI (41 and 136 micromol kg(-1), i.p.) also reduced the capsaicin-induced nociceptive response (by 51 to 79%). TKI (41 micromol kg(-1), i.p. or 410 micromol kg(-1), s.c.) reduced the oedematogenic response, from the second to the fifth hour after carrageenin injection by 36 to 30% or by 47 to 39%, respectively. Pretreatment with TKI (41 micromol kg(-1), i.p.) reduced the capsaicin-induced neurogenic inflammation in the mouse ear by 54%. It is concluded that TKI presents antinociceptive and antiinflammatory activities mediated by inhibition of kinin formation by tissue kallikrein in mice. The results also indicate that the tissue kallikrein-dependent pathway contributes to kinin generation in nociceptive and inflammatory processes in mice.

Effect of azelastine on endotoxin-induced airway hyperresponsiveness in mice.

We examined the role of lipopolysaccharide (LPS) on the pulmonary inflammatory process in mice, including the release of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) by macrophages, and investigated the mechanism of action of azelastine (AZ) on the release of these two cytokines. Intratracheal instillation of 1.0 microgram/ml LPS into BALB/c mice caused a significant increase in both IL-1 beta and TNF-alpha in aqueous lung extracts. These changes were modified, under control conditions, by a single dose of 0.05 mg/kg of AZ administered 1 and 11 h after LPS infusion. Intratracheal instillation of LPS also caused a significant increase in bronchial hyperresponsiveness to methacholine (Mch). AZ significantly inhibited Mch responsiveness in LPS-infused mice compared with nontreated control mice. Our results suggested that intratracheal instillation of LPS induces the secretion of macrophage cytokines in the airways of mice, accounting, at least partly, for LPS-induced airway hyperresponsiveness. Our results also indicate that the attenuating effect of AZ on LPS-induced airway hyperresponsiveness could be explained by its inhibitory effect on macrophage cytokine production.

Polymorphonuclear leukocyte-inhibitory factor of Bordetella pertussis. III. Inhibition of Arthus reaction and peritoneal infiltration of PMN.

In vivo biologic effects of the polymorphonuclear leukocyte-inhibitory factor (PIF) of Bordetella pertussis were tested by using two experimentally induced inflammatory processes in mice. The intravenous injection of a partially purified extract from phase I bacteria strongly inhibited the glycogen-induced peritoneal infiltration of polymorphonuclear leukocytes (PMN) and the Arthus reactions, whereas little inhibitory activity was found in the extract from phase III bacteria. The activity was localized in the outer membrane of phase I bacteria, as was the in vitro PIF activity, and the two activities gave the same behavior in DEAE-cellulose chromatography. Therefore the observed suppression of inflammatory processes in mice is probably due to the inhibitory action of PIF on the function of PMN in vivo.