Effect of IL-1β Receptor Antagonist on Lipid Peroxidation in the Liver in Stress

The content of molecular LPO products increased in the liver of rats exposed to daily 1-h immobilization. IL-1β receptor antagonist limited the stress-induced intensifi cation of LPO.     

IL-6-deficient Mice Are Susceptible to Ethanol-induced Hepatic Steatosis： IL-6 Protects against Ethanol-induced Oxidative Stress and Mitochondrial Permeability Transition in the Liver

Interleukin-6 (IL-6)-deficient mice are prone to ethanol-induced apoptosis and steatosis in the liver; however,the underlying mechanism is not fully understood. Mitochondrial dysfunction caused by oxidative stress is an early event that plays an important role in the pathogenesis of alcoholic liver disease. Therefore, we hypothesize that the protective role of IL-6 in ethanol-induced liver injury is mediated via suppression of ethanol-induced oxidative stress and mitochondrial dysfunction. To test this hypothesis, we examined the effects of IL-6 on ethanol-induced oxidative stress, mitochondrial injury, and energy depletion in the livers of IL-6 (-/-) mice and hepatocytes from ethanol-fed rats. Ethanol consumption leads to stronger induction of malondialdehyde (MDA) in IL-6 (-/-) mice compared to wild-type control mice, which can be corrected by administration of IL-6. In vitro,IL-6 treatment prevents ethanol-mediated induction of reactive oxygen species (ROS), MDA, mitochondrial permeability transition (MPT), and ethanol-mediated depletion of adenosine triphosphate (ATP) in hepatocytes from ethanol-fed rats. Administration of IL-6 in vivo also reverses ethanol-induced MDA and ATP depletion in hepatocytes. Finally, IL-6 treatment induces metallothionein protein expression, but not superoxide dismutase and glutathione peroxidase in cultured hepatocytes. In conclusion, IL-6 protects against ethanol-induced oxidative stress and mitochondrial dysfunction in hepatocytes v/a induction of metallothionein protein expression, which mav account for the nrotective role of IL-6 in alcoholic liver disease.     

Intensity of Proliferative Processes and Degree of Oxidative Stress in the Mucosa of the Ileum in Crohn’s Disease

The intensity of proliferative processes (estimated from Ki-67 expression) and degree oxidative stress (chemiluminescence assay) in biopsy specimens from the terminal portion of the ileal mucosa were studied in patients with Crohn’s disease. Crohn’s disease is characterized by hyper-regenerative processes in the ileal mucosa. The labeling index (Ki-67 expression) in biopsy specimens from the intact ileal mucosa in patients with the irritable bowel syndrome (reference group) was 10.64 ± 0.62%. The corresponding values in patients receiving monotherapy with mesalazine (group 1) and combination therapy with mesalazine and dalargin (group 2) were 24.05 ± 1.17 and 22.90 ± 0.92%, respectively. Analysis of free radical oxidation showed that this state is accompanied oxidative stress. Spontaneous and H₂O₂-induced luminol-dependent chemiluminescence in biopsy specimens from the ileal mucosa was 1.8-2.3-fold higher compared to the reference group. After therapy, the labeling index in groups 1 and 2 decreased to 18.60 ± 1.18 and 14.38 ± 0.81%, respectively. Histologically, normalization of the disease symptoms was more pronounced after combination therapy. The decrease in free radical oxidation in this group of patients was more pronounced than after mesalazine monotherapy. Our results suggest that oxidative stress plays a role in the hyper-regenerative reaction.     

Plumbagin Prevents IL-1β-Induced Inflammatory Response in Human Osteoarthritis Chondrocytes and Prevents the Progression of Osteoarthritis in Mice

Inflammation and inflammatory cytokines have been reported to play vital roles in the development of osteoarthritis (OA). Plumbagin, a quinonoid compound extracted from the roots of medicinal herbs of the Plumbago genus, has been reported to have anti-inflammatory effects. However, the anti-inflammatory effects of plumbagin on OA have not been reported. This study aimed to assess the effects of plumbagin on human OA chondrocytes and in a mouse model of OA induced by destabilization of the medial meniscus (DMM). In vitro, human OA chondrocytes were pretreated with plumbagin (2, 5, 10 μM) for 2 h and subsequently stimulated with IL-1β for 24 h. Production of NO, PGE2, MMP-1, MMP-3, and MMP-13 was evaluated by the Griess reagent and ELISAs. The messenger RNA (mRNA) expression of COX-2, iNOS, MMP-1, MMP-3, MMP-13, aggrecan, and collagen-II was measured by real-time PCR. The protein expression of COX-2, iNOS, p65, p-p65, IκBα, and p-IκBα was detected by Western blot. The protein expression of collagen-II was evaluated by immunofluorescence. In vivo, the severity of OA was determined by histological analysis. We found that plumbagin significantly inhibited the IL-1β-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-1, MMP-3, and MMP-13; and degradation of aggrecan and collagen-II. Furthermore, plumbagin dramatically suppressed IL-1β-stimulated NF-κB activation. In vivo, treatment of plumbagin not only prevented the destruction of cartilage and the thickening of subchondral bone but also relieved synovitis in mice OA models. Taken together, these results suggest that plumbagin may be a potential agent in the treatment of OA.     

Effect of IFN-α on CC1<Subscript>4</Subscript>-Induced Fibrosis of the Liver and Immune Status in Mice of Different Age

In young, adult, and old mice fibrosis was induced by administration of CC1₄ and treated with IFN-α. Liver fibrosis was evaluated by morphometry of argyrophilic fibers, immune status by the splenocyte proliferative response. Minimum immunosuppression and maximum antifibrotic effect were observed in young mice, while adult mice exhibited pronounced immunotoxicity and weak response to interferon therapy.__________Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 139, No. 3, pp. 303–306, March, 2005     

Effect of Interleukin-1β on Lipid Peroxidation in Emotiogenic Structures of the Brain in Rats during Acute Stress

We studied the effects of immunomodulatory cytokine interleukin-1β on lipid peroxidation in emotiogenic structures of the brain (hypothalamus, sensorimotor cortex, and amygdala) of behaviorally active and passive rats with different prognostic resistance to stress. Immobilization of animals with simultaneous electrocutaneous stimulation (1 h) served as the model of acute emotional stress. Intraperitoneal injection of IL-1β (5 μg/kg) was followed by accumulation of malonic dialdehyde (end-product of lipid peroxidation) in all structures of the brain in passive rats, as well as in the hypothalamus of active animals. As differentiated from active rats, stress exposure in passive specimens was accompanied by a selective increase in malonic dialdehyde content in the sensorimotor cortex and amygdala. Pretreatment with IL-1β prevented activation of lipid peroxidation in the studied structures of the brain in passive rats after stress exposure. Our results show the specifi c effect of IL-1β on free-radical processes in the hypothalamus, sensorimotor cortex, and amygdala in rats with various behavioral parameters. Regional features of lipid peroxidation in emotiogenic structures of the brain in animals with different emotional reactivity probably contribute to the existence of signifi cant variations in the individual resistance to emotional stress.     

Gender-related Distribution of the Interleukin-1β and Interleukin-1 Receptor Antagonist Gene Polymorphisms in Patients with End-stage Liver Disease

Interleukin-1β (IL-1β) genetic polymorphisms and IL-1 receptor antagonist (IL1RN) variable number tandem repeat (VNTR) seem to be related with the occurrence of chronic diseases. This study aimed to verify whether IL-1β -511>C/T, -31>T/C, +3953>C/T and IL1RN VNTR were associated to the development of liver cirrhosis. Two hundred forty cirrhotic patients were involved in the study. A significant trend was detected, for increasing cirrhosis frequencies, grouping the patients as follows: females and males carrying neither the IL-1β (-511 -31) T-C/T-C or T-C/(T-T or C-C) diplotypes nor any IL1RN A2 allele (138/292), males carrying either the IL-1β T-C/T-C or T-C/(T-T or C-C) diplotypes or at least one IL1RN A2 allele (74/147) and males carrying either the IL-1β T-C/T-C or T-C/(T-T or C-C) diplotypes and at least one IL1RN A2 allele (28/37) (p?<?0.01). IL-1β polymorphisms are associated with the occurrence of end stage liver disease. IL-1β inflammatory activity appears more pronounced in males.     

The Effects of One-Step Self-Etch Adhesives on the Induction of Oxidative Stress and Production of TGF-β1 and BMP-2 by Human Gingival Fibroblasts

The aim of this study was to evaluate and compare the effects of two self-etch adhesive materials on the induction of oxidative stress and production of transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-2 (BMP-2) by cultured human gingival fibroblasts (HGF). Inflammation-free attached gingiva was obtained from healthy donors under informed consent. Following 24- and 72-h exposure of HGF to two different elutes of the test materials, cell viability was determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Lipid peroxidation, a major indicator of oxidative stress, was measured by the thiobarbituric acid reactive substance (TBARS) assay. TGF-β1 and BMP-2 levels in cell-free culture media were determined by enzyme-linked immunosorbent assay (ELISA). Cell viability of the test groups was significantly lower than those of control at 24 and 72 h (P < 0.001), but showed an increase at 72 h (P < 0.001). The TBARS levels of both test groups were significantly greater than that of control (P < 0.05), and displayed similar values at 72 h (P > 0.05). For both materials, the levels of TGF-β1 and BMP-2 were significantly greater than that of control (P < 0.05). Both test groups showed increased TGF-β1 levels. These results indicate that the tested self-etch adhesives might be capable of inducing production of TGF-β1 and BMP-2 in cultured HGF, despite their cytotoxic and oxidative stress-producing potential.     

Inhalation of Carbon Monoxide Ameliorates Collagen-induced Arthritis in Mice and Regulates the Articular Expression of IL-1β and MCP-1

Carbon monoxide (CO), long considered a toxic gas, has recently been shown to mediate anti-inflammatory effects in various animal models. The aim of this study was to investigate whether the inhalation of CO ameliorated collagen-induced arthritis (CIA) in mice. CIA was induced in female DBA/1 mice by the injection of an anti-type II collagen antibody and lipopolysaccharide. The CO treatment group was exposed to CO gas at a concentration of 200 ppm in a closed cage starting on the day of the injection with an anti-type II collagen antibody and throughout the remaining study period. The clinical arthritis scores was examined daily for swelling of the paws as a sign of arthritis. For histopathology, the sections of the hind legs were evaluated by hematoxylin-eosin staining. Moreover, we evaluated the expression of interleukin (IL)-1β and monocyte chemoattractant protein-1 (MCP-1) mRNA in the hind paws. Both clinical arthritis scores as well as histological findings of joint inflammation were significantly reduced in mice treated with CO gas inhalation compared to untreated mice. Further, CO significantly inhibited the increased expression of IL-1β and MCP-1 mRNA in paws at day 3 after the induction of arthritis. In conclusion, the inhalation of CO protected mice from the synovial inflammation of CIA. Based on these data, the beneficial effects of CO in murine RA model may be attributed to its anti-inflammatory properties.     

Effect of Tilorone on the Dynamics of Viral Load and the Levels of Interferons and Interleukin-1β in the Lung Tissue and Blood Serum of Mice with Experimental Influenza

Bulletin of Experimental Biology and Medicine - We studied the effect of tilorone on the dynamics of IFNα, IFNγ, and IL-1β levels in the lung tissue and blood serum in relation to...     

Deletion of the Coffin–Lowry Syndrome Gene Rsk2 in Mice is Associated With Impaired Spatial Learning and Reduced Control of Exploratory Behavior

Coffin–Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions. Edited by Andrew Holmes     

Analysis of Polymorphisms in Genes (AGT,MTHFR, GPIIIa,and GSTP1) Associated with Hypertension,Thrombophilia and Oxidative Stress in Mestizo and Amerindian Populations of México

Several polymorphisms related to hypertension, thrombophilia, and oxidative stress has been associated with the development of cardiovascular disease. We analyzed the frequency of M235T angiotensinogen (AGT), A222V 5,10 methylenete-trahydrofolate reductase (MTHFR), L33P glycoprotein IIIa (GPIIIa), and I105V glutathione S-transferase P1 (GSTP1) polymorphisms in 285 individuals belonging to Mexican-Mestizo and five Amerindian population from México, by real time PCR allelic discrimination. Allele and genotype frequencies were compared using χ² tests.All populations followed the Hardy Weinberg equilibrium for assay markers with the exception of the Triki, whose were in Hardy Weinberg dysequilibrium for the glutathione S-transferase P1 polymorphism.Interestingly, according to all the analyzed single nucleotide polymorphisms (SNPs), the Triki population was the most differentiated and homogeneous group of the six populations analyzed. A comparison of our data with those previously published for some Caucasian, Asian and Black populations showed quite significant differences. These differences were remarkable with all the Mexican populations having a lower frequency of the 105V allele of the glutathione S-transferase P1 and reduced occurrence of the 222A allele of the 5,10 methylenetetrahydrofolate reductase. Our results show the genetic diversity among different Mexican populations and with other racial groups.     

Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases

The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell types in health, but is released upon necrotic cell death as a bioactive mediator. IL-1α is also expressed by infiltrating myeloid cells within injured tissues. The cytokine binds the IL-1 receptor 1 (IL-1R1), as does IL-1β, and induces the same pro-inflammatory effects. Being a bioactive precursor released upon tissue damage and necrotic cell death, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation. These include conditions affecting the lung and respiratory tract, dermatoses and inflammatory skin disorders, systemic sclerosis, myocarditis, pericarditis, myocardial infarction, coronary artery disease, inflammatory thrombosis, as well as complex multifactorial conditions such as COVID-19, vasculitis and Kawasaki disease, Behcet’s syndrome, Sjogren Syndrome, and cancer.This review illustrates the clinical relevance of IL-1α to the pathogenesis of inflammatory diseases, as well as the rationale for the targeted inhibition of this cytokine for treatment of these conditions. Three biologics are available to reduce the activities of IL-1α; the monoclonal antibody bermekimab, the IL-1 soluble receptor rilonacept, and the IL-1 receptor antagonist anakinra. These advances in mechanistic understanding and therapeutic management make it incumbent on physicians to be aware of IL-1α and of the opportunity for therapeutic inhibition of this cytokine in a broad spectrum of diseases.     

Production of TNF-α and IL-1β by Peripheral Blood Mononuclear Cells in Carriers of Different Allele Variants of the Gene

Associations of cytokine production by mononuclear cells and the TNF-α genetic polymorphism in positions -238, -308, -376, -857, -1031, and of IL-1β in positions -31 and +3954 were studied. The data on distribution of allele and genotype incidence and on the level of spontaneous and mitogen-induced production of these cytokines by donor mononuclear cells demonstrated a statistically significant association of TNF-α production by mononuclear cells with polymorphic variants of the gene promoter regions -238 > A (rs361525) and -857C > T (rs1799724). Carriers of -238GG/-308GG/-857CC/-1031NC genotype were characterized by low production of TNF-α, while carriers of -31TT/+3954CT genotype were characterized by low IL-1β stimulation index in response to mitogen in comparison with carriers of other genotype combinations.     

The effects of running exercise on oxidative capacity and PGC-1α mRNA levels in the soleus muscle of rats with metabolic syndrome

Skeletal muscles in animals with metabolic syndrome exhibit reduced oxidative capacity. We investigated the effects of running exercise on fiber characteristics, oxidative capacity, and mRNA levels in the soleus muscles of rats with metabolic syndrome [SHR/NDmcr-cp (cp/cp); CP]. We divided 5-week-old CP rats into non-exercise (CP) and exercise (CP-Ex) groups. Wistar-Kyoto rats (WKY) were used as the control group. CP-Ex rats were permitted voluntary exercise on running wheels for 10 weeks. Triglyceride levels were higher and adiponectin levels lower in the CP and CP-Ex groups than in the WKY group. However, triglyceride levels were lower and adiponectin levels higher in the CP-Ex group than in the CP group. The soleus muscles in CP-Ex rats contained only high-oxidative type I fibers, whereas those in WKY and CP rats contained type I, IIA, and IIC fibers. Muscle succinate dehydrogenase (SDH) activity was higher in the CP-Ex group than in the CP group; there was no difference in SDH activity between the WKY and CP-Ex groups. Muscle proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA levels were higher in the CP-Ex group than in the CP group; there was no difference in PGC-1α mRNA levels between the WKY and CP-Ex groups. In CP-Ex rats, longer running distance was associated with increased muscle SDH activity and PGC-1α mRNA levels. We concluded that running exercise restored decreased muscle oxidative capacity and PGC-1α mRNA levels and improved hypertriglyceridemia in rats with metabolic syndrome.     

Two QTLs Located on Chromosomes 1 and 5 Modulate Different Aspects of the Performance of Mice of the B × D Ty RI Strain Series in the Morris Navigation Task

The Morris navigation task is widely used to study spatial abilities in rodents; namely, to analyze the effects of mutations in genetically engineered mice. Although quantitative and Mendelian genetic studies have shown that the variation of these abilities is partly under genetic control, little is known about these genetic factors. In order to analyze the genetic architecture of spatial navigation in mice, a wide genome scan was performed to map the QTLs that control various aspects of the performance, using the RI strain methodology. Latencies to locate the submerged platform across learning sessions and performance to the spatial probe test were analyzed in the 26 strains of the B × D RI series. Both cluster analysis of behavioral measurements and QTL mapping confirmed previous data showing that the escape latencies and the spatial bias rely on two distinct components of the task, controlled by different loci. A QTL on chromosome 1 influenced escape latencies during the four training sessions, whereas another QTL, located on chromosome 5, was shown to control spatial performance at the probe trial and also exhibited epistatic interactions with two other QTLs on chromosomes 2 and 13. The function of these QTLs is examined in the broader context of hippocampal-dependent learning processes and in relation to QTLs already found in similar positions in other behavioral traits.     

PGC-1α mRNA level and oxidative capacity of the plantaris muscle in rats with metabolic syndrome, hypertension, and type 2 diabetes

We examined the fiber profiles and the mRNA levels of peroxisome proliferator-activated receptors (PPARα and PPARδ/β) and of the PPARγ coactivator-1α (PGC-1α) in the plantaris muscles of 15-week-old control (WR), metabolic syndrome (CP), hypertensive (SHR), and type 2 diabetic (GK) rats. The deep regions in the muscles of SHR and GK rats exhibited lower percentages of high-oxidative type I and IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR and CP rats. The surface regions in the muscles of CP, SHR, and GK rats exhibited lower percentages of high-oxidative type IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR rats. The muscles of SHR and GK rats had lower oxidative enzyme activity compared with WR rats. The muscles of SHR rats had the lowest PPARδ/β mRNA level. In addition, the muscles of SHR and GK rats had lower PGC-1α mRNA level compared with WR and CP rats. We concluded that the plantaris muscles of rats with hypertension and type 2 diabetes have lower oxidative capacity, which is associated with the decreased level of PGC-1α mRNA.