Serum Concentrations Of Proinflammatory Cytokines Research Articles

Role of SDF-1/CXCR4 and cytokines in the development of ovary injury in chemotherapy drug induced premature ovarian failure mice

ObjectiveTo explore the mechanism of chemotherapy drug induced ovarian injury in premature ovarian failure (POF) mice. MethodsC57BL/6 mice were treated with Cyclophosphamide and Busulfan by intraperitoneal injection. One week after treatment, the estrous cycles, folliculogenesis, ovarian endocrine function and ovarian histopathological changes were evaluated the ovarian function. The serum levels of cytokines, follicle stimulating hormone (FSH) and estradiol (E2) were measured by enzyme-linked immunosorbent assay (ELISA). The protein levels of SDF-1/CXCR4 and FSHR in ovary were evaluated by immunohistochemistry and Western blot analysis. The ovarian cells apoptosis was measured by TUNEL Assay. ResultsThe ovaries from POF mice show the evidence of reduced ovarian function such as irregular estrous cycles, stromal hyperplasia, decreased follicle numbers, atresia follicles and less granular cell layer as well as corpora luteum. The lower levels of E2 and higher levels of FSH in serum characterize the ovarian injury; a great number of granular apoptotic cells were observed in the POF mice; the serum concentrations of pro-inflammatory cytokines of IL-6, IL-8 and TNF-α level were increased but anti-inflammatory cytokine of IL-10 was decreased. SDF-1/CXCR4 and FSHR expressed in ovaries were detected in the cytoplasm of preantral and antral follicles; the expression of SDF-1/CXCR4 was increased and FSHR was decreased in POF mice. ConclusionOur data suggest that the inflammatory regulation, SDF-1/CXCR4 and cellular apoptosis in ovarian tissues are involved in the development of ovarian injury of POF. These data provide useful information to develop new therapeutic approach to treat POF disorders in the future.

Dietary Supplementation With Nonfermentable Fiber Alters the Gut Microbiota and Confers Protection in Murine Models of Sepsis.

Links between microbial alterations and systemic inflammation have been demonstrated in chronic disease, but little is known about these interactions during acute inflammation. This study investigates the effect of dietary supplementation with cellulose, a nonfermentable fiber, on the gut microbiota, inflammatory markers, and survival in two murine models of sepsis. Prospective experimental study. University laboratory. Six-week-old male C57BL/6 wild-type mice. Mice were assigned to low-fiber, normal-fiber, or high-fiber diets with or without antibiotics for 2 weeks and then subjected to sepsis by cecal ligation and puncture or endotoxin injection. Fecal samples were collected for microbiota analyses before and after dietary interventions. Mice that received a high-fiber diet demonstrated increased survival after cecal ligation and puncture relative to mice receiving low-fiber or normal-fiber diets. The survival benefit was associated with decreased serum concentration of pro-inflammatory cytokines, reduced neutrophil infiltration in the lungs, and diminished hepatic inflammation. The high-fiber diet also increased survival after endotoxin injection. Bacterial 16S ribosomal RNA gene sequences from each sample were amplified, sequenced, and analyzed. Fiber supplementation yielded an increase in relative abundance of the genera Akkermansia and Lachnospiraceae, taxa commonly associated with metabolic health. Administration of antibiotics to mice on the high-fiber diet negated the enrichment of Akkermansia species and the survival benefit after cecal ligation and puncture. Dietary supplementation with cellulose offers a microbe-mediated survival advantage in murine models of sepsis. Improved understanding of the link between diet, the microbiota, and systemic illness may yield new therapeutic strategies for patients with sepsis.

Inflammatory Markers and Frailty in Long-Term Care Residents.

To determine whether proinflammatory biomarkers are associated with frailty assessed according to functional status, mobility, mental health, and falls over 24 months. Secondary analysis of a 2-year double-blind clinical trial for osteoporosis. Nursing homes and assisted living facilities. Women aged 65 and older with osteoporosis in long-term care (LTC) (N = 178). Baseline serum concentrations of proinflammatory cytokines and soluble receptors (high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNFα) and its two receptors (TNFα-R1 and TNFα-R2), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), IL-10), functional status assessed according to activities of daily living, the Nursing Home Physical Performance Test, gait speed, cognitive status, mental health, and falls. At baseline, older age was moderately associated with higher serum concentrations of hs-CRP (correlation coefficient (r) = 0.22), TNFα-R1 (r = 0.36), TNFα-R2 (r = 0.34), and IL-10 (r = 0.16) (all P < .05). Frail participants had significantly higher hs-CRP, TNFα-R1, TNFα-R2, IL-6, and IL-6-sR levels (all P < .05) than those nonfrail participants. Higher baseline hs-CRP and IL-6 levels were associated with worse physical performance and gait speed at 12 months independent of age, zoledronic acid use, and comorbidity (|r| = 0.25-0.30; all P < .05). Inflammatory markers were not significantly associated with incident falls. Higher proinflammatory biomarker levels are associated with frailty and poorer function and mobility in older women residing in LTC facilities.

The Evaluation of Antioxidant and Anti-Inflammatory Effects of Eucommia ulmoides Flavones Using Diquat-Challenged Piglet Models.

This study was designed to evaluate the antioxidant and anti-inflammatory effects of Eucommia ulmoides flavones (EUF) using diquat-challenged piglet models. A total of 96 weaned piglets were randomly allotted to 1 of 3 treatments with 8 replication pens per treatment and 4 piglets per pen. The treatments were basal diet, basal diet + diquat, and 100 mg/kg EUF diet + diquat. On day 7 after the initiation of treatment, the piglets were injected intraperitoneally with diquat at 8 mg/kg BW or the same amount of sterilized saline. The experiment was conducted for 21 days. EUF supplementation improved the growth performance of diquat-treated piglets from day 14 to 21. Diquat also induced oxidative stress and inflammatory responses and then impaired intestinal morphology. But EUF addition alleviated these negative effects induced by diquat that showed decreasing serum concentrations of proinflammatory cytokines but increasing antioxidant indexes and anti-inflammatory cytokines on day 14. Supplementation of EUF also increased villi height and villous height, crypt depth, but decreased the histopathological score and MPO activity compared with those of diquat-challenged pigs fed with the basal diet on day 14. Results indicated that EUF attenuated the inflammation and oxidative stress of piglets caused by diquat injection.

ОЦЕНКА ЭФФЕКТИВНОСТИ ВЛИЯНИЯ ПОДКОЖНОЙ ФОРМЫ МЕТОТРЕКСАТА НА УРОВЕНЬ ПРОВОСПАЛИТЕЛЬНОЙ ЦИТОКИНЕМИИ И МОРФО-ФУНКЦИОНАЛЬНОЕ СОСТОЯНИЕ СОСУДИСТОЙ СТЕНКИ У БОЛЬНЫХ РЕВМАТОИДНЫМ АРТРИТОМ

Objective: To assess the effect of the subcutaneous form of methotrexatum (metoject) on the level of pro-inflammatory cytokinemia and the morphofunctional characteristics of the vascular wall in patients with rheumatoid arthritis. Methods: The level of pro-inflammatory cytokinemia and the morphofunctional characteristics of carotid arteries were studied in 94 patients with rheumatoid arthritis (RA) positive for RF-IgM and/or anti-citrullinated protein antibody (ACPA). Results: It has been established that in patients with RA as a result of an increase in the serum concentration of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) the subclinical lesion of the major arteries, manifested by an increase in the thickness of the intima-media complex (IMC) and the stiffness index of the common carotid artery (CCA) was observed, the magnitude of which was correlated with the duration of RA, the activity index of DAS28, the level of RF and the concentration of ACPA. The use of metoject in RA patients led to a statistically significant decrease in the DAS28 index, a decrease in pro-inflammatory cytokinemia with attainment of control values in the early stages of the disease, a decrease in the thickness of IMC of the CCA, and local (carotid) rigidity of the vascular bed, which is more pronounced with RA duration less than 2 years. It was demonstrated that metoject therapy along with high anti-inflammatory activity, possesses a vasoprotective effect, which is characterized by a decrease in remodeling signs of CCA. Conclusion: The results of the study confirm not only the high clinical efficiency and good tolerancy of the subcutaneous form of metoject, but also show that it possesses a high anti-inflammatory activity, which provides a vasoprotective effect on large vessels of the elastic type (aorta and common carotid arteries). Keywords: Rheumatoid arthritis, methotrexatum, metoject, thickness of intima-media complex, common carotid artery, pro-inflammatory cytokines.

Zhikang Capsule ameliorates dextran sodium sulfate-induced colitis by inhibition of inflammation, apoptosis, oxidative stress and MyD88-dependent TLR4 signaling pathway

Ethnopharmacological relevanceZhikang Capsule (ZKC) is a traditional Chinese medicine (TCM) modified from classic formulas Qi-Li-San (an ancient formula dating to Qing Dynasty) and Fu-Jin-Sheng-Ji-San (written into The Golden Mirror of Medicine). ZKC contains 14 kinds of materials and has been widely used for the clinical therapy of inflammatory bowel diseases (IBD) for a long time. However, the therapeutic mechanisms of ZKC are still unclear. Aim of the studyTo determine the protective effect of ZKC on dextran sodium sulfate (DSS)-induced colitis and explore the underlying mechanisms. Materials and methodsC57BL/6 mice were fed with 3% DSS in drinking water for one week to induce experimental colitis. They were randomly assigned to six groups according to the treatment conditions. The histological changes of colon tissues were observed by hematoxylin and eosin (H&E) staining. The serum concentration of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-12) and anti-inflammatory mediators (IL-4 and IL-10) was detected by enzyme-linked immune sorbent assays (ELISAs). The production of MPO, SOD, MDA, NO, and caspase-3 was assessed by biochemical assay kits. The expression of iNOS, ICAM-1, and NF-ΚB was evaluated by immunohistochemistry staining. The levels of TLR4, MyD88, and TRAF6 were determined by western blot. ResultsHistologic analysis exhibited that ZKC alleviated the inflammation, loss of goblet cells, and submucosal edema induced by DSS. ZKC significantly suppressed the pro-inflammatory cytokines and promoted the anti-inflammatory mediators. The antioxidation of ZKC was indicated by increased activity of SOD and reduced production of MDA, NO, and iNOS in ZKC-treated mice. Furthermore, ZKC repressed the colonic expression of caspase-3 and the activity of the MyD88-dependent TLR4 signaling pathway. ConclusionsThis research demonstrated the protective effect of ZKC on DSS-induced colitis. For the first time, we identified four therapeutic mechanisms of ZKC, including effective inhibition of the inflammatory responses, significant alleviation of intestinal epithelium apoptosis, considerable prevention of oxidative stress, and selective down-regulation of the MyD88-dependent TLR4 signaling pathway. With high therapeutic effects and low toxic effects, ZKC exhibits great superiority over western medicines in IBD treatment.

Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial.

Cytokines are involved in the development of metabolic abnormalities that may result in metabolic syndrome (MetS). Since curcumin has shown anti-inflammatory properties, the aim of this study was to evaluate the effect of curcumin supplementation on serum cytokines concentrations in subjects with MetS. This study was a post-hoc analysis of a randomized controlled trial in which males and females with diagnosis of MetS, according to the criteria defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines, were studied. Subjects who met the inclusion criteria were randomly assigned to either curcumin (daily dose of 1g/day) or a matched placebo for a period of 8 weeks. One hundred and seventeen subjects were assigned to either curcumin (n=59) or placebo (n=58) groups. Within-group analysis revealed significant reductions in serum concentrations of TNF-α, IL-6, TGF-β and MCP-1 following curcumin supplementation (p<0.001). In the placebo group, serum levels of TGF-β were decreased (p=0.003) but those of IL-6 (p=0.735), TNF-α (p=0.138) and MCP-1 (p=0.832) remained unaltered by the end of study. Between-group comparison suggested significantly greater reductions in serum concentrations of TNF-α, IL-6, TGF-β and MCP-1 in the curcumin versus placebo group (p<0.001). Apart from IL-6, changes in other parameters remained statistically significant after adjustment for potential confounders including changes in serum lipids and glucose levels, and baseline serum concentration of the cytokines. Results of the present study suggest that curcumin supplementation significantly decreases serum concentrations of pro-inflammatory cytokines in subjects with MetS.

The Roles of Adipokines, Proinflammatory Cytokines, and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction.

The roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in obesity-associated insulin resistance have been explored in both animal and human studies. However, our current understanding of obesity-associated insulin resistance relies on studies of artificial metabolic extremes. The purpose of this study was to explore the roles of adipokines, proinflammatory cytokines, and adipose tissue macrophages in human patients with modest obesity and early metabolic dysfunction. We obtained omental adipose tissue and fasting blood samples from 51 females undergoing gynecologic surgery. We investigated serum concentrations of proinflammatory cytokines and adipokines as well as the mRNA expression of proinflammatory and macrophage phenotype markers in visceral adipose tissue using ELISA and quantitative RT-PCR. We measured adipose tissue inflammation and macrophage infiltration using immunohistochemical analysis. Serum levels of adiponectin and leptin were significantly correlated with HOMA-IR and body mass index. The levels of expression of MCP-1 and TNF-α in visceral adipose tissue were also higher in the obese group (body mass index ≥ 25). The expression of mRNA MCP-1 in visceral adipose tissue was positively correlated with body mass index (r = 0.428, p = 0.037) but not with HOMA-IR, whereas TNF-α in visceral adipose tissue was correlated with HOMA-IR (r = 0.462, p = 0.035) but not with body mass index. There was no obvious change in macrophage phenotype or macrophage infiltration in patients with modest obesity or early metabolic dysfunction. Expression of mRNA CD163/CD68 was significantly related to mitochondrial-associated genes and serum inflammatory cytokine levels of resistin and leptin. These results suggest that changes in the production of inflammatory biomolecules precede increased immune cell infiltration and induction of a macrophage phenotype switch in visceral adipose tissue. Furthermore, serum resistin and leptin have specific roles in the regulation of adipose tissue macrophages in patients with modest obesity or early metabolic dysfunction.

Salmon-derived thrombin inhibits development of chronic pain through an endothelial barrier protective mechanism dependent on APC

Many neurological disorders are initiated by blood–brain barrier breakdown, which potentiates spinal neuroinflammation and neurodegeneration. Peripheral neuropathic injuries are known to disrupt the blood-spinal cord barrier (BSCB) and to potentiate inflammation. But, it is not known whether BSCB breakdown facilitates pain development. In this study, a neural compression model in the rat was used to evaluate relationships among BSCB permeability, inflammation and pain-related behaviors. BSCB permeability increases transiently only after injury that induces mechanical hyperalgesia, which correlates with serum concentrations of pro-inflammatory cytokines, IL-7, IL-12, IL-1α and TNF-α. Mammalian thrombin dually regulates vascular permeability through PAR1 and activated protein C (APC). Since thrombin protects vascular integrity through APC, directing its affinity towards protein C, while still promoting coagulation, might be an ideal treatment for BSCB-disrupting disorders. Salmon thrombin, which prevents the development of mechanical allodynia, also prevents BSCB breakdown after neural injury and actively inhibits TNF-α-induced endothelial permeability in vitro, which is not evident the case for human thrombin. Salmon thrombin's production of APC faster than human thrombin is confirmed using a fluorogenic assay and APC is shown to inhibit BSCB breakdown and pain-related behaviors similar to salmon thrombin. Together, these studies highlight the impact of BSCB on pain and establish salmon thrombin as an effective blocker of BSCB, and resulting nociception, through its preferential affinity for protein C.

Polyphenol-rich propolis extracts from China and Brazil exert anti-inflammatory effects by modulating ubiquitination of TRAF6 during the activation of NF-κB

Propolis has documented anti-inflammatory properties, although its mechanisms of action are poorly understood. In this study, the anti-inflammatory effects of polyphenol-rich propolis extracts (PPE) from China (CPPE) and Brazil (BPPE) were examined. Oral administration of PPE to lipopolysaccharide (LPS)-challenged mice decreased serum proinflammatory cytokine concentrations and inhibited pulmonary nuclear factor (NF)-κB activation. Both PPE types modulated LPS-induced key inflammatory mediators production in RAW 264.7 macrophages. They also suppressed NF-κB activation in HEK 293T cells, correlating well with their inhibitory effects on IκB phosphorylation and p65 nuclear translocation in LPS-activated macrophages. We found PPE suppressed NF-κB activation through delaying the ubiquitination of TRAF6 in HeLa-T6RZC stable cells and by directly disrupting the polyubiquitin synthesis in an in vitro kinase assay system. Overall, analysis showed substantial compositional differences between CPPE and BPPE; nevertheless, they both displayed similar anti-inflammatory properties through NF-κB-responsive inflammatory gene expressions by inhibiting TRAF6 dependent canonical NF-κB pathway.

Effects of thymosin β4 on a rat model of severe acute pancreatitis.

The aim of the present study was to investigate the effects of thymosin β4 on a rat model of severe acute pancreatitis (SAP) induced by sodium taurocholate (STC) and the underlying mechanism. SAP was induced by the retrograde infusion of 5% STC (1 ml/kg) into the bile-pancreatic duct. In certain rats, thymosin β4 (30 mg/kg) was administered intraperitoneally 30 min prior to the infusion of STC. The severity of pancreatitis was evaluated by the measurement of serum amylase, lipase, tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and myeloperoxidase (MPO) levels, and histological grading. Nuclear factor (NF)-κB activation was evaluated by immunohistochemistry and western blot analysis. Intercellular adhesion molecule (ICAM)-1 protein expression in the pancreas was studied using western blot analysis. Prophylactic administration of thymosin β4 was found to attenuate serum amylase and lipase activity and the serum concentrations of proinflammatory cytokines. In addition, it attenuated pathological pancreatic injury, pancreatic MPO activity, and the activation of NF-κB and ICAM-1 in the pancreas. These results suggest that thymosin β4 exerts a protective effect against STC-induced pancreatic injury.

An Animal Model of Trichloroethylene-Induced Skin Sensitization in BALB/c Mice.

Trichloroethylene (TCE) is a major occupational hazard and environmental contaminant that can cause multisystem disorders in the form of occupational medicamentosa-like dermatitis. Development of dermatitis involves several proinflammatory cytokines, but their role in TCE-mediated dermatitis has not been examined in a well-defined experimental model. In addition, few animal models of TCE sensitization are available, and the current guinea pig model has apparent limitations. This study aimed to establish a model of TCE-induced skin sensitization in BALB/c mice and to examine the role of several key inflammatory cytokines on TCE sensitization. The sensitization rate of dorsal painted group was 38.3%. Skin edema and erythema occurred in TCE-sensitized groups, as seen in 2,4-dinitrochlorobenzene (DNCB) positive control. Trichloroethylene sensitization-positive (dermatitis [+]) group exhibited increased thickness of epidermis, inflammatory cell infiltration, swelling, and necrosis in dermis and around hair follicle, but ear painted group did not show these histological changes. The concentrations of serum proinflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-2 were significantly increased in 24, 48, and 72 hours dermatitis [+] groups treated with TCE and peaked at 72 hours. Deposition of TNF-α, IFN-γ, and IL-2 into the skin tissue was also revealed by immunohistochemistry. We have established a new animal model of skin sensitization induced by repeated TCE stimulations, and we provide the first evidence that key proinflammatory cytokines including TNF-α, IFN-γ, and IL-2 play an important role in the process of TCE sensitization.

CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury.

C-C chemokine receptor 5 (CCR5) regulates leukocyte chemotaxis and activation, and its deficiency exacerbates development of nephritis. Therefore, we investigated the role of CCR5 during lipopolysaccharide (LPS)-induced acute kidney injury. CCR5-deficient (CCR5-/-) and wild-type (CCR5+/+) mice, both aged about 10months, had acute renal injury induced by intraperitoneal injection of LPS (10mg/kg). Compared with CCR5+/+ mice, CCR5-/- mice showed increased mortality and renal injury, including elevated creatinine and blood urea nitrogen levels, following LPS challenge. Compared to CCR5+/+ mice, CCR5-/- mice also exhibited greater increases in the serum concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β following LPS challenge. Furthermore, infiltration of macrophages and neutrophils, expression of intracellular adhesion molecule (ICAM)-1, and the number of apoptotic cells were more greatly increased by LPS treatment in CCR5-/- mice than in CCR5+/+ mice. The concentrations of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β were also significantly increased in the kidney of CCR5-/- mice after LPS challenge. Moreover, primary kidney cells from CCR5-/- mice showed greater increases in TNF-α production and p38 MAP kinase activation following treatment with LPS compared with that observed in the cells from CCR5+/+ mice. LPS-induced TNF-α production and apoptosis in the primary kidney cells from CCR5-/- mice were inhibited by treatment with p38 MAP kinase inhibitor. These results suggest that CCR5 deficiency increased the production of TNF-α following LPS treatment through increased activation of the p38 pathway in the kidney, resulting in renal apoptosis and leukocyte infiltration and led to exacerbation of LPS-induced acute kidney injury.

Depletion of B220+NK1.1+ cells enhances the rejection of established melanoma by tumor-specific CD4+ T cells

Five-year survival rates for patients diagnosed with metastatic melanoma are less than 5%. Adoptive cell transfer (ACT) has achieved an objective response of 50% by Response Evaluation Criteria in Solid Tumors (RECIST) in this patient population. For ACT to be maximally effective, the host must first be lymphodepleted. It is hypothesized that lymphodepletion may remove regulatory elements and cytokine sinks, or increase the activation and availability of antigen presenting cells (APCs). We use an in vivo model to study the ACT of tumor-associated antigen (TAA)-specific CD4+ T cells (TRP-1 cells). We have discovered that depletion of NK1.1+ cells enhances the rejection of established melanoma tumors by adoptively transferred TRP-1 CD4+ T cells. NK1.1+ cell depletion increases the number of CD4+ T cells, the serum concentration of pro-inflammatory cytokines, autoimmune vitiligo, host survival and prevented recurrence after ACT. Because multiple cells express NK1.1, we targeted different NK1.1+ cell populations using antibodies specific for NK cells, pre-mNK cells, and innate lymphoid cells (ILCs). Our data suggests that NK1.1+B220+ pre-mNK cells (also known as interferon-producing killer dendritic cells; IKDCs) are an important inhibitor of the CD4+ T cell response to melanoma. Understanding this mechanism may help design new immunotherapies to modulate the activity of pre-mNKs in the face of an antitumor immune response and inhibit their suppression of adoptively transferred T cells.

Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus.

Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.

Inhibition of glycogen synthase kinase-3β attenuates acute kidney injury in sodium taurocholate‑induced severe acute pancreatitis in rats.

The aim of the present study was to investigate the efficacy of 4‑benzyl‑2‑methyl‑1,2,4‑thiadiazolidine‑3,5‑dione (TDZD‑8), the selective inhibitor of glycogen synthase kinase‑3β (GSK‑3β), on the development of acute kidney injury in an experimental model of sodium taurocholate‑induced severe acute pancreatitis (SAP) in rats. The serum amylase, lipase, interleukin‑1β and interleukin‑6 levels, and the pancreatic pathological score were examined to determine the magnitude of pancreatitis injury. The serum creatinine and blood urea nitrogen levels, myeloperoxidase (MPO) activity and renal histological grading were measured to assess the magnitude of SAP‑induced acute kidney injury. The activation of nuclear factor‑κB (NF‑κB) was examined using an immunohistochemistry assay. The expression of GSK‑3β, phospho‑GSK‑3β (Ser9), tumour necrosis factor‑α (TNF‑α), intercellular adhesion molecule‑1 (ICAM‑1) and inducible nitric oxide synthase (iNOS) protein in the kidney was characterised using western blot analysis. TDZD‑8 attenuated (i) serum amylase, lipase and renal dysfunction; (ii) the serum concentrations of proinflammatory cytokines; (iii) pancreatic and renal pathological injury; (iv) renal MPO activity and (v) NF‑κB activation and TNF‑α, ICAM‑1 and iNOS protein expression in the kidney. The results obtained in the present study suggest that the inhibition of GSK‑3β attenuates renal disorders associated with SAP through the inhibition of NF‑κB activation and the downregulation of the expression of proinflammatory cytokines, TNF‑α, ICAM‑1 and iNOS in rats. Blocking GSK‑3β protein kinase activity may be a novel approach to the treatment of this inflammatory condition.

The effects of adipocytokines on the endocrino-metabolic features and obstetric outcome in pregnant obese women with polycystic ovary syndrome

To estimate the effects of adipocytokines on the metabolic and endocrine features, and the obstetric outcome in pregnant women with polycystic ovary syndrome (PCOS). Prospective cross sectional study. Main outcome measures: plasma concentration of adipocytokines, insulin resistance/hyperinsulinism (IR/HI), lipid profile, androgens and obstetric outcome. The study included hundred pregnant PCOS (PPCOS) women with android obesity (group 1), 100 pregnant non-PCOS women with android obesity (group 2), 100 PPCOS women with gynoid obesity (group 3), and 100 pregnant non-PCOS women with gynoid obesity (group 4). All patients in the four groups were primigravidae and women with PCOS (groups 1 and 3) became pregnant after treatment with clomiphene citrate and/or gonadotropins. Plasma concentrations of fasting glucose, fasting serum insulin, insulin sensitivity by quantitative insulin sensitivity check index (QUICKI), serum concentrations of triglycerides (TGs), total cholesterol (TC), high density lipoprotein cholesterol, (HDL-c), low density lipoprotein cholesterol (LDL-c); plasma adipocytokines: interleukin (IL)-10, adiponectin (both are insulin sensitizers and anti-inflammatory), pro-inflammatory cytokines: IL-6, prothrombin activator inhibitor-1(PAI-1), high sensitivity C-reactive protein (hsCRP); serum total testosterone (TT), sex-hormone binding globulin (SHBG), free androgen index (FAI) were estimated for the four groups between 22 and 24 weeks’ gestation Glucose loading test was done at 22–24 weeks’ gestation to check for gestational diabetes mellitus and if normal it was repeated at 30–34 weeks. Gestational hypertension (GH), preeclampsia (PE) and preterm labor (PTL) (delivery <37 weeks’ gestation) were recorded. Groups 1 and 2 with android obesity had IR/HI, (QUICKI < 0.331 ± 0.010). Groups 3 and 4 with gynoid obesity had normal insulin sensitivity (NIS), (QUICKI > 0.331 ± 0.010). Serum concentration of TGs, LDL-c, and plasma concentration of IL-6, PAI-1, hsCRP were significantly higher in groups 1 and 2 than groups 3 and 4. Serum HDL-c, plasma IL-10 and adiponectin were significantly higher in groups 3 and 4 than groups 1 and 2. Serum TT and FAI were significantly higher in groups 1 and 3 (cases of PPCOS) than their controls. There was no significant difference in the serum concentration of TC between the four groups. Incidence of spontaneous early miscarriage (SM) in groups 1, 2, 3, and 4 was 36%, 12%, 33%, and 11% respectively. Incidence of SM was significantly higher in PPCOS than non-PCOS pregnancy irrespective of the type of obesity. Rate of late pregnancy complications, GDM, GH, PE and PTL was significantly higher in groups 1 and 2 with android obesity than groups 3 and 4 with gynoid obesity. There was no significant difference in the rates of cesarean section (CS) between the 4 groups. The rates of neonatal complications and perinatal mortality were significantly higher in groups 1 and 2 (android obesity) than groups 3 and 4 (gynoid obesity). 1. TT and FAI were significantly higher in PPCOS with android obesity than PPCOS with gynoid obesity. 2. Incidence of early SM (9–12 weeks) was significantly higher in PPCOS than in non-PCOS pregnancy irrespective of the type of obesity. 3. Incidence of late-onset pregnancy complications, GDM, GH, PE and PTL was significantly higher in patients with android obesity than patients with gynoid obesity. PCOS per se seemed to be not related to the incidence of late-onset pregnancy complications. Pregnant patients with android obesity, (both PCOS and non-PCOS) with diminished serum concentration of anti-inflammatory cytokines, and increased serum concentration of pro-inflammatory cytokines had IR/HI and dyslipidemia. Pregnant patients with gynoid obesity, (both PCOS and non-PCOS) with normal serum concentration of anti- and pro-inflammatory cytokines had NIS and normal lipid profile. 4. In pregnancy with android obesity patients had reduced plasma concentration of IL-10 and increased concentration of IL-6 which may impair the development of the placenta with increased risk of PTL. 5. Neonatal complications and perinatal mortality were significantly higher in PPCOS with android obesity than PPCOS with gynoid obesity.

The effects of celiprolol on serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats

BackgroundA growing body of evidence suggests that some cardiovascular drugs could modulate the level of proinflammatory cytokines. Therefore, the aim of the present study was to investigate whether celiprolol, a third generation β-adrenoceptor blocker, affects lipopolysaccharide (LPS)-induced serum concentrations of TNF-α, IL-1β, IL-6 in normotensive (WKY) and spontaneously hypertensive (SHR) rats. MethodsCeliprolol (150mgkg−1) or vehicle was administered by gavage once daily for 21 days. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Serum concentrations of proinflammatory cytokines were measured with enzyme-linked immunosorbent assay kits. Additionally, plasma concentrations of total cholesterol, HDL-cholesterol and triglycerides were evaluated. ResultsIn normotensive WKY rats celiprolol did not affect heart rate, blood pressure, or the serum concentrations of triglycerides, total cholesterol or HDL-cholesterol. In hypertensive animals the drug decreased lipid parameters, increased diastolic and mean blood pressure after the first week of administration, and produced a small but significant decrease in heart rate after the first two weeks of the treatment. In both groups of animals, celiprolol decreased LPS-stimulated serum concentration of IL-6 but did not affect levels of TNF-α and IL-1β. ConclusionsIt is suggested that the IL-6-modulating properties of celiprolol could provide additional value to the therapeutic effectiveness of the drug in the treatment of hypertension.

Effects of Dominant/Subordinate Social Status on Formalin-Induced Pain and Changes in Serum Proinflammatory Cytokine Concentrations in Mice

Current investigations regarding social stress primarily focus on the health consequences of being in stressful social hierarchies. The repetitive nature of social conflicts seems to favor an induction of hyperalgesia or hypoalgesia, both in rodents and humans. Additionally, social conflicts may affect the immune system. In order to better establish the pain and immune responses to stress, the present study implemented a sensory contact model on 32 male BALB/c mice. Subsequent to establishing a dominance/submissive social relationship, each mouse was injected with formalin (20 μl, 2%) and their pain behavior was scored and serum concentrations of proinflammatory cytokines IL-1 and IL-6, and corticosterone were also measured. Test results revealed that subordinate mice were hypoalgesic during chronic phase of formalin test compared to control and dominant mice (P<0.05). On the other hand, subordinate mice were hyperalgesic compared to dominant mice during the whole acute phase of formalin test (P<0.05). Corticosterone, IL-1 and IL-6 concentrations were much higher in serum of dominant and subordinate mice than in the control group (p<0.05). The results indicated that, although both dominant and subordinate animals displayed an increase in serum corticosterone and proinflammatory cytokines during social interactions, their response to pain perception differently was affected with the social status.

Protective Effects of Human Lactoferrin during Aggregatibacter actinomycetemcomitans-Induced Bacteremia in Lactoferrin-Deficient Mice

Aggregatibacter actinomycetemcomitans, a periodontopathogen, has been associated with several systemic diseases. Herein, we report the protective effect of human lactoferrin (hLF) during A. actinomycetemcomitans bacteremia in lactoferrin knockout (LFKO(-/-)) mice. The prophylactic, concurrent, and therapeutic intravenous (i.v.) administrations of hLF significantly cleared the bacteria from blood and organs. Nevertheless, all modes of hLF administration significantly decreased the concentrations of serum proinflammatory cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12p70. Additionally, hLF administration significantly decreased hepatic and splenic proinflammatory cytokine expression levels compared to those in the non-hLF-treated group. Furthermore, administration of hLF decreased the serum C-reactive protein level, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) gene expression levels in liver and spleen. hLF treatment has also resulted in a 6-fold decrease in spleen weight with the migration of typical inflammatory cells in infected mice as a result of decreased inflammatory response. These results reveal that hLF protects against A. actinomycetemcomitans bacteremia, as indicated by rapid bacterial clearance and decreased host proinflammatory mediators.