Abstract Simão AP, Avelar NC, Tossige-Gomes R, Neves CD, Mendonça VA, Miranda AS, Teixeira MM, Teixeira AL, Andrade AP, Coimbra CC, Lacerda AC. Functional performance and inflammatory cytokines after ...squat exercises and whole-body vibration in elderly individuals with knee osteoarthritis. Objective To investigate the effects of squat exercises combined with whole-body vibration on the plasma concentration of inflammatory markers and the functional performance of elderly individuals with knee osteoarthritis (OA). Design Clinical, prospective, randomized, single-blinded study. Setting Exercise physiology laboratory. Participants Elderly subjects with knee OA (N=32) were divided into 3 groups: (1) squat exercises on a vibratory platform (platform group, n=11); (2) squat exercises without vibration (squat group, n=10); and (3) the control group (n=11). Interventions The structured program of squat exercises in the platform and squat groups was conducted 3 times per week, on alternate days, for 12 weeks. Main Outcome Measures Plasma soluble tumor necrosis factor-α receptors 1 (sTNFR1) and 2 (sTNFR2) were measured using immunoassays (the enzyme-linked immunosorbent assay method). The Western Ontario and McMaster Universities Osteoarthritis Index questionnaire was used to evaluate self-reported physical function, pain, and stiffness. The 6-minute walk test, the Berg Balance Scale, and gait speed were used to evaluate physical function. Results In the platform group, there were significant reductions in the plasma concentrations of the inflammatory markers sTNFR1 and sTNFR2 ( P <.001 and P <.05, respectively) and self-reported pain ( P <.05) compared with the control group, and there was an increase in balance ( P <.05) and speed and distance walked ( P <.05 and P <.001, respectively). In addition, the platform group walked faster than the squat group ( P <.01). Conclusions The results suggest that whole-body vibration training improves self-perception of pain, balance, gait quality, and inflammatory markers in elderly subjects with knee OA.
Background and Purpose
Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain. Current therapies are often ineffective in ...reducing gout‐related pain. Resolvin D1 (RvD1) is a specialized pro‐resolving lipid mediator with anti‐inflammatory and analgesic proprieties. In this study, we evaluated the effects and mechanisms of action of RvD1 in an experimental mouse model of gouty arthritis, an aim that was not pursued previously in the literature.
Experimental Approach
Male mice were treated with RvD1 (intrathecally or intraperitoneally) before or after intraarticular stimulation with MSU. Mechanical hyperalgesia was assessed using an electronic von Frey aesthesiometer. Leukocyte recruitment was determined by knee joint wash cell counting and immunofluorescence. IL‐1β production was measured by ELISA. Phosphorylated NF‐kB and apoptosis‐associated speck‐like protein containing CARD (ASC) were detected by immunofluorescence, and mRNA expression was determined by RT‐qPCR. CGRP release was determined by EIA and immunofluorescence. MSU crystal phagocytosis was evaluated by confocal microscopy.
Key Results
RvD1 inhibited MSU‐induced mechanical hyperalgesia in a dose‐ and time‐dependent manner by reducing leukocyte recruitment and IL‐1β production in the knee joint. Intrathecal RvD1 reduced the activation of peptidergic neurons and macrophages as well as silenced nociceptor to macrophage communication and macrophage function. CGRP stimulated MSU phagocytosis and IL‐1β production by macrophages. RvD1 downmodulated this phenomenon directly by acting on macrophages, and indirectly by inhibiting CGRP release and CGRP‐dependent activation of macrophages.
Conclusions and Implications
This study reveals a hitherto unknown neuro‐immune axis in gouty arthritis that is targeted by RvD1.
Abstract Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C–C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C–C ...chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3−/− and CCR1−/− mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3−/− mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3−/− and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3.
This study assessed the effect of in ovo threonine supplementation on the response of broiler chicks challenged with Salmonella Enteritidis, considering bacterial counts in cecal contents, intestinal ...morphology, body weight, and weight gain. Fertilized eggs were inoculated in the amniotic fluid with saline (NT) or 3.5% threonine (T) solution at day 17.5 of incubation. At hatch, chicks were individually weighed and cloacal swabs were screened for Salmonella. At 2 days of age, half of the birds from each in ovo treatment were given either 0.5 mL of nutrient broth (sham-inoculated) or nalidixic acid-resistant Salmonella Enteritidis (SE NalR) in nutrient broth (8.3 × 107 colony forming units (CFU) SE NalR/mL). The birds were distributed using a completely randomized design with four treatments after the Salmonella challenge: no in ovo Thr supplementation and sham-inoculated in the posthatch challenge (NT-SHAM), in ovo Thr supplementation and sham-inoculated (T-SHAM), no in ovo Thr supplementation and SE NalR-challenged (NT-SE), and in ovo Thr supplementation and SE NalR-challenged (T-SE). In ovo threonine supplementation reduced Salmonella Enteritidis colonization 168-hour postinoculation and reduced the negative effects associated with Salmonella infection on intestinal morphology and performance, with results similar to those of the sham-inoculated birds. In ovo Thr supplementation increased the expression of MUC2 at hatch and the expression of MUC2 and IgA at 2 days of age and 168-hour postinoculation. Our results suggest that providing in ovo threonine promotes intestinal health in broilers challenged with Salmonella Enteritidis in the first days of life.
Macrophages are important effectors of inflammation resolution that contribute to the elimination of pathogens and apoptotic cells and restoration of homeostasis. Pre-clinical studies have evidenced ...the anti-inflammatory and pro-resolving actions of GILZ (glucocorticoid-induced leucine zipper). Here, we evaluated the role of GILZ on the migration of mononuclear cells under nonphlogistic conditions and
evoked peritonitis. TAT-GILZ (a cell-permeable GILZ-fusion protein) injection into the pleural cavity of mice induced monocyte/macrophage influx alongside increased CCL2, IL-10 and TGF-β levels. TAT-GILZ-recruited macrophages showed a regulatory phenotype, exhibiting increased expression of CD206 and YM1. During the resolving phase of
-induced peritonitis, marked by an increased recruitment of mononuclear cells, lower numbers of these cells and CCL2 levels were found in the peritoneal cavity of GILZ-deficient mice (GILZ
) when compared to WT. In addition, GILZ
showed higher bacterial loads, lower apoptosis/efferocytosis counts and a lower number of macrophages with pro-resolving phenotypes. TAT-GILZ accelerated resolution of
evoked neutrophilic inflammation, which was associated with increased peritoneal numbers of monocytes/macrophages, enhanced apoptosis/efferocytosis counts and bacterial clearance through phagocytosis. Taken together, we provided evidence that GILZ modulates macrophage migration with a regulatory phenotype, inducing bacterial clearance and accelerating the resolution of peritonitis induced by
.
Transplacental transmission of Zika virus (ZIKV) during early pregnancy may lead to several neurological alterations, known as congenital Zika syndrome. We have previously shown that intravaginal ...infection of immunocompetent dams with ZIKV during the early stage of pregnancy triggers neuroinflammation in fetuses, characterized by increased brain expression of inflammatory factors, including IL-6, IL-18, CCL2, CXCL1, and CXCL10. The present study sought to understand the long-term consequences of these early cerebral alterations. For that, pregnant FVB/NJ immunocompetent females were infected intravaginally on the gestational day (GD) 4.5 and experiments were performed when offspring reached between 4 to 5 months of age. The exposure to ZIKV promoted significant neuronal cell loss detected in the CA1 region of the hippocampus of adult mice. However, only females showed reduced expression levels of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), and syntaxin-1A, which are important genes related to neuronal function and synaptic plasticity. Moreover, the protein levels of the pre- and postsynaptic markers, SNAP25 and PSD95, respectively, were decreased exclusively in ZIKV-exposed female mice, indicating that ZIKV exposure in utero induces synaptic loss. Additionally, only females exposed to ZIKV showed risk-taking behavior and hippocampal-dependent spatial memory deficit. Together, these results demonstrate that intravaginal infection of mice on GD4.5 induces neurological alterations in the offspring detectable in their adulthood and that female mice, rather than male mice, are more susceptible to ZIKV-induced neurobehavioral alterations.
Summary Statement
In utero exposure to ZIKV leads to decreased number of neurons in adult mice. Female mice exposed to ZIKV in utero exhibit lower levels of BDNF, a decrease in synaptic markers, memory deficits, and risk-taking behavior during adulthood.
Yellow fever (YF) is a viral hemorrhagic fever that typically involves the liver. Brazil recently experienced its largest recorded YF outbreak, and the disease was fatal in more than a third of ...affected individuals, mostly because of acute liver failure. Affected individuals are generally treated only supportively, but during the recent Brazilian outbreak, selected patients were treated with liver transplant. We took advantage of this clinical experience to better characterize the clinical and pathological features of YF‐induced liver failure and to examine the mechanism of hepatocellular injury in YF, to identify targets that would be amenable to therapeutic intervention in preventing progression to liver failure and death. Patients with YF liver failure rapidly developed massive transaminase elevations, with jaundice, coagulopathy, thrombocytopenia, and usually hepatic encephalopathy, along with pathological findings that included microvesicular steatosis and lytic necrosis. Hepatocytes began to express the type 3 isoform of the inositol trisphosphate receptor (ITPR3), an intracellular calcium (Ca2+) channel that is not normally expressed in hepatocytes. Experiments in an animal model, isolated hepatocytes, and liver‐derived cell lines showed that this new expression of ITPR3 was associated with increased nuclear Ca2+ signaling and hepatocyte proliferation, and reduced steatosis and cell death induced by the YF virus. Conclusion: Yellow fever often induces liver failure characterized by massive hepatocellular damage plus steatosis. New expression of ITPR3 also occurs in YF‐infected hepatocytes, which may represent an endogenous protective mechanism that could suggest approaches to treat affected individuals before they progress to liver failure, thereby decreasing the mortality of this disease in a way that does not rely on the costly and limited resource of liver transplantation.
1
The nuclear translocation of transcription factors may be a critical factor in the intracellular pathway involved in ischaemia/reperfusion (I/R) injury. Here, we examined whether NF‐κB and AP‐1 ...participated in the cascade of events leading to TNF‐α production, neutrophil recruitment, tissue injury and lethality following intestinal I/R.
2
The superior mesenteric artery (SMA) of mice was made ischaemic for 60 min followed by 30 min of reperfusion. The effects of NF‐κB and AP‐1 were studied by the administration of the thioredoxin inhibitor, MOL‐294 (methyl 4‐hydroxy‐4‐(8‐methyl‐1,3‐dioxo‐2‐phenyl‐2,3,5,8‐tetrahydro‐1H‐1,2,4triazolo1,2‐apyridazin‐5‐yl)but‐2‐ynoate), and the AP‐1 inhibitor, PNRI‐299 (N‐benzyl‐2‐(3‐cyanophenyl)‐1,3,7‐trioxo‐2,3,7,8‐tetrahydro‐1H‐1,2,4triazolo1,2‐apyridazine‐5‐carboxamide). After I/R, there was increase of translocation of NF‐κB, but not of AP‐1, in the intestine and lungs, as assessed by a gel shift assay.
3
Treatment with MOL‐294 inhibited the increase in vascular permeability, neutrophil accumulation, hemorrhage and proinflammatory cytokine levels, induced by intestinal I/R injury in the intestine. In the lungs, MOL‐294 partially inhibited edema formation, TNF‐α production, but did not alter neutrophil recruitment.
4
Treatment with MOL‐294 inhibited reperfusion‐associated lethality, an effect likely to be secondary to the inhibition of systemic TNF‐α levels. PNRI‐299 had no effects on the inflammatory changes or lethality induced by I/R injury.
5
Our results point to an important role for NF‐κB in triggering endogenous proinflammatory networks during intestinal I/R injury. Inhibition of NF‐κB prevents tissue injury and lethality, and this was associated with inhibition of TNF‐α production and decrease in neutrophil recruitment.
British Journal of Pharmacology (2005) 145, 246–254. doi:10.1038/sj.bjp.0706190
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