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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. [Copyright &y& Elsevier]

Abstract: Salmonella spp. are Gram-negative, facultative, intracellular pathogens that cause several diarrheal diseases ranging from self-limiting gastroenteritis to typhoid fever. Previous results from our laboratory showed that Saccharomyces cerevisiae strain UFMG 905 isolated from ‘cachaça’ production presented probiotic properties due to its ability to protect against experimental infection with Salmonella enterica serovar Typhimurium. In this study, the effects of oral treatment with S. cerevisiae 905 were evaluated at the immunological level in a murine model of typhoid fever. Treatment with S. cerevisiae 905 inhibited weight loss and increased survival rate after Salmonella challenge. Immunological data demonstrated that S. cerevisiae 905 decreased levels of proinflammatory cytokines and modulated the activation of mitogen-activated protein kinases (p38 and JNK, but not ERK1/2), NF-κB and AP-1, signaling pathways which are involved in the transcriptional activation of proinflammatory mediators. Experiments in germ-free mice revealed that probiotic effects were due, at least in part, to the binding of Salmonella to the yeast. In conclusion, S. cerevisiae 905 acts as a potential new biotherapy against S. Typhimurium infection due to its ability to bind bacteria and modulate signaling pathways involved in the activation of inflammation in a murine model of typhoid fever. [Copyright &y& Elsevier]

Abstract: Background: Left ventricular dysfunction (LVd) is the main predictor of mortality in Chagas disease (ChD). Aims: To compare the diagnostic performance of the conventional approach (ECG and chest X-ray) in the recognition of LVd in ChD, with a new strategy, in which BNP is measured in patients with an abnormal ECG. Methods: Consecutive ChD patients recruited at an Outpatient Reference Center in Belo Horizonte, Brazil, without other systemic diseases, in 1998–99 (sample 1, n =165) and in 2001–02 (sample 2, n =62) underwent ECG, chest X-ray, BNP measurement and echocardiography. Results: The prevalence of LVd (ejection fraction ≤0.40) was 9.1% in the sample 1. The conventional strategy recognized all patients with LVd (sensitivity: 100%, 95% CI: 79.6–100% and negative predictive value −PV 100%, 92.1–100%), but with low specificity (30%, 95% CI: 23.2–37.8) and +PV (12.5%, 95% IC: I7.7–19.6). The BNP/ECG strategy showed significantly better specificity (96.0%, 95% CI: 91.5–98.2, p <0.001) and +PV (66.7%, 95% CI: 43.7–83.7, p <0.001), and non-significantly lower sensitivity (80.0%, 95% CI: 54.8–93.0, p =0.25) and −PV (98.0%,95% CI: 94.2–99.3, p =0.08). Overall accuracy was improved with the new strategy. (94.5%,95% CI: 90.0–97.1×36.4%, 95% CI: 29.4–43.9, p <0.001). Similar results were obtained for the sample 2. Conclusions: The BNP-based strategy was more accurate than the conventional approach in the detection of LVd in ChD patients and should be considered as a valid option. [Copyright &y& Elsevier]

Major advances have recently been achieved in the area of microbial recognition by the innate immune system. In this Forum, we discuss important issues related to innate recognition of bacteria and protozoan parasites. In particular, we highlight the structural characterization of pathogen-associated molecular patterns (PAMPs); the definition of the receptors required for recognition of PAMPs, especially the Toll-like receptors (TLRs); the signaling pathways triggered by PAMPs/PAMPs receptor interaction; and the functional consequences of these interactions for pathogenesis during microbial infection. [Copyright &y& Elsevier]

The inflammatory response that follows the infection with Trypanosoma cruzi is essential for host resistance to infection but is also responsible for the diverse pathology observed in Chagas disease. Here, we examine the stimuli and mechanisms underlying chemokine production following infection in vitro and in vivo, and the ability of chemokines to coordinate the influx of inflammatory and immune cells to the site of parasite infection, and to control T. cruzi growth. [Copyright &y& Elsevier]

Examines the capacity of phosphodiesterase type 4 (PDE4) inhibitors to exert anti-inflammatory actions. Discussion on the potential of this class of drugs to take their place as novel therapeutic agents for a variety of inflammatory diseases; Mechanisms of the anti-inflammatory action of PDE4 inhibitors; Clinical prospects. INSETS: Box 1. Possible mechanisms involved in the anti-inflammatory..;Chemical names..

Immune status changes during pregnancy, with pro-inflammatory and anti-inflammatory contexts at different stages, making pregnant women potentially more susceptible to various infections. Infection by Zika virus during pregnancy can cause developmental damage to the fetus, and the altered immune response during pregnancy could contribute to disease during Zika infection. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to determine the safety and efficacy of renin-angiotensin system (RAS) inhibitors and β-blockers in chronic Chagas cardiomyopathy. Background: Chronic Chagas cardiomyopathy causes substantial morbidity and mortality in Latin America. Whether RAS inhibitors and β-blockers are safe and beneficial has been challenged because of the lack of formal trials. Methods: We conducted a double-blind, placebo-controlled, and randomized trial in 42 patients with Trypanosoma cruzi infection and cardiomyopathy. All patients received enalapril (up-titrated to 20 mg BID) and spironolactone (25 mg QD). Subsequently, the patients were randomly assigned to receive placebo (n = 20) or carvedilol up-titrated to 25 mg BID (n = 19). The primary end points were change in left ventricular ejection fraction (LVEF) after RAS inhibition and that after the addition of carvedilol. The secondary end points were changes in other echocardiographic parameters, Framingham score, quality of life (36-item Short-Form Health Survey), New York Heart Association class, radiographic indices, brain natriuretic peptide levels, and chemokines as well as safety end points. Results: Optimization of RAS inhibition was safe, hemodynamically well tolerated, and associated with improvements in Framingham score (P = .001) and quality of life as well as reductions in the cardiothoracic index (P = .002), brain natriuretic peptide level (P = .032), and RANTES (regulated on activation, normal T expressed and secreted) level (P = .001). Left ventricular ejection fraction increased by 2.3% (P = .25); in patients with an LVEF ≤45% at baseline, it increased by 2.8% (P = .017). Treatment with carvedilol was associated with a trend toward an increase in LVEF (absolute difference between groups, 2.3%; P = .094). The addition of carvedilol was safe, hemodynamically well tolerated, and not associated with symptomatic bradycardia. Conclusions: In patients with chronic Chagas cardiomyopathy, optimization of treatment with enalapril and spironolactone and subsequent addition of carvedilol were safe and associated with benefits in cardiac function and clinical status. Larger trials are needed to show effects on mortality and/or hospitalization. [Copyright &y& Elsevier]

Human infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects ∼17 million people in Latin America. A significant percentage of the infected population will develop clinical symptoms or present changes in laboratory and/or image evaluation. The existence of a large spectrum of clinical manifestations – with patients ranging from asymptomatic to severe cardiac involvement – emphasizes the need to use standardized and well-defined clinical criteria among different research groups. In this article, we carry out a systematic review of the immunology in human Chagas disease, discussing recent findings in the context of a clinical perspective. [Copyright &y& Elsevier]

The termination of inflammation is governed by endogenous molecules collectively referred to as 'mediators of resolution' of inflammation. There is now strong evidence to suggest that failed resolution may underpin autoimmune and inflammatory diseases and could thus be targeted to decrease inflammation. There are many molecules that have been described as mediators of resolution, and new players are still being continuously discovered. To support the emerging field of 'resolution pharmacology', here we discuss the scientific strategies required to qualify a molecule as a resolution mediator. Systematic definition of the players of resolution, their receptors, and downstream mechanisms remains a necessary knowledge to move the field forward and suggest new targets for the development of novel therapies to treat inflammatory diseases. Highlights A successful inflammatory response tends to resolve in a coordinated series of molecular and cellular events, including the resolving phase of inflammation. Exciting new discoveries have revealed a post-resolution phase of inflammation, composed of a third wave of leukocyte influx that seemingly links innate and adaptive immune systems. Recent discoveries have suggested that failed or impaired resolution of inflammation may underpin the pathogenesis of certain chronic inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis. The identification of failed resolution as an underlying cause or contributing factor to certain human inflammatory diseases has brought new exciting therapeutic opportunities for treating inflammation, based on promoting events associated with resolution, rather than simply blocking proinflammatory pathways. Recently, the potential of human translation is reflected by the identification/quantification of proresolving molecules and pathways in humans, and by the pioneering use of human models of inflammation to test the efficacy of proresolving agonists. In order to effectively translate the knowledge of resolution biology into potential new therapeutics for a variety of inflammation-associated diseases, precise definitions of the cellular players, molecular mediators, receptors, and signaling pathways engaged during inflammation resolution are necessary. [ABSTRACT FROM AUTHOR]

COVID-19 affects primarily the lung. However, several other systemic alterations, including muscle weakness, fatigue and myalgia have been reported and may contribute to the disease outcome. We hypothesize that changes in the neuromuscular system may contribute to the latter symptoms observed in COVID-19 patients. Here, we showed that C57BL/6J mice inoculated intranasally with the murine betacoronavirus hepatitis coronavirus 3 (MHV-3), a model for studying COVID-19 in BSL-2 conditions that emulates severe COVID-19, developed robust motor alterations in muscle strength and locomotor activity. The latter changes were accompanied by degeneration and loss of motoneurons that were associated with the presence of virus-like particles inside the motoneuron. At the neuromuscular junction level, there were signs of atrophy and fragmentation in synaptic elements of MHV-3-infected mice. Furthermore, there was muscle atrophy and fiber type switch with alteration in myokines levels in muscles of MHV-3-infected mice. Collectively, our results show that acute infection with a betacoronavirus leads to robust motor impairment accompanied by neuromuscular system alteration. • Betacoronavirus infection causes motor impairment. • Motoneuron loss is caused by betacoronavirus infection. • Betacoronavirus infection causes neuromuscular junction degeneration. • Skeletal muscle atrophy is developed after betacoronavirus infection. [ABSTRACT FROM AUTHOR]

Annexin A1 (AnxA1) is a glucocorticoid-regulated protein known for its anti-inflammatory and pro-resolving effects. We have shown previously that the cAMP-enhancing compounds rolipram (ROL; a PDE4 inhibitor) and Bt2cAMP (a cAMP mimetic) drive caspase-dependent resolution of neutrophilic inflammation. In this follow-up study, we investigated whether AnxA1 could be involved in the pro-resolving properties of these compounds using a model of LPS-induced inflammation in BALB/c mice. The treatment with ROL or Bt2cAMP at the peak of inflammation shortened resolution intervals, improved resolution indices, and increased AnxA1 expression. In vitro studies showed that ROL and Bt2cAMP induced AnxA1 expression and phosphorylation, and this effect was prevented by PKA inhibitors, suggesting the involvement of PKA in ROL-induced AnxA1 expression. Akin to these in vitro findings, H89 prevented ROL- and Bt2cAMP-induced resolution of inflammation, and it was associated with decreased levels of intact AnxA1. Moreover, two different strategies to block the AnxA1 pathway (by usingN-t-Boc-Met-Leu-Phe, a nonselective AnxA1 receptor antagonist, or by using an anti-AnxA1 neutralizing antiserum) prevented ROL- and Bt2cAMP-induced resolution and neutrophil apoptosis. Likewise, the ability of ROL or Bt2cAMP to induce neutrophil apoptosis was impaired in AnxA-knock-out mice. Finally, in in vitro settings, ROL and Bt2cAMP overrode the survival-inducing effect ofLPSinhumanneutrophils in anAnxA1-dependent manner. Our results show that AnxA1 is at least one of the endogenous determinants mediating the pro-resolving properties of cAMP-elevating agents and cAMP-mimetic drugs. [ABSTRACT FROM AUTHOR]

The chemokine CXCL12 or stromal cell-derived factor 1/SDF-1 attracts hematopoietic progenitor cells and mature leukocytes through the G protein-coupled CXC chemokine receptor 4 (CXCR4). In addition, it interacts with atypical chemokine receptor 3 (ACKR3 or CXCR7) and glycosaminoglycans. CXCL12 activity is regulated through posttranslational cleavage by CD26/dipeptidyl peptidase 4 that removes two NH 2 -terminal amino acids. CD26-truncated CXCL12 does not induce calcium signaling or chemotaxis of mononuclear cells. CXCL12(3–68) was chemically synthesized de novo for detailed biological characterization. Compared to unmodified CXCL12, CXCL12(3–68) was no longer able to signal through CXCR4 via inositol trisphosphate (IP 3 ), Akt or extracellular signal-regulated kinases 1 and 2 (ERK1/2). Interestingly, the recruitment of β-arrestin 2 to the cell membrane via CXCR4 by CXCL12(3–68) was abolished, whereas a weakened but significant β-arrestin recruitment remained via ACKR3. CXCL12-induced endothelial cell migration and signal transduction was completely abrogated by CD26. Intact CXCL12 hardly induced lymphocyte migration upon intra-articular injection in mice. In contrast, oral treatment of mice with the CD26 inhibitor sitagliptin reduced CD26 activity and CXCL12 cleavage in blood plasma. The potential of CXCL12 to induce intra-articular lymphocyte infiltration was significantly increased in sitagliptin-treated mice and CXCL12(3–68) failed to induce migration under both CD26-inhibiting and non-inhibiting conditions. In conclusion, CD26-cleavage skews CXCL12 towards β-arrestin dependent recruitment through ACKR3 and destroys the CXCR4-mediated lymphocyte chemoattractant properties of CXCL12 in vivo . Hence, pharmacological CD26-blockade in tissues may enhance CXCL12-induced inflammation. [ABSTRACT FROM AUTHOR]

Millions of people died during the COVID-19 pandemic, but the vast majority of infected individuals survived. Now, some consequences of the disease, known as long COVID, are been revealed. Although the respiratory system is the target of Sars-CoV-2, COVID-19 can influence other parts of the body, including bone. The aim of this work was to investigate the impact of acute coronavirus infection in bone metabolism. We evaluated RANKL/OPG levels in serum samples of patients with and without acute COVID-19. In vitro , the effects of coronavirus in osteoclasts and osteoblasts were investigated. In vivo, we evaluated the bone phenotype in a BSL2 mouse model of SARS-like disease induced by murine coronavirus (MHV-3). Patients with acute COVID-19 presented decreased OPG and increased RANKL/OPG ratio in the serum versus healthy individuals. In vitro , MHV-3 infected macrophages and osteoclasts, increasing their differentiation and TNF release. Oppositely, osteoblasts were not infected. In vivo , MHV-3 lung infection triggered bone resorption in the femur of mice, increasing the number of osteoclasts at 3dpi and decreasing at 5dpi. Indeed, apoptotic-caspase-3+ cells have been detected in the femur after infection as well as viral RNA. RANKL/OPG ratio and TNF levels also increased in the femur after infection. Accordingly, the bone phenotype of TNFRp55−/− mice infected with MHV-3 showed no signs of bone resorption or increase in the number of osteoclasts. Coronavirus induces an osteoporotic phenotype in mice dependent on TNF and on macrophage/osteoclast infection. [ABSTRACT FROM AUTHOR]

Alcoholism is a multifactorial and complex disorder responsible for 5.9% of deaths worldwide. Excessive consumption of ethanol (Et-OH) induces alcoholic liver disease (ALD), a condition comprising a spectrum of clinical signs and morphological changes, ranging from fatty liver (steatosis) to more severe forms of chronic liver injury. Secondary cofactors, such as nutritional and hepatotoxic comorbid conditions, can also contribute to liver disease development. Here we investigated the effects in the progression of ALD following short-term exposure to diet high in refined carbohydrates (HC), a high-sugar and -butter (HSB) hypercaloric diet and acute Et-OH consumption. HSB diet increased the body weight (BW) and adiposity independently of acute Et-OH consumption. HC diet did not affect BW but increased the adiposity, while acute Et-OH alone did not affect BW and adiposity. All groups of mice developed steatosis except the control group. Exposure to acute Et-OH and HSB diet increased the number of neutrophils and macrophages, and apoptosis in the liver. This combination also increased the number of circulating neutrophils and reduced mononuclear cells in the blood. Thus, short-term exposure to HSB diet and acute Et-OH intake is linked to increased liver injury. These findings offer important clues to understand the hepatic injuries associated with short exposure to hypercaloric diets and acute Et-OH. [ABSTRACT FROM AUTHOR]

Klebsiella pneumoniae (Kp) a common cause of pneumonia leads to intense lung injury and mortality that are correlated with infective exacerbations. Probiotics are a class of microorganisms that have immunomodulatory effects to benefit health. We investigated whether the probiotic Bifidobacterium longum 5 1A induces protection in mice against lung infection induced by Kp and the potential involved mechanisms. Kp infection induced secretion of pro-inflammatory cytokines, neutrophil recruitment, significant bacterial load in the lung and 50% lethality. However, treatment with live B. longum 5 1A induced faster resolution of inflammation associated with an increased production of IL-10, decreased lung damage with significantly reduction of bacterial burden that contributed to rescue 100% of mice from death. We found that these effects could be attributed, at least in part, to activation of the Toll-like receptor (TLR) adapter protein Mal, since B. longum 5 1A treatment in Mal-deficient infected mice did not show the protection observed in wild type infected mice. Thus, we propose that live B. longum 5 1A activates TLR-signaling pathway that results in ROS production and protects the host against pneumonia-induced death by finely tuning the inflammatory response and contributing to faster return to lung homeostasis. [ABSTRACT FROM AUTHOR]