Recent advances have improved our understanding of the renin‐angiotensin system (RAS). These have included the recognition that angiotensin (Ang)‐(1‐7) is a biologically active product of the RAS ...cascade. The identification of the ACE homologue ACE2, which forms Ang‐(1‐7) from Ang II, and the GPCR Mas as an Ang‐(1‐7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang‐(1‐7). Most available evidence supports a counter‐regulatory role for Ang‐(1‐7) by opposing many actions of Ang II on AT1 receptors, especially vasoconstriction and proliferation. Many studies have now shown that Ang‐(1‐7) by acting via Mas receptor exerts inhibitory effects on inflammation and on vascular and cellular growth mechanisms. Ang‐(1‐7) has also been shown to reduce key signalling pathways and molecules thought to be relevant for fibrogenesis. Here, we review recent findings related to the function of the ACE2/Ang‐(1‐7)/Mas axis and focus on the role of this axis in modifying processes associated with acute and chronic inflammation, including leukocyte influx, fibrogenesis and proliferation of certain cell types. More attention will be given to the involvement of the ACE2/Ang‐(1‐7)/Mas axis in the context of renal disease because of the known relevance of the RAS for the function of this organ and for the regulation of kidney inflammation and fibrosis. Taken together, this knowledge may help in paving the way for the development of novel treatments for chronic inflammatory and renal diseases.
Chagas cardiomyopathy is the most severe and life-threatening manifestation of human Chagas disease--a 'neglected' tropical disease caused by the protozoan parasite Trypanosoma cruzi. The disease is ...endemic in all continental Latin American countries, but has become a worldwide problem because of migration of infected individuals to developed countries, mainly in Europe and North America. Chagas cardiomyopathy results from the combined effects of persistent parasitism, parasite-driven tissue inflammation, microvascular and neurogenic dysfunction, and autoimmune responses triggered by the infection. Clinical presentation varies widely according to the extent of myocardial damage, and manifests mainly as three basic syndromes that can coexist in an individual patient: heart failure, cardiac arrhythmia, and thromboembolism. NYHA functional class, left ventricular systolic function, and nonsustained ventricular tachycardia are important prognostic markers of the risk of death. Management of Chagas cardiomyopathy focuses on the treatment of the three main syndromes. The use of β-blockers in patients with Chagas disease and heart failure is safe, well tolerated, and should be encouraged. Most specialists and international institutions now recommend specific antitrypanosomal treatment of patients with chronic Chagas disease, even in the absence of evidence obtained from randomized clinical trials. Further research on the management of patients with Chagas cardiomyopathy is necessary.
•The torsional ductility of RC beams with rectangular cross section is studied.•A torsional ductility index is defined to characterize the torsional ductility.•The influence of important variable ...studies is studied and discussed.•A comparative analysis with the rules from some codes of practice is performed.•Some codes are too much restrictive as far as torsional ductility is concerned.
In this article, the torsional ductility of reinforced concrete (RC) beams with rectangular cross section is studied. For this, the experimental results of several RC beams found in the literature were compiled and analyzed. A torsional ductility index was used to characterize the torsional ductility of the studied beams. The following variables study were considered: compressive concrete strength, torsional reinforcement ratio and cross section type (plain or hollow). The influence of each variable study on the torsional ductility is studied and important findings are pointed out which could help for the design of RC beams under torsion. An additional comparative analysis with the rules from some codes of practice in use is also performed. It is shown that, in general, the codes are too much restrictive as far as the maximum torsional reinforcement is concerned. As a consequence, this can leads to the unacceptance of several beams with ductile behavior.
Chagas disease caused by
Trypanosoma cruzi
remains an important neglected tropical disease and a cause of significant morbidity and mortality. No longer confined to endemic areas of Latin America, it ...is now found in non-endemic areas due to immigration. The parasite may persist in any tissue, but in recent years, there has been increased recognition of adipose tissue both as an early target of infection and a reservoir of chronic infection. The major complications of this disease are cardiomyopathy and megasyndromes involving the gastrointestinal tract. The pathogenesis of Chagas disease is complex and multifactorial involving many interactive pathways. The significance of innate immunity, including the contributions of cytokines, chemokines, reactive oxygen species, and oxidative stress, has been emphasized. The role of the components of the eicosanoid pathway such as thromboxane A
2
and the lipoxins has been demonstrated to have profound effects as both pro- and anti-inflammatory factors. Additionally, we discuss the vasoconstrictive actions of thromboxane A
2
and endothelin-1 in Chagas disease. Human immunity to
T. cruzi
infection and its role in pathogen control and disease progression have not been fully investigated. However, recently, it was demonstrated that a reduction in the anti-inflammatory cytokine IL-10 was associated with clinically significant chronic chagasic cardiomyopathy.
During orthodontic tooth movement, there is local production of chemokines and an
influx of leukocytes into the periodontium. CCL5 plays an important role in
osteoclast recruitment and activation. ...This study aimed to investigate whether the
CCR5-receptor influences these events and, consequently, orthodontic tooth movement.
An orthodontic appliance was placed in wild-type mice (WT) and CCR5-deficient mice
(CCR5−/−). The expression of mediators involved in bone remodeling was
evaluated in periodontal tissues by Real-time PCR. The number of TRAP-positive
osteoclasts and the expression of cathepsin K, RANKL, and MMP13 were significantly
higher in CCR5−/−. Meanwhile, the expression of two osteoblastic
differentiation markers, RUNX2 and osteocalcin, and that of bone resorption
regulators, IL-10 and OPG, were lower in CCR5−/−. Analysis of the data
also showed that CCR5−/− exhibited a greater amount of tooth movement
after 7 days of mechanical loading. The results suggested that CCR5 might be a
down-regulator of alveolar bone resorption during orthodontic movement.
The neutrophil is an important cell in host defense against infections, acting as the first line of microorganism control. However, this cell exhibits dysregulated activity in sepsis and may ...contribute to the pathogenesis of the disease. This systematic review aimed to highlight the major scientific findings regarding neutrophil activity in sepsis reported in clinical and experimental research published in the last 10 years. The search was conducted in the Virtual Health Library of PAHO-WHO (BVS) and PubMed databases, and articles published between January 2007 and May 2017 in Portuguese, English, and Spanish were eligible. Article selection was carried out independently by two reviewers (CB and IB). A total of 233 articles were found, of which 87 were identified on PubMed and 146 on BVS. Eighty-two articles were duplicates. Of the remaining 151 articles, 19 met the inclusion criteria after title, abstract, and full-text analysis. Overall, research in clinical samples and animal models of sepsis showed reduced capacity of neutrophils to migrate and delayed apoptosis, but there was no consensus on the phagocytic activity of neutrophils in sepsis. Molecules, such as pentraxin 3 (PTX3), have been analyzed as potential diagnostic markers in sepsis but the diversity of soluble molecules detected in blood samples of sepsis patients did not enable further understanding of the correlation of these circulating molecules with neutrophil activity during sepsis. Optimal understanding of the function of neutrophils in sepsis remains a challenge that, if overcome, would eventually allow targeted therapeutic interventions in patients affected by this severe syndrome.
Immunotherapy has revolutionized cancer treatment by harnessing the immune system to enhance antitumor responses while minimizing off-target effects. Among the promising cancer-specific therapies, ...tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted significant attention.
Here, we developed an ionizable lipid nanoparticle (LNP) platform to deliver TRAIL mRNA (LNP-TRAIL) directly to the tumor microenvironment (TME) to induce tumor cell death. Our LNP-TRAIL was formulated via microfluidic mixing and the induction of tumor cell death was assessed in vitro. Next, we investigated the ability of LNP-TRAIL to inhibit colon cancer progression in vivo in combination with a TME normalization approach using Losartan (Los) or angiotensin 1-7 (Ang(1-7)) to reduce vascular compression and deposition of extracellular matrix in mice.
Our results demonstrated that LNP-TRAIL induced tumor cell death in vitro and effectively inhibited colon cancer progression in vivo, particularly when combined with TME normalization induced by treatment Los or Ang(1-7). In addition, potent tumor cell death as well as enhanced apoptosis and necrosis was found in the tumor tissue of a group treated with LNP-TRAIL combined with TME normalization.
Together, our data demonstrate the potential of the LNP to deliver TRAIL mRNA to the TME and to induce tumor cell death, especially when combined with TME normalization. Therefore, these findings provide important insights for the development of novel therapeutic strategies for the immunotherapy of solid tumors.
Acetaminophen (APAP) is usually safe when administrated in therapeutic doses; however, APAP overdose can lead to severe liver injury. APAP can cause direct hepatocyte damage, and stimulates an ...inflammatory response leading to oxidative stress. Supressor of Cytokine Signaling (SOCS) 2 modulates cytokine and growth factor signaling, and plays a role in the regulation of hepatic cellular processes. Our study evaluated the role of SOCS2 in APAP liver injury. The administration of a toxic dose (600 mg/kg) of APAP caused significant liver necrosis in WT mice. In SOCS2
mice, there was significantly more necrosis, neutrophil recruitment, and expression of the neutrophil-active chemokine CXCL-1. Expression of proinflammatory cytokines, such as TNF-α and IL-6, was elevated, while expression of anti-inflammatory cytokines, IL-10 and TGF-β, was diminished.
, SOCS2
hepatocytes expressed more p-NF-kB and produced more ROS than WT hepatocytes when exposed to APAP. SOCS2
hepatocytes were more sensitive to cell death in the presence of IL-6 and hydrogen peroxide. The administration of catalase
and
resulted in a pronounced reduction of cells/mice death and necrosis in the SOCS2
group. We have demonstrated that SOCS2 has a protective role in the liver by controlling pro-oxidative and inflammatory mechanisms induced by APAP.
Objectives: A wide range of compounds inhibit formation of new blood vessels in a variety of models, accompanied by decreases in pro-angiogenic cytokines. The authors sought a surrogate marker for ...the complex process of neovascularization by correlating inhibition of cytokine production with anti-angiogenic effect.
Methods: Three anti-angiogenic compounds, clotrimazole (120 mg kg−1 day−1), thalidomide (100 mg kg−1 day−1), and rosiglitazone (10 mg kg−1 day−1), were used to inhibit angiogenesis developing over 9 days, in sponges implanted subcutaneously in Swiss mice. Angiogenesis was assessed by hemoglobin content and by histology. Content of cytokines in implants was measured by specific immunoassays and accumulation of neutrophils or macrophages in implants by measuring myeloperoxidase or N-acetylglucosaminidase activity, respectively.
Results: These compounds caused equal inhibition of angiogenesis (about 40%). However, implant levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF-α) or the macrophage chemoattractant cytokine, CCL2/MCP-1/JE, and accumulation of macrophages were more variably inhibited. Only the neutrophil chemokine, CXCL2/KC, was inhibited equally by the three compounds, in this model.
Conclusions: Anti-angiogenic effect was most clearly and closely correlated with levels of the chemokine KC. Thus, measurement of the chemokine KC might provide an adequate surrogate marker for the functional process of neovascularization in our model.
The purpose of this study was to investigate the role of pentraxin 3 (PTX3), a pivotal component of the innate immune system, in gout. Levels of PTX3 and IL-1β in human samples were evaluated by ...ELISA. Development of murine gout was evaluated through the levels of cytokines (PTX3, CXCL1, and IL-1β) and neutrophil recruitment into the joint cavity. Phagocytosis of monosodium urate (MSU) crystals and caspase-1 activation were determined by flow cytometer. Acute gout patients showed elevated concentration of PTX3 in plasma and synovial fluid as compared with healthy and osteoarthritic subjects. Moreover, there was a positive correlation between intra-articular PTX3 and IL-1β levels. PTX3 was induced in the periarticular tissue of mice postinjection of MSU crystals. Importantly, Ptx3-deficient mice showed reduced inflammation in response to MSU crystal injection compared with wild-type mice, including reduction of neutrophil recruitment into the joint cavity and IL-1β and CXCL1 production. Interestingly, addition of PTX3 in vitro enhanced MSU crystal phagocytosis by monocytes and resulted in higher production of IL-1β by macrophages. This contribution of PTX3 to the phagocytosis of MSU crystals and consequent production of IL-1β occurred through a mechanism mainly dependent on FcγRIII. Thus, our results suggest that PTX3 acts as a humoral pattern recognition molecule in gout facilitating MSU crystal phagocytosis and contributing to the pathogenesis of gouty arthritis.
PDF
