The contribution of T cells in severe malaria pathogenesis has been described. Here, we provide evidence for the potential role of angiotensin II (Ang II) in modulating splenic T cell responses in a rodent model of cerebral malaria. T cell activation induced by infection, determined by 3 to 4-fold enhancement in CD69 expression, was reduced to control levels when mice were treated with 20 mg/kg losartan (IC50 = 0.966 mg/kg/d), an AT1 receptor antagonist, or captopril (IC50 = 1.940 mg/kg/d), an inhibitor of angiotensin-converting enzyme (ACE). Moreover, the production of interferon-γ and interleukin-17 by CD4+ T cells diminished 67% and 70%, respectively, by both treatments. Losartan reduced perforin expression in CD8+ T cells by 33% while captopril completely blocked it. The upregulation in chemokine receptor expression (CCR2 and CCR5) observed during infection was abolished and CD11a expression was partially reduced when mice were treated with drugs. T cells activated by Plasmodium berghei ANKA antigens showed 6-fold enhance in AT1 levels in comparison with naive cells. The upregulation of AT1 expression was reduced by losartan (80%) but not by captopril. Our results suggest that the AT1/Ang II axis has a role in the establishment of an efficient T cell response in the spleen and therefore could participate in a misbalanced parasite-induced T cell immune response during P. berghei ANKA infection.
The role of albumin overload in proximal tubules (PT) in the development of tubulointerstitial injury and, consequently, in the progression of renal disease has become more relevant in recent years. Despite the importance of leukotrienes (LTs) in renal disease, little is known about their role in tubulointerstitial injury. The aim of the present work was to investigate the possible role of LTs on tubulointerstitial injury induced by albumin overload. An animal model of tubulointerstitial injury challenged by bovine serum albumin was developed in SV129 mice (wild-type) and 5-lipoxygenase-deficient mice (5-LO–/–). The changes in glomerular morphology and nestin expression observed in wild-type mice subjected to kidney insult were also observed in 5-LO–/– mice. The levels of urinary protein observed in the 5-LO–/– mice subjected or not to kidney insult were lower than those observed in respective wild-type mice. Furthermore, the increase in lactate dehydrogenase activity, a marker of tubule damage, observed in wild-type mice subjected to kidney insult did not occur in 5-LO–/– mice. LTB4 and LTD4, 5-LO products, decreased the uptake of albumin in LLC-PK1 cells, a well-characterized porcine PT cell line. This effect correlated with activation of protein kinase C and inhibition of protein kinase B. The level of proinflammatory cytokines, tumor necrosis factor-α and interleukin (IL)-6, increased in mice subjected to kidney insult but this effect was not modified in 5-LO–/– mice. However, 5-LO–/– mice subjected to kidney insult presented lower macrophage infiltration and higher levels of IL-10 than wild-type mice. Our results reveal that LTs have an important role in tubulointerstitial disease induced by albumin overload.
Angiotensin II (Ang II) is a natural mammalian hormone that has been described to exhibit antiplasmodial activity therefore constituting a promising alternative for the treatment of malaria. Despite its promise, the development of Ang II as an antimalarial is limited by its potent induction of vasoconstriction and its rapid degradation within minutes. Here, we used peptide design to perform targeted chemical modifications to Ang II to generate conformationally restricted (disulfide-crosslinked) peptide derivatives with suppressed vasoconstrictor activity and increased stability. Designed constrained peptides were synthesized chemically and then tested for antiplasmodial activity. Two lead constrained peptides were identified (i.e., peptides 1 and 2), each composed of 10 amino acid residues. These peptides exhibited very promising activity in both our Plasmodium gallinaceum (>80%) and Plasmodium falciparum (>40%) models, an activity that was equivalent to that of Ang II, and led to complete suppression of vasoconstriction. In addition, peptide 5 exhibited selective activity towards the pre-erythrocytic stage (98% of activity against P. gallinaceum), thus suggesting that it may be possible to design peptides that target specific stages of the malaria life cycle. The Ang II derived stable scaffolds presented here may provide the basis for development of a new generation of peptide-based drugs for the treatment of malaria.
Group V (GV) phospholipase A2 (PLA2) is a member of the family of secreted PLA2 (sPLA2) enzymes. This enzyme has been identified in several organs, including the kidney. However, the physiologic role of GV sPLA2 in the maintenance of renal function remains unclear. We used mice lacking the gene encoding GV sPLA2 (Pla2g5−/−) and wild-type breeding pairs in the experiments. Mice were individually housed in metabolic cages and 48-h urine was collected for biochemical assays. Kidney samples were evaluated for glomerular morphology, renal fibrosis, and expression/activity of the (Na+ + K+)-ATPase α1 subunit. We observed that plasma creatinine levels were increased in Pla2g5−/− mice following by a decrease in creatinine clearance. The levels of urinary protein were higher in Pla2g5−/− mice than in the control group. Markers of tubular integrity and function such as γ-glutamyl transpeptidase, lactate dehydrogenase, and sodium excretion fraction (FENa+) were also increased in Pla2g5−/− mice. The increased FENa+ observed in Pla2g5−/− mice was correlated to alterations in cortical (Na+ + K+) ATPase activity/ expression. In addition, the kidney from Pla2g5−/− mice showed accumulation of matrix in corticomedullary glomeruli and tubulointerstitial fibrosis. These data suggest GV sPLA2 is involved in the maintenance of tubular cell function and integrity, promoting sodium retention through increased cortical (Na+ + K+)-ATPase expression and activity.
The escalating demand for natural resources within the construction industry is progressing upward. At the same time, however, there is a great concern regarding the depletion of these resources. This review paper emphasizes the significance of utilizing alternative aggregate materials in concrete. Particularly, it aims to explore replacing natural sand with stone dust. On the one hand, the depletion of primary sources of natural sand worldwide, combined with environmental and ecological concerns, drives the adoption of alternative aggregate materials for sustainable concrete construction. On the other hand, stone dust, a waste from the quarrying industry, offers a cost-effective and practical solution for producing concrete. This article presents a comprehensive literature review of the main trends in utilizing stone dust in recycled aggregates in the past decade and its influence on concrete properties. It addresses critical research questions regarding the physical and chemical properties of stone dust aggregates compared to natural sand; the impact of stone dust on the workability, mechanical, physical, and durability properties of recycled concrete; and the potential reduction of environmental impacts in terms of energy consumption and emissions through the replacement of natural sand with stone dust. Ultimately, this paper proposes future investigative work based on identified research gaps.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.