COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to ...promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppress macrophage anti-inflammation and efficient tissue repair programs and provide mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.
In northeastern Brazil, grape pomace has become a potential alternative byproduct because of the recover phenolic compounds from the vinification process. Comparative analyses were performed between ...lyophilized extract of grape skins from pomace, described as fermented (FGS), and fresh, unfermented (UGS) grape skins to show the relevant brand's composition upon the first maceration in winemaking.
The use of in vitro testing such as Folin-Ciocalteu's, DPPH free radical scavenger and HPLC methods were performed to evidence antioxidant effect and phenolic compounds. Additionally, vascular reactivity studies were performed in third-order branches of rat superior mesenteric arteries, which were obtained and placed in organ baths containing Krebs-Henseleit solution, maintained at 37 °C, gassed with a mixture of 95% O
and 5% CO
, and maintained at pH 7.4. The in situ formation of reactive oxygen species (ROS) was evaluated in small mesenteric rings using oxidative fluorescent dihydroethidium dye.
We found higher phenolic content and antioxidant activity in FGS when compared to UGS. HPLC analyses identified a significant number of phenolic compounds with antioxidant potential in both samples. The vasorelaxant effect induced by FGS was more potent than that induced by UGS, and the activity was attenuated after removal of vascular endothelium or by blockade of endothelium-derived relaxing factors, such as NO and EDHF.
The FGS extract may be a great source of natural polyphenol products with potent antioxidant effects and endothelium-dependent vasodilatory actions involving NO and EDHF pathways.
Single dose of diethylcarbamazine (DEC) used in control programs is effective in breaking the transmission of filariasis. In order to investigate the effect of aggressive therapy on
Wuchereria ...bancrofti (
Wb) microfilariae, DEC was given to 29 patients who were positive for the circulating filarial antigen (CFA) assay but did not have clinical manifestations of filariasis, at 6
mg/kg/day for 12 days and again six months later using the same dosing regimen. For each patient, microfilarial density and serum CFA were followed up for two years. Ultrastructural analyses on
Wb microfilariae obtained after repeated treatment with DEC were also performed. Microfilaremia and antigenemia decreased significantly after 12 months but returned to the initial levels after 24 months. This could indicate, as shown by other authors, that aggressive repeated therapy with DEC alone is ineffective in eradicating adult
W. bancrofti, particularly in infected but asymptomatic individuals. The objective of the present study was to analyze the microfilaremic and antigenemic behavior and ultrastructural changes caused by different DEC concentrations
in vitro in
Wb microfilariae obtained from individuals who were sensitive and refractory to treatment. After
in vitro treatment of the microfilariae using 5 and 10
μg/ml of DEC for 1
h, ultrastructural analysis revealed low levels of cell damage compared with embryos obtained from individuals from a different area who had never received DEC treatment before. The results obtained suggest that microfilariae from patients who receive repeated aggressive therapy are less sensitive to DEC
in vitro.
The aim of this study was to investigate the pharmacological effects of discretamine, an isoquinoline alkaloid isolated from Duguetia magnolioidea Maas, on the cardiovascular system, using a combined ...in vivo and in vitro approach. Blood pressure and heart rate measurements, as well as changes in isometric tension in rat superior mesenteric arterial rings, elicited by discretamine were recorded. In normotensive non-anaesthetized rats (n = 6), discretamine (0.01; 0.05; 0.1; 0.5; 1, 5 and 10 mg/kg i.v., randomly) injections produced hypotension (-5.2 +/- 1.7; -5.1 +/- 2.1; -7.7 +/- 2; -8.9 +/- 1.7; -9.6 +/- 2.2; -16.8 +/- 2.8 and -13.4 +/- 1.3 mmHg, respectively) accompanied by tachycardia (24.2 +/- 6.1; 36.8 +/- 11.3; 44.2 +/- 7.7; 45.9 +/- 6.4; 48.2 +/- 9.1; 72.1 +/- 14.5 and 64 +/- 17 bpm, respectively). Hypotensive and tachycardic responses were significantly attenuated after L-NAME (20 mg/kg, i.v.) administration. In isolated rat mesenteric artery rings, with endothelium intact, discretamine (10(-12) - 10(-5) M) induced concentration-dependent relaxation of the contractions induced by phenylephrine (10 microM) pD2 = 6.8 +/- 0.1. The effect of the discretamine on phenylephrine induced contractions was significantly attenuated after removal of the vascular endothelium pD2 = 5.8 +/- 0.04. Similar results were obtained after pre-treatment with L-NAME 100 microM pD2 = 5.8 +/- 0.04, L-NAME 300 microM pD2 = 5.9 +/- 0.06, Hydroxocobalamin 30 microM pD2 = 5.8 +/- 0.06 or ODQ 10 microM pD2 = 5.8 +/- 0.04. In addition, in rabbit aorta endothelial cell line, discretamine significantly increased NO3- levels. These results suggest that the hypotensive effect induced by discretamine is probably due to a peripheral vasodilatation, at least, in part, due to the release of NO from vascular endothelium and consequent activation of soluble guanylyl cyclase (GC) in the vascular smooth muscle cells.
CBA/J mice are resistant to Leishmania major infection but are permissive to L. amazonensis infection. In addition, CBA/J macrophages control L. major but not L. amazonensis infection in vitro. ...Phagocytosis by macrophages is known to determine the outcome of Leishmania infection. Pattern recognition receptors (PRR) adorning antigen presenting cell surfaces are known to coordinate the link between innate and adaptive immunity. The macrophage receptor with collagenous structure (MARCO) is a PRR that is preferably expressed by macrophages and is capable of binding Gram-positive and Gram-negative bacteria. No research on the role of MARCO in Leishmania-macrophage interactions has been reported. Here, we demonstrate, for the first time, that MARCO expression by CBA/J macrophages is increased in response to both in vitro and in vivo L. major infections, but not to L. amazonensis infection. In addition, a specific anti-MARCO monoclonal antibody reduced L. major infection of macrophages by 30%-40% in vitro. The draining lymph nodes of anti-MARCO-treated mice displayed a reduced presence of immunolabelled parasite and parasite antigens, as well as a reduced inflammatory response. These results support the hypothesis that MARCO has a role in macrophage infection by L. major in vitro as well as in vivo.
This long-term extension of an 8-week randomized, naturalistic study in patients with panic disorder with or without agoraphobia compared the efficacy and safety of clonazepam (n = 47) and paroxetine ...(n = 37) over a 3-year total treatment duration. Target doses for all patients were 2 mg/d clonazepam and 40 mg/d paroxetine (both taken at bedtime). This study reports data from the long-term period (34 months), following the initial 8-week treatment phase. Thus, total treatment duration was 36 months. Patients with a good primary outcome during acute treatment continued monotherapy with clonazepam or paroxetine, but patients with partial primary treatment success were switched to the combination therapy. At initiation of the long-term study, the mean doses of clonazepam and paroxetine were 1.9 (SD, 0.30) and 38.4 (SD, 3.74) mg/d, respectively. These doses were maintained until month 36 (clonazepam 1.9 SD, 0.29 mg/d and paroxetine 38.2 SD, 3.87 mg/d). Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression (CGI)-Improvement rating than treatment with paroxetine (mean difference: CGI-Severity scale -3.48 vs -3.24, respectively, P = 0.02; CGI-Improvement scale 1.06 vs 1.11, respectively, P = 0.04). Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine (28.9% vs 70.6%, P < 0.001). The efficacy of clonazepam and paroxetine for the treatment of panic disorder was maintained over the long-term course. There was a significant advantage with clonazepam over paroxetine with respect to the frequency and nature of adverse events.
Abstract Schistosomiasis treatment is dependent on a single drug, praziquantel (PZQ). The development of resistance of PZQ has drawn the attention of many researchers to alternative drugs. One viable ...and promising treatment is the study of medicinal plants as a new approach to the experimental treatment for Schistosomiasis. The present work aimed to evaluate in vivo antischistosomal activity of effect of Mentha x villosa Oil Essential (Mv-EO) and rotundifolone (ROT) against Schistosoma mansoni. Thirty-day-old female Swiss webster mice (Mus musculus) weighing 50 grams were used. Mice were infected with 80 cercariae of S. mansoni (BH strain) and orally administered Mv-EO (50, 100 and 200 mg/Kg) and ROT (35.9, 70.9 and 141.9 mg/Kg) at 45-days post infection for 5 consecutive days. All mice were euthanized 60 days after infection. Praziquantel was the positive control in the experiment. Doses of 200 mg/kg (Mv-EO) and ROT (141.9 mg/Kg) resulted in a significant reduction in fluke burden (72.44% and 74.48%, respectively). There was also marked reduction in liver, intestinal and faecal and changed oogram pattern, compared to infected untreated mice. Considering the results obtained, further biological studies are required in order to elucidate the mechanism of schistosomicidal action on against adult S. mansoni.
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