Pentamidine reduces viability of Trypanosoma cruzi and decreases the parasite infection in vitro and in vivo. Also, pentamidine inhibits the polyamine transport in the parasite.
•We studied the ...effect of pentamidine against Trypanosoma cruzi both in vitro and in vivo.•Pentamidine decreases the viability of isolated trypomastigotes of T. cruzi.•Pentamidine decreases the parasite burden in T. cruzi-infected cells.•Pentamidine improves the disease outcome in T. cruzi-infected mice.•Pentamidine inhibits the polyamine transport in isolated parasites.
Pentamidine is an antiprotozoal and fungicide drug used in the treatment of leishmaniasis and African trypanosomiasis. Despite its extensive use as antiparasitic drug, little evidence exists about the effect of pentamidine in Trypanosoma cruzi, the etiological agent of Chagas’ disease. Recent studies have shown that pentamidine blocks a polyamine transporter present in Leishmania major; consequently, its might also block these transporters in T. cruzi. Considering that T. cruzi lacks the ability to synthesize putrescine de novo, the inhibition of polyamine transport can bring a new therapeutic target against the parasite. In this work, we show that pentamidine decreases, not only the viability of T. cruzi trypomastigotes, but also the parasite burden of infected cells. In T. cruzi-infected mice pentamidine decreases the inflammation and parasite burden in hearts from infected mice. The treatment also decreases parasitemia, resulting in an increased survival rate. In addition, pentamidine strongly inhibits the putrescine and spermidine transport in T. cruzi epimastigotes and amastigotes. Thus, this study points to reevaluate the utility of pentamidine and introduce evidence of a potential new action mechanism. In the quest of new therapeutic strategies against Chagas disease, the extensive use of pentamidine in human has led to a well-known clinical profile, which could be an advantage over newly synthesized molecules that require more comprehensive trials prior to their clinical use.
The isozymes of photosynthetic phosphoenolpyruvate carboxylase from C4 plants (PEPC-C4) play a critical role in their atmospheric CO2 assimilation and productivity. They are allosterically activated ...by phosphorylated trioses or hexoses, such as d-glucose 6-phosphate, and inhibited by l-malate or l-aspartate. Additionally, PEPC-C4 isozymes from grasses are activated by glycine, serine, or alanine, but the allosteric site for these compounds remains unknown. Here, we report a new crystal structure of the isozyme from Zea mays (ZmPEPC-C4) with glycine bound at the monomer–monomer interfaces of the two dimers of the tetramer, making interactions with residues of both monomers. This binding site is close to, but different from, the one proposed to bind glucose 6-phosphate. Docking experiments indicated that d/l-serine or d/l-alanine could also bind to this site, which does not exist in the PEPC-C4 isozyme from the eudicot plant Flaveria, mainly because of a lysyl residue at the equivalent position of Ser-100 in ZmPEPC-C4. Accordingly, the ZmPEPC-C4 S100K mutant is not activated by glycine, serine, or alanine. Amino acid sequence alignments showed that PEPC-C4 isozymes from the monocot family Poaceae have either serine or glycine at this position, whereas those from Cyperaceae and eudicot families have lysine. The size and charge of the residue equivalent to Ser-100 are not only crucial for the activation of PEPC-C4 isozymes by neutral amino acids but also affect their affinity for the substrate phosphoenolpyruvate and their allosteric regulation by glucose 6-phosphate and malate, accounting for the reported kinetic differences between PEPC-C4 isozymes from monocot and eudicot plants.
Desalination brines from direct seawater intake that get discharged to coastal areas may produce stress responses on benthic marine communities, mostly due to its excess salinity, and especially on ...sessile organisms; in this context, macroalgae have been understudied in desalination ecotoxicological investigations. In this study, we assessed the short- and long-term cellular tolerance responses in two brown species of the macroalgae genus
Dictyota
through controlled laboratory conditions.
Dictyota kunthii
was collected from the eastern Pacific Ocean (average salinity, ~34 psu), whereas
Dictyota dichotoma
was from the Mediterranean Sea (average salinity, ~37 psu). Each macroalgae species was exposed for up to 7 days to two conditions with increased salinity values: +2 and +7 psu above their natural average salinity. Photosynthetic parameters and oxidative stress measurements were determined. The results showed that, in both
Dictyota
species, high salinity values induced reduced photoinhibition (
F
v
/F
m
) but increased the primary productivity (ETR
max
) and light requirement (Ek
ETR
) especially after 7 days. Conversely, the photosynthetic efficiency (α
ETR
) decreased in hypersalinity treatments in
D. dichotoma
, while there were no changes in
D. kunthii
. The reactive oxygen species hydrogen peroxide (H
2
O
2
) was greater at high salinity values at 3 days for
D. dichotoma
and after 7 days in
D. kunthii
, while lipid peroxidation decreases under hypersalinity with time in both species. Despite the evident H
2
O
2
accumulation in both species against hypersalinity, it did not produce oxidative damage and important impairment in the photosynthetic apparatus. These results contribute to understanding the tolerance strategies at the cellular level of
Dictyota
spp., which may be considered as potential candidates for biomonitoring of desalination impacts in the field.
The phase function of the dust coma of comet 67P has been determined from Rosetta/OSIRIS images. This function shows a deep minimum at phase angles near 100°, and a strong backscattering enhancement. ...These two properties cannot be reproduced by regular models of cometary dust, most of them based on wavelength-sized and randomly oriented aggregate particles. We show, however, that an ensemble of oriented elongated particles of a wide variety of aspect ratios, with radii r 10 m, and whose long axes are perpendicular to the direction of the solar radiation, are capable of reproducing the observed phase function. These particles must be absorbing, with an imaginary part of the refractive index of about 0.1 to match the expected geometric albedo, and with porosity in the 60%-70% range.
The current trends of unhealthy lifestyle behaviors in underserved communities are disturbing. Thus, effective health promotion strategies constitute an unmet need.
The purpose of this study was to ...assess the impact of 2 different lifestyle interventions on parents/caregivers of children attending preschools in a socioeconomically disadvantaged community.
The FAMILIA (Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health) study is a cluster-randomized trial involving 15 Head Start preschools in Harlem, New York. Schools, and their children’s parents/caregivers, were randomized to receive either an “individual-focused” or “peer-to-peer–based” lifestyle intervention program for 12 months or control. The primary outcome was the change from baseline to 12 months in a composite health score related to blood pressure, exercise, weight, alimentation, and tobacco (Fuster-BEWAT Score FBS), ranging from 0 to 15 (ideal health = 15). To assess the sustainability of the intervention, this study evaluated the change of FBS at 24 months. Main pre-specified secondary outcomes included changes in FBS subcomponents and the effect of the knowledge of presence of atherosclerosis as assessed by bilateral carotid/femoral vascular ultrasound. Mixed-effects models were used to test for intervention effects.
A total of 635 parents/caregivers were enrolled: mean age 38 ± 11 years, 83% women, 57% Hispanic/Latino, 31% African American, and a baseline FBS of 9.3 ± 2.4 points. The mean within-group change in FBS from baseline to 12 months was ∼0.20 points in all groups, with no overall between-group differences. However, high-adherence participants to the intervention exhibited a greater change in FBS than their low-adherence counterparts: 0.30 points (95% confidence interval: 0.03 to 0.57; p = 0.027) versus 0.00 points (95% confidence interval: −0.43 to 0.43; p = 1.0), respectively. Furthermore, the knowledge by the participant of the presence of atherosclerosis significantly boosted the intervention effects. Similar results were sustained at 24 months.
Although overall significant differences were not observed between intervention and control groups, the FAMILIA trial highlights that high adherence rates to lifestyle interventions may improve health outcomes. It also suggests a potential contributory role of the presentation of atherosclerosis pictures, providing helpful information to improve future lifestyle interventions in adults.
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The muscle evaluation of this case study was applied to a group of workers from the Colombian company, Enel-Codensa. To achieve this, eight muscles were evaluated in which electromyography (EMG) was ...used in 20 volunteer participants, consisting of 12 electrical technicians and eight volunteers. The aim of the study was to determine whether a decrease in muscular effort occurred when the workers used the exoskeleton, to compare experienced and inexperienced subjects, and ultimately to analyze whether muscular activity varied with the use of an exoskeleton. As a result, muscular effort was lower in all the muscles when using the exoskeleton. However, the activity remained above 10% of muscular effort on average, which can generate muscular fatigue such activity is maintained during an 8-hour day. The analysis showed that there is no difference when performing the activity with or without an exoskeleton except for the flexor carpi radialis muscle. Alternatively, when comparing the two groups, experts, and novices, it was found that the muscular activity of the experts was greater by 1%. As the study was performed, it was found that among this group, there was an equality of measurements in six of the eight muscles. In conclusion, the scaffold erection test demonstrated muscular effort in the forearm and arm for both samples. To reduce this muscular effort, it is recommended to provide tools or redesign the task.
La evaluación muscular del caso de estudio se realizó a un grupo de trabajadores de la empresa colombiana Enel-Codensa. Para lograrlo, se evaluaron ocho músculos. Se hizo uso de electromiografía (EMG) en 20 participantes voluntarios, doce lineros de alta tensión y ocho voluntarios. Lo anterior, con el fin de determinar si existe o no disminución en el esfuerzo muscular al usar el exoesqueleto; y comparar también si entre sujetos con experiencia y sin experiencia, la actividad muscular varia al usar el exoesqueleto. Como resultado se obtuvo que el esfuerzo muscular es menor en todos los músculos al usar el exoesqueleto. Sin embargo, la actividad se mantiene por encima del 10% de esfuerzo muscular en promedio, lo que puede generar fatiga muscular si se mantiene durante una jornada de ocho horas. El análisis estadístico de diferencia de medias dio como resultado que no existe diferencia entre realizar la actividad con o sin exoesqueleto excepto para el musculo Flexor Carpi Radial. Por otra parte, al realizar el comparativo entre los dos grupos, expertos y novatos, se encontró que la actividad muscular de los expertos es mayor en un 1%. Cuando se realizaron pruebas estadísticas de comparación de medias entre este grupo se encontró igualdad de medias en seis de los ocho músculos. En conclusión, para la prueba de armado de andamio, hay esfuerzo muscular en el antebrazo y brazo para ambas muestras. Para disminuir el esfuerzo muscular se recomienda brindar herramientas que contribuyan a una disminución de este o rediseñar la tarea.
The International Initiative on Thrombosis and Cancer is an independent academic working group of experts aimed at establishing global consensus for the treatment and prophylaxis of cancer-associated ...thrombosis. The 2013, 2016, and 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines have been made available through a free, web-based mobile phone application. The 2022 clinical practice guidelines, which are based on a literature review up to Jan 1, 2022, include guidance for patients with cancer and with COVID-19. Key recommendations (grade 1A or 1B) include: (1) low-molecular-weight heparins (LMWHs) for the initial (first 10 days) treatment and maintenance treatment of cancer-associated thrombosis; (2) direct oral anticoagulants for the initial treatment and maintenance treatment of cancer-associated thrombosis in patients who are not at high risk of gastrointestinal or genitourinary bleeding, in the absence of strong drug–drug interactions or of gastrointestinal absorption impairment; (3) LMWHs or direct oral anticoagulants for a minimum of 6 months to treat cancer-associated thrombosis; (4) extended prophylaxis (4 weeks) with LMWHs to prevent postoperative venous thromboembolism after major abdominopelvic surgery in patients not at high risk of bleeding; and (5) primary prophylaxis of venous thromboembolism with LMWHs or direct oral anticoagulants (rivaroxaban or apixaban) in ambulatory patients with locally advanced or metastatic pancreatic cancer who are treated with anticancer therapy and have a low risk of bleeding.
Postreperfusion liver biopsy (PRB) can assess the degree of ischemia/reperfusion injury (IRI) after orthotopic liver transplantation (OLT). The influence of IRI on graft outcomes and overall survival ...is controversial.
To determine the correlation between the severity of IRI in PRB and overall graft and patient survival and, secondarily, to identify factors on PRB that predict poor graft outcomes.
This is a retrospective analysis of all patients who underwent OLT using donation after brain death (DBD) with PRB. The severity of IRI in PRB was graded. Predictors of IRI were assessed using univariate and multivariate analysis and the Kaplan–Meier with log rank test for the graft and overall survival, respectively.
We included 280 OLTs (64.7%). The histopathological assessment of IRI severity was as follows: no IRI (N = 96, 34.3%), mild IRI (N = 65; 23.2%), moderate IRI (N = 101; 36.1%), and severe IRI (N = 18; 6.4%). The incidence rates of initial good graft function (IGGF), primary nonfunction and early allograft dysfunction (EAD) were 32.5%, 3.9%, and 18.6%, respectively. Severe IRI was associated with a lower incidence of IGGF (OR: 0.34, 95% CI 0.12–0.92; P = 0.03). Patients with severe IRI tended to have a higher incidence of EAD (33.2% vs. 18.6, P = 0.23). The cold ischemia time was an independent predictor of severe IRI on the multivariate analysis. Severe IRI was associated with poor 1- and 5-year overall survival rates (67% and 44%, respectively, compared with 84 and 68% in nonsevere IRI). Patients with severe IRI exhibited worse graft and overall survival.
Cold ischemia time predicts the development of severe IRI. Patients with severe IRI show worse graft and overall survival and a lower incidence of IGGF, suggesting that histopathological findings could be useful for identifying patients at high risk of worse outcomes after OLT.
Indomethacin is a non-selective NSAID used against pain and inflammation. Although cyclooxygenase (COX) inhibition is considered indomethacin’s primary action mechanism, COX-independent ways are ...associated with beneficial effects in cancer. In colon cancer cells, the activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) is related to the increase in spermidine/spermine-Nsup.1 -acetyltransferase-1 (SSAT-1), a key enzyme for polyamine degradation, and related to cell cycle arrest. Indomethacin increases the SSAT-1 levels in lung cancer cells; however, the mechanism relying on the SSAT-1 increase is unclear. Thus, we asked for the influence of the PPAR-γ on the SSAT-1 expression in two lung cancer cell lines: H1299 and A549. We found that the inhibition of PPAR-γ with GW9662 did not revert the increase in SSAT-1 induced by indomethacin. Because the mRNA of SSAT-1 suffers a pre-translation retention step by nucleolin, a nucleolar protein, we explored the relationship between indomethacin and the upstream translation regulators of SSAT-1. We found that indomethacin decreases the nucleolin levels and the cyclin-dependent kinase 1 (CDK1) levels, which phosphorylates nucleolin in mitosis. Overexpression of nucleolin partially reverts the effect of indomethacin over cell viability and SSAT-1 levels. On the other hand, Casein Kinase, known for phosphorylating nucleolin during interphase, is not modified by indomethacin. SSAT-1 exerts its antiproliferative effect by acetylating polyamines, a process reverted by the polyamine oxidase (PAOX). Recently, methoctramine was described as the most specific inhibitor of PAOX. Thus, we asked if methoctramine could increase the effect of indomethacin. We found that, when combined, indomethacin and methoctramine have a synergistic effect against NSCLC cells in vitro. These results suggest that indomethacin increases the SSAT-1 levels by reducing the CDK1-nucleolin regulatory axis, and the PAOX inhibition with methoctramine could improve the antiproliferative effect of indomethacin.
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