Publications by authors named "Aline de Souza"

92 Publications

Equine parvovirus-hepatitis is detected in South America, Brazil.

Transbound Emerg Dis 2021 Jul 8. Epub 2021 Jul 8.

Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brasil.

The equine parvovirus-hepatitis (EqPV-H), recently identified in association with serum hepatitis in horses (also known as Theiler's disease), has been so far described in horses from North America, Asia and Europe. There is no information regarding its circulation in South America. Our retrospective study (2013-2016) screened by EqPV-H nested-PCR a total of 96 Brazilian horses grouped according to previous status of infection: Known to be positive for one or more horse "hepatitis viruses" (equine hepacivirus, equine pegivirus-EPgV and Theiler's disease-associated virus) and known to be negative. Serum biochemical parameters (aspartate aminotransferase, gamma-glutamyl transferase and glutamate dehydrogenase) were evaluated in EqPV-H positive horses. Molecular characteristics of the isolates were analyzed by DNA sequencing and phylogenetic analysis. EqPV-H DNA was detected in 12.5% (12/96) of horses from 46.6% (7/15) of the farms evaluated. Similar results were obtained between coinfected group (12.3%, 7/57) and non-coinfected group (12.8%, 5/39). Coinfection with EPgV was the most frequent (5/7). Altered serum biochemical parameters suggested a subclinical hepatopathy in some animals (3/12), but the majority presented no clinical or laboratory signs of infection. Nucleotide identity was higher than 94% in comparison with previous isolates. In conclusion, we demonstrated, for the first time in South America, the circulation of EqPV-H. The Brazilian isolates presented a low genetic variability, thus corroborating previous evidence.
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http://dx.doi.org/10.1111/tbed.14226DOI Listing
July 2021

Cattle In Vitro Induced Pluripotent Stem Cells Generated and Maintained in 5 or 20% Oxygen and Different Supplementation.

Cells 2021 Jun 17;10(6). Epub 2021 Jun 17.

Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo (USP), Pirassununga 13635-000, Brazil.

The event of cellular reprogramming into pluripotency is influenced by several factors, such as in vitro culture conditions (e.g., culture medium and oxygen concentration). Herein, bovine iPSCs (biPSCs) were generated in different levels of oxygen tension (5% or 20% of oxygen) and supplementation (bFGF or bFGF + LIF + 2i-bFL2i) to evaluate the efficiency of pluripotency induction and maintenance in vitro. Initial reprogramming was observed in all groups and bFL2i supplementation initially resulted in a superior number of colonies. However, bFL2i supplementation in low oxygen led to a loss of self-renewal and pluripotency maintenance. All clonal lines were positive for alkaline phosphatase; they expressed endogenous pluripotency-related genes , and . However, expression was decreased throughout the passages without the influence of oxygen tension. and were upregulated by low oxygen. The biPSCs were immunofluorescence-positive stained for OCT4 and SOX2 and they formed embryoid bodies which differentiated in ectoderm and mesoderm (all groups), as well as endoderm (one line from bFL2i in high oxygen). Our study is the first to compare high and low oxygen environments during and after induced reprogramming in cattle. In our conditions, a low oxygen environment did not favor the pluripotency maintenance of biPSCs.
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http://dx.doi.org/10.3390/cells10061531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234940PMC
June 2021

Caloric Restriction and Cardiovascular Health: the Good, the Bad, and the Renin-Angiotensin System.

Physiology (Bethesda) 2021 07;36(4):220-234

Division of Nephrology and Hypertension, Department of Medicine, Georgetown University, Washington, District of Columbia.

Much excitement exists over the cardioprotective and life-extending effects of caloric restriction (CR). This review integrates population studies with experimental animal research to address the positive and negative impact of mild and severe CR on cardiovascular physiology and pathophysiology, with a particular focus on the renin-angiotensin system (RAS). We also highlight the gaps in knowledge and areas ripe for future physiological research.
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http://dx.doi.org/10.1152/physiol.00002.2021DOI Listing
July 2021

Estimation of Health-Related Quality of Life Losses Owing to a Technological Disaster in Brazil Using EQ-5D-3L: A Cross-Sectional Study.

Value Health Reg Issues 2021 Jun 10;26:66-74. Epub 2021 Jun 10.

School of Medicine, University of Leeds, Leeds, England, UK.

Objectives: In 2015, a dam collapsed at Samarco iron ore mine in the municipality of Mariana, Brazil, and contaminated more than 600 km of watercourses and destroyed almost 1600 acres of vegetation. Nineteen people died and more than 600 families lost their homes. This study aimed to estimate health-related quality of life (HRQoL) losses owing to this disaster.

Methods: We collected data from a probabilistic sample of 459 individuals aged 15 years or older. Household face-to-face interviews were conducted in December 2018. Pre-event data were not available for this population, so respondents were asked to evaluate at present and in retrospect their health status using EQ-5D-3L. The Minas Gerais societal value sets for EQ-5D-3L health preferences, estimated in 2011, were used to calculate utility losses. The health loss estimation from EQ-5D will form the basis for the calculation of compensation payments for the victims.

Results: Approximately 74% of the study population suffered some HRQoL loss. On average, EQ-5D index values decreased from 0.95 to 0.76. The greatest effects were observed for the anxiety/depression dimension, followed by pain/discomfort. Before the tragedy, the proportion of individuals with severe anxiety/depression and pain/discomfort was equal to 1% rising to 23% and 11%, respectively.

Conclusions: Catastrophic losses owing to the Samarco disaster were found. The EQ-5D-3L instrument showed feasibility and sensitiveness to measure HRQoL losses owing to a negative health shock in a low-income Brazilian population.
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http://dx.doi.org/10.1016/j.vhri.2021.02.003DOI Listing
June 2021

Porcine Primordial Germ Cell-Like Cells Generated from Induced Pluripotent Stem Cells Under Different Culture Conditions.

Stem Cell Rev Rep 2021 Jun 11. Epub 2021 Jun 11.

Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, SP, Brazil.

Culture conditions regulate the process of pluripotency acquisition and self-renewal. This study aimed to analyse the influence of the in vitro environment on the induction of porcine induced pluripotent stem cell (piPSCs) differentiation into primordial germ cell-like cells (pPGCLCs). piPSC culture with different supplementation strategies (LIF, bFGF, or LIF plus bFGF) promoted heterogeneous phenotypic profiles. Continuous bFGF supplementation during piPSCs culture was beneficial to support a pluripotent state and the differentiation of piPSCs into pPGCLCs. The pPGCLCs were positive for the gene and protein expression of pluripotent and germinative markers. This study can provide a suitable in vitro model for use in translational studies and to help answer numerous remaining questions about germ cells.
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http://dx.doi.org/10.1007/s12015-021-10198-8DOI Listing
June 2021

Dynapenia, abdominal obesity or both: which accelerates the gait speed decline most?

Age Ageing 2021 Jun 3. Epub 2021 Jun 3.

Physical Therapy Postgraduate Program, Federal University of Sao Carlos, Sao Carlos, Brazil.

Objective: to investigate whether the combination of dynapenia and abdominal obesity is worse than these two conditions separately regarding gait speed decline over time.

Methods: a longitudinal study was conducted involving 2,294 individuals aged 60 years or older free of mobility limitation at baseline (gait speed >0.8 m/s) who participated in the English Longitudinal Study of Ageing. Dynapenia was determined as a grip strength <26 kg for men and <16 kg for women. Abdominal obesity was determined as a waist circumference >102 cm for men and >88 cm for women. The participants were divided into four groups: non-dynapenic/non-abdominal obese (ND/NAO); only abdominal obese (AO); only dynapenic (D) and dynapenic/abdominal obese (D/AO). Generalised linear mixed models were used to analyse gait speed decline (m/s) as a function of dynapenia and abdominal obesity status over an 8-year follow-up period.

Results: over time, only the D/AO individuals had a greater gait speed decline (-0.013 m/s per year, 95% CI: -0.024 to -0.002; P < 0.05) compared to ND/NAO individuals. Neither dynapenia nor abdominal obesity only was associated with gait speed decline.

Conclusion: dynapenic abdominal obesity is associated with accelerated gait speed decline and is, therefore, an important modifiable condition that should be addressed in clinical practice through aerobic and strength training for the prevention of physical disability in older adults.
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http://dx.doi.org/10.1093/ageing/afab093DOI Listing
June 2021

Are biomechanical strategies to perform functional activities different between individuals with subacute and chronic stroke?

NeuroRehabilitation 2021 May 6. Epub 2021 May 6.

Department of Physical Therapy, Federal University of Rio Grande do Norte, Natal-RN, Brazil.

Objective: To evaluate if the capacity to perform functional mobility activities change within the first year post-stroke using the Timed "Up and Go" Assessment of Biomechanical Strategies (TUG-ABS).

Methods: A cross-sectional study was conducted with thirty-eight stroke individuals. A motion analysis system was used during the Timed "Up and Go" (TUG) test to evaluate the following activities: sit-to-stand, gait, turn, and stand-to-sit. Kinematic variables related to each activity were obtained in addition to TUG-ABS scores. The ability to perform the activities was compared between subacute (up to 3 months post-stroke, n = 21) and chronic participants (4 to 12 months post-stroke, n = 17) using Mann-Whitney U tests (α= 5%).

Results: Results were expressed as median difference (MD) and 95% confidence intervals (95% CI). TUG-ABS scores: Sit-to-stand (MD = 0, 95% CI = 0.0 to 1), gait (MD = 0, 95% CI = 0.0 to 1), stand-to-sit (MD = 0, 95% CI = 0.0 to 1), and total score (MD = 2.0, 95% CI = 0.0 to 6) were not different between groups. Subacute participants presented significant better scores during turn activity (MD = 2.0, 95% CI 0.0 to 2.0). All kinematic variables were not different between participants.

Conclusions: Capacity to perform functional activities was not different within the first year post-stroke, suggesting that biomechanical strategies are developed within the first three months following stroke.
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http://dx.doi.org/10.3233/NRE-210027DOI Listing
May 2021

Preliminary study of ovariectomy and chronic losartan-induced alterations in brain AT receptors.

Brain Res 2021 Sep 13;1766:147520. Epub 2021 May 13.

College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, United States; Department of Pharmacology and Physiology, School of Medicine, Georgetown University, Washington, DC, United States. Electronic address:

Women who undergo oophorectomy prior to the age of natural menopause have a higher risk of neurological and psychological impairment. Treatment with the angiotensin receptor blocker (ARB) losartan for 10 weeks following ovariectomy of Long-Evans rats at 3 months of age reduced the ovariectomy-induced cognitive decrements. Following completion of the behavioral experiments, (Campos et al., 2019), the brains were harvested for preliminary receptor autoradiographic studies of AT receptor (ATR) binding in selected brain regions using quantitative densitometric analysis of autoradiograms of I-sarcosine, isoleucine angiotensin II binding. Four of the brain regions (amygdala, ventral subiculum, piriform cortex, and cingulate cortex) are associated with cognitive and emotional behavior while one (lateral hypothalamus) is associated with homeostasis. The density of ATR varied by region: ventral subiculum > amygdala and cingulate cortex, and piriform cortex > cingulate cortex. Losartan treatment decreased ATR binding in the ventral subiculum of sham and ovariectomized rats by 41.6%, and 46% in the piriform cortex of the sham rats, but tended to increase ATR binding in the piriform cortex and cingulate cortex 77% and 107%, respectively, in the ovariectomized rats. ATR binding did not differ significantly between intact male and sham-vehicle female rats among surveyed brain regions. These results suggest that losartan-induced changes in brain ATR expression may contribute to the reduced anxiety-like behavior and memory impairments seen in ovariectomized rats, but replication of these observations will be needed to determine the extent to which brain ATR changes mediate the adverse behavioral effects of ovariectomy.
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http://dx.doi.org/10.1016/j.brainres.2021.147520DOI Listing
September 2021

C-PK11195 plasma metabolization has the same rate in multiple sclerosis patients and healthy controls: a cross-sectional study.

Neural Regen Res 2021 Dec;16(12):2494-2498

Laboratory of Nuclear Medicine (LIM43), Department of Radiology and Oncology; Department of Neurology, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.

C-PK11195 is a positron emitter tracer used for Positron Emission Tomography (PET) imaging of innate immune cell activation in studies of neuroinflammatory diseases. For the image quantitative analysis, it is necessary to quantify the intact fraction of this tracer in the arterial plasma during imaging acquisition (plasma intact fraction). Due to the complexity and costs involved in this analysis it is important to evaluate the real necessity of individual analysis in each C-PK11195 PET imaging acquisition. The purpose of this study is to compare C-PK11195 plasma metabolization rate between healthy controls and multiple sclerosis (MS) patients and evaluate the interference of sex, age, treatment, and disease phenotype in the tracer intact fraction measured in arterial plasma samples. C-PK11195 metabolization rate in arterial plasma was quantified by high performance liquid chromatography in samples from MS patients (n = 50) and healthy controls (n = 23) at 20, 45, and 60 minutes after C-PK11195 injection. Analyses were also stratified by sex, age, treatment type, and MS phenotype. The results showed no significant differences in the metabolization rate of healthy controls and MS patients, or in the stratified samples. In conclusion, C-PK11195 metabolization has the same rate in patients with MS and healthy controls, which is not affected by sex, age, treatment, and disease phenotype. Thus, these findings could contribute to exempting the necessity for tracer metabolization determination in all C-PK11195 PET imaging acquisition, by using a population metabolization rate average. The study procedures were approved by the Ethics Committee for Research Projects Analysis of the Hospital das Clinicas of the University of Sao Paulo Medical School (approval No. 624.065) on April 23, 2014.
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http://dx.doi.org/10.4103/1673-5374.313062DOI Listing
December 2021

Proteinase-activated receptor-2 (PAR2) on blood pressure and electrolyte handling in the late pregnant rat.

Exp Physiol 2021 Jun 12;106(6):1373-1379. Epub 2021 May 12.

Department of Biology, Appalachian State University, North Carolina Research Campus, Kannapolis, North Carolina, USA.

New Findings: What is the central question of this study? Pregnancy requires marked renal sodium and potassium retention and cumulative plasma volume expansion, in the setting of reduced blood pressure. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in virgin and normal pregnant rats. What is the main finding and its importance? PAR2 expression and sensitivity to activation are increased in pregnancy. This implicates a possible role for PAR2 in supporting the renal/vascular adaptations of pregnancy required for normal maternal plasma volume expansion.

Abstract: A healthy pregnancy involves renal and systemic haemodynamic adaptations, which allow renal sodium and potassium retention and cumulative plasma volume expansion, accompanied by a decline in blood pressure attributable to a reduction in the total peripheral vascular resistance. When these adaptations do not occur, pregnancy is compromised. The mechanisms permitting these opposing adaptations are largely unknown. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in female virgin and normal late pregnant (LP) rats. We measured the mRNA expression of PAR2 in the renal cortex, outer medulla and inner medulla of virgin and LP rats using quantitative real-time PCR. We also measured in vivo blood pressure, natriuretic and kaliuretic responses to PAR2-activating peptide (SLIGRL-NH ) in anaesthetized virgin and LP rats. We found that PAR2 mRNA was increased in the inner medulla of LP rats. We also found that LP rats had larger decreases in blood pressure and increases in net sodium retention compared with virgin rats. These findings suggest that pregnancy enhances sensitivity to the blood pressure-lowering and sodium-retaining effects of PAR2.
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http://dx.doi.org/10.1113/EP088170DOI Listing
June 2021

Male bias in ACE2 basic science research: missed opportunity for discovery in the time of COVID-19.

Am J Physiol Regul Integr Comp Physiol 2021 06 13;320(6):R925-R937. Epub 2021 Apr 13.

Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University, Washington, District of Columbia.

Throughout the world, including the United States, men have worse outcomes from COVID-19 than women. SARS-CoV-2, the causative virus of the COVID-19 pandemic, uses angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. ACE2 is a member of the renin-angiotensin system (RAS) and plays an important role in counteracting the harmful effects mediated by the angiotensin type 1 receptor. Therefore, we conducted Ovid MEDLINE and Embase database searches of basic science studies investigating the impact of the biological variable of sex on ACE2 expression and regulation from 2000, the year ACE2 was discovered, through December 31, 2020. Out of 2,131 publications, we identified 853 original research articles on ACE2 conducted in primary cells, tissues, and/or whole mammals excluding humans. The majority (68.7%) of these studies that cited the sex of the animal were conducted in males, while 11.2% were conducted solely in females; 9.26% compared ACE2 between the sexes, while 10.8% did not report the sex of the animals used. General findings are that sex differences are tissue-specific and when present, are dependent upon gonadal state. Renal, cardiac, and adipose ACE2 is increased in both sexes under experimental conditions that model co-morbidities associated with worse COVID-19 outcomes including hypertension, obesity, and renal and cardiovascular diseases; however, ACE2 protein was generally higher in the males. Studies in knockout mice indicate ACE2 plays a greater role in protecting the female from developing hypertension than the male. Studying the biological variable of sex in ACE2 research provides an opportunity for discovery in conditions involving RAS dysfunction and will shed light on sex differences in COVID-19 severity.
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http://dx.doi.org/10.1152/ajpregu.00356.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203415PMC
June 2021

Step by Step about Germ Cells Development in Canine.

Animals (Basel) 2021 Feb 25;11(3). Epub 2021 Feb 25.

Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga 13635-900, Brazil.

Primordial germ cells (PGCs) have been described as precursors of gametes and provide a connection within generations, passing on the genome to the next generation. Failures in the formation of gametes/germ cells can compromise the maintenance and conservation of species. Most of the studies with PGCs have been carried out in mice, but this species is not always the best study model when transposing this knowledge to humans. Domestic animals, such as canines (canine), have become a valuable translational research model for stem cells and therapy. Furthermore, the study of canine germ cells opens new avenues for veterinary reproduction. In this review, the objective is to provide a comprehensive overview of the current knowledge on canine germ cells. The aspects of canine development and germ cells have been discussed since the origin, specifications, and development of spermatogonial canine were first discussed. Additionally, we discussed and explored some in vitro aspects of canine reproduction with germ cells, such as embryonic germ cells and spermatogonial stem cells.
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http://dx.doi.org/10.3390/ani11030598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996183PMC
February 2021

Characterization of class II fumarase from Schistosoma mansoni provides the molecular basis for selective inhibition.

Int J Biol Macromol 2021 Apr 4;175:406-421. Epub 2021 Feb 4.

Laboratório de Cristalografia de Proteínas, Departamento de Ciências BioMoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. Electronic address:

Schistosomiasis is a neglected tropical disease that affects more than 250 million people worldwide. The only drug available for its treatment undergoes first-pass hepatic metabolism and is not capable of preventing reinfection, which makes the search of new therapies urgently needed. Due to the essential role of fumarases in metabolism, these enzymes represent potential targets for developing novel schistosomiasis treatments. Here, we evaluate the expression profiles for class I and class II fumarases from Schistosoma mansoni (SmFH and SmFH, respectively), and report the complete characterization of SmFH. The first SmFH structure in complex with L-malate was determined at 1.85 Å resolution. The significant thermoshift observed for SmFH in the presence of identified ligands makes the differential scanning fluorimetry an adequate technique for ligand screening. A complete kinetic characterization of SmFH was performed, and comparison with the human fumarase (HsFH) revealed differences regarding the turnover number (k). Structural characterization allowed us to identify differences between SmFH and HsFH that could be explored to design new selective inhibitors. This work represents the very first step towards validate the fumarases as drug targets to treat schistosomiasis. Our results provide the structural basis to rational search for selective ligands.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.01.180DOI Listing
April 2021

Clinical hematological and biochemical parameters in Swiss, BALB/c, C57BL/6 and B6D2F1 .

Animal Model Exp Med 2020 Dec 18;3(4):304-315. Epub 2020 Dec 18.

Health Sciences Center Institute of Microbiology Paulo de Góes Federal University of Rio de Janeiro Rio de Janeiro RJ Brazil.

Background: Animal models are widely used in scientific research in order to obtain information from a whole organism under a specific set of experimental conditions. Various lineages of mice have been used to investigate diseases and new therapeutic strategies, and, consequently, hematological and biochemical tests in these laboratory animals are essential to validate scientific studies. Our study seeks to establish reference values for hematological and biochemical parameters of four lineages of mice.

Methods: We evaluated the hematological and biochemical profiles of 20 males and 20 females from the lineages Swiss (heterogeneous), BALB/c and C57BL/6 (isogenic), and B6D2F1 (hybrid), totaling 160 mice. Analysis were standardized using the systems pocH-100iV ™ for 19 hematological parameters and VITROS 350 for 12 biochemical parameters.

Results: Results are shown as means and standard deviation, grouped by lineage and genre. Comparing the values obtained in this study with the values from previous studies, some variations were detected, which could be explained by differences in methodologies or individual variability.

Conclusion: Thus our study shows that knowledge and disclosure of the values of physiological parameters of laboratory animals is necessary, and emphasises the importance of considering variations influenced by gender, lineage and genotype in the choice of the best experimental model.
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http://dx.doi.org/10.1002/ame2.12139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824965PMC
December 2020

Young haploidentical donor versus fully matched elderly donor: An observational study on patients aged 50 years or older underwent hematopoietic progenitor cells transplantation.

Transfus Apher Sci 2021 Apr 29;60(2):103032. Epub 2020 Dec 29.

Hospital Israelita Albert Einstein, Brazil.

Introduction: Stem cell transplantation has been a therapeutic option for increasingly older patients but the search for the donor is an additional question in this context. Currently the ideal donor is a sibiling with fully compatible human leukocyte antigens, but when it is an elderly patient there is a high probability that this donor is also elderly, and the donor age has been related to worse outcomes and the possible comorbidities may render the donor ineligible.

Objective: To compare, in patients aged 50 years or older, the overall survival of patients whose donor had haploidentical HLA compatibility and under 50 years of age ("young" donor) versus patients whose donor had a total HLA compatibility and 50 years of age or older ("elderly" donor).

Methods: This is a consecutive retrospective descriptive observational epidemiological study. All patients were treated during the period from January, 2010 to April, 2019. Overall survival of patients 50 years of age and older was the primary outcome of the study.

Result: We included 53 patients. In the multivariate analysis we found no statistically significant difference in overall survival between patients whose donor had fully HLA compatible aged 50 years and older and patients whose donor had haploidentical HLA compatible and aged up to 50 years (p = 0.135).

Conclusion: The results obtained in the study show that for patients aged 50 years or older, a donor with haploidentical human leukocyte antigen compatibility and age below 50 years can be chosen without impairing overall survival.
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http://dx.doi.org/10.1016/j.transci.2020.103032DOI Listing
April 2021

Lipid-based nanocarriers co-loaded with artemether and triglycerides of docosahexaenoic acid: Effects on human breast cancer cells.

Biomed Pharmacother 2021 Feb 24;134:111114. Epub 2020 Dec 24.

Laboratory of Pharmaceutics and Nanotechnology (LDGNano), School of Pharmacy, Federal University of Ouro Preto, Minas Gerais, Brazil; Doctoral Program in Pharmaceutical Nanotechnology (NanoFarma Network), School of Pharmacy, Federal University of Ouro Preto, Minas Gerais, Brazil. Electronic address:

Artemether (ART) was combined with triglyceride of docosahexaenoic acid (DHA) as the lipid-core in nanoemulsions (NE), nanostructured lipid carriers (NLC), and PEG-PLA nanocapsules (NC) formulations, and their effects on human breast cancer cells were evaluated. ART has been extensively used for malaria and has also therapeutic potential against different tumor cells in a repositioning strategy. The concentration-dependent cytotoxicity in vitro was determined in tumor lineages, MDA-MB-231 and MCF-7, and non-tumor MCF-10A cells for free-ART/DHA combination and its formulations. The cells were monitored for viability, effects on cell migration and clonogenicity, cell death mechanism, and qualitative and quantitative cell uptake of nanocarriers. The lipid-nanocarriers showed mean sizes over the range of 110 and 280 nm with monodisperse populations and zeta potential values ranging from -21 to -67 mV. The ART encapsulation efficiencies varied from 57 to 83 %. ART/DHA co-loaded in three different lipid nanocarriers reduced the MDA-MB-231 and MCF-7 viability in a dose-dependent manner with enhanced selectivity toward tumor cell lines. They also reduced clonogenicity and the ability of cells to migrate showing antimetastatic potential in both cell lines and triggered apoptosis in MCF-7 cells. Confocal microscopy and flow cytometry analysis showed that NC, NLC, and NE were rapidly internalized by cells, with higher interaction displayed by NE with MCF-7 cells compared to NC and NLC that was correlated with the strongest NE-fluorescence in cells. Therefore, this study not only demonstrated the value of this new combination of ART/DHA as a new strategy for breast cancer therapy but also showed enhanced cytotoxicity and potential metastatic activity of lipid-based formulations against human breast cancer cells that indicate great potential for pre-clinical and clinical translation.
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http://dx.doi.org/10.1016/j.biopha.2020.111114DOI Listing
February 2021

Generation of neural progenitor cells from porcine-induced pluripotent stem cells.

J Tissue Eng Regen Med 2020 12 23;14(12):1880-1891. Epub 2020 Nov 23.

Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga, Brazil.

In this study, porcine embryonic fibroblasts (pEFs) were reprogrammed into porcine-induced pluripotent stem cells (piPSCs) using either human or mouse specific sequences for the OCT4, SOX2, c-Myc, and KLF4 transcription factors. In total, three pEFs lines were reprogrammed, cultured for at least 15 passages, and characterized regarding their pluripotency status (alkaline phosphatase expression, embryoid body formation, expression of exogenous and endogenous genes, and immunofluorescence). Two piPSC lines were further differentiated, using chemical inhibitors, into putative neural progenitor-like (NPC-like) cells with subsequent analyses of their morphology and expression of neural markers such as NESTIN and GFAP as well as immunofluorescent labeling of NESTIN, β-TUBULIN III, and VIMENTIN. NPC-like cells were positive for all the neural markers tested. These results evidence of the generation of porcine NPC-like cells after in vitro induction with chemical inhibitors, representing an adequate model for future regenerative and translational medicine research.
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http://dx.doi.org/10.1002/term.3143DOI Listing
December 2020

Cost-effectiveness of serological tests for human visceral leishmaniasis in the Brazilian scenario.

PLoS Negl Trop Dis 2020 10 8;14(10):e0008741. Epub 2020 Oct 8.

Pesquisa Clínica e Políticas Públicas em Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz, Barro Preto, Belo Horizonte, Minas Gerais, Brasil.

Human visceral leishmaniasis (VL) is a severe and potentially fatal parasitic disease if not correctly diagnosed and treated. Brazil is one of the three countries most endemic for VL and, like most countries affected by this disease, has a large budget constraint for the incorporation of new health technologies. Although different diagnostic tests for VL are currently available in the country, economic studies evaluating diagnostic kits are scarce. The objective of this study was to conduct a cost-effectiveness analysis of the nine available diagnostic tests for human VL in HIV-infected and uninfected patients in Brazil. The perspective of analysis was the Brazilian public health system, and the outcome of interest was "cases diagnosed correctly". The costs of the tests were estimated using the microcosting technique, and comparisons were performed with decision trees. Sensitivity analyses were explored applying variations in cost and effectiveness values. For VL diagnosis among HIV-uninfected patients, using blood samples for the rapid tests (RDTs), the noncommercial direct agglutination test (DAT-LPC) and IT-LEISH were cost-effective tests compared with the baseline OnSite test, but they presented different incremental cost-effectiveness ratios (ICER) of US$7.04 and US$ 205.40, respectively. Among HIV-infected patients, DAT-LPC was the most cost-effective diagnostic test. Comparisons among the tests with the same methodology, based on the low ICER values, revealed that IT-LEISH was the most cost-effective test among the RDTs and the Ridascreen Leishmania Ab among the ELISA tests. These results confirm that cost-effectiveness analyses can provide useful information to support the incorporation of new health technologies within a known scenario and willingness to pay threshold. It was observed that tests based on the same methodologies presented different cost-effectiveness ratios for the same group of patients and that different tests should be recommended for different patient groups. DAT-LPC was an important cost-effective strategy for all patients, requiring minimum laboratorial infrastructure, and IT-LEISH was the cost-effective test for VL screening in HIV-uninfected patients. IT-LEISH and DAT-LPC have complementary profiles and should both be provided by the Brazilian health system.
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http://dx.doi.org/10.1371/journal.pntd.0008741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544087PMC
October 2020

subsp. Strains Fb7 and 9a5c from Citrus Display Differential Behavior, Secretome, and Plant Virulence.

Int J Mol Sci 2020 Sep 15;21(18). Epub 2020 Sep 15.

Institute of Biotechnology, Federal University of Uberlandia, Av. Amazonas, Bloco 2E, Campus Umuarama, 38400-902 Uberlandia MG, Brazil.

colonizes the xylem of various cultivated and native plants worldwide. Citrus production in Brazil has been seriously affected, and major commercial varieties remain susceptible to Citrus Variegated Chlorosis (CVC). Collective cellular behaviors such as biofilm formation influence virulence and insect transmission of . The reference strain 9a5c produces a robust biofilm compared to Fb7 that remains mostly planktonic, and both were isolated from symptomatic citrus trees. This work deepens our understanding of these distinct behaviors at the molecular level, by comparing the cellular and secreted proteomes of these two CVC strains. Out of 1017 identified proteins, 128 showed differential abundance between the two strains. Different protein families were represented such as proteases, hemolysin-like proteins, and lipase/esterases, among others. Here we show that the lipase/esterase LesA is among the most abundant secreted proteins of CVC strains as well, and demonstrate its functionality by complementary activity assays. More severe symptoms were observed in inoculated with strain Fb7 compared to 9a5c. Our results support that systemic symptom development can be accelerated by strains that invest less in biofilm formation and more in plant colonization. This has potential application in modulating the bacterial-plant interaction and reducing disease severity.
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http://dx.doi.org/10.3390/ijms21186769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555403PMC
September 2020

Association of Serum 25-Hydroxyvitamin D Deficiency with Risk of Incidence of Disability in Basic Activities of Daily Living in Adults >50 Years of Age.

J Nutr 2020 11;150(11):2977-2984

Postgraduate Program in Physical Therapy, Federal University of São Carlos, São Carlos, Brazil.

Background: Vitamin D deficiency compromises muscle function and is related to the etiology of several clinical conditions that can contribute to the development of disability. However, there are few epidemiological studies investigating the association between vitamin D deficiency and the incidence of disability.

Objectives: We aimed to assess whether vitamin D deficiency is associated with the incidence of disability in basic activities of daily living (BADL) and to verify whether there are sex differences in this association.

Methods: A 4-y follow-up study was conducted involving individuals aged 50 y or older who participated in ELSA (English Longitudinal Study of Ageing). The sample consisted of 4814 participants free of disability at baseline according to the modified Katz Index. Vitamin D was assessed by serum 25-hydroxyvitamin D [25(OH)D] concentrations and the participants were classified as sufficient (>50 nmol/L), insufficient (>30 to ≤50 nmol/L), or deficient (≤30 nmol/L). Sociodemographic, behavioral, and clinical characteristics were also investigated. BADL were re-evaluated after 2 and 4 y of follow-up. The report of any difficulty to perform ≥1 BADL was considered as an incident case of disability. Poisson models stratified by sex and controlled for sociodemographic, behavioral, and clinical characteristics were carried out.

Results: After 4-y follow-up, deficient serum 25(OH)D was a risk factor for the incidence of BADL disability in both women (IRR: 1.53; 95% CI: 1.16, 2.03) and men (IRR: 1.44; 95% CI: 1.02, 2.02). However, insufficient serum 25(OH)D was not a risk factor for the incidence of BADL disability in either men or women.

Conclusions: Independently of sex, deficient serum 25(OH)D concentrations were associated with increased risk of incidence of BADL disability in adults >50 y old and should be an additional target of clinical strategies to prevent disability in these populations.
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http://dx.doi.org/10.1093/jn/nxaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675030PMC
November 2020

PLA-PEG nanospheres decorated with phage display selected peptides as biomarkers for detection of human colorectal adenocarcinoma.

Drug Deliv Transl Res 2020 12;10(6):1771-1787

Laboratory of Pharmaceutics and Nanobiotechnology (LDGNano), School of Pharmacy, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.

Peptide-mediated targeting to colorectal cancer can increase selectivity and specificity of this cancer diagnosis acting as biomarkers. The present work aimed to select peptides using the phage display technique and associate the peptides with polymeric nanospheres in order to evaluate their cytotoxicity and selectivity during cell interaction with Caco-2 human colon tumor cell line. Two peptides identified by phage display (peptide-1 and peptide-2) were synthesized and exhibited purity higher than 84%. Poly(lactic acid)-block-polyethylene glycol nanospheres were prepared by nanoprecipitation and double emulsion methods in order to load the two peptides. Nanoparticles ranged in size from 114 to 150 nm and peptide encapsulation efficiency varied from 16 to 32%, depending on the methodology. No cytotoxic activity was observed towards Caco-2 tumor cell line, either free or loaded peptides in concentrations up to 3 μM at incubation times of 6 and 24 h, indicating safety as biomarkers. Fluorescein isothiocyanate-labeled peptides allowed evaluating selective interactions with Caco-2 cells, where peptide-1 entrapped in nanospheres showed greater intensity of co-localized cell fluorescence, in comparison to peptide-2. Peptide-1 loaded in nanospheres revealed promising to be investigated in further studies of selectivity with other human colon rectal cells as a potential biomarker.Graphical abstract.
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http://dx.doi.org/10.1007/s13346-020-00826-0DOI Listing
December 2020

Cancer treatment in the lymphatic system: A prospective targeting employing nanostructured systems.

Int J Pharm 2020 Sep 1;587:119697. Epub 2020 Aug 1.

Faculty of Pharmaceutical Sciences, Department of Pharmacy, University of Sao Paulo, Avenida Professor Lineu Prestes 508, Butantan, Sao Paulo, SP, Brazil. Electronic address:

Cancer related to lymphangiogenesis has gained a great deal of attention in recent decades ever since specific markers of this intriguing system were discovered. Unlike the blood system, the lymphatic system has unique features that can advance cancer in future metastasis, or, conversely, can provide an opportunity to prevent or treat this disease that affects people worldwide. The aim of this review is to show the recent research of cancer treatment associated with the lymphatic system, considered one of the main gateways for disseminating metastatic cells to distant organs. Nanostructured systems based on theranostics and immunotherapies can offer several options for this complex disease. Precision targeting and accumulation of nanomaterials into the tumor sites and their elimination, or targeting the specific immune defense cells to promote optimal regression of cancer cells are highlighted in this paper. Moreover, therapies based on nanostructured systems through lymphatic systems may reduce the side effects and toxicity, avoid first pass hepatic metabolism, and improve patient recovery. We emphasize the general understanding of the association between the immune and lymphatic systems, their interaction with tumor cells, the mechanisms involved and the recent developments in several nanotechnology treatments related to this disease.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119697DOI Listing
September 2020

Persistent Renin-Angiotensin System Sensitization Months After Body Weight Recovery From Severe Food Restriction in Female Fischer Rats.

J Am Heart Assoc 2020 07 17;9(14):e017246. Epub 2020 Jul 17.

Department of Medicine Georgetown University Washington DC.

Background Prior exposure to periods of severe food restriction (sFR) is associated with increased risk of developing hypertension and cardiovascular disease later in life. Methods and Results To investigate the mechanism of these long-term adverse effects of sFR, 4-month-old female Fischer rats were divided in 2 groups and maintained on a normal diet ad libitum (control) or on an sFR diet with 60% reduction in daily food intake for 2 weeks that resulted in a 15% reduction in body weight. After the 2-week sFR period ended, both groups received normal chow ad libitum for 3 months. Within 2 weeks after refeeding was initiated in the sFR group, body weight was restored to control levels; however, plasma angiotensinogen (1.3-fold; <0.05), Ang-[1-8] (2.0-fold; <0.05), and angiotensin-converting enzyme activity (1.1-fold; <0.01) were all elevated 3 months after refeeding. Angiotensin type 1 receptor activity was also increased as evidenced by augmented pressor responses to angiotensin-[1-8] (<0.01) and depressor responses to the angiotensin type 1 receptor antagonist, losartan (<0.01) in the sFR group. Conclusions These results indicate that sensitization of the renin-angiotensin system persisted months after the sFR period ended. These findings may have implications for women who voluntarily or involuntarily experience an extended period of sFR and thus may be at increased risk of developing cardiovascular disease through sensitization of the renin-angiotensin system even though their body weight, mean arterial pressure, and heart rate appear normal.
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http://dx.doi.org/10.1161/JAHA.120.017246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660733PMC
July 2020

Near-miss analysis in a large hospital in southern Brazil: A 5-year retrospective study.

Int J Risk Saf Med 2020 ;31(4):247-258

Hospital Moinhos de Vento, Porto Alegre, Brazil.

Background: Near-miss analysis is an effective method for preventing serious adverse events, including never events such as wrong-site surgery.

Objective: To analyze all near-miss incidents reported in a large general hospital in southern Brazil between January 2013 and August 2017.

Method: We performed a descriptive retrospective study of near-miss incidents recorded in the hospital's electronic reporting system in a large non-profit hospital (497 beds). The results are expressed as absolute (n) and relative frequencies (%). Pearson's chi-square test, Fisher's exact test (Monte Carlo simulation) and linear regression were used.

Results: A total of 12,939 near-miss incidents were recorded during the study period, with linear growth in the number of reports. Near-miss incidents were most frequent for medication, followed by processes unspecified in the International Classification for Patient Safety framework, followed by information control (patient chart and fluid balance data), followed by venous/vascular puncture. The highest prevalence of reports was observed in inpatient wards, in adult, pediatric, and neonatal intensive care units, and in the surgical center/post-anesthesia care unit. Pharmacists and nursing personnel recorded most of the reports during the day shift.

Conclusion: The most frequent categories of near-miss incidents were medication processes, other institutional protocols, information control issues, and venous/vascular puncture. The significant number of reported near-miss incidents reflects good adherence to the reporting system.
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http://dx.doi.org/10.3233/JRS-194050DOI Listing
January 2020

Sex-Specific Modulation of Blood Pressure and the Renin-Angiotensin System by ACE (Angiotensin-Converting Enzyme) 2.

Hypertension 2020 08 22;76(2):478-487. Epub 2020 Jun 22.

From the Division of Nephrology and Hypertension, Department of Medicine (H.J., A.M.A.d.S., B.B., W.Z., X.W., K.S.), Georgetown University, Washington, DC.

We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-[1-8] (angiotensin [1-8])-induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-[1-8] infusion. This sex difference was attenuated in ACE2 KO mice. Ang-[1-8] infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of abolished this effect. In contrast, Ang-[1-8] infusion increased glomerular AT1R binding in WT male mice by 1.2-fold, and this effect of Ang-[1-8] persisted in Ace2 KO male mice (1.3-fold). ACE2 also had an effect on renal protein expression of the neutral endopeptidase NEP (neprilysin), the enzyme that catabolizes Ang-[1-10] (angiotensin [1-10]), the precursor of Ang-[1-8]. Ang-[1-8] infusion downregulated NEP protein expression by 20% in WT male, whereas there was a slight increase in NEP expression in WT female mice. Deletion of Ace2 resulted in lowered NEP expression after Ang-[1-8] infusion in both sexes. These findings suggest sex-specific ACE2 regulation of the renin-angiotensin system contributes to female protection from Ang-[1-8]-induced hypertension. These findings have ramifications for the current coronavirus disease 2019 (COVID-19) pandemic, especially in hypertension since ACE2 is the SARS-CoV-2 receptor and hypertension is a major risk factor for poor outcomes.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365573PMC
August 2020

Assertiveness training during early undergraduate years has the potential to increase students' confidence and ability to act as patient advocates.

Evid Based Nurs 2021 04 17;24(2):40. Epub 2020 Jun 17.

Quality and Safety, Hospital Moinhos de Vento, Porto Alegre, Rio Grande do Sul, Brazil.

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http://dx.doi.org/10.1136/ebnurs-2019-103235DOI Listing
April 2021

Improved Outcomes after Reperfusion Therapies for Ischemic Stroke: A "Real-world" Study in a Developing Country.

Curr Neurovasc Res 2020 ;17(4):361-375

Post-Graduation Program on Health and Environment, University of the Region of Joinville, Santa Catarina 88330- 622, Brazil.

Background: It is unknown if improvements in ischemic stroke (IS) outcomes reported after cerebral reperfusion therapies (CRT) in developed countries are also applicable to the "real world" scenario of low and middle-income countries. We aimed to measure the long-term outcomes of severe IS treated or not with CRT in Brazil.

Methods: Patients from a stroke center of a state-run hospital were included. We compared the survival probability and functional status at 3 and 12 months in patients with severe IS treated or not with CRT. From 2010 to 2011, we performed intravenous reperfusion when patients arrived within 4.5 h time-window (IVT group) and after 2011, mechanical thrombectomy (MT) combined or not with intravenous alteplase (IAT group). Those who arrived >4.5 h in 2010-2011 and >6 h in 2012-2017 did not undergo CRT (NCRT group).

Results: From 2010 to 2017, we registered 917 patients: 74% (677/917) in the NCRT group, 19% (178/917) in the IVT group and 7% (62/917) in the IAT group. Compared to the NCRT group, IVT patients had a 28% higher (HR: 0.72; 95% CI 0.53-0.96) 3-month adjusted probability of survival and risk of functional dependence was 19% lower (adjusted RR: 0.81; 95% CI 0.73-0.91). For those who underwent MT, the adjusted probability of survival was 59 % higher (HR: 0.41; 95% CI 0.21-0.77) and the risk of functional dependence was 21% lower (adjusted RR: 0.79; 95% CI 0.66-094). These outcomes remained significantly better throughout the first year.

Conclusion: CRT led to better outcomes in patients with severe IS in Brazil.
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http://dx.doi.org/10.2174/1567202617666200521083132DOI Listing
January 2020

A new medium-throughput screening design approach for the development of hydroxymethylnitrofurazone (NFOH) nanostructured lipid carrier for treating leishmaniasis.

Colloids Surf B Biointerfaces 2020 Sep 1;193:111097. Epub 2020 May 1.

University of São Paulo, Faculty of Pharmaceutical Sciences, São Paulo, SP, Brazil. Electronic address:

Hydroxymethilnitrofurazone (NFOH) is a nitrofurazone derivative and has potential use in treating leishmaniasis. However, due to low water solubility and bioavailability, NFOH has failed in in vivo tests. Nanostructured lipid carrier (NLC) is an alternative to overcome these limitations by improving pharmacokinetics and modifying drug delivery. This work is focused on developing a novel NFOH-loaded NLC (NLC-NFOH) using a D-optimal mixture statistical design and high-pressure homogenization, for oral administration to treat leishmaniasis. The optimized NLC-NFOH consisted of Mygliol® 840, Gelucire® 50/13, and Precirol® ATO 5 as lipids. These lipids were selected using a rapid methodology Technobis Crystal 16 T M, microscopy, and DSC. Different tools for selecting lipids provided relevant scientific knowledge for the development of the NLC. NLC-NFOH presented a z-average of 198.6 ± 5.4 nm, PDI of 0.11 ± 0.01, and zeta potential of -13.7 ± 0.7 mV. A preliminary in vivo assay was performed by oral administration of NLC-NFOH (2.8 mg/kg) in one healthy male Wistar rat (341 g) by gavage. Blood from the carotid vein was collected, and the sample was analyzed by HPLC. The plasma concentration of NFOH after 5 h of oral administration was 0.22 μg/mL. This same concentration was previously found using free NFOH in the DMSO solution (200 mg/kg), which is an almost 100-fold higher dose. This study allowed a design space development approach of the first NLC-NFOH with the potential to treat leishmaniasis orally.
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http://dx.doi.org/10.1016/j.colsurfb.2020.111097DOI Listing
September 2020

Short-term very low caloric intake causes endothelial dysfunction and increased susceptibility to cardiac arrhythmias and pathology in male rats.

Exp Physiol 2020 07 8;105(7):1172-1184. Epub 2020 Jun 8.

Department of Medicine, Georgetown University, Washington, DC, USA.

New Findings: What is the central question of this study? What are the effects of a 2 week period of severe food restriction on vascular reactivity of resistance arteries and on cardiac structure and function? What is the main finding and its importance? This study showed, for the first time, that a 2 week period of severe food restriction in adult male Fischer rats caused endothelial dysfunction in mesenteric arteries and increased the susceptibility to ischaemia-reperfusion-induced arrhythmias and cardiac pathology. Our findings might have ramifications for cardiovascular risk in people who experience periods of inadequate caloric intake.

Abstract: Severe food restriction (sFR) is a common dieting strategy for rapid weight loss. Male Fischer rats were maintained on a control (CT) or sFR (40% of CT food intake) diet for 14 days to mimic low-calorie crash diets. The sFR diet reduced body weight by 16%. Haematocrits were elevated by 10% in the sFR rats, which was consistent with the reduced plasma volume. Mesenteric arteries from sFR rats had increased sensitivity to vasoconstrictors, including angiotensin II [maximum (%): CT, 1.30 ± 0.46 versus sFR, 11.5 ± 1.6; P < 0.0001; n = 7] and phenylephrine [maximum (%): CT, 78.5 ± 2.8 versus sFR, 94.5 ± 1.7; P < 0.001; n = 7] and reduced sensitivity to the vasodilator acetylcholine [EC (nm): CT, 49.2 ± 5.2 versus sFR, 71.6 ± 6.8; P < 0.05; n = 7]. Isolated hearts from sFR rats had a 1.7-fold increase in the rate of cardiac arrhythmias in response to ischaemia-reperfusion and more cardiac pathology, including myofibrillar disarray with contractions and cardiomyocyte lysis, than hearts from CT rats. The sFR dietary regimen is similar to very low-calorie commercial and self-help weight-loss programmes, which provide ∼800-1000 kcal day . Therefore, these findings in rats warrant the study of cardiovascular function in individuals who engage in extreme dieting or are subjected to bouts of very low caloric intake for other reasons, such as socioeconomic factors and natural disasters.
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http://dx.doi.org/10.1113/EP088434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496402PMC
July 2020

Sepsis Impairs Thyroid Hormone Signaling and Mitochondrial Function in the Mouse Diaphragm.

Thyroid 2020 07 24;30(7):1079-1090. Epub 2020 Apr 24.

Laboratory of Translational Endocrinology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Sepsis can cause the nonthyroidal illness syndrome (NTIS), resulting in perturbed thyroid hormone (TH) signaling and reduced thyroxine (T4) levels. TH is a major regulator of muscle function, via its influence on mitochondria. This study aimed at evaluating the relationship between TH signaling, mitochondrial function, and the antioxidant defense system in the diaphragms of septic mice. Male C57Bl/6 mice were divided into two groups: cecal ligation and puncture (CLP) and sham. Twenty-four hours after surgery, plasma, diaphragms, and livers were collected. TH metabolism and responses were analyzed by measuring messenger RNA (mRNA) expression of in the liver, and , , 2, , and (encodes MCT 10 and 8), in the diaphragm. T4 plasma levels were measured by radioimmunoassay. Damage to diaphragm mitochondria was assessed by electron microscopy and real-time polymerase chain reaction (qPCR), and function with oxygraphy. The diaphragm antioxidative defense system was examined by qPCR, analyzing superoxide dismutase (SOD) 1 (), mitochondrial superoxide dismutase (SOD 2; ), extracellular superoxide dismutase (SOD 3; ), glutathione peroxidase 1 (), and catalase () expression. The effect of TH replacement was tested by treating the mice with T4 and triiodothyronine (T3) (CLP+TH) after surgery. CLP mice presented reduced total plasma T4 concentrations, downregulated , and upregulated mRNA expression in the liver. CLP mice also displayed downregulated , and expression in the diaphragm, suggesting that TH signaling was compromised. The expression of (encoding PGC1a) was downregulated, which correlated with the decrease in the number of total mitochondria, increase in the percentage of injured mitochondria, downregulation of respiratory chain complex 2 and 3 mRNA expression, and reduced maximal respiration. In addition, septic animals presented a three-fold increase in and expression; downregulated , , and expression; and upregulated expression, potentially due to elevated reactive oxygen species levels. The mitochondrial number and the percentage of injured mitochondrial were similar between sham and CLP+TH mice. Sepsis induced responses consistent with NTIS, resulted in mitochondrial damage and functional impairment, and modulated the expression of key antioxidant enzymes in the diaphragm. Thus, impaired diaphragm function during sepsis seems to involve altered local TH signaling, mitochondrial dysfunction, and oxidative stress defense.
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http://dx.doi.org/10.1089/thy.2019.0124DOI Listing
July 2020
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