Publications by authors named "André Marques"

129 Publications

High-Throughput Genomic Data Reveal Complex Phylogenetic Relationships in Sw (Leguminosae).

Front Genet 2021 23;12:727314. Epub 2021 Sep 23.

Laboratory of Genetic Resources, Federal University of Alagoas, Arapiraca, Brazil.

Allopolyploidy is widely present across plant lineages. Though estimating the correct phylogenetic relationships and origin of allopolyploids may sometimes become a hard task. In the genus Sw. (Leguminosae), an important legume crop, allopolyploidy is a key speciation force. This makes difficult adequate species recognition and breeding efforts on the genus. Based on comparative analysis of nine high-throughput sequencing (HTS) samples, including three allopolyploids (. Vogel cv. "Campo Grande," . "RS024" and . Vogel) and six diploids (. Taub, . (L.) Sw., . M. B. Ferreira and Sousa Costa, . (Aubl.) Sw., . M. B. Ferreira and Sousa Costa and . B. L. Maass & 't Mannetje) we provide a working pipeline to identify organelle and nuclear genome signatures that allowed us to trace the origin and parental genome recognition of allopolyploids. First, organelle genomes were assembled and used to identify maternal genome donors by alignment-based phylogenies and synteny analysis. Second, nuclear-derived reads were subjected to repetitive DNA identification with RepeatExplorer2. Identified repeats were compared based on abundance and presence on diploids in relation to allopolyploids by comparative repeat analysis. Third, reads were extracted and grouped based on the following groups: chloroplast, mitochondrial, satellite DNA, ribosomal DNA, repeat clustered- and total genomic reads. These sets of reads were then subjected to alignment and assembly free phylogenetic analyses and were compared to classical alignment-based phylogenetic methods. Comparative analysis of shared and unique satellite repeats also allowed the tracing of allopolyploid origin in , especially those with high abundance such as the StyloSat1 in the Scabra complex. This satellite was mapped in the proximal region of the chromosomes and made it possible to identify its previously proposed parents. Hence, with simple genome skimming data we were able to provide evidence for the recognition of parental genomes and understand genome evolution of two allopolyploids.
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http://dx.doi.org/10.3389/fgene.2021.727314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495327PMC
September 2021

In Vitro Phenotypic Activity and In Silico Analysis of Natural Products from Brazilian Biodiversity on .

Molecules 2021 Sep 18;26(18). Epub 2021 Sep 18.

Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Avenida Brasil 4365, Manguinhos, Rio de Janeiro 210360-040, Brazil.

Chagas disease (CD) affects more than 6 million people worldwide. The available treatment is far from ideal, creating a demand for new alternative therapies. Botanical diversity provides a wide range of novel potential therapeutic scaffolds. Presently, our aim was to evaluate the mammalian host toxicity and anti- activity of botanic natural products including extracts, fractions and purified compounds obtained from Brazilian flora. In this study, 36 samples of extracts and fractions and eight pure compounds obtained from seven plant species were evaluated. The fraction dichloromethane from var. (AFfPD) and the crude extract of (PTFrE) showed promising trypanosomicidal activity. AFfPD and PTFrE presented EC values 10.7 ± 2.8 μg/mL and 12.85 ± 1.52 μg/mL against intracellular forms (Tulahuen strain), respectively. Additionally, both were active upon bloodstream trypomastigotes (Y strain), exhibiting EC 2.2 ± 1.0 μg/mL and 38.8 ± 2.1 μg/mL for AFfPD and PTFrE, respectively. Importantly, AFfPD is about five-fold more potent than Benznidazole (Bz), the reference drug for CD, also reaching lower EC value (7.92 ± 2.2 μg/mL) as compared to Bz (23.3 ± 0.6 μg/mL). Besides, anti-parasitic effect of eight purified botanic substances was also investigated. Aurelianolide A and B (compounds and ) from and compound from displayed the best trypanosomicidal effect. Compounds , and showed EC of 4.6 ± 1.3 μM, 1.6 ± 0.4 μM and 8.1 ± 0.9 μM, respectively against intracellular forms. In addition, in silico analysis of these three biomolecules was performed to predict parameters of absorption, distribution, metabolism and excretion. The studied compounds presented similar ADMET profile as Bz, without presenting mutagenicity and hepatotoxicity aspects as predicted for Bz. Our findings indicate that these natural products have promising anti- effect and may represent new scaffolds for future lead optimization.
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http://dx.doi.org/10.3390/molecules26185676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472459PMC
September 2021

Cholesteryl hemiazelate causes lysosome dysfunction impacting vascular smooth muscle cell homeostasis.

J Cell Sci 2022 Mar 22;135(5). Epub 2021 Oct 22.

Chronic Diseases Research Centre (CEDOC), NOVA Medical School, NOVA University Lisbon, 1169-056 Lisboa, Portugal.

In atherosclerotic lesions, vascular smooth muscle cells (VSMCs) represent half of the foam cell population, which is characterized by an aberrant accumulation of undigested lipids within lysosomes. Loss of lysosome function impacts VSMC homeostasis and disease progression. Understanding the molecular mechanisms underlying lysosome dysfunction in these cells is, therefore, crucial. We identify cholesteryl hemiazelate (ChA), a stable oxidation end-product of cholesteryl-polyunsaturated fatty acid esters, as an inducer of lysosome malfunction in VSMCs. ChA-treated VSMCs acquire a foam-cell-like phenotype, characterized by enlarged lysosomes full of ChA and neutral lipids. The lysosomes are perinuclear and exhibit degradative capacity and cargo exit defects. Lysosome luminal pH is also altered. Even though the transcriptional response machinery and autophagy are not activated by ChA, the addition of recombinant lysosomal acid lipase (LAL) is able to rescue lysosome dysfunction. ChA significantly affects VSMC proliferation and migration, impacting atherosclerosis. In summary, this work shows that ChA is sufficient to induce lysosomal dysfunction in VSMCs, that, in ChA-treated VSMCs, neither lysosome biogenesis nor autophagy are triggered, and, finally, that recombinant LAL can be a therapeutic approach for lysosomal dysfunction.
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http://dx.doi.org/10.1242/jcs.254631DOI Listing
March 2022

Medicinal Plants as Efficacious Agents for Diabetic Foot Ulcers: A Systematic Review of Clinical Studies.

Wounds 2021 Aug;33(8):207-218

Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.

A diabetic foot ulcer (DFU) is a chronic, nonhealing wound that occurs in approximately 15% to 25% of patients with diabetes, and amputation is necessary in approximately 5% to 24% of these patients. Medicinal plants have demonstrated promising wound healing activities in animal models of DFUs as well as in clinical studies. These plants, which are described as medicinal in different regions of the world, are not considered to be standard medicinal treatments in Western medicine at this time. Some medicinal products, such as bromelain-an herbal protease currently used for enzymatic debridement of wounds-have been obtained from plants, showing the important role of these natural products as sources of wound healing agents. This paper aims to review clinical studies on the effects of medicinal plants in patients with DFUs based on the improvement of local and systemic parameters related to wound healing. Electronic databases including PubMed, Scopus, and Cochrane Library were searched for studies from inception through May 2019 using the keywords "diabetic foot ulcer" and "plant," "phytochemical," "extract," or "herb." Inclusion criteria were controlled or before-after clinical studies with English-language full-text in which topical or systemic herbal preparations for DFUs were evaluated by considering outcomes such as reduction of wound healing time and wound area, markers of inflammation and oxidative stress, and number of cases requiring amputation. Studies on non-herbal materials and human studies other than clinical trials were excluded. Fourteen studies were included in the present review. Herbal medicines were administered as add-on therapy to standard wound care in the form of topical (cream, gel, oil) or systemic (capsule, decoction, injection) preparations. Parameters such as ulcer width and depth, phagocytic function, tumor necrosis factor α level, epithelialization, vascularization, and wound closure were evaluated in clinical trials, several of which were significantly improved in patients compared with their baseline values or control group. Per the studies included in this review, medicinal plants can be recommended as promising adjuvant therapies to conventional wound care to accelerate wound healing in patients with DFUs.
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August 2021

Assessment of Attentional Functioning in Health Professionals of a Brazilian Tertiary Referral Hospital for COVID-19.

Behav Neurol 2021 25;2021:6655103. Epub 2021 Jun 25.

Department of Neurology, University Hospital Gaffrée and Guinle, Federal University of the State of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

This study is aimed at assessing differences in basic attentional functioning between substantial and minimal work-related exposure to COVID-19 patients in professionals working in a tertiary referral hospital in Rio de Janeiro, Brazil. Therefore, hospital employees performed a Continuous Visual Attention Test. This test consisted of a 90-second Go/No-Go task with 72 (80%) targets and 18 (20%) nontargets. For each participant, reaction time and intraindividual variability of reaction times of all correct target responses, as well as the number of omission and commission errors, were evaluated. Participants were divided into 2 groups based on their exposure to COVID-19 patients (substantial versus minimal exposure). The substantial exposure group consisted of participants with 24 hours/week or more direct contact with COVID-19 patients. This cut-off was based on the clear division between professionals working and not working with COVID-19 patients and considered that 12-hour and 24-hour daily shifts are common for hospital employees in Brazil. A MANCOVA was performed to examine between-group differences, using age, sleep quality, sex, education level, previous COVID-19 infection, and profession as covariates. Of 124 participants, 80 had substantial exposure and 44 had minimal exposure to COVID-19. The overall MANCOVA reached statistical significance ( = 0.048). Post hoc ANCOVA analysis showed that the substantial exposure group had a statistically significantly higher intraindividual variability of reaction time of all correct target responses ( = 0.017, Cohen's  = -0.55). This result remained after removing those with a previous COVID-19 infection ( = 0.010, Cohen's  = -0.64) and after matching groups for sample size ( = 0.004, Cohen's  = -0.81). No other variables reached statistical significance. Concluding, hospital professionals with a substantial level of exposure to patients with COVID-19 show a significant attention decrement and, thus, may be at a higher risk of accidental SARS-CoV-2 infection.
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http://dx.doi.org/10.1155/2021/6655103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238622PMC
July 2021

Plastome evolution in the Caesalpinia group (Leguminosae) and its application in phylogenomics and populations genetics.

Planta 2021 Jul 8;254(2):27. Epub 2021 Jul 8.

Laboratory of Plant Cytogenetics and Evolution, Department of Botany, Federal University of Pernambuco, Recife, Brazil.

Main Conclusion: The chloroplast genomes of Caesalpinia group species are structurally conserved, but sequence level variation is useful for both phylogenomic and population genetic analyses. Variation in chloroplast genomes (plastomes) has been an important source of information in plant biology. The Caesalpinia group has been used as a model in studies correlating ecological and genomic variables, yet its intergeneric and infrageneric relationships are not fully solved, despite densely sampled phylogenies including nuclear and plastid loci by Sanger sequencing. Here, we present the de novo assembly and characterization of plastomes from 13 species from the Caesalpinia group belonging to eight genera. A comparative analysis was carried out with 13 other plastomes previously available, totalizing 26 plastomes and representing 15 of the 26 known Caesalpinia group genera. All plastomes showed a conserved quadripartite structure and gene repertoire, except for the loss of four ndh genes in Erythrostemon gilliesii. Thirty polymorphic regions were identified for inter- or intrageneric analyses. The 26 aligned plastomes were used for phylogenetic reconstruction, revealing a well-resolved topology, and dividing the Caesalpinia group into two fully supported clades. Sixteen microsatellite (cpSSR) loci were selected from Cenostigma microphyllum for primer development and at least two were cross-amplified in different Leguminosae subfamilies by in vitro or in silico approaches. Four loci were used to assess the genetic diversity of C. microphyllum in the Brazilian Caatinga. Our results demonstrate the structural conservation of plastomes in the Caesalpinia group, offering insights into its systematics and evolution, and provides new genomic tools for future phylogenetic, population genetics, and phylogeographic studies.
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http://dx.doi.org/10.1007/s00425-021-03655-8DOI Listing
July 2021

Analysis of cathepsin B and cathepsin L treatment to clear toxic lysosomal protein aggregates in neuronal ceroid lipofuscinosis.

Biochim Biophys Acta Mol Basis Dis 2021 10 30;1867(10):166205. Epub 2021 Jun 30.

Institute of Biochemistry, Christian-Albrechts-University Kiel, 24118 Kiel, Germany. Electronic address:

Proteolysis mediated by lysosomal cathepsin proteases maintains a physiological flow in autophagy, phagocytosis and endocytosis. Neuronal Ceroid Lipofuscinosis (NCL) is a childhood neurodegenerative disorder characterized by disturbed autophagic flow and pathological accumulation of proteins. We demonstrated a therapeutic clearance of protein aggregates after dosing NCL10 mice with recombinant human pro-cathepsin-D. Prompted by these results and speculating that cathepsins may act in a redundant and in an hierarchical manner we envisaged that a treatment with human recombinant cysteine proteases pro-cathepsin-L (proCTSL) and pro-cathepsin-B (proCTSB) could similarly be used to induce protein degradation. Both enzymes were taken up by mannose 6-phosphate receptor- and LRP-receptor-mediated endocytosis and processed to the lysosomal mature cathepsins. In murine NCL10 astrocytes an abnormal increase in LAMP1 and saposin expression was revealed. Although proCTSB application did not improve this phenotype, proCTSL treatment led to reduced saposin-C levels in this model as well as in an acute brain slice model. Intracerebral dosing in a NCL10 mouse model revealed cellular and lysosomal uptake of both enzymes. Only proCTSL mildly reduced saposin-C levels and attenuated reactive astrogliosis. Application of both proteases did not improve weight loss and mortality of mutant mice. Our data reveal that although recombinant lysosomal proteases can be efficiently delivered to neuronal lysosomes cysteine proteases are less efficient in protein aggregates clearance as compared to the cathepsin-D treatment. Our data including in vitro degradation assays support the idea that bulk proteolysis requires a hierarchical process in which both aspartyl and cysteine hydrolases play a role.
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http://dx.doi.org/10.1016/j.bbadis.2021.166205DOI Listing
October 2021

Silencing of Transposable Elements Mediated by 5-mC and Compensation of the Heterochromatin Content by Presence of B Chromosomes in .

Cells 2021 05 11;10(5). Epub 2021 May 11.

Post Graduate Program in Evolutionary Genetics and Molecular Biology, Department of Genetics and Evolution, Federal University of São Carlos, Rodovia Washington Luís Km 235, São Carlos 13565-905, SP, Brazil.

The way in which transcriptional activity overcomes the physical DNA structure and gene regulation mechanisms involves complex processes that are not yet fully understood. Modifications in the cytosine-guanine sequence of DNA by 5-mC are preferentially located in heterochromatic regions and are related to gene silencing. Herein, we investigate evidence of epigenetic regulation related to the B chromosome model and transposable elements in . Indirect immunofluorescence using anti-5-mC to mark methylated regions was employed along with quantitative ELISA to determine the total genomic DNA methylation level. 5-mC signals were dispersed in the chromosomes of both females and males, with preferential accumulation in the B chromosome. In addition to the heterochromatic methylated regions, our results suggest that methylation is associated with transposable elements (LINE and Tc1-Mariner). Heterochromatin content was measured based on the C-band length in relation to the size of chromosome 1. The B chromosome in comprises heterochromatin located in the pericentromeric region of both arms of this isochromosome. In this context, individuals with B chromosomes should have an increased heterochromatin content when compared to individuals that do not. Although, both heterochromatin content and genome methylation showed no significant differences between sexes or in relation to the occurrence of B chromosomes. Our evidence suggests that the B chromosome can have a compensation effect on the heterochromatin content and that methylation possibly operates to silence TEs in . This represents a sui generis compensation and gene activity buffering mechanism.
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http://dx.doi.org/10.3390/cells10051162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151356PMC
May 2021

Aiming off the target: recycling target capture sequencing reads for investigating repetitive DNA.

Ann Bot 2021 11;128(7):835-848

Laboratory of Plant Cytogenetics and Evolution, Department of Botany, Federal University of Pernambuco, Recife-PE, Brazil.

Background And Aims: With the advance of high-throughput sequencing, reduced-representation methods such as target capture sequencing (TCS) emerged as cost-efficient ways of gathering genomic information, particularly from coding regions. As the off-target reads from such sequencing are expected to be similar to genome skimming (GS), we assessed the quality of repeat characterization in plant genomes using these data.

Methods: Repeat composition obtained from TCS datasets of five Rhynchospora (Cyperaceae) species were compared with GS data from the same taxa. In addition, a FISH probe was designed based on the most abundant satellite found in the TCS dataset of Rhynchospora cephalotes. Finally, repeat-based phylogenies of the five Rhynchospora species were constructed based on the GS and TCS datasets and the topologies were compared with a gene-alignment-based phylogenetic tree.

Key Results: All the major repetitive DNA families were identified in TCS, including repeats that showed abundances as low as 0.01 % in the GS data. Rank correlations between GS and TCS repeat abundances were moderately high (r = 0.58-0.85), increasing after filtering out the targeted loci from the raw TCS reads (r = 0.66-0.92). Repeat data obtained by TCS were also reliable in developing a cytogenetic probe of a new variant of the holocentromeric satellite Tyba. Repeat-based phylogenies from TCS data were congruent with those obtained from GS data and the gene-alignment tree.

Conclusions: Our results show that off-target TCS reads can be recycled to identify repeats for cyto- and phylogenomic investigations. Given the growing availability of TCS reads, driven by global phylogenomic projects, our strategy represents a way to recycle genomic data and contribute to a better characterization of plant biodiversity.
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http://dx.doi.org/10.1093/aob/mcab063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577205PMC
November 2021

Meiosis Progression and Recombination in Holocentric Plants: What Is Known?

Front Plant Sci 2021 22;12:658296. Epub 2021 Apr 22.

Department of Chromosome Biology, Max Planck Institute for Plant Breeding Research, Cologne, Germany.

Differently from the common monocentric organization of eukaryotic chromosomes, the so-called holocentric chromosomes present many centromeric regions along their length. This chromosomal organization can be found in animal and plant lineages, whose distribution suggests that it has evolved independently several times. Holocentric chromosomes present an advantage: even broken chromosome parts can be correctly segregated upon cell division. However, the evolution of holocentricity brought about consequences to nuclear processes and several adaptations are necessary to cope with this new organization. Centromeres of monocentric chromosomes are involved in a two-step cohesion release during meiosis. To deal with that holocentric lineages developed different adaptations, like the chromosome remodeling strategy in or the inverted meiosis in plants. Furthermore, the frequency of recombination at or around centromeres is normally very low and the presence of centromeric regions throughout the entire length of the chromosomes could potentially pose a problem for recombination in holocentric organisms. However, meiotic recombination happens, with exceptions, in those lineages in spite of their holocentric organization suggesting that the role of centromere as recombination suppressor might be altered in these lineages. Most of the available information about adaptations to meiosis in holocentric organisms is derived from the animal model . As holocentricity evolved independently in different lineages, adaptations observed in probably do not apply to other lineages and very limited research is available for holocentric plants. Currently, we still lack a holocentric model for plants, but good candidates may be found among Cyperaceae, a large angiosperm family. Besides holocentricity, chiasmatic and achiasmatic inverted meiosis are found in the family. Here, we introduce the main concepts of meiotic constraints and adaptations with special focus in meiosis progression and recombination in holocentric plants. Finally, we present the main challenges and perspectives for future research in the field of chromosome biology and meiosis in holocentric plants.
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http://dx.doi.org/10.3389/fpls.2021.658296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100227PMC
April 2021

Lysosome (Dys)function in Atherosclerosis-A Big Weight on the Shoulders of a Small Organelle.

Front Cell Dev Biol 2021 29;9:658995. Epub 2021 Mar 29.

iNOVA4Health, Chronic Diseases Research Center (CEDOC), NOVA Medical School (NMS), Universidade NOVA de Lisboa, Lisbon, Portugal.

Atherosclerosis is a progressive insidious chronic disease that underlies most of the cardiovascular pathologies, including myocardial infarction and ischemic stroke. The malfunctioning of the lysosomal compartment has a central role in the etiology and pathogenesis of atherosclerosis. Lysosomes are the degradative organelles of mammalian cells and process endogenous and exogenous substrates in a very efficient manner. Dysfunction of these organelles and consequent inefficient degradation of modified low-density lipoproteins (LDL) and apoptotic cells in atherosclerotic lesions have, therefore, numerous deleterious consequences for cellular homeostasis and disease progression. Lysosome dysfunction has been mostly studied in the context of the inherited lysosomal storage disorders (LSDs). However, over the last years it has become increasingly evident that the consequences of this phenomenon are more far-reaching, also influencing the progression of multiple acquired human pathologies, such as neurodegenerative diseases, cancer, and cardiovascular diseases (CVDs). During the formation of atherosclerotic plaques, the lysosomal compartment of the various cells constituting the arterial wall is under severe stress, due to the tremendous amounts of lipoproteins being processed by these cells. The uncontrolled uptake of modified lipoproteins by arterial phagocytic cells, namely macrophages and vascular smooth muscle cells (VSMCs), is the initial step that triggers the pathogenic cascade culminating in the formation of atheroma. These cells become pathogenic "foam cells," which are characterized by dysfunctional lipid-laden lysosomes. Here, we summarize the current knowledge regarding the origin and impact of the malfunctioning of the lysosomal compartment in plaque cells. We further analyze how the field of LSD research may contribute with some insights to the study of CVDs, particularly how therapeutic approaches that target the lysosomes in LSDs could be applied to hamper atherosclerosis progression and associated mortality.
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http://dx.doi.org/10.3389/fcell.2021.658995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039146PMC
March 2021

GCase and LIMP2 Abnormalities in the Liver of Niemann Pick Type C Mice.

Int J Mol Sci 2021 Mar 3;22(5). Epub 2021 Mar 3.

Department Medical Biochemistry, Leiden University, 2333 CC Leiden, The Netherlands.

The lysosomal storage disease Niemann-Pick type C (NPC) is caused by impaired cholesterol efflux from lysosomes, which is accompanied by secondary lysosomal accumulation of sphingomyelin and glucosylceramide (GlcCer). Similar to Gaucher disease (GD), patients deficient in glucocerebrosidase (GCase) degrading GlcCer, NPC patients show an elevated glucosylsphingosine and glucosylated cholesterol. In livers of mice lacking the lysosomal cholesterol efflux transporter NPC1, we investigated the expression of established biomarkers of lipid-laden macrophages of GD patients, their GCase status, and content on the cytosol facing glucosylceramidase GBA2 and lysosomal integral membrane protein type B (LIMP2), a transporter of newly formed GCase to lysosomes. Livers of 80-week-old mice showed a partially reduced GCase protein and enzymatic activity. In contrast, GBA2 levels tended to be reciprocally increased with the GCase deficiency. In liver, increased expression of lysosomal enzymes (cathepsin D, acid ceramidase) was observed as well as increased markers of lipid-stressed macrophages (GPNMB and galectin-3). Immunohistochemistry showed that the latter markers are expressed by lipid laden Kupffer cells. Earlier reported increase of LIMP2 in liver was confirmed. Unexpectedly, immunohistochemistry showed that LIMP2 is particularly overexpressed in the hepatocytes of the liver. LIMP2 in these hepatocytes seems not to only localize to (endo)lysosomes. The recent recognition that LIMP2 harbors a cholesterol channel prompts the speculation that LIMP2 in hepatocytes might mediate export of cholesterol into the bile and thus protects the hepatocytes.
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http://dx.doi.org/10.3390/ijms22052532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959463PMC
March 2021

Apoptotic effect of β-pinene on oral squamous cell carcinoma as one of the major compounds from essential oil of medicinal plant Kunth.

Nat Prod Res 2021 Mar 7:1-5. Epub 2021 Mar 7.

Basic Science Department, ISNF/UFF, Nova Friburgo, RJ, Brazil.

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck malignancy. Research on essential oils (EOs) has shown important cytotoxic and anti-tumor properties, among others. Piperaceae species are rich in EOs and here we highlight Kunth. We investigated the crude EOs from , their pure major constituents and an enriched fraction with the main EO compounds (EF) as cytotoxic and selective OSCC agents. EOs presented as main compounds (-)-α-pinene, (-)-β-pinene and limonene. EOs showed an IC lower than all isolated compounds, except for (-)-β-pinene in OSCC cells. The (-)-β-pinene induced cell death with apoptotic characteristics. Commercial standards showed greater selectivity than EOs, and (-)-β-pinene was the most selective among them. EF showed higher selectivity compared to crude EOs and carboplatin, turning it into a good candidate as an anticancer fraction. These results are important for the possible development of new treatments for OSCC.
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http://dx.doi.org/10.1080/14786419.2021.1895148DOI Listing
March 2021

Analysis of Posterior Tibial Slope as Risk Factor to Anterior Cruciate Ligament Tear.

Rev Bras Ortop (Sao Paulo) 2021 Feb 22;56(1):47-52. Epub 2020 Sep 22.

Centro de Cirurgia do Joelho, Instituto Nacional de Traumatologia e Ortopedia (INTO), Rio de Janeiro, RJ, Brasil.

 The objective of the present study was to evaluate the relationship between patients with anterior cruciate ligament (ACL) injury by indirect trauma and increased posterior tibial inclination.  Retrospective study, performed by analysis of medical records and digital radiographs of patients, present in a database of a tertiary orthopedic hospital. The sample consisted of two groups, the first group consisting of patients diagnosed with ACL injury by indirect trauma, and a control group matched by age.  Each group consisted of 275 patients, whose measurements of posterior tibial inclination were measured by three specialists. It was observed that the group of patients with ACL lesion presented a significantly higher tibial slope (in degrees) than the control group in the total sample and in the subsamples stratified by gender. The best cutoff point for the first group was identified as a posterior tibial inclination ≥ 8°, achieving a sensitivity of 63.3% and a specificity of 62.5%. The first group also had a tibial slope ratio ≥ 8° (63.3%), significantly higher than the control group (37.5%), with an odds ratio of 2.8.  It was concluded that the increase of the posterior tibial inclination is associated with an increased risk for injury of the ACL by indirect trauma, mainly for values ≥ 8°.
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http://dx.doi.org/10.1055/s-0040-1712495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895634PMC
February 2021

Human glucocerebrosidase mediates formation of xylosyl-cholesterol by β-xylosidase and transxylosidase reactions.

J Lipid Res 2021 Jan 6;62:100018. Epub 2021 Jan 6.

Department of Medical Biochemistry, Leiden Institute of Chemistry, Leiden University, The Netherlands. Electronic address:

Deficiency of glucocerebrosidase (GBA), a lysosomal β-glucosidase, causes Gaucher disease. The enzyme hydrolyzes β-glucosidic substrates and transglucosylates cholesterol to cholesterol-β-glucoside. Here we show that recombinant human GBA also cleaves β-xylosides and transxylosylates cholesterol. The xylosyl-cholesterol formed acts as an acceptor for the subsequent formation of di-xylosyl-cholesterol. Common mutant forms of GBA from patients with Gaucher disease with reduced β-glucosidase activity were similarly impaired in β-xylosidase, transglucosidase, and transxylosidase activities, except for a slightly reduced xylosidase/glucosidase activity ratio of N370S GBA and a slightly reduced transglucosylation/glucosidase activity ratio of D409H GBA. XylChol was found to be reduced in spleen from patients with Gaucher disease. The origin of newly identified XylChol in mouse and human tissues was investigated. Cultured human cells exposed to exogenous β-xylosides generated XylChol in a manner dependent on active lysosomal GBA but not the cytosol-facing β-glucosidase GBA2. We later sought an endogenous β-xyloside acting as donor in transxylosylation reactions, identifying xylosylated ceramide (XylCer) in cells and tissues that serve as donor in the formation of XylChol. UDP-glucosylceramide synthase (GCS) was unable to synthesize XylChol but could catalyze the formation of XylCer. Thus, food-derived β-D-xyloside and XylCer are potential donors for the GBA-mediated formation of XylChol in cells. The enzyme GCS produces XylCer at a low rate. Our findings point to further catalytic versatility of GBA and prompt a systematic exploration of the distribution and role of xylosylated lipids.
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http://dx.doi.org/10.1194/jlr.RA120001043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903134PMC
January 2021

Holocentric Karyotype Evolution in Is Marked by Intense Numerical, Structural, and Genome Size Changes.

Front Plant Sci 2020 10;11:536507. Epub 2020 Sep 10.

Laboratório de Citogenética e Diversidade Vegetal, Departamento de Biologia Geral, CCB, Universidade Estadual de Londrina, Londrina, Brazil.

Cyperaceae is a family of Monocotyledons comprised of species with holocentric chromosomes that are associated with intense dysploidy and polyploidy events. Within this family the genus has recently become the focus of several studies that characterize the organization of the holocentric karyotype and genome structures. To broaden our understanding of genome evolution in this genus, representatives of were studied to contrast chromosome features, C-CMA/DAPI band distribution and genome sizes. Here, we carried out a comparative analysis for 35 taxa of , and generated new genome size estimates for 20 taxa. The DNA 2C-values varied up to 22-fold, from 2C = 0.51 pg to 11.32 pg, and chromosome numbers ranged from 2 = 4 to 61. At least 37% of our sampling exhibited 2 different from the basic number = 5, and chromosome rearrangements were also observed. A large variation in C-CMA/DAPI band accumulation and distribution was observed as well. We show that genome variation in is much larger than previously reported. Phylogenetic analysis showed that most taxa were grouped in clades corresponding to previously described taxonomic sections. Basic chromosome numbers are the same within every section, however, changes appeared in all the clades. Ancestral chromosome number reconstruction revealed = 5 as the most likely ancestral complements, but = 10 appears as a new possibility. Chromosome evolution models point to polyploidy as the major driver of chromosome evolution in , followed by dysploidy. A negative correlation between chromosome size and diploid number open the discussion for holokinetic drive-based genome evolution. This study explores relationships between karyotype differentiation and genome size variation in , and contrasts it against the phylogeny of this holocentric group.
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http://dx.doi.org/10.3389/fpls.2020.536507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533669PMC
September 2020

Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis.

Cells 2020 09 23;9(10). Epub 2020 Sep 23.

CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.

Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders' burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis.
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http://dx.doi.org/10.3390/cells9102146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598292PMC
September 2020

Lithium Intoxication after Bariatric Surgery: A Case Report.

Acta Med Port 2021 May 16;34(5):382-386. Epub 2019 Sep 16.

Departamento de Psiquiatria e Saúde Mental. Hospital Distrital de Santarém. Santarém. Portugal.

Bariatric surgery is a therapeutic option to treat obesity in (carefully selected) patients with psychiatric disorders. About half of the patients referred for bariatric surgery have a diagnosis of (at least one) mental disorder and most of them are treated with psychotropic drugs. This procedure may modify the bioavailability of drugs and lithium is no exception. However, although absorption seems to decrease in most drugs, in the case of lithium, there is a high risk of toxicity. In this article, we describe the case of a 44-year-old female patient with lithium intoxication after bariatric surgery. We conducted a review of the published clinical cases in the scientific literature about lithium toxicity after bariatric surgery, and we propose potential preventive clinical solutions. It is essential to increase awareness of changes to the absorption of psychotropic drugs in the post-surgery period, particularly in the case of lithium. Regular postoperative clinical and laboratory monitoring of lithium serum levels is strongly recommended.
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http://dx.doi.org/10.20344/amp.12868DOI Listing
May 2021

Effect of Occlusal Adjustment on Postoperative Pain after Root Canal Treatment: A Randomized Clinical Trial.

Braz Dent J 2020 Sep 4;31(4):353-359. Epub 2020 Sep 4.

Dental school, UFAM - Federal University of Amazonas, Manaus, AM, Brazil.

The aim of this prospective, randomized, clinical study was to analyze the influence of occlusal adjustment on the prevalence of postoperative pain after endodontic treatment. Seventy-eight patients, diagnosed with symptomatic irreversible pulpitis with indication for endodontic treatment, were selected to participate in the study. The participants were randomized and divided into two groups: in the occlusal adjustment group (OAG), endodontic treatment was performed with subsequent occlusal adjustment. In the control group (CG), endodontic treatment was performed without occlusal adjustment. Treatments were performed by the same operator. Pain occurrence and intensity were recorded on two scales: the verbal rating scale (VRS) and numerical rating scale (NRS). Pain assessment was carried out by a second examiner, blinded to the experiment, 6, 24 and 72 h after endodontic treatment. Data were analyzed using Mann-Whitney, chi-squared, and Fisher's exact tests. In the occlusal adjustment group, 71.1% reported postoperative pain and 67.5% reported pain in the control group. At the 6-hour assessment, 21 individuals reported pain in the occlusal adjustment group and 24 in the control group (p=0.672). At the 24-hour assessment, 18 and 19 individuals reported pain (p=0.991) and at the 72-hour assessment, 8 and 4 reported pain (p=0.219), respectively. Occlusal adjustment did not influence the prevalence of postoperative pain of endodontically treated teeth with symptomatic irreversible pulpitis.
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http://dx.doi.org/10.1590/0103-6440202003248DOI Listing
September 2020

Takotsubo Multicenter Registry (REMUTA) - Clinical Aspects, In-Hospital Outcomes, and Long-Term Mortality.

Arq Bras Cardiol 2020 08;115(2):207-216

Casa de Saúde São José,Rio de Janeiro, RJ - Brasil.

Background: Takotsubo syndrome (TTS) is an acquired form of cardiomyopathy. National Brazilian data on this condition are scarce. The Takotsubo Multicenter Registry (REMUTA) is the first to include multicenter data on this condition in Brazil.

Objective: To describe the clinical characteristics, prognosis, in-hospital treatment, in-hospital mortality, and mortality during 1 year of follow-up.

Methods: This is an observational, retrospective registry study including patients admitted to the hospital with diagnosis of TTS and patients admitted for other reasons who developed this condition. Evaluated outcomes included triggering factor, analysis of exams, use of medications, complications, in-hospital mortality, and mortality during 1 year of follow-up. A significance level of 5% was adopted.

Results: The registry included 169 patients from 12 centers in the state of Rio de Janeiro, Brazil. Mean age was 70.9 ± 14.1 years, and 90.5% of patients were female; 63% of cases were primary TTS, and 37% were secondary. Troponin I was positive in 92.5% of patients, and median BNP was 395 (176.5; 1725). ST-segment elevation was present in 28% of patients. Median left ventricular ejection fraction was 40 (35; 48)%. We observed invasive mechanical ventilation in 25.7% of cases and shock in 17.4%. Mechanical circulatory support was used in 7.7%. In-hospital mortality was 10.6%, and mortality at 1 year of follow-up was 16.5%. Secondary TTS and cardiogenic shock were independent predictors of mortality.

Conclusion: The results of the REMUTA show that TTS is not a benign pathology, as was once thought, especially regarding the secondary TTS group, which has a high rate of complications and mortality. (Arq Bras Cardiol. 2020; 115(2):207-216).
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http://dx.doi.org/10.36660/abc.20190166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384277PMC
August 2020

Acute Cardiorenal Syndrome: Which Diagnostic Criterion to Use And What is its Importance for Prognosis?

Arq Bras Cardiol 2020 07 7;115(1):127-133. Epub 2020 Aug 7.

Faculdade de Medicina, Universidade Federal Fluminense, Niterói, RJ, Brasil.

The absence of a consensus about the diagnostic criteria for acute cardiorenal syndrome (ACRS) affects its prognosis. This study aimed at assessing the diagnostic criteria for ACRS and their impact on prognosis. A systematic review was conducted using PRISMA methodology and PICO criteria in the MEDLINE, EMBASE and LILACS databases. The search included original publications, such as clinical trials, cohort studies, case-control studies, and meta-analyses, issued from January 1998 to June 2018. Neither literature nor heart failure guidelines provided a clear definition of the diagnostic criteria for ACRS. The serum creatinine increase by at least 0.3 mg/dL from baseline creatinine is the most used diagnostic criterion. However, the definition of baseline creatinine, as well as which serum creatinine should be used as reference for critical patients, is still controversial. This systematic review suggests that ACRS criteria should be revised to include the diagnosis of ACRS on hospital admission. Reference serum creatinine should reflect baseline renal function before the beginning of acute kidney injury.
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http://dx.doi.org/10.36660/abc.20190207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384316PMC
July 2020

Super-Resolution Microscopy Reveals Diversity of Plant Centromere Architecture.

Int J Mol Sci 2020 May 15;21(10). Epub 2020 May 15.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, 06466 Seeland, Germany.

Centromeres are essential for proper chromosome segregation to the daughter cells during mitosis and meiosis. Chromosomes of most eukaryotes studied so far have regional centromeres that form primary constrictions on metaphase chromosomes. These monocentric chromosomes vary from point centromeres to so-called "meta-polycentromeres", with multiple centromere domains in an extended primary constriction, as identified in and species. However, in various animal and plant lineages centromeres are distributed along almost the entire chromosome length. Therefore, they are called holocentromeres. In holocentric plants, centromere-specific proteins, at which spindle fibers usually attach, are arranged contiguously (line-like), in clusters along the chromosomes or in bands. Here, we summarize findings of ultrastructural investigations using immunolabeling with centromere-specific antibodies and super-resolution microscopy to demonstrate the structural diversity of plant centromeres. A classification of the different centromere types has been suggested based on the distribution of spindle attachment sites. Based on these findings we discuss the possible evolution and advantages of holocentricity, and potential strategies to segregate holocentric chromosomes correctly.
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http://dx.doi.org/10.3390/ijms21103488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278974PMC
May 2020

Microvascular Effects of Echinodorus grandiflorus on Cardiovascular Disorders.

Planta Med 2020 Apr 13;86(6):395-404. Epub 2020 Mar 13.

Laboratory of Immunopharmacology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.

is a semiaquatic plant native to Brazil and belongs to the Alismataceae family. Infusion preparations of the leaves of this plant are often used due to its diuretic, blood pressure lowering, and anti-inflammatory properties. Our aim was to investigate the effects of chronic treatment with the crude hydroalcoholic extract of on central and peripheral microvascular changes induced in a model of hypertension and diabetes. The hemodynamic and microvascular effects of extract (50, 100, or 200 mg/kg/day for 28 days) or the isolated major diterpene from (3 to 10 mg/kg i. v.) were evaluated in spontaneously hypertensive rats using tail plethysmography and intravital fluorescence videomicroscopy, respectively, and were compared to vehicle-treated normotensive Wistar-Kyoto rats. We also investigated the protective effects of chronic treatment with (100 mg/kg/day) in brain capillary density and leukocyte-endothelium interactions on the brain vessels of DM-spontaneously (DM: diabetes mellitus) hypertensive rats. Chronically treating spontaneously hypertensive rats with increasing doses of crude hydroalcoholic extract resulted in significant dose-dependent reductions in systolic blood pressure and an anti-inflammatory effect on the brain microcirculation of DM-spontaneously hypertensive rat animals. Using laser speckle contrast imaging, we observed that intravenous administration of the major isolated clerodane diterpene metabolite (1 - 10 mg/kg) increased microvascular blood flow by 25% in spontaneously hypertensive rat skeletal muscle. The results of this study show that extracts can be useful in the prevention and reduction of microcirculatory damage in arterial hypertension and other diseases that involve microvascular dysfunction.
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http://dx.doi.org/10.1055/a-1118-9341DOI Listing
April 2020

Surgical Treatment for Chronic Rupture of the Patellar Tendon Performed in 2 Stages.

Arthrosc Tech 2020 Jan 31;9(1):e159-e166. Epub 2019 Dec 31.

Knee Surgery Center, National Institute of Traumatology and Orthopedics of Brazil, Rio de Janeiro, Brazil.

Patellar tendon rupture is an uncommon but disabling lesion. It usually occurs in men younger than 40 years, through direct or indirect trauma. Obtaining satisfactory results with treatment of chronic injuries and re-ruptures in which the patella retracts owing to quadriceps contraction is a challenge. This is of major concern especially in cases in which the patella cannot be positioned in its anatomic position when distal traction is performed. In these cases, V-Y stretching of the quadriceps can be performed in an attempt to perform reconstruction in 1 stage. Instead, a 2-stage procedure can be chosen, in which the first stage relies on patellar trans-skeletal traction to achieve distalization of the patella. In 1981, a technique for the treatment of chronic injuries of the patellar tendon in 2 stages was described. In that procedure, the first stage consisted of transpatellar traction and the second stage was tendon-tendon suturing with fascia lata reinforcement. We describe a surgical technique performed in 2 stages; in the first stage, trans-skeletal traction is performed, and in the second stage, the technique of Kelikian et al. with our modification is performed. This technique is used in patients with chronic rupture of the patellar tendon associated with a high patella with nonreducible quadriceps shortening.
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http://dx.doi.org/10.1016/j.eats.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993262PMC
January 2020

High-quality genome sequence of white lupin provides insight into soil exploration and seed quality.

Nat Commun 2020 01 24;11(1):492. Epub 2020 Jan 24.

BPMP, Univ Montpellier, CNRS, INRAE, SupAgro, Montpellier, France.

White lupin (Lupinus albus L.) is an annual crop cultivated for its protein-rich seeds. It is adapted to poor soils due to the production of cluster roots, which are made of dozens of determinate lateral roots that drastically improve soil exploration and nutrient acquisition (mostly phosphate). Using long-read sequencing technologies, we provide a high-quality genome sequence of a cultivated accession of white lupin (2n = 50, 451 Mb), as well as de novo assemblies of a landrace and a wild relative. We describe a modern accession displaying increased soil exploration capacity through early establishment of lateral and cluster roots. We also show how seed quality may have been impacted by domestication in term of protein profiles and alkaloid content. The availability of a high-quality genome assembly together with companion genomic and transcriptomic resources will enable the development of modern breeding strategies to increase and stabilize white lupin yield.
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http://dx.doi.org/10.1038/s41467-019-14197-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981116PMC
January 2020

Apical Transportation and Centering Ability After Root Canal Filling Removal Using Reciprocating and Continuous Rotary Systems: A CBCT Study.

Eur J Dent 2019 Oct 31;13(4):613-618. Epub 2019 Dec 31.

Superior School of Health Sciences, State University of Amazonas, Manaus, Amazonas, Brazil.

Objective: To evaluate the apical transportation and centering ability promoted by reciprocating and continuous rotary systems after root canal filling removal.

Materials And Methods: After obturation, 40 mesial root canals of mandibular molars were distributed into four groups ( = 20) for filling material removal: PTU group-F2 instrument (25.08) of ProTaper Universal system; R25 group-R25 instrument (25.08) of Reciproc system; X2 group-X2 instrument (25.06) of ProTaper Next system and X3 group-X2 instrument (25.06) of ProTaper Next system, followed by X3 instrument (30.07). Cone-beam computed tomographic analysis was performed before and after filling material removal for acquisition of apical images. Apical transportation (AT) and its direction, and centering ability (CA), were assessed using the equations AT = (X1-X2)-(Y1-Y2) and CA = (X1-X2/Y1-Y2 or Y1-Y2/X1-X2), respectively. Data were submitted to the nonparametric Kruskal-Wallis and Dunn multiple comparison tests ( < 0.05) for statistical analysis.

Results: There was no statistically significant difference among groups for AT ( > 0.05), with a tendency toward transportation in the distal direction. Also, there was no statistically significant difference among groups regarding CA ( > 0.05).

Conclusions: The different systems, including ProTaper Next, caused AT within the acceptable clinical limit after filling removal. In addition, none of the tested systems presented adequate CA.
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http://dx.doi.org/10.1055/s-0039-3399407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938415PMC
October 2019

Comparison of the effect of photobiomodulation therapy and Ibuprofen on postoperative pain after endodontic treatment: randomized, controlled, clinical study.

Lasers Med Sci 2020 Jun 7;35(4):971-978. Epub 2019 Dec 7.

Dental School, Federal University of Amazonas, R. Mins Waldemar Pedrosa, n. 1539, Praça 14 de Janeiro, Manaus, AM, 69025-050, Brazil.

The aim of the study was to compare the effect of Ibuprofen and the application of photobiomodulation therapy protocol on the reduction of postoperative pain in endodontically treated teeth using a randomized clinical trial design. Seventy patients, diagnosed with symptomatic irreversible pulpitis, were selected. Treatment was performed by a single operator; a reciprocal system was used to prepare the canals; they were obturated using the Tagger's hybrid technique and coronally sealed with glass-ionomer cement. After treatment, patients were randomly divided into 2 groups. In the active control group, two Ibuprofen 600 mg tablets were administered within a 12-h interval. In the photobiomodulation therapy group, the irradiation was applied after treatment. The evaluation of postoperative pain was performed by another researcher blinded to the groups at 6, 12, 24, and 72 h intervals after treatment. To measure the outcome, two pain scales were used: numerical rate scale (NRS) and verbal rate scale (VRS). Data were analyzed using the chi-square, Mann-Whitney, and Wilcoxon paired tests. Outcome was superior with photobiomodulation therapy at 6 h (p < 0.001), 12 h (p = 0.005), and 24 h (p < 0.001) intervals compared with Ibuprofen. The results for the 72 h (p = 0.317) interval were similar, both in the VRS and NRS scales. It may be concluded that the use of photobiomodulation therapy was effective in reducing pain within the first 24 h when compared with the administration of Ibuprofen 600 mg.
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http://dx.doi.org/10.1007/s10103-019-02929-8DOI Listing
June 2020

The Iminosugar AMP-DNM Improves Satiety and Activates Brown Adipose Tissue Through GLP1.

Diabetes 2019 12 2;68(12):2223-2234. Epub 2019 Oct 2.

Laboratory of Endocrinology, Department of Endocrinology and Metabolism, Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Obesity is taking on worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar N-adamantine-methyloxypentyl-deoxynojirimycin (AMP-DNM), which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in obese rodents. Moreover, we demonstrate that the mechanism mediating these favorable actions depends on oral, but not central, administration of AMP-DNM, which ultimately stimulates systemic glucagon-like peptide 1 (GLP1) secretion. We evidence an essential role of brain GLP1 receptors (GLP1r), as AMP-DNM fails to promote satiety and activate BAT in mice lacking the brain GLP1r as well as in mice treated intracerebroventricularly with GLP1r antagonist exendin-9. In conclusion, AMP-DNM markedly ameliorates metabolic abnormalities in obese rodents by restoring satiety and activating BAT through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r.
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http://dx.doi.org/10.2337/db19-0049DOI Listing
December 2019

Complete mitochondrial genomes of the Spondias tuberosa Arr. Cam and Spondias mombin L. reveal highly repetitive DNA sequences.

Gene 2019 Dec 1;720:144026. Epub 2019 Aug 1.

Laboratory of Genetics Resources, Campus Arapiraca, Universidade Federal de Alagoas, Brazil. Electronic address:

Mitogenomes in plants are well-known as exhibiting high diversity in genome size architecture and repetitive DNA sequences. In this research study, we report on the complete mitochondrial genomes of S. tuberosa and S. mombin using Illumina paired-end and mate-pair end reads. These genomes were obtained by a combination of methods of de novo assembly and contig extension. The mitogenomes of S. tuberosa and S. mombin showed 779,106 bp and 685,788 bp in length, with a total of 35 genes. Genome comparisons showed many rearrangements that were mediated by repetitive DNA, and also high incorporation of DNA from chloroplast. In summary, we demonstrate: (1) first complete mitochondrial genomes for the genus Spondias; (2) the synteny between S. tuberosa and S. mombin showed rearrangements, mediated by repetitive DNA; (3) that gene content in Spondias mitogenomes is highly conserved; and (4) the high incorporation DNA from chloroplast genome, (5) the mitogenome size is due intergenic spacers and (6) the non-tandem repeats contributes for giant intergenic spacers.
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http://dx.doi.org/10.1016/j.gene.2019.144026DOI Listing
December 2019

Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis.

Autophagy 2020 05 16;16(5):811-825. Epub 2019 Jul 16.

Institute of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.

CTSD (cathepsin D) is one of the major lysosomal proteases indispensable for the maintenance of cellular proteostasis by turning over substrates of endocytosis, phagocytosis and autophagy. Consequently, CTSD deficiency leads to a strong impairment of the lysosomal-autophagy machinery. In mice and humans CTSD dysfunction underlies the congenital variant (CLN10) of neuronal ceroid lipofuscinosis (NCL). NCLs are distinct lysosomal storage disorders (LSDs) sharing various hallmarks, namely accumulation of protein aggregates and ceroid lipofuscin leading to neurodegeneration and blindness. The most established and clinically approved approach to treat LSDs is enzyme replacement therapy (ERT) aiming to replace the defective hydrolase with an exogenously applied recombinant protein. Here we reveal that recombinant human pro-CTSD produced in a mammalian expression system can be efficiently taken up by a variety of cell models, is correctly targeted to lysosomes and processed to the active mature form of the protease. In proof-of-principle experiments we provide evidence that recombinant human CTSD (rhCTSD) can improve the biochemical phenotype of CTSD-deficient hippocampal slice cultures and retinal cells . Furthermore, we demonstrate that dosing of rhCTSD in the murine CLN10 model leads to a correction of lysosomal hypertrophy, storage accumulation and impaired autophagic flux in the viscera and central nervous system (CNS). We establish that direct delivery of the recombinant protease to the CNS is required for improvement of neuropathology and lifespan extension. Together these data support the continuation of the pre-clinical studies for the application of rhCTSD in the treatment of NCL. AIF1/IBA1: allograft inflammatory factor 1; BBB: blood brain barrier; CNS: central nervous system; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; ERT: enzyme replacement therapy; GFAP: glial fibrillary acidic protein; INL: inner nuclear layer; LAMP1: lysosomal-associated membrane protein 1; LAMP2: lysosomal-associated membrane protein 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LDL: low-density lipoprotein; LRP1: low density lipoprotein receptor-related protein 1; LSD: lysosomal storage disorder; MEFs: mouse embryonic fibroblasts; M6P: mannose 6-phosphate; mCTSD: mature CTSD; NCL: neuronal ceroid lipofuscinosis; ONL: outer nuclear layer; PB: phosphate buffer; proCTSD: pro-cathepsin D; LRPAP1: low density lipoprotein receptor-related protein associated protein 1; rhCTSD: human recombinant CTSD; SAPC: saposin C; SAPD: saposin D; ATP5G1: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit C1 (subunit 9); SQSTM1/p62: sequestosome 1; TPP1: tripeptidyl peptidase I.
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http://dx.doi.org/10.1080/15548627.2019.1637200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158922PMC
May 2020
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