Inheritable testicular metabolic memory of high-fat diet causes transgenerational sperm defects in mice

Funding Information: This work was supported by the Portuguese Foundation for Science and Technology: L. Crisóstomo (SFRH/ BD/128584/2017), M.G. Alves (IFCT2015 and PTDC/MEC-AND/28691/2017), P.F. Oliveira (IFCT2015), UMIB (UIDB/00215/2020 and UIDP/00215/2020) and QOPNA (UID/QUI/00062/2019) co-funded by FEDER funds (POCI/COMPETE 2020); by the Portuguese Society of Diabetology: L. Crisóstomo and M.G. Alves (“Nuno Castel-Branco” research grant and Group of Fundamental and Translational Research); and by the European Foundation for the Study of Diabetes: L. Crisóstomo (Albert Renold Travel Grant). NMR data was collected at the UC-NMR facility which is supported in part by FEDER—European Regional Development Fund through the COMPETE Programme (Operational Programme for Competitiveness) and by National Funds through FCT— Fundação para a Ciência e a Tecnologia (Portuguese Foundation for Science and Technology) through grants REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07-CT62-FEDER-002012, and Rede Nacional de Ressonância Magnética Nuclear (RNRMN). We thank Prof. Pedro N. Oliveira (University of Porto, Portugal) and Matthieu Bourgery (University of Turku, Finland) for their advice in Statistical Analysis. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.The consumption of energy-dense diets has contributed to an increase in the prevalence of obesity and its comorbidities worldwide. The adoption of unhealthy feeding habits often occurs at early age, prompting the early onset of metabolic disease with unknown consequences for reproductive function later in life. Recently, evidence has emerged regarding the intergenerational and transgenerational effects of high-fat diets (HFD) on sperm parameters and testicular metabolism. Hereby, we study the impact of high-fat feeding male mice (F0) on the testicular metabolome and function of their sons (F1) and grandsons (F2). Testicular content of metabolites related to insulin resistance, cell membrane remodeling, nutritional support and antioxidative stress (leucine, acetate, glycine, glutamine, inosine) were altered in sons and grandsons of mice fed with HFD, comparing to descendants of chow-fed mice. Sperm counts were lower in the grandsons of mice fed with HFD, even if transient. Sperm quality was correlated to testicular metabolite content in all generations. Principal Component Analysis of sperm parameters and testicular metabolites revealed an HFD-related phenotype, especially in the diet-challenged generation and their grandsons. Ancestral HFD, even if transient, causes transgenerational “inherited metabolic memory” in the testicular tissue, characterized by changes in testicular metabolome and function.publishersversionpublishe

Sarcoma granulocítico multicêntrico como recidiva de leucemia mieloide aguda

Sarcoma granulocítico (SG) é um tumor sólido extramedular, constituído por células precursoras de granulócitos. É geralmente associado a leucemia mieloide aguda ou raramente a outras desordens mieloproliferativas. O tumor geralmente ocorre precedendo uma leucemia mieloide aguda, durante o seu curso ou após a remissão ter sido alcançada. O prognóstico é pobre e tem como principais modalidades terapêuticas a quimioterapia e a radioterapia. Relata- se um caso de SG multicêntrico, de evolução rápida, com acometimento difuso de pele, mamas, gânglios linfáticos, tecido celular subcutâneo e líquor, em mulher de 45 anos, fora de tratamento para leucemia mieloide aguda e em remissão hematológica há 18 meses. A paciente apresentava dor intensa em membro inferior direito há uma semana e estava em anticoagulação oral há seis meses por trombose venosa profunda neste membro. Diagnosticado o SG, a paciente foi tratada com radioterapia e quimioterapia com boa resposta. Após três meses de seguimento, em vigência do tratamento quimioterápico, evoluiu com recidiva do SG neste membro, associado ao acometimento das mamas e posteriormente do sistema nervoso central, evoluindo para óbito em aplasia e sepses

Photobiomodulation reduces the cytokine storm syndrome associated with Covid-19 in the zebrafish model

Although the exact mechanism of the pathogenesis of COVID-19 is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red PBM as an attractive therapy to downregulate the cytokine storm caused by COVID-19 from a zebrafish model. RT-PCR analyses and protein-protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that rSpike was responsible for generating systemic inflammatory processes with significantly increased pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a, coa1) mRNA markers, with a pattern like those observed in COVID-19 cases in humans. On the other hand, PBM treatment decreased the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most impacted metabolic pathways between PBM and the rSpike-treated groups were related to steroid metabolism, immune system, and lipids metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19, and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials.publishedVersio

Effect of Uncaria tomentosa

Background/Aim. The use of herbal products as a supplement to minimize the effects of chemotherapy for cancer treatment requires further attention with respect to the activity and toxicity of chemotherapy. Uncaria tomentosa extract, which contains oxindole alkaloids, is one of these herbal products. The objective of this study was to evaluate whether Uncaria tomentosa extract modulates apoptosis induced by chemotherapy exposure. Materials and Methods. Colorectal adenocarcinoma cells (HT29 cells) were grown in the presence of oxaliplatin and/or Uncaria tomentosa extract. Results. The hydroalcoholic extract of Uncaria tomentosa enhanced chemotherapy-induced apoptosis, with an increase in the percentage of Annexin positive cells, an increase in caspase activities, and an increase of DNA fragments in culture of the neoplastic cells. Moreover, antioxidant activity may be related to apoptosis. Conclusion. Uncaria tomentosa extract has a role for cancer patients as a complementary therapy. Further studies evaluating these beneficial effects with other chemotherapy drugs are recommended

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt