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The extracellular matrix (ECM) is an essential component of the heart that imparts fundamental cellular processes during organ development and homeostasis. Most cardiovascular diseases involve severe remodeling of the ECM, culminating in the formation of fibrotic tissue that is deleterious to organ function. Treatment schemes effective at managing fibrosis and promoting physiological ECM repair are not yet in reach. Of note, the composition of the cardiac ECM changes significantly in a short period after birth, concurrent with the loss of the regenerative capacity of the heart. This highlights the importance of understanding ECM composition and function headed for the development of more efficient therapies. In this review, we explore the impact of ECM alterations, throughout heart ontogeny and disease, on cardiac cells and debate available approaches to deeper insights on cell–ECM interactions, toward the design of new regenerative therapies.

The Wilson Cycle, a cornerstone of plate tectonic theory, describes the cyclical evolution of ocean basins from rifting and spreading to closure via subduction and continental collision and assembly. While pivotal for understanding plate boundary processes, it remains limited in addressing intraplate deformation. This study revisits the Wilson Cycle by investigating intraplate deformation and mechanisms of tectonic stress partitioning in (Pre)Cambrian cratons and different orogen types in Southeast Brazil, Southeast Colombia, and Peninsular India. We focus on cratonic areas (Amazon, São Francisco and Dharwar Cratons) that are traditionally considered stable since their incorporation in Gondwana and its subsequent disintegration. We also consider some of the fringing orogens or mobile belts (Brasília and Araçuaí Orogens). Using apatite fission-track thermochronology, we analyze the timing, magnitude, and drivers of deformation and show significant variability in tectonic responses. Some cratons (Amazon and Dharwar) demonstrate unexpected exhumation driven by extensional tectonics, while others (São Francisco Craton) exhibit only localized reactivations and remain largely stable. Similarly, orogens follow distinct evolutionary paths: e.g. the Brasília Orogen became resistant to post-Gondwana deformation, effectively stagnating the Wilson Cycle, while the Araçuaí Orogen experienced intense reactivation and renewed tectonic activity. These examples give new insights into the traditional Wilson Cycle, demonstrating that intraplate deformation plays a critical role in sustaining or altering the cycle, implying the traditional concept is in need of significant revision.

Antimicrobial polymers represent a very promising class of therapeutics with unique characteristics for fighting microbial infections. As the classic antibiotics exhibit an increasingly low capacity to effectively act on microorganisms, new solutions must be developed. The importance of this class of materials emerged from the uncontrolled use of antibiotics, which led to the advent of multidrug-resistant microbes, being nowadays one of the most serious public health problems. This review presents a critical discussion of the latest developments involving the use of different classes of antimicrobial polymers. The synthesis pathways used to afford macromolecules with antimicrobial properties, as well as the relationship between the structure and performance of these materials are discussed.

Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying KMT2A gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have garnered attention for their potential therapeutic efficacy in treating KMT2A-rearranged acute leukemias. However, resistance to menin inhibition poses challenges, and identifying which patients would benefit from revumenib treatment is crucial. Here, we investigated the in vitro response to revumenib in KMT2A-rearranged ALL and AML. While ALL samples show rapid, dose-dependent induction of leukemic cell death, AML responses are much slower and promote myeloid differentiation. Furthermore, we reveal that acquired resistance to revumenib in KMT2A-rearranged ALL cells can occur either through the acquisition of MEN1 mutations or independently of mutations in MEN1. Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia.

In Alzheimer’s disease, the accumulation of amyloid-beta (Aβ) in the brain occurs in the parenchyma and cerebrovasculature. Several evidences support that the neuronal demise is potentiated by vascular alterations in the early stages of the disease, but the mechanisms responsible for the dysfunction of brain endothelial cells that underlie these cerebrovascular changes are unknown. Using rat brain microvascular endothelial cells, we found that short-term treatment with a toxic dose of Aβ 1-40 inhibits the Ca 2+ refill and retention ability of the endoplasmic reticulum and enhances the mitochondrial and cytosolic response to adenosine triphosphate (ATP)-stimulated endoplasmic reticulum Ca 2+ release. Upon prolonged Aβ 1-40 exposure, Ca 2+ homeostasis was restored concomitantly with a decrease in the levels of proteins involved in its regulation operating at the plasma membrane, endoplasmic reticulum, and mitochondria. Along with perturbations in Ca 2+ regulation, an early increase in the levels of oxidants and a decrease in the ratio between reduced and oxidized glutathione were observed in Aβ 1-40 -treated endothelial cells. Under these conditions, the nuclear levels of oxidative stress-related transcription factors, namely, hypoxia-inducible factor 1α and nuclear factor (erythroid-derived 2)-related factor 2, were enhanced as well as the protein levels of target genes. In conclusion, Aβ 1-40 affects several mechanisms involved in Ca 2+ homeostasis and impairs the redox homeostasis simultaneously with stimulation of protective stress responses in brain endothelial cells. However, the imbalance between cell death and survival pathways leads to endothelial dysfunction that in turn contributes to cerebrovascular impairment in Alzheimer’s disease.

Calcineurin inhibitors are used in immunosuppressive therapy applied after transplantation, but they are associated with major metabolic side effects including the development of new onset diabetes. Previously, we have shown that the calcineurin inhibiting drugs tacrolimus and cyclosporin A reduce adipocyte and myocyte glucose uptakes by reducing the amount of glucose transporter type 4 (GLUT4) at the cell surface, due to an increased internalization rate. However, this happens without alteration in total protein and phosphorylation levels of key proteins involved in insulin signalling or in the total amount of GLUT4. The present study evaluates possible pathways involved in the altered internalization of GLUT4 and consequent reduction of glucose uptake provoked by calcineurin inhibitors in human subcutaneous adipose tissue. Short- and long-term treatments with tacrolimus, cyclosporin A or another CNI deltamethrin (herbicide) decreased basal and insulin-dependent glucose uptake in adipocytes, without any additive effects observed when added together. However, no tacrolimus effects were observed on glucose uptake when gene transcription and protein translation were inhibited. Investigation of genes potentially involved in GLUT4 trafficking showed only a small effect on ARHGEF11 gene expression ( p < 0.05). In conlusion, the specific inhibition of calcineurin, but not that of protein phosphatases, decreases glucose uptake in human subcutaneous adipocytes, suggesting that calcineurin is an important regulator of glucose transport. This inhibitory effect is mediated via gene transcription or protein translation; however, expression of genes potentially involved in GLUT4 trafficking and endocytosis appears not to be involved in these effects.

Industrial wastewater from petrochemical processes is an essential source of the synthetic phenolic phosphite antioxidant (Irgafos P-168), which negatively affects the environment. For the determination and analysis of Irgafos P-168, DSC, HPLC-MS, and FTIR methodologies were used. Solid phase extraction (SPE) proved to be the best technique for extracting Irgafos from wastewater. HPLC-MS and SPE determined the repeatability, reproducibility, and linearity of the method and the SPE of the standards and samples. The relative standard deviations, errors, and correlation coefficients for the repeatability and reproducibility of the calibration curves were less than 4.4% and 4.2% and greater than 0.99955, respectively. The analysis of variance (ANOVA), using the Fisher method with confidence in 95% of the data, did not reveal significant differences between the mentioned parameters. The removal of the antioxidant from the wastewater by SPE showed recovery percentages higher than 91.03%, and the chemical characterization of this antioxidant by FTIR spectroscopy, DSC, TGA, and MS showed it to be structurally the same as the Irgafos P-168 molecule. The recovered Irgafos was added to the polypropylene matrix, significantly improving its oxidation times. An OIT analysis, performed using DSC, showed that the recovered Irgafos-blended polypropylene (PP) demonstrated oxidative degradation at 8 min. With the addition of the Irgafos, the oxidation time was 13 min. This increases the polypropylene’s useful life and minimizes the environmental impact of the wastewater.

Although the majority of the global population lives in developing countries, most of the epidemiological data related to intensive care unit (ICU) acute kidney injury (AKI) comes from developed countries. This systematic review aims to ascertain the methodology of studies on ICU AKI patients in developing and developed countries, to determine whether epidemiological comparisons between these two settings are possible, and to present a summary estimate of AKI incidence. A systematic review of published studies reporting AKI in intensive care units (2005-2015) identified in PubMed, LILACS, and IBECs databases was conducted. We compared developed and developing countries by evaluating study methodology, AKI reference serum creatinine definitions, population characteristics, AKI incidence and mortality. AKI incidence was calculated with a random-effects model. Ninety-two studies were included, one of which reported data from both country categories: 60 from developed countries (1,057,332 patients) and 33 from developing countries (34,539 patients). In 78% of the studies, AKI was defined by the RIFLE, AKIN or KDIGO criteria. Oliguria had 11 different definitions and reference creatinine 23 different values. For the meta-analysis, 38 studies from developed and 18 from developing countries were selected, with similar AKI incidence: 39.3% and 35.1%, respectively. The need for dialysis, length of ICU stay and mortality were higher in developing countries. Although patient characteristics and AKI incidence were similar in developed and developing countries, main outcomes were worse in developing country studies. There are significant caveats when comparing AKI epidemiology in developed and developing countries, including lack of standardization of reference serum creatinine, oliguria and the timeframe for AKI assessment. Larger, prospective, multicenter studies from developing countries are urgently needed to capture AKI data from the overall population without ICU access.

Childhood obesity is a serious public health problem associated with the development of several chronic diseases, such as type 2 diabetes mellitus, dyslipidemia, and hypertension. The elevated prevalence of obesity is mostly due to inadequate diet and lifestyle, but it is also influenced by genetic factors. To review recent advances in the field of the genetics of obesity. We summarize the list of genes associated with the rare non-syndromic forms of obesity, and explain their function. Furthermore, we discuss the technologies that are available for the genetic diagnosis of obesity. Several studies reported that single gene variants cause Mendelian forms of obesity, determined by mutations of major effect in single genes. Rare, non-syndromic forms of obesity are a result of loss-of-function mutations in genes that act on the development and function of the hypothalamus or the leptin-melanocortin pathway. These variants disrupt enzymes and receptors that play a role in energy homeostasis, resulting in severe early-onset obesity and endocrine dysfunctions. Different approaches and technologies have been used to understand the genetic background of obesity. Currently, whole genome and whole exome sequencing are important diagnostic tools to identify new genes and variants associated with severe obesity, but other approaches are also useful at individual or population levels, such as linkage analysis, candidate gene sequencing, chromosomal microarray analysis, and genome-wide association studies. The understanding of the genetic causes of obesity and the usefulness and limitations of the genetic diagnostic approaches can contribute to the development of new personalized therapeutic targets against obesity. •Most non-syndromic forms of obesity are a result of mutations in genes that act on the leptin-melanocortin pathway.•These mutations can be dominant (BDNF, NTRK2, SIM1, MC4R, SH2B1, MRAP2, LRP2) or recessive (LEP, LEPR, POMC, MCR4, PCSK1, TUB).•The genetic diagnosis of obesity can be obtained through approaches conducted at individual, familial or populational levels.•Next generation sequencing can contribute to the development of new therapeutic targets for Mendelian obesity.

Background/Objectives: Epicardial adipose tissue (EAT) is metabolically active and is in dynamic crosstalk with the surrounding cardiomyocytes, modulating their function and metabolism. Oxidative stress is a key contributor to cell death and cardiac remodeling, is a hallmark of diabetes (DM) and cardiovascular disease, such as coronary artery disease (CAD). However, little is known about these processes in EAT from patients undergoing cardiac surgery. This study investigates changes in mitochondrial dynamics, reactive oxygen species (ROS) production, and antioxidant defense levels in EAT compared to subcutaneous adipose tissue (SAT) in patients undergoing cardiac surgery, with a focus on the impact of DM and CAD. Methods: Adipose tissue biopsies were collected from 128 patients undergoing surgical cardiac intervention. Mitochondrial dynamics and oxidative stress markers were analyzed. Results: EAT exhibited increased expression of mitochondrial fusion markers [mitofusin 1 (p ≤ 0.001), mitofusin 2 (p = 0.038), and optic atrophy 1 (p ≤ 0.001)], as well as fission markers [fission 1 (p ≤ 0.001) and dynamin-related protein 1 (p ≤ 0.001)] relative to SAT. Additionally, ROS levels (dihydroethidium, p = 0.004) were elevated, while lipid peroxidation (malondialdehyde, p ≤ 0.001) was reduced in EAT compared to SAT. Reduced glutathione (GSH) levels (p ≤ 0.001) and the redox buffer ratio between reduced and oxidized glutathione (GSH/GSSG, p ≤ 0.001) were significantly increased in EAT. Interestingly, glutathione peroxidase activity (p ≤ 0.001) and the antioxidant defense markers catalase (p ≤ 0.001) and superoxide dismutase 2 (p = 0.001) were significantly reduced in EAT compared to SAT. Conclusions: The findings provide a unique molecular insight into the mitochondrial dynamics and oxidative stress profiles of EAT, highlighting potential avenues for a novel diagnostic method and therapeutic strategies for cardiac disease.