Mapping the lipidome in mitochondria-associated membranes (MAMs) in an in vitro model of Alzheimer's disease.

The disruption of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) plays a relevant role in Alzheimer's disease (AD). MAMs have been implicated in neuronal dysfunction and death since it is associated with impairment of functions regulated in this subcellular domain, including lipid synthesis and trafficking, mitochondria dysfunction, ER stress-induced unfolded protein response (UPR), apoptosis, and inflammation. Since MAMs play an important role in lipid metabolism, in this study we characterized and investigated the lipidome alterations at MAMs in comparison with other subcellular fractions, namely microsomes and mitochondria, using an in vitro model of AD, namely the mouse neuroblastoma cell line (N2A) over-expressing the APP familial Swedish mutation (APPswe) and the respective control (WT) cells. Phospholipids (PLs) and fatty acids (FAs) were isolated from the different subcellular fractions and analyzed by HILIC-LC-MS/MS and GC-MS, respectively. In this in vitro AD model, we observed a down-regulation in relative abundance of some phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE) species with PUFA and few PC with saturated and long-chain FA. We also found an up-regulation of CL, and antioxidant alkyl acyl PL. Moreover, multivariate analysis indicated that each organelle has a specific lipid profile adaptation in N2A APPswe cells. In the FAs profile, we found an up-regulation of C16:0 in all subcellular fractions, a decrease of C18:0 levels in total fraction (TF) and microsomes fraction, and a down-regulation of 9-C18:1 was also found in mitochondria fraction in the AD model. Together, these results suggest that the over-expression of the familial APP Swedish mutation affects lipid homeostasis in MAMs and other subcellular fractions and supports the important role of lipids in AD physiopathology.

PI3K signaling promotes formation of lipid-laden foamy macrophages at the spinal cord injury site.

After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the cellular pathology of SCI, investigation of the foamy macrophage phenotype in vitro revealed a pro-inflammatory profile, increased reactive oxygen species (ROS) production, and mitochondrial dysfunction. Bioinformatic analysis identified PI3K as a regulator of inflammation in foamy macrophages, and inhibition of this pathway decreased their lipid content, inflammatory cytokines, and ROS production. Macrophage-specific inhibition of PI3K using liposomes significantly decreased foamy macrophages at the injury site after a mid-thoracic contusive SCI in mice. RNA sequencing and in vitro analysis of foamy macrophages revealed increased autophagy and decreased phagocytosis after PI3K inhibition as potential mechanisms for reduced lipid accumulation. Together, our data suggest that the formation of pro-inflammatory foamy macrophages after SCI is due to the activation of PI3K signaling, which increases phagocytosis and decreases autophagy.

CCL21-CCR7 signaling promotes microglia/macrophage recruitment and chemotherapy resistance in glioblastoma.

Glioblastoma (GBM) is the most common and fatal primary tumor of the central nervous system (CNS) and current treatments have limited success. Chemokine signaling regulates both malignant cells and stromal cells of the tumor microenvironment (TME), constituting a potential therapeutic target against brain cancers. Here, we investigated the C-C chemokine receptor type 7 (CCR7) and the chemokine (C-C-motif) ligand 21 (CCL21) for their expression and function in human GBM and then assessed their therapeutic potential in preclinical mouse GBM models. In GBM patients, CCR7 expression positively associated with a poor survival. CCL21-CCR7 signaling was shown to regulate tumor cell migration and proliferation while also controlling tumor associated microglia/macrophage recruitment and VEGF-A production, thereby controlling vascular dysmorphia. Inhibition of CCL21-CCR7 signaling led to an increased sensitivity to temozolomide-induced tumor cell death. Collectively, our data indicate that drug targeting of CCL21-CCR7 signaling in tumor and TME cells is a therapeutic option against GBM.

Cellular mechanisms of mtDNA heteroplasmy dynamics.

Heteroplasmy refers to the coexistence of more than one variant of the mitochondrial genome (mtDNA). Mutated or partially deleted mtDNAs can induce chronic metabolic impairment and cause mitochondrial diseases when their heteroplasmy levels exceed a critical threshold. These mutant mtDNAs can be maternally inherited or can arise de novo. Compelling evidence has emerged showing that mutant mtDNA levels can vary and change in a nonrandom fashion across generations and amongst tissues of an individual. However, our lack of understanding of the basic cellular and molecular mechanisms of mtDNA heteroplasmy dynamics has made it difficult to predict who will inherit or develop mtDNA-associated diseases. More recently, with the advances in technology and the establishment of tractable model systems, insights into the mechanisms underlying the selection forces that modulate heteroplasmy dynamics are beginning to emerge. In this review, we summarize evidence from different organisms, showing that mutant mtDNA can experience both positive and negative selection. We also review the recently identified mechanisms that modulate heteroplasmy dynamics. Taken together, this is an opportune time to survey the literature and to identify key cellular pathways that can be targeted to develop therapies for diseases caused by heteroplasmic mtDNA mutations.

COVID-19 inpatient mortality in Brazil from 2020 to 2022: a cross-sectional overview study based on secondary data.

BACKGROUND: In Brazil, the COVID-19 pandemic found the universal and public Unified Health System (SUS) with problems accumulated over time, due, among other reasons, to low investments, and disparities in resource distribution. The preparedness and response of the healthcare system, involving the SUS and a private sector, was affected by large socioeconomic and healthcare access inequities. This work was aimed at offering an overview of COVID-19 inpatient mortality during the pandemic in Brazil, exploring factors associated with its variations and, specifically, differences across public, private (for-profit) and philanthropic (private non-profit) inpatient healthcare units, providers, and non-providers of services to the SUS. METHODS: This cross-sectional study used public secondary data. The main data source was the SIVEP-Gripe, which comprises data on severe acute respiratory illness records prospectively collected. We also employed the National Record of Health Establishments, the SUS' Hospitalization Information System and municipalities' data from IBGE. We considered adult COVID-19 hospitalizations registered in SIVEP-Gripe from February 2020 to December 2022 in inpatient healthcare units with a minimum of 100 cases in the period. Data analyses explored the occurrence of inpatient mortality, employing general linear mixed models to identify the effects of patients', health care processes', healthcare units' and municipalities' characteristics on it. RESULTS: About 70% of the COVID-19 hospitalizations in Brazil were covered by the SUS, which attended the more vulnerable population groups and had worse inpatient mortality. In general, non-SUS private and philanthropic hospitals, mostly reimbursed by healthcare insurance plans accessible for more privileged socioeconomic classes, presented the best outcomes. Southern Brazil had the best performance among the macro-regions. Black and indigenous individuals, residents of lower HDI municipalities, and those hospitalized out of their residence city presented higher odds of inpatient mortality. Moreover, adjusted inpatient mortality rates were higher in the pandemic peak moments and were significantly reduced after COVID-19 vaccination reaching a reasonable coverage, from July 2021. CONCLUSIONS: COVID-19 exposed socioeconomic and healthcare inequalities and the importance and weaknesses of SUS in Brazil. This work indicates the need to revert the disinvestment in the universal public system, a fundamental policy for reduction of inequities in the country.

ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction, which are key events in the initiation and/or progression of several diseases, are correlated with alterations at ER-mitochondria contact sites, the so-called "Mitochondria-Associated Membranes" (MAMs). These intracellular structures are also implicated in NLRP3 inflammasome activation which is an important driver of sterile inflammation, however, the underlying molecular basis remains unclear. This work aimed to investigate the role of ER-mitochondria communication during ER stress-induced NLRP3 inflammasome activation in both peripheral and central innate immune systems, by using THP-1 human monocytes and BV2 microglia cells, respectively, as in vitro models. Markers of ER stress, mitochondrial dynamics and mass, as well as NLRP3 inflammasome activation were evaluated by Western Blot, IL-1ß secretion was measured by ELISA, and ER-mitochondria contacts were quantified by transmission electron microscopy. Mitochondrial Ca2+ uptake and polarization were analyzed with fluorescent probes, and measurement of aconitase and SOD2 activities monitored mitochondrial ROS accumulation. ER stress was demonstrated to activate the NLRP3 inflammasome in both peripheral and central immune cells. Studies in monocytes indicate that ER stress-induced NLRP3 inflammasome activation occurs by a Ca2+-dependent and ROS-independent mechanism, which is coupled with upregulation of MAMs-resident chaperones, closer ER-mitochondria contacts, as well as mitochondrial depolarization and impaired dynamics. Moreover, enhanced ER stress-induced NLRP3 inflammasome activation in the immune system was found associated with pathological conditions since it was observed in monocytes derived from bipolar disorder (BD) patients, supporting a pro-inflammatory status in BD. In conclusion, by demonstrating that ER-mitochondria communication plays a key role in the response of the innate immune cells to ER stress, this work contributes to elucidate the molecular mechanisms underlying NLRP3 inflammasome activation under stress conditions, and to disclose novel potential therapeutic targets for diseases associated with sterile inflammation.

Adiponectin, the adiponectin paradox, and Alzheimer's Disease: Is this association biologically plausible?

Dementia, especially Alzheimer's Disease (AD) and vascular dementia, is a major public health problem that continues to expand in both economically emerging and hegemonic countries. In 2017, the World Alzheimer Report estimated that over 50 million people were living with dementia globally. Metabolic dysfunctions of brain structures such as the hippocampus and cerebral cortex have been implicated as risk factors for dementia. Several well-defined metabolic risk factors for AD include visceral obesity, chronic inflammation, peripheral and brain insulin resistance, type 2 diabetes mellitus (T2DM), hypercholesterolemia, and others. In this review, we describe the relationship between the dysmetabolic mechanisms, although still unknown, and dementia, particularly AD. Adiponectin (ADPN), the most abundant circulating adipocytokine, acts as a protagonist in the metabolic dysfunction associated with AD, with unexpected and intriguing dual biological functions. This contradictory role of ADPN has been termed the adiponectin paradox. Some evidence suggests that the adiponectin paradox is important in amyloidogenic evolvability in AD. We present cumulative evidence showing that AD and T2DM share many common features. We also review the mechanistic pathways involving brain insulin resistance. We discuss the importance of the evolvability of amyloidogenic proteins (APs), defined as the capacity of a system for adaptive evolution. Finally, we describe potential therapeutic strategies in AD, based on the adiponectin paradox.

Exploiting the Integrated Valorization of Eucalyptus globulus Leaves: Chemical Composition and Biological Potential of the Lipophilic Fraction before and after Hydrodistillation.

E. globulus leaves have been mainly exploited for essential oil recovery or for energy generation in industrial pulp mills, neglecting the abundance of valuable families of extractives, namely, triterpenic acids, that might open new ways for the integrated valorization of this biomass. Therefore, this study highlights the lipophilic characterization of E. globulus leaves before and after hydrodistillation, aiming at the integrated valorization of both essential oils and triterpenic acids. The lipophilic composition of E. globulus leaves after hydrodistillation is reported for the first time. Extracts were obtained by dichloromethane Soxhlet extraction and analyzed by gas chromatography-mass spectrometry. In addition, their cytotoxicity on different cell lines representative of the innate immune system, skin, liver, and intestine were evaluated. Triterpenic acids, such as betulonic, oleanolic, betulinic and ursolic acids, were found to be the main components of these lipophilic extracts, ranging from 30.63-37.14 g kg-1 of dry weight (dw), and representing 87.7-89.0% w/w of the total content of the identified compounds. In particular, ursolic acid was the major constituent of all extracts, representing 46.8-50.7% w/w of the total content of the identified compounds. Other constituents, such as fatty acids, long-chain aliphatic alcohols and ß-sitosterol were also found in smaller amounts in the studied extracts. This study also demonstrates that the hydrodistillation process does not affect the recovery of compounds of greatest interest, namely, triterpenic acids. Therefore, the results establish that this biomass residue can be considered as a promising source of value-added bioactive compounds, opening new strategies for upgrading pulp industry residues within an integrated biorefinery context.

Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia.

Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1-PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer's and Parkinson's diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.

Relevance of the Exocyst in Arabidopsis exo70e2 Mutant for Cellular Homeostasis under Stress.

Plants must adapt to cope with adverse environmental conditions that affect their growth and development. To overcome these constraints, they can alter their developmental patterns by modulating cellular processes and activating stress-responsive signals. Alongside the activation of the antioxidant (AOX) system, a high number of genes are expressed, and proteins must be distributed to the correct locations within the cell. The endomembrane system and associated vesicles thus play an important role. Several pathways have been associated with adverse environmental conditions, which is the case for the exocyst-positive organelle-EXPO. The present work, using Arabidopsis mutants with T-DNA insertions in the gene EXO70, essential for EXPO vesicles formation, was designed to characterise the anatomical (morphology and root length), biochemical (quantification of stress markers and antioxidant system components), and molecular responses (gene expression) to abiotic stresses (saline, drought, oxidative, and metal-induced toxicity). The results obtained showed that mutant plants behave differently from the wild type (WT) plants. Therefore, in the exo70 mutant, morphological changes were more noticeable in plants under stress, and the non-enzymatic component of the antioxidant system was activated, with no alterations to the enzymatic component. Furthermore, other defence strategies, such as autophagy, did not show important changes. These results confirmed the EXPO as an important structure for tolerance/adaptation to stress.

SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway.

Nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with obesity and insulin resistance, is characterized by hepatic lipid accumulation and activation of the endoplasmic reticulum (ER) stress response. The sirtuin 2 (SIRT2) protein deacetylase is emerging as a new player in metabolic homeostasis, but its role in the development of hepatic steatosis and its link with ER stress activation remains unknown. SIRT2-knockout (SIRT2-KO) and wild-type mice were fed either a control or a high-fat diet (HFD) for 4 weeks. Genetic manipulation of SIRT2 levels was performed in human hepatic cells. Although apparently normal under a control diet, SIRT2-KO mice showed accelerated body weight gain and adiposity on a HFD, accompanied by severe insulin resistance. Importantly, SIRT2-KO mice exhibited worsened hepatic steatosis independently from diet, consistent with upregulated gene expression of lipogenic enzymes and increased expression of ER stress markers. Exposure of hepatic cells to palmitate induced lipid accumulation, increased ER stress, and decreased SIRT2 expression. Moreover, SIRT2-silenced cells showed enhanced lipid accumulation and ER stress activation under basal conditions, whereas SIRT2 overexpression abrogated palmitate-induced lipid deposition and ER stress activation. Our findings reveal a role for SIRT2 in the regulation of hepatic lipid homeostasis, potentially through the ER stress response, suggesting that SIRT2 activation might constitute a therapeutic strategy against obesity and its metabolic complications.

Forest Biomass as a Promising Source of Bioactive Essential Oil and Phenolic Compounds for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting elderly people worldwide. Currently, there are no effective treatments for AD able to prevent disease progression, highlighting the urgency of finding new therapeutic strategies to stop or delay this pathology. Several plants exhibit potential as source of safe and multi-target new therapeutic molecules for AD treatment. Meanwhile, Eucalyptus globulus extracts revealed important pharmacological activities, namely antioxidant and anti-inflammatory properties, which can contribute to the reported neuroprotective effects. This review summarizes the chemical composition of essential oil (EO) and phenolic extracts obtained from Eucalyptus globulus leaves, disclosing major compounds and their effects on AD-relevant pathological features, including deposition of amyloid-ß (Aß) in senile plaques and hyperphosphorylated tau in neurofibrillary tangles (NFTs), abnormalities in GABAergic, cholinergic and glutamatergic neurotransmission, inflammation, and oxidative stress. In general, 1,8-cineole is the major compound identified in EO, and ellagic acid, quercetin, and rutin were described as main compounds in phenolic extracts from Eucalyptus globulus leaves. EO and phenolic extracts, and especially their major compounds, were found to prevent several pathological cellular processes and to improve cognitive function in AD animal models. Therefore, Eucalyptus globulus leaves are a relevant source of biological active and safe molecules that could be used as raw material for nutraceuticals and plant-based medicinal products useful for AD prevention and treatment.

Activation of transcription factor Nrf2 to counteract mitochondrial dysfunction in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, for which no disease-modifying therapies are available to date. Although understanding of the precise aetiology of PD is incomplete, it is clear that age, genetic predisposition and environmental stressors increase the risk. At the cellular level, oxidative stress, chronic neuroinflammation, mitochondrial dysfunction and aberrant protein aggregation have been implicated as contributing factors. These detrimental processes are counteracted by elaborate networks of cellular defence mechanisms, one of which is orchestrated by transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2; gene name NFE2L2). A wealth of preclinical evidence suggests that Nrf2 activation is beneficial in cellular and animal models of PD. In this review, we summarise the current understanding of mitochondrial dysfunction in PD, the role of Nrf2 in mitochondrial function and explore the potential of Nrf2 as a therapeutic target for mitochondrial dysfunction in PD.

Therapies for Alzheimer's disease: a metabolic perspective.

Alzheimer's disease (AD) is one of the most common forms of dementia in the elderly. Currently, there are over 50 million cases of dementia worldwide and it is expected that it will reach 136 million by 2050. AD is described as a neurodegenerative disease that gradually compromises memory and learning capacity. Patients often exhibit brain glucose hypometabolism and are more susceptible to develop type 2 diabetes or insulin resistance in comparison with age-matched controls. This suggests that there is a link between both pathologies. Glucose metabolism and the tricarboxylic acid cycle are tightly related to mitochondrial performance and energy production. Impairment of both these pathways can evoke oxidative damage on mitochondria and key proteins linked to several hallmarks of AD. Glycation is also another type of post-translational modification often reported in AD, which might impair the function of proteins that participate in metabolic pathways thought to be involved in this illness. Despite needing further research, therapies based on insulin treatment, usage of anti-diabetes drugs or some form of dietary intervention, have shown to be promising therapeutic approaches for AD in its early stages of progression and will be unveiled in this paper.

GANT-61 Induces Autophagy and Apoptosis in Glioblastoma Cells despite their heterogeneity.

Glioblastoma (GBM) is the most common adult primary tumor of the CNS characterized by rapid growth and diffuse invasiveness into the brain parenchyma. The GBM resistance to chemotherapeutic drugs may be due to the presence of cancer stem cells (CSCs). The CSCs activate the same molecular pathways as healthy stem cells such as WNT, Sonic hedgehog (SHH), and Notch. Mutations or deregulations of those pathways play a key role in the proliferation and differentiation of their surrounding environment, leading to tumorigenesis. Here we investigated the effect of SHH signaling pathway inhibition in human GBM cells by using GANT-61, considering stem cell phenotype, cell proliferation, and cell death. Our results demonstrated that GANT-61 induces apoptosis and autophagy in GBM cells, by increasing the expression of LC3 II and cleaved caspase 3 and 9. Moreover, we observed that SHH signaling plays a crucial role in CSC phenotype maintenance, being also involved in the epithelial-mesenchymal transition (EMT) phenotype. We also noted that SHH pathway modulation can regulate cell proliferation as revealed through the analysis of Ki-67 and c-MYC expressions. We concluded that SHH signaling pathway inhibition may be a promising therapeutic approach to treat patients suffering from GBM refractory to traditional treatments.

Inflammation in Bipolar Disorder (BD): Identification of new therapeutic targets.

Bipolar disorder (BD) is a chronic and cyclic mental disorder, characterized by unusual mood swings between mania/hypomania and depression, raising concern in both scientific and medical communities due to its deleterious social and economic impact. Polypharmacy is the rule due to the partial effectiveness of available drugs. Disease course is often unremitting, resulting in frequent cognitive deficits over time. Despite all research efforts in identifying BD-associated molecular mechanisms, current knowledge remains limited. However, the involvement of inflammation in BD pathophysiology is increasingly consensual, with the immune system and neuroinflammation playing a key role in disease course. Evidence includes altered levels of cytokines and acute-phase proteins, pathological microglial activation, deregulation of Nrf2-Keap1 system and changes in biogenic amines neurotransmitters, whose expression is regulated by TNF-α, a pro-inflammatory cytokine highly involved in BD, pointing out inflammation as a novel and attractive therapeutic target for BD. As result, new therapeutic agents including non-steroidal anti-inflammatory drugs, N-acetylcysteine and GSK3 inhibitors have been incorporated in BD treatment. Taking into consideration the latest pre-clinical and clinical trials, in this review we discuss recent data regarding inflammation in BD, unveiling potential therapeutic approaches through direct or indirect modulation of inflammatory response.

Patterns of hospital utilization in the Unified Health System in six Brazilian capitals: comparison between the year before and the first six first months of the COVID-19 pandemic.

OBJECTIVE: To analyze the temporal evolution of the pattern of hospital use in the context of the COVID-19 pandemic in Brazil. METHODS: This retrospective observational study compared hospital use and mortality in the Brazilian Unified Health System (SUS) in the first six months of the COVID-19 pandemic with the year before the onset of the pandemic in six Brazilian capitals (São Paulo, Rio de Janeiro, Manaus, Fortaleza, Recife, and Brasilia). It was based on secondary administrative data from the SUS Hospital Information System (SIH), focusing on the number of hospitalizations per fortnight, age, and gender of patients, hospital length of stay, and the proportions of surgical, elective, with the use of ICU, and resulting in death hospitalizations. It also compared the number of hospitalizations and mortality related to frequent diagnostic groups. RESULTS: A significant drop was identified in the number of hospitalizations as of March 2020, with the first peak of COVID-19 hospitalizations in five capitals recorded in May 2020. In the six capitals, we observed significant reductions in the mean number of hospitalizations per fortnight from the beginning of the pandemic. We also identified an increase in the mean age of the patients and the proportion of male patients. The proportion of surgical and elective hospitalizations dropped significantly in all capitals, while the proportion of hospitalizations with ICU use increased significantly. Significant increases in-hospital mortality were also recorded in the six capitals with the pandemic, including or excluding COVID-19 hospitalizations from the comparison. CONCLUSION: The pandemic caused changes in the pattern of use and hospital indicators in the first six months in the cities considered, evidencing the need for attention to diseases with a hospital production altered by the COVID-19 course and health system performance problems in the face of challenges.

Abiotic Stress Triggers the Expression of Genes Involved in Protein Storage Vacuole and Exocyst-Mediated Routes.

Adverse conditions caused by abiotic stress modulate plant development and growth by altering morphological and cellular mechanisms. Plants' responses/adaptations to stress often involve changes in the distribution and sorting of specific proteins and molecules. Still, little attention has been given to the molecular mechanisms controlling these rearrangements. We tested the hypothesis that plants respond to stress by remodelling their endomembranes and adapting their trafficking pathways. We focused on the molecular machinery behind organelle biogenesis and protein trafficking under abiotic stress conditions, evaluating their effects at the subcellular level, by looking at ultrastructural changes and measuring the expression levels of genes involved in well-known intracellular routes. The results point to a differential response of the endomembrane system, showing that the genes involved in the pathway to the Protein Storage Vacuole and the exocyst-mediated routes are upregulated. In contrast, the ones involved in the route to the Lytic Vacuole are downregulated. These changes are accompanied by morphological alterations of endomembrane compartments. The data obtained demonstrate that plants' response to abiotic stress involves the differential expression of genes related to protein trafficking machinery, which can be connected to the activation/deactivation of specific intracellular sorting pathways and lead to alterations in the cell ultrastructure.

Luminescent Ln-Ionic Liquids beyond Europium.

Searching in the Web of Knowledge for "ionic liquids" AND "luminescence" AND "lanthanide", around 260 entries can be found, of which a considerable number refer solely or primarily to europium (90%, ~234). Europium has been deemed the best lanthanide for luminescent applications, mainly due to its efficiency in sensitization, longest decay times, and the ability to use its luminescence spectra to probe the coordination geometry around the metal. The remaining lanthanides can also be of crucial importance due to their different colors, sensitivity, and capability as probes. In this manuscript, we intend to shed some light on the existing published work on the remaining lanthanides. In some cases, they appear in papers with europium, but frequently in a subordinate position, and in fewer cases then the main protagonist of the study. All of them will be assessed and presented in a concise manner; they will be divided into two main categories: lanthanide compounds dissolved in ionic liquids, and lanthanide-based ionic liquids. Finally, some analysis of future trends is carried out highlighting some future promising fields, such as ionogels.

Saliva NMR-Based Metabolomics in the War Against COVID-19.

COVID-19 is an emergent, worldwide public health concern. Joint efforts have been made by scientific communities of various fields to better understand the mechanisms of action of SARS-CoV-2. The need to understand the pathophysiological fingerprint and pathways of this disease make metabolomics-related approaches an indispensable tool for properly answering concerns relating to disease course. Determination of the metabolomic profile may help to explain the heterogeneous spectra of COVID-19 clinical phenotypes and be useful in monitoring disease progression as well as therapeutic treatments. In this sense, saliva has proven to be a strategic biofluid, owing not only to its appeal as a noninvasive sampling method but also due to the capacity of the virus to invade epithelial cells of the oral mucosa and salivary gland ducts via ACE2 receptors. Accordingly, important changes in metabolism have been described relating to COVID-19, indicating that metabolomics may open new avenues for understanding the pathophysiology of this disease, especially via longitudinal study designs. Thus, we discuss the importance of comprehending the SARS-CoV-2 salivary metabolomic fingerprint and also highlight the situation of Brazil on the frontlines of the war against COVID-19.