Teixobactin kills bacteria by a two-pronged attack on the cell envelope.

Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1-3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a ß-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.

Synthetic Cannabinoids: A Pharmacological and Toxicological Overview.

Synthetic cannabinoids (SCs) are a chemically diverse group of new psychoactive substances (NPSs) that target the endocannabinoid system, triggering a plethora of actions (e.g., elevated mood sensation, relaxation, appetite stimulation) that resemble, but are more intense than, those induced by cannabis. Although some of these effects have been explored for therapeutic applications, anticipated stronger psychoactive effects than cannabis and reduced risk perception have increased the recreational use of SCs, which have dominated the NPS market in the United States and Europe over the past decade. However, rising SC-related intoxications and deaths represent a major public health concern and embody a major challenge for policy makers. Here, we review the pharmacology and toxicology of SCs. A thorough characterization of SCs' pharmacodynamics and toxicodynamics is important to better understand the main mechanisms underlying acute and chronic effects of SCs, interpret the clinical/pathological findings related to SC use, and improve SC risk awareness.

Climate determines transmission hotspots of Polycystic Echinococcosis, a life-threatening zoonotic disease, across Pan-Amazonia.

Polycystic Echinococcosis (PE), a neglected life-threatening zoonotic disease caused by the cestode Echinococcus vogeli, is endemic in the Amazon. Despite being treatable, PE reaches a case fatality rate of around 29% due to late or missed diagnosis. PE is sustained in Pan-Amazonia by a complex sylvatic cycle. The hunting of its infected intermediate hosts (especially the lowland paca Cuniculus paca) enables the disease to further transmit to humans, when their viscera are improperly handled. In this study, we compiled a unique dataset of host occurrences (~86000 records) and disease infections (~400 cases) covering the entire Pan-Amazonia and employed different modeling and statistical tools to unveil the spatial distribution of PE's key animal hosts. Subsequently, we derived a set of ecological, environmental, climatic, and hunting covariates that potentially act as transmission risk factors and used them as predictors of two independent Maximum Entropy models, one for animal infections and one for human infections. Our findings indicate that temperature stability promotes the sylvatic circulation of the disease. Additionally, we show how El Niño-Southern Oscillation (ENSO) extreme events disrupt hunting patterns throughout Pan-Amazonia, ultimately affecting the probability of spillover. In a scenario where climate extremes are projected to intensify, climate change at regional level appears to be indirectly driving the spillover of E. vogeli. These results hold substantial implications for a wide range of zoonoses acquired at the wildlife-human interface for which transmission is related to the manipulation and consumption of wild meat, underscoring the pressing need for enhanced awareness and intervention strategies.

Recombinant Bacillus Calmette-Guérin Expressing SARS-CoV-2 Chimeric Protein Protects K18-hACE2 Mice against Viral Challenge.

COVID-19 has accounted for more than 6 million deaths worldwide. Bacillus Calmette-Guérin (BCG), the existing tuberculosis vaccine, is known to induce heterologous effects over other infections due to trained immunity and has been proposed to be a potential strategy against SARS-CoV-2 infection. In this report, we constructed a recombinant BCG (rBCG) expressing domains of the SARS-CoV-2 nucleocapsid and spike proteins (termed rBCG-ChD6), recognized as major candidates for vaccine development. We investigated whether rBCG-ChD6 immunization followed by a boost with the recombinant nucleocapsid and spike chimera (rChimera), together with alum, provided protection against SARS-CoV-2 infection in K18-hACE2 mice. A single dose of rBCG-ChD6 boosted with rChimera associated with alum elicited the highest anti-Chimera total IgG and IgG2c Ab titers with neutralizing activity against SARS-CoV-2 Wuhan strain when compared with control groups. Importantly, following SARS-CoV-2 challenge, this vaccination regimen induced IFN-γ and IL-6 production in spleen cells and reduced viral load in the lungs. In addition, no viable virus was detected in mice immunized with rBCG-ChD6 boosted with rChimera, which was associated with decreased lung pathology when compared with BCG WT-rChimera/alum or rChimera/alum control groups. Overall, our study demonstrates the potential of a prime-boost immunization system based on an rBCG expressing a chimeric protein derived from SARS-CoV-2 to protect mice against viral challenge.

Fin ray branching is defined by TRAP+ osteolytic tubules in zebrafish.

The shaping of bone structures relies on various cell types and signaling pathways. Here, we use the zebrafish bifurcating fin rays during regeneration to investigate bone patterning. We found that the regenerating fin rays form via two mineralization fronts that undergo an osteoblast-dependent fusion/stitching until the branchpoint, and that bifurcation is not simply the splitting of one unit into two. We identified tartrate-resistant acid phosphatase-positive osteolytic tubular structures at the branchpoints, hereafter named osteolytic tubules (OLTs). Chemical inhibition of their bone-resorbing activity strongly impairs ray bifurcation, indicating that OLTs counteract the stitching process. Furthermore, by testing different osteoactive compounds, we show that the position of the branchpoint depends on the balance between bone mineralization and resorption activities. Overall, these findings provide a unique perspective on fin ray formation and bifurcation, and reveal a key role for OLTs in defining the proximo-distal position of the branchpoint.

Bidirectional relation between dipeptidyl peptidase 4 and angiotensin II type I receptor signaling.

Cardiometabolic diseases are often associated with heightened levels of angiotensin II (Ang II), which accounts for the observed oxidative stress, inflammation, and fibrosis. Accumulating evidence indicates a parallel upregulation of dipeptidyl dipeptidase 4 (DPP4) activity in cardiometabolic diseases, with its inhibition shown to mitigate oxidative stress, inflammation, and fibrosis. These findings highlight an overlap between the pathophysiological mechanisms used by Ang II and DPP4. Recent evidence demonstrates that targeted inhibition of DPP4 prevents the rise in Ang II and its associated molecules in experimental models of cardiometabolic diseases. Similarly, inhibitors of the angiotensin I-converting enzyme (ACE) or Ang II type 1 receptor (AT1R) blockers downregulate DPP4 activity, establishing a bidirectional relationship between DPP4 and Ang II. Here, we discuss the current evidence supporting the cross talk between Ang II and DPP4, along with the potential mechanisms promoting this cross regulation. A comprehensive analysis of this bidirectional relationship across tissues will advance our understanding of how DPP4 and Ang II collectively promote the development and progression of cardiometabolic diseases.

Distinguishing Different Hydrogen-Bonded Helices in Proteins by Efficient 1H-Detected Three-Dimensional Solid-State NMR.

Helical structures in proteins include not only α-helices but also 310 and π helices. These secondary structures differ in the registry of the C═O···H-N hydrogen bonds, which are i to i + 4 for α-helices, i to i + 3 for 310 helices, and i to i + 5 for π-helices. The standard NMR observable of protein secondary structures are chemical shifts, which are, however, insensitive to the precise type of helices. Here, we introduce a three-dimensional (3D) 1H-detected experiment that measures and assigns CO-HN cross-peaks to distinguish the different types of hydrogen-bonded helices. This hCOhNH experiment combines efficient cross-polarization from CO to HN with 13C, 15N, and 1H chemical shift correlation to detect the relative proximities of the COi-Hi+jN spin pairs. We demonstrate this experiment on the membrane-bound transmembrane domain of the SARS-CoV-2 envelope (E) protein (ETM). We show that the C-terminal five residues of ETM form a 310-helix, whereas the rest of the transmembrane domain have COi-Hi+4N hydrogen bonds that are characteristic of α-helices. This result confirms the recent high-resolution solid-state NMR structure of the open state of ETM, which was solved in the absence of explicit hydrogen-bonding restraints. This C-terminal 310 helix may facilitate proton and calcium conduction across the hydrophobic gate of the channel. This hCOhNH experiment is generally applicable and can be used to distinguish not only different types of helices but also different types of ß-strands and other hydrogen-bonded conformations in proteins.

Unveiling the phenology and associated floral regulatory pathways of Humulus lupulus L. in subtropical conditions.

MAIN CONCLUSION: The hop phenological cycle was described in subtropical condition of Brazil showing that flowering can happen at any time of year and this was related to developmental molecular pathways. Hops are traditionally produced in temperate regions, as it was believed that vernalization was necessary for flowering. Nevertheless, recent studies have revealed the potential for hops to flower in tropical and subtropical climates. In this work, we observed that hops in the subtropical climate of Minas Gerais, Brazil grow and flower multiple times throughout the year, independently of the season, contrasting with what happens in temperate regions. This could be due to the photoperiod consistently being inductive, with daylight hours below the described threshold (16.5 h critical). We observed that when the plants reached 7-9 nodes, the leaves began to transition from heart-shaped to trilobed-shaped, which could be indicative of the juvenile to adult transition. This could be related to the fact that the 5th node (in plants with 10 nodes) had the highest expression of miR156, while two miR172s increased in the 20th node (in plants with 25 nodes). Hop flowers appeared later, in the 25th or 28th nodes, and the expression of HlFT3 and HlFT5 was upregulated in plants between 15 and 20 nodes, while the expression of HlTFL3 was upregulated in plants with 20 nodes. These results indicate the role of axillary meristem age in regulating this process and suggest that the florigenic signal should be maintained until the hop plants bloom. In addition, it is possible that the expression of TFL is not sufficient to inhibit flowering in these conditions and promote branching. These findings suggest that the reproductive transition in hop under inductive photoperiodic conditions could occur in plants between 15 and 20 nodes. Our study sheds light on the intricate molecular mechanisms underlying hop floral development, paving the way for potential advancements in hop production on a global scale.

Impact of the COVID-19 Pandemic on the Outcomes of Patients Undergoing Oncological Surgeries: CORONAL Study.

BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) on postoperative recovery from oncology surgeries should be understood for the clinical decision-making. Therefore, this study was designed to evaluate the postoperative cumulative 28-day mortality and the morbidity of surgical oncology patients during the COVID-19 pandemic. METHODS: This retrospective cohort study included patients consecutively admitted to intensive care units (ICU) of three centres for postoperative care of oncologic surgeries between March to June 2019 (first phase) and March to June 2020 (second phase). The primary outcome was cumulative 28-day postoperative mortality. Secondary outcomes were postoperative organic dysfunction and the incidence of clinical complications. Because of the possibility of imbalance between groups, adjusted analyses were performed: Cox proportional hazards model (primary outcome) and multiple logistic regression model (secondary outcomes). RESULTS: After screening 328 patients, 291 were included. The proportional hazard of cumulative 28-day mortality was higher in the second phase than that in the first phase in the Cox model, with the adjusted hazard ratio of 4.35 (95% confidence interval [CI] 2.15-8.82). The adjusted incidences of respiratory complications (odds ratio [OR] 5.35; 95% CI 1.42-20.11) and pulmonary infections (OR 1.53; 95% CI 1.08-2.17) were higher in the second phase. However, the adjusted incidence of other infections was lower in the second phase (OR 0.78; 95% CI 0.67-0.91). CONCLUSIONS: Surgical oncology patients who underwent postoperative care in the intensive care unit during the COVID-19 pandemic had higher hazard of 28-day mortality. Furthermore, these patients had higher odds of respiratory complications and pulmonary infections. Trials registration The study is registered in the Brazilian Registry of Clinical Trials under the code RBR-8ygjpqm, UTN code U1111-1293-5414.

Obesity, diabetes and risk of bone fragility: How BMAT behavior is affected by metabolic disturbances and its influence on bone health.

PURPOSE: Osteoporosis is a metabolic bone disease characterized by decreased bone strength and mass, which predisposes patients to fractures and is associated with high morbidity and mortality. Like osteoporosis, obesity and diabetes are systemic metabolic diseases associated with modifiable risk factors and lifestyle, and their prevalence is increasing. They are related to decreased quality of life, functional loss and increased mortality, generating high costs for health systems and representing a worldwide public health problem. Growing evidence reinforces the role of bone marrow adipose tissue (BMAT) as an influential factor in the bone microenvironment and systemic metabolism. Given the impact of obesity and diabetes on metabolism and their possible effect on the bone microenvironment, changes in BMAT behavior may explain the risk of developing osteoporosis in the presence of these comorbidities. METHODS: This study reviewed the scientific literature on the behavior of BMAT in pathological metabolic conditions, such as obesity and diabetes, and its potential involvement in the pathogenesis of bone fragility. RESULTS: Published data strongly suggest a relationship between increased BMAT adiposity and the risk of bone fragility in the context of obesity and diabetes. CONCLUSION: By secreting a broad range of factors, BMAT modulates the bone microenvironment and metabolism, ultimately affecting skeletal health. A better understanding of the relationship between BMAT expansion and metabolic disturbances observed in diabetic and obese patients will help to identify regulatory pathways and new targets for the treatment of bone-related diseases, with BMAT as a potential therapeutic target.

The central role of pyruvate metabolism on the epigenetic maturation and transcriptional profile of bovine oocytes.

In brief: Pyruvate metabolism is one of the main metabolic pathways during oocyte maturation. This study demonstrates that pyruvate metabolism also regulates the epigenetic and molecular maturation in bovine oocytes. Abstract: Pyruvate, the final product of glycolysis, undergoes conversion into acetyl-CoA within the mitochondria of oocytes, serving as a primary fuel source for the tricarboxylic acid (TCA) cycle. The citrate generated in the TCA cycle can be transported to the cytoplasm and converted back into acetyl-CoA. This acetyl-CoA can either fuel lipid synthesis or act as a substrate for histone acetylation. This study aimed to investigate how pyruvate metabolism influences lysine 9 histone 3 acetylation (H3K9ac) dynamics and RNA transcription in bovine oocytes during in vitro maturation (IVM). Bovine cumulus-oocyte complexes were cultured in vitro for 24 h, considering three experimental groups: Control (IVM medium only), DCA (IVM supplemented with sodium dichloroacetate, a stimulant of pyruvate oxidation into acetyl-CoA), or IA (IVM supplemented with sodium iodoacetate, a glycolysis inhibitor). The results revealed significant alterations in oocyte metabolism in both treatments, promoting the utilization of lipids as an energy source. These changes during IVM affected the dynamics of H3K9ac, subsequently influencing the oocyte's transcriptional activity. In the DCA and IA groups, a total of 148 and 356 differentially expressed genes were identified, respectively, compared to the control group. These findings suggest that modifications in pyruvate metabolism trigger the activation of metabolic pathways, particularly lipid metabolism, changing acetyl-CoA availability and H3K9ac levels, ultimately impacting the mRNA content of in vitro matured bovine oocytes.

BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability.

BACKGROUND: Prostate cancer (PrCa) is the most frequently diagnosed cancer in men. Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (< 56 years) and/or with familial aggregation of the disease. Considering that BubR1 is an essential component of the mitotic spindle assembly checkpoint, we hypothesized that monoallelic BUB1B variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis. METHODS: To unveil BUB1B as a new PrCa predisposing gene, we performed targeted next-generation sequencing in germline DNA from 462 early-onset/familial PrCa patients and 1,416 cancer patients fulfilling criteria for genetic testing for other hereditary cancer syndromes. To explore the pan-cancer role of BUB1B, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients' tumors and peripheral blood lymphocytes. RESULTS: Rare BUB1B variants were found in ~ 1.9% of the early-onset/familial PrCa cases and in ~ 0.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that BUB1B variants lead to decreased BubR1 expression and/or stability, which promotes increased premature chromatid separation and, consequently, triggers CIN, driving resistance to Taxol-based therapies. CONCLUSIONS: Our study shows that different BUB1B variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of BUB1B as a (pan)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making.

Prevalence of non-neurogenic male lower urinary tract symptoms after kidney transplantation.

OBJECTIVE: This review investigates the prevalence of male non-neurogenic lower urinary tract symptoms (LUTS) after renal transplant, as kidney transplantation is a transformative intervention for patients with end-stage renal disease significantly enhancing quality of life that might be diminished by LUTS. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. A systematic search in the PubMed and Scopus databases was performed using specific terms. Inclusion criteria considered male kidney transplant recipients, analysing outcomes in English-language studies. Discrepancies were resolved by consultation. RESULTS: Among 18 studies involving 29 086 recipients, the prevalence of non-neurogenic LUTS ranged from 5.8% to 33.0%. Studies predominantly used the International Prostate Symptom Score for evaluation. Surgical interventions, mostly for benign prostatic obstruction, ranged from 2.5% to 20.0%. Voiding and post-micturition symptoms were under-represented. CONCLUSION: This review found varied non-neurogenic LUTS prevalence and characteristics in male kidney transplant recipients, emphasising the need for standardised assessments, prospective studies, and improved understanding of LUTS mechanisms. Enhanced knowledge can guide interventions, additionally benefiting recipient quality of life.

Local recurrence after endoscopic submucosal dissection of gastric neoplastic lesions: special attention should be given also to safety margins.

INTRODUCTION: The incidence of local recurrence following gastric endoscopic submucosal dissection (ESD) remains a clinical concern. We aimed to evaluate the impact of narrow safety margin (< 1 mm) on the recurrence rate. METHODS: A retrospective cohort study was conducted across two centers. Cases of R0-ESD with subsequent recurrence were compared to matched controls in a 1:2 ratio in a case-cohort analysis. RESULTS: Over a median period of 25 months (IQR 14-43), a recurrence rate of 3% (95%CI 1.7-4.3) was observed, predominantly (13/21) following R0 resections with favourable histology. Endoscopic retreatment was feasible in 18 of 21 recurrences. The proportion of R0-cases where the safety margin in both horizontal (HM) and vertical (VM) margin exceeded 1 mm was similarly distributed in the recurrence and non-recurrence group, representing nearly 20% of cases. However, cases with HM less than 1 mm, despite VM greater than 1 mm, nearly doubled in the recurrence group (7.7% vs. 3.9%), and tripled when both margins were under 1 mm (23.1% vs. 7.7%). Despite this trend, statistical significance was not achieved (p = 0.05). In the overall cohort, the only independent risk factor significantly associated with local recurrence was the presence of residual tumor at the HM (HM1) or not assessable HM (HMx) (OR 16.5 (95%CI 4.4-61.7), and OR 11.7 (95%CI 1.1-124.1), respectively). CONCLUSIONS: While not common or typically challenging to manage, recurrence post-ESD warrants attention and justifies rigorous post-procedural surveillance, especially in patients with HM1, HMx, and probably also in those with R0 resections but narrow safety margin.

From Angstroms to Nanometers: Measuring Interatomic Distances by Solid-State NMR.

Internuclear distances represent one of the main structural constraints in molecular structure determination using solid-state NMR spectroscopy, complementing chemical shifts and orientational restraints. Although a large number of magic-angle-spinning (MAS) NMR techniques have been available for distance measurements, traditional 13C and 15N NMR experiments are inherently limited to distances of a few angstroms due to the low gyromagnetic ratios of these nuclei. Recent development of fast MAS triple-resonance 19F and 1H NMR probes has stimulated the design of MAS NMR experiments that measure distances in the 1-2 nm range with high sensitivity. This review describes the principles and applications of these multiplexed multidimensional correlation distance NMR experiments, with an emphasis on 19F- and 1H-based distance experiments. Representative applications of these long-distance NMR methods to biological macromolecules as well as small molecules are reviewed.

The urinary and prostatic microbiome in non-neurogenic male LUTS/BPH: A systematic review.

INTRODUCTION: Despite advancements in the treatment of benign prostatic hyperplasia (BPH), the mechanisms underlying BPH development and progression remain elusive and lacks a one-size-fits-all therapeutic solution. Prostatic inflammation contributes to BPH and lower urinary tract symptoms (LUTS), but the initial trigger remains unknown. Current research suggests dysbiosis of the urinary microbiome as a potential culprit. This systematic review explores the emerging field of the male urinary and prostatic microbiome and its relationship with BPH/LUTS. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. A systematic search in the Pubmed and Scopus databases was performed using specific terms. Inclusion criteria considered male non-neurogenic patients with LUTS due to BPH with analyses of urinary microbiome, concerning evaluation of English-language publications with relevance. RESULTS: Among seven articles involving 542 patients, there was an association between male LUTS/BPH and the urinary microbiome. Findings indicate a correlation between urinary microbiome dysbiosis and LUTS severity, with specific bacterial genera such as Streptococcus and Haemophilus linked to higher International Prostate Symptom Score (IPSS) scores and PSA levels. The fecal microbiome may be associated with LUTS, although contradictory findings are reported. The review also highlights methodological inconsistencies, small sample sizes, few negative controls and a lack of comprehensive clinical data as major limitations. CONCLUSIONS: While there is an undeniable correlation between the microbiome and LUTS/BPH, future research should aim to standardize sampling techniques and expand the score to include functional microbiome characterization, potentially leading to novel, microbiome-targeted therapeutic strategies for BPH.

RecQ helicase expression in patients with telomeropathies.

BACKGROUND: Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies. METHODS AND RESULTS: Here we investigated the expression of RecQ (RECQL1, BLM, WRN, RECQL4, and RECQL5) and RTEL1 helicase genes in peripheral blood mononuclear cells (PBMCs) from human telomeropathy patients. The mRNA expression levels of all RecQ helicases, but not RTEL1, were significantly downregulated in patients' primary cells. Reduced RecQ expression was not attributable to cell proliferative exhaustion, as RecQ helicases were not attenuated in T cells exhausted in vitro. An additional fifteen genes involved in DNA damage repair and RecQ functional partners also were downregulated in the telomeropathy cells. CONCLUSION: These findings indicate that the expression of RecQ helicases and functional partners involved in DNA repair is downregulated in PBMCs of telomeropathy patients.

Lisdexamfetamine dimesylate-exposition in male rats during the peripubertal period impairs inflammatory mechanisms, antioxidant activity, and apoptosis process in kidneys of male pubertal rats.

Lisdexamfetamine dimesylate (LDX) is a prodrug of dextroamphetamine, which has been widely recommended for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). There are still no data in the literature relating the possible toxic effects of LDX in the kidney. Therefore, the present study aims to evaluate the effects of LDX exposure on morphological, oxidative stress, cell death and inflammation parameters in the kidneys of male pubertal Wistar rats, since the kidneys are organs related to the excretion of most drugs. For this, twenty male Wistar rats were distributed randomly into two experimental groups: LDX group-received 11,3 mg/kg/day of LDX; and Control group-received tap water. Animals were treated by gavage from postnatal day (PND) 25 to 65. At PND 66, plasma was collected to the biochemical dosage, and the kidneys were collected for determinations of the inflammatory profile, oxidative status, cell death, and for histochemical, and morphometric analyses. Our results show that there was an increase in the number of cells marked for cell death, and a reduction of proximal and distal convoluted tubules mean diameter in the group that received LDX. In addition, our results also showed an increase in MPO and NAG activity, indicating an inflammatory response. The oxidative status showed that the antioxidant system is working undisrupted and avoiding oxidative stress. Therefore, LDX-exposition in male rats during the peripubertal period causes renal changes in pubertal age involving inflammatory mechanisms, antioxidant activity and apoptosis process.

Identification of key neuronal mechanisms triggered by dimethyl fumarate in SH-SY5Y human neuroblastoma cells through a metabolomic approach.

Dimethyl fumarate (DMF) is an old drug used for psoriasis treatment that has recently been repurposed to treat relapse-remitting multiple sclerosis, mostly due to its neuro- and immunomodulatory actions. However, mining of a pharmacovigilance database recently ranked DMF as the second pharmaceutical most associated with cognitive adverse events. To our best knowledge, the signaling mechanisms underlying its therapeutic and neurotoxic outcomes remain mostly undisclosed. This work thus represents the first-hand assessment of DMF-induced metabolic changes in undifferentiated SH-SY5Y human neuroblastoma cells, through an untargeted metabolomic approach using gas chromatography-mass spectrometry (GC-MS). The endometabolome was analyzed following 24 h and 96 h of exposure to two pharmacologically relevant DMF concentrations (0.1 and 10 µM). None of these conditions significantly reduced metabolic activity (MTT reduction assay). Our data showed that 24 h-exposure to DMF at both concentrations tested mainly affected metabolic pathways involved in mitochondrial activity (e.g., citric acid cycle, de novo triacylglycerol biosynthesis), and the synthesis of catecholamines and serotonin by changing the levels of their respective precursors, namely phenylalanine (0.68-fold decrease for 10 µM DMF vs vehicle), and tryptophan (1.36-fold increase for 0.1 µM DMF vs vehicle). Interestingly, taurine, whose levels can be modulated via Nrf2 signaling (DMF's primary target), emerged as a key mediator of DMF's neuronal action, displaying a 3.86-fold increase and 0.27-fold decrease for 10 µM DMF at 24 h and 96 h, respectively. A 96 h-exposure to DMF seemed to mainly trigger pathways associated with glucose production (e.g., gluconeogenesis, glucose-alanine cycle, malate-aspartate shuttle), possibly related to the metabolism of DMF into monomethyl fumarate and its further conversion into glucose via activation of the citric acid cycle. Overall, our data contribute to improving the understanding of the events associated with neuronal exposure to DMF.

Analgesic efficacy of erector spinae plane block versus paravertebral block in lung surgeries-A non-inferiority randomised controlled trial.

BACKGROUND: Pain management plays an essential role in postoperative recovery after lung surgeries. The Erector Spinae Plane Block (ESPB) is a widely used regional anaesthesia technique; however, few clinical trials have compared this block to active control in thoracic surgeries. This study evaluated the non-inferiority of the analgesia provided by ESPB when compared to paravertebral block (PVB) in lung surgeries. METHODS: Randomised, active-controlled, blinded for patients and assessors, non-inferiority trial. Patients who underwent unilateral lung surgeries were divided into two groups according to the regional anaesthesia technique-continuous ESPB or PVB at the T5 level. The primary outcome was to assess pain using a numerical rating scale (NRS) with a test of the interaction of three measures over 24 h postoperatively. An NRS score ≥ 7 was considered analgesia failure, and the prespecified non-inferiority margin was 10%. RESULTS: In the interim analysis that terminated this study, 120 participants were enrolled. ESPB patients reported higher mean NRS general values over 24 h, 4.6 ± 3.2 in the ESPB group versus 3.9 ± 2.9 in the PVB group, with a difference of -0.67 (-15.2%) and 95%CI: -1.29 to -0.05 (p = .02), demonstrating not non-inferiority. In addition, the ESPB group presented higher NRS failure of analgesia over 24 h (p < .01) and required more postoperative opioids (p = .01 over 24 h). There was no difference in patient satisfaction between groups. CONCLUSION: This trial demonstrated that a continuous erector spinae plane block was not non-inferior to a continuous paravertebral block for analgesia after lung surgery but resulted in higher levels of postoperative pain and opioid consumption.