Journals
2024 EN
Bernardi Luis Pedro · Schlickmann Thomas Hugentobler · CarelloCollar Giovanna
+3 more
Abstract Background Ischemic stroke (IS) is a risk factor for developing Alzheimer’s disease (AD). In this context, microglial activation is a shared cellular response to these two conditions that can be either beneficial or detrimental. Previous research has established that mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) treatment leads to enhanced functional recovery and reduced brain infarct volume in animal IS models. However, current literature findings are unclear when addressing the effects of MSC‐EVs treatment on microglial activation. Thus, we aimed to investigate how MSC‐EVs treatment alters microglial activation parameters in IS models. Method The protocol of this systematic review was registered in PROSPERO (CRD42023463152) and followed the PRISMA 2020 statement. We searched EMBASE, PubMed, and Web of Science from database inception to October 2023 for studies with animal or cell culture IS models using MSC‐EVs as intervention and measuring microglial activation outcomes compared to control. We performed a random‐effects meta‐analysis using standardized mean differences (SMD) as the effect measure with the metafor and metaviz packages in R (v4.2.1) (FDR‐adjusted p‐value<0.05). Result The database search identified 294 records, from which 27 were included (Fig. 1). Meta‐analysis showed that in vivo MSC‐EVs treatment resulted in a lower number of total microglia (Iba1+ cells) (SMD = ‐1.45 [‐2.19,‐0.71 95%CI] p<0.001, Fig. 2A) and CD16+ microglia (SMD = ‐1.84 [‐2.62,‐1.05 95%CI] p<0.001, Fig. 2B), but in a higher number of CD206+ microglia (SMD = 1.95 [1.01,2.88 95%CI] p<0.001, Fig. 2C) in the brain across different IS models and age groups. In microglia cell cultures submitted to oxygen‐glucose deprivation, MSC‐EVs treatment decreased the levels of TNF‐α (SMD = ‐3.32 [‐4.95,‐1.69 95%CI] p<0.001, Fig. 3A), IL‐1β (SMD = ‐3.45 [‐5.57,‐1.32 95%CI] p<0.001, Fig. 3B), and IL‐6 (SMD = ‐2.95 [‐4.50,‐1.40 95%CI] p<0.001, Fig. 3C) in the culture medium, while increasing the gene expression levels of Arg‐1 (SMD = 5.41[3.54,7.29 95%CI] p<0.001, Fig. 3D). Conclusion We demonstrated that MSC‐EVs treatment in IS models reduces the expression of pro‐inflammatory microglial activation markers (CD16) and cytokines (TNF‐α, IL‐1β, IL‐6) while increasing the expression of anti‐inflammatory markers (CD206, Arg‐1). Our results suggest that MSC‐EVs treatment modulates microglia towards a pro‐resolutive state, potentially contributing to the recovery of damaged brain tissue in IS and, consequently, in AD.
Journals
2024 EN
Rohden Francieli · Moreira João Victor Matos e · Bernardi Luis Pedro
+5 more
Abstract Background Systemic Arterial Hypertension (SAH), distinguished by a persistent elevation of blood pressure, emerges as a risk factor for stroke and Alzheimer’s Disease (AD). Additionally, recent evidence suggests that stroke may adversely affect memory, potentially playing a role in the development of AD. This study aimed to investigate the influence of permanent focal ischemic stroke on memory, as well as on sensorimotor function (asymmetry of the front paws) and cerebral infarct size in adult male spontaneously hypertensive rats (SHR), compared to normotensive Wistar Kyoto (WKY) rats. Method We assessed the stroke effects on short‐ and long‐term memory through the open field task (7 and 21 days after stroke), on sensorimotor functions through the cylinder test and adhesive removal test (over 42 days after stroke), and on infarction volume through 2,3,5‐Triphenyltetrazolium chloride staining (3 and 7 days after stroke). Result Short‐term memory was observed in both naive WKY and naive SHR rats, while SHR naive animals did not exhibit long‐term memory. Stroke disrupted short‐term memory in both WKY and SHR rats and long‐term memory in WKY rats (Fig. 01). In regards to the sensorimotor function, (cylinder test and adhesive removal) WKY rats totally recovered from the stroke‐induced asymmetry in the front paws, while SHR rats did not (Fig. 02). Concerning infarction volume, WKY rats showed decreased infarction volume from the third to the seventh day after stroke, while SHR rats did not exhibit this reduction (Fig. 03). Conclusion These results emphasize the impact of hypertension on memory, as well as on motor outcomes and brain infarct size following stroke, potentially contributing to the risk for AD.
Journals
2024 EN
Holt Kristjan · Taylor Lewis W. · McGeachan Robert I.
+10 more
Abstract Background Synapse loss represents the closest correlate of cognitive decline in Alzheimer’s Disease (AD). Standard microscopy, due to increased diffraction of light with tissue depth, imposes a limit on axial resolution extending to ∼ 700nm. Array tomography (AT) , developed by Micheva & Smith (2007), extends this axial limit via physical sectioning of resin‐embedded tissue into ribbons of 70nm contiguous sections that are serially imaged and reconstructed into 3D volumes; thus, allowing for nanometric synaptic puncta to be resolved at the mesoscale. Our group has, for the past decade, adapted AT to investigate synapse loss in human post‐mortem brain tissue from people who died with Alzheimer’s disease; other neurodegenerative diseases, and control subjects. We have published recent developments to AT that further improve X‐Y resolution, permitting in‐depth investigation of synapse‐protein interactions. Highlighted here are Förster Resonance Energy Transfer (FRET), Reconstruction Microscopy (dsSTORM) and DNA‐PAINT to assess interactions between Aβ, tau and protein binding partners, at the synapse . This work was funded by Cognition Therapeutics, Medical Research Council (MRC), UK Dementia Research Institute (UKDRI) and Race Against Dementia . Method Fixation, embedding, sectioning and immunostaining are detailed in work published previously by Kay et al. (2013). Advances to AT presented here include FRET, dsSTORM, DNA‐PAINT, and investigation of synaptic composition in organotypic human brain slices from surgical resections challenged with disease‐relevant proteins. Further, we report advances in our image analysis pipeline with scripts available to use on https://github.com/Spires‐Jones‐Lab . Result FRET‐AT has been used to profile over 1 million individual synaptic puncta in the temporal cortex and generates sufficient signal to indicate molecular interaction between Aβ and putative binding partners including TMEM97 in control (n = 9) and Alzheimer’s disease (n = 11) human brain tissue. FRET‐AT also suggests interaction between p‐tau Ser356 and synaptic terminals (n = 5/group). This, coupled with evidence of synaptic tau from dsSTORM/DNA‐PAINT, provides indirect evidence of disease progression via tau‐synapse interaction. Conclusion AT can be combined with other methodologies, allowing for in‐depth investigation of synapse‐protein interactions at a scale larger than afforded by electron microscopy (EM). This provides important insight into neurodegenerative disease and presents targets for potential therapeutics disrupting protein‐protein interactions.
Journals
2024 EN
Silveira Victória Akemi Itakura · Filipe Giovanna Amaral · Bigotto Briani Gisele
+8 more
This study aimed to synthesize silver nanoparticles with sophorolipids (AgNP‐SL) and develop starch nanocomposite films with improved properties to be explored in food packaging applications. AgNP‐SL were spherical and highly stable, with an average size of 61.46 nm. They also demonstrated potent antibacterial action against Escherichia coli and Staphylococcus aureus , revealing its promising application for antimicrobial packaging. The addition of AgNP‐SL into films resulted in color changes, which could contribute to a better UV‐barrier capacity. Nanoparticles and tartaric acid incorporation resulted in a heterogeneous matrix, suggesting chemical interactions between the compounds and the biopolymer. The nanocomposite films presented thermal stability, enhanced flexibility, and antimicrobial action against E. coli , Salmonella enterica serovar Enteritidis, and S. aureus. The combination of AgNP‐SL and tartaric acid resulted in pronounced bactericidal properties. The results demonstrate the great potential of these nanocomposite films as an effective packaging material against foodborne pathogens.
Journals
2024 EN
Fernandes Natacha Cintia Ferreira · Branco Érika · Freire Elisa Carla Barra
+4 more
Choloepus didactylus has reduced metabolism and difficulty in thermoregulation owing to its low body mass, and there are few studies related to the vascularization of abdominal and thoracic organs in this species. Therefore, we macroscopically described the arteries that comprise the aortic arch, thoracic aorta, and abdominal aorta. Six specimens were used, and their arterial systems filled with red latex before fixation in 10% formaldehyde, and fragments of the rete mirabile were processed for histological analysis using light and scanning electron microscopy. In these species, the aortic arch had two branches: the brachiocephalic trunk and left subclavian artery. The initial portion of the abdominal aorta presented four different ramifications, besides to the peculiarities of the adrenal, renal, and iliac arteries. Microscopy of the rete mirabile revealed a muscular artery surrounded by smaller muscular arteries, veins, nerves, and lymphatic tissue joined by connective tissue. Thus, the data obtained have clinical and surgical importance, with applicability in procedures involving vascularization of the thoracic and abdominal organs. We suggest that the rete mirabile is an efficient thermoregulatory structure because it allows the accumulation of blood and the countercurrent heat exchange, as there is no blood mixing.
Journals
2024 EN
Rosa Ernani Bohrer · Correia Jamile Dutra · Silveira Daniélle Bernardi
+6 more
Background Craniofacial microsomia (CM) is characterized by changes in the first and second branchial arches. It is a clinical condition whose etiology is still uncertain, but studies have shown that genetic, nutritional, and environmental factors can result in disorders of blastogenesis of the branchial arches. This study evaluates gestational aspects, focusing on possible risk factors associated with CM. Methods This is a case–control study conducted with patients monitored at a medical genetics service and compared to a control group of patients without evidence of malformations, born in a mother and child hospital, both located in Porto Alegre, Southern Brazil. Mothers’ data were obtained using questionnaires and by reviewing medical records. The sample consisted of 43 patients with CM (cases) and 129 patients without evidence of malformations (controls), paired by sex, totaling three controls for each case. Data analysis was performed using the two‐tailed Fisher's exact test, Pearson's chi‐square test, and the t ‐test. Results We identified several factors associated with the development of CM, including the use of abortion methods by the mothers of these babies ( p = .001), maternal diabetes ( p = .009), advanced maternal age ( p = .035), and a history of vaginal bleeding ( p < .001). Furthermore, these patients exhibited a tendency to be born prematurely ( p = .027), with low birth weight ( p = .007), and lower Apgar scores ( p = .003) when compared to healthy infants. Using a multivariate model, the use of abortion methods ( p = .003) and vaginal bleeding ( p = .032) remained independently associated with craniofacial microsomia. Conclusions We have identified several risk factors for the development of CM, including a propensity for premature birth, low birth weight, and respiratory difficulties. Additionally, women of advanced maternal age and/or those who used abortion methods and/or have diabetes have a higher risk of giving birth to a baby with CM. This information can be valuable in clinical practice, especially for the prevention of future cases.
Journals
2024 EN
Ozawa Ryota · Sonehara Kei · Hachiya Tsutomu
+10 more
Abstract Introduction Chemoimmunotherapy is widely used as the first‐line management of advanced non‐small cell lung cancer (NSCLC) in clinical settings. However, predictive factors associated with the development of immune‐related adverse events (irAEs) and prognostic factors for NSCLC patients undergoing chemoimmunotherapy remains largely unexplored. Therefore, in this study, we aimed to evaluate predictive factors for irAE development and prognostic factors associated with chemoimmunotherapy in NSCLC patients. Methods This study enrolled 199 patients with advanced and recurrent NSCLC who underwent chemoimmunotherapy across eight institutions in Nagano prefecture from December 2018 to January 2023. We examined predictive factors associated with irAE development and prognostic factors associated with overall survival (OS). Results Among the patients, 106 experienced irAEs, while 93 patients did not. A total of 44 (22.1%) patients developed multiple irAEs. High serum albumin levels (Alb >3.5 g/dL) emerged as an independent predictive factor associated with irAE development in logistic regression analysis (odds ratio; 2.35, 95% confidence interval 1.27–4.34, p = 0.007). Furthermore, the development of multiple irAEs ( p = 0.016), lower lactate dehydrogenase level (<223 U/L, p = 0.002), and decreased neutrophil‐to‐lymphocyte ratio (<3, p = 0.049) were identified as independent favorable prognostic factors associated with OS in multivariate Cox hazard analyses. Conclusion The study results suggest that high serum Alb is a predictive factor for irAE development and that the presence of multiple irAEs is a favorable prognostic indicator for NSCLC patients undergoing chemoimmunotherapy.
Journals
2024 EN
Elghonemy Mai M. · Essa Ahmed F. · Osman Abeer F.
+5 more
Abstract The essential oils of Senecio plants have been used to treat a wide range of ailments. The current study aimed to extract the essential oil of Senecio glaucus obtained from Egypt's Nile delta and determine its chemical profile using GC‐MS and NMR analysis. Then, the antimicrobial activity of the oil has been investigated against different fungal and bacterial strains. In addition, its activity as radical scavenger has been evaluated using DPPH, ABTS, and metal chelating techniques. The results revealed the identification of 50 compounds representing 98.80 % of the oil total mass. Sesquiterpenes, including dehydrofukinone (27.15 %) and 4,5‐di‐epi‐aristolochene (10.27 %), as well as monoterpenes, including p ‐cymene (4.77 %), represented the most predominant constituents. The dehydrofukinone has been isolated and structurally confirmed using 1D and 2D NMR techniques. The oil has showed remarkable antifungal activity against Candida glabrata and C. albicans where the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values were 3.13 μg/mL and 1.50 μg/mL and 12.50 μg/mL and 6.30 μg/mL, respectively that could be attributed to the sesquiterpene ketones present in the aerial tissues of the plant. Also, this oil inhibited the growth of the tested bacteria with MIC ranging from 12.50–100.00 μg/mL. In comparison to ascorbic acid and Trolox, the EO had remarkable scavenging activity of DPPH, ABTS and metal chelating with IC 50 values of 313.17±13.4, 493.83±20.1, and 409.13±16.7 μg/mL. The docking studies of the identified compounds of the oil to different microbial targets, including Gyrase B and α ‐sterol demethylase, showed that the phytol possessed the best binding affinities toward the active sites of both enzymes with ΔG=−7.42 and −7.78 kcal/mol, respectively. In addition, the phytol revealed the highest binding affinity to tyrosine kinase Hck with ΔG=−7.44 kcal/mol.
Journals
2024 EN
Bernardi Fernando L. M. · Abizaid Alexandre · Sândoli de Brito Fábio
+7 more
Abstract Background Conflicting data yet exists regarding the clinical outcomes of transcatheter aortic valve replacement (TAVR) using balloon‐expandable (BEV) and self‐expanding valves (SEV). Aim To compare the in‐hospital outcomes of TAVR performed with new‐generation BEV vs. SEV in a real‐world population. Methods Retrospective study using data from the Brazilian TAVR registry. All consecutive native tricuspid TAVR procedures using new‐generation valves were included. Transapical procedures were excluded. Patients were analyzed according to the type of prosthesis implanted (BEV vs. SEV). Unadjusted and propensity‐score matching comparisons were made. Primary outcome was in‐hospital mortality. Secondary outcomes included major vascular complication, major or life‐threatening bleeding, any stroke, and new pacemaker implantation. Results A total of 1706 patients from 25 centers were included in the analysis, 887 in the BEV and 819 in the SEV groups. Mean age was 80.7 ± 7.2 years and 48.9% were women. The SEV group had a higher proportion of female patients (53.5% vs. 44.6%, p ≤ 0.001) and more comorbidities, yielding a higher EuroSCORE‐2 (3.4 [2–6.4] vs. 4.5 [2.5–8.2], p < 0.001). The Sapien 3/Ultra (Edwards Lifescience, Irvine, CA, USA) and the Evolut R/PRO (Medtronic, Minneapolis, MN, USA) accounted for 97.8% and 72.6% of BEV and SEV cases, respectively. Pre‐ and postdilatation was more common for SEV (both p < 0.001). Valve embolization, the need for a second valve, and coronary occlusion were rare but more frequent for SEV. There was no difference in the unadjusted in‐hospital mortality (BEV = 3.6% vs. SEV = 4.8%, p = 0.27) and after propensity‐score matching (3.5% vs. 5.0%, p = 0.16). There were also no significant differences between groups in vascular complications, bleeding, stroke, and the need for a new pacemaker. Logistic regression adjusted for sex, EuroSCORE‐2, and vascular access also indicated similar mortality between both valves (OR 1.22, p = 0.4). Sensitivity analysis, including only Sapien 3 and Evolut cases, showed consistent results with the primary analysis. Conclusion In real‐world all‐comers TAVR patients, from Brazil procedures performed with newer generation BEV and SEV devices had comparable in‐hospital outcomes.
Journals
2024 EN
Ohama Hideko · Hiraoka Atsushi · Tada Toshifumi
+41 more
Aims The aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment. Methods A total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression‐free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c‐index) and Akaike information criterion (AIC) results. Results Cox‐hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI‐De) scoring system. For IMABALI‐De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively ( p < .001; AIC 2788.67, c‐index 0.699), while for CRAFITY scores of 0, 1, and 2, OS was 26.11, 20.29, and 11.32 months, respectively ( p < .001; AIC 2864.54, c‐index 0.606). PFS periods for those IMABALI‐De scores were 21.75, 12.89, 9.18, 8.0, 5.0, and 3.75 months, respectively ( p < .001; AIC 5203.32, c‐index 0.623) and for the CRAFITY scores were 10.32, 7.68, and 3.57 months, respectively ( p < .001; AIC 5246.61, c‐index 0.574). As compared with CRAFITY score, IMABALI‐De score had better AIC and c‐index results for both OS and PFS. Conclusion The present results indicated that the proposed IMABALI‐De score may be favorable for predicting prognosis of uHCC patients receiving Atez/Bev therapy.