Mejerhaslund8706

The envenomation caused by the Bothrops pauloensis snake leads to severe local and systemic effects including acute kidney injury. In this study, we investigated the renal effects by phospholipases A2 (PLA2s), divided into two main subgroups, Asp-49 and Lys-49, isolated from the Bothrops pauloensis snake venom (BpV) in isolated rat kidney system. Both PLA2s (3 μg/mL), added alone to the perfusion system and analyzed for 120 min, had significant effects on isolated rat kidney. Asp-49 reduced Glomerular Filtration Rate (GFR) at 60, 90 and 120 min, and the percentage of total tubular sodium transport (%TNa+) and potassium transport (%TK+) at 120 min. Lys-49 increased Perfusion Pressure (PP) at 120 min and reduced GFR, %TNa+ and the percentage of total tubular chloride transport (%TCl-) at 60, 90 and 120 min. Cytokine release in the kidney tissues were increased with Asp-49 PLA2 (IL-10) and Lys-49 PLA2 (TNF-α, IL-1β, IL-10). Both increased MPO activity. Asp-49 PLA2 decreased Glutathione (GSH) and increased nitrite levels, while Lys-49 PLA2 increased Malondialdehyde (MDA), GSH and nitrite levels. Histological analysis of the perfused kidneys revealed the presence of glomerular degeneration and atrophy, deposit of proteinaceous material in Bowman's space and intratubular with both PLA2s. These findings indicated that both PLA2s modified the functional parameters in an isolated perfused kidney model with increased oxidative stress and cytokine release. PLA2s are one of the components at high concentration in BpV and our results provide important knowledge about their involvement with the nephrotoxic mechanism.Current COVID-19 pandemic poses an unprecedented threat to global health and healthcare systems. The most amount of the death toll is accounted by old people affected by age-related diseases that develop a hyper-inflammatory syndrome. In this regard, we hypothesized that COVID-19 severity may be linked to inflammaging. Here, we examined 30 serum samples from patients enrolled in the clinical trial NCT04315480 assessing the clinical response to a single-dose intravenous infusion of the anti-IL-6 receptor drug Tocilizumab (TCZ) in COVID-19 patients with multifocal interstitial pneumonia. In these serum samples, as well as in 29 age- and gender-matched healthy control subjects, we assessed a set of microRNAs that regulate inflammaging, i.e. miR-146a-5p, miR-21-5p, and miR-126-3p, which were quantified by RT-PCR and Droplet Digital PCR. We showed that COVID-19 patients who did not respond to TCZ have lower serum levels of miR-146a-5p after the treatment (p = 0.007). Among non-responders, those with the lowest serum levels of miR-146a-5p experienced the most adverse outcome (p = 0.008). Our data show that a blood-based biomarker, such as miR-146a-5p, can provide clues about the molecular link between inflammaging and COVID-19 clinical course, thus allowing to better understand the use of biologic drug armory against this worldwide health threat.A human microfluidic four-cell liver acinus microphysiology system (LAMPS), was evaluated for reproducibility and robustness as a model for drug pharmacokinetics and toxicology. The model was constructed using primary human hepatocytes or human induced pluripotent stem cell (iPSC)-derived hepatocytes and 3 human cell lines for the endothelial, Kupffer and stellate cells. The model was tested in two laboratories and demonstrated to be reproducible in terms of basal function of hepatocytes, Terfenadine metabolism, and effects of Tolcapone (88 μM), Troglitazone (150 μM), and caffeine (600 μM) over 9 days in culture. Additional experiments compared basal outputs of albumin, urea, lactate dehydrogenase (LDH) and tumor necrosis factor (TNF)α, as well as drug metabolism and toxicity in the LAMPS model, and in 2D cultures seeded with either primary hepatocytes or iPSC-hepatocytes. Further experiments to study the effects of Terfenadine (10 μM), Tolcapone (88 μM), Trovafloxacin (150 μM with or without 1 μg/mL lipopolysaccharide), Troglitazone (28 μM), Rosiglitazone (0.8 μM), Pioglitazone (3 μM), and caffeine (600 μM) were carried out over 10 days. We found that both primary human hepatocytes and iPSC-derived hepatocytes in 3D culture maintained excellent basal liver function and Terfenadine metabolism over 10 days compared the same cells in 2D cultures. In 2D, non-overlay monolayer cultures, both cell types lost hepatocyte phenotypes after 48 h. With respect to drug effects, both cell types demonstrated comparable and more human-relevant effects in LAMPS, as compared to 2D cultures. Overall, these studies show that LAMPS is a robust and reproducible in vitro liver model, comparable in performance when seeded with either primary human hepatocytes or iPSC-derived hepatocytes, and more physiologically and clinically relevant than 2D monolayer cultures.The kidney has extraordinary metabolic demands to sustain the active transport of solutes that is critical to renal filtration and clearance. Mitochondrial health is vital to meet those demands and maintain renal fitness. Decades of studies have linked poor mitochondrial health to kidney disease. Key regulators of mitochondrial health-adenosine monophosphate kinase, sirtuins, and peroxisome proliferator-activated receptor γ coactivator-1α-have all been shown to play significant roles in renal resilience against disease. This review will summarize the latest research into the activities of those regulators and evaluate the roles and therapeutic potential of targeting those regulators in acute kidney injury, glomerular kidney disease, and renal fibrosis.Ravulizumab, a long-acting complement C5 inhibitor engineered from eculizumab, allows extending maintenance dosing from every 2-3 weeks to every 4-8 weeks depending on bodyweight. Here, we evaluated the efficacy and safety of ravulizumab in complement inhibitor-naïve children (under 18 years) with atypical hemolytic uremic syndrome. In this phase III, single-arm trial, ravulizumab was administered every eight weeks in patients 20 kg and over, and four weeks in patients under 20 kg. The primary endpoint was a complete thrombotic microangiopathy response (normalization of platelet count and lactate dehydrogenase, and a 25% or more improvement in serum creatinine) through 26 weeks. Secondary endpoints included change in hematologic parameters and kidney function. 18 patients with a median age of 5.2 years were evaluated. At baseline, symptoms of atypical hemolytic uremic syndrome outside the kidney were present in 72.2% of patients and 38.9% had been in intensive care. Baseline estimated glomerular filtration rate was 22 mL/min/1.73 m2. By week 26, 77.8% of patients achieved a complete thrombotic microangiopathy response; 94.4%, 88.9% and 83.3% of patients achieved platelet normalization, lactate dehydrogenase normalization and a 25% or more improvement in serum creatinine, respectively. By week 50, 94.4% patients had achieved a complete thrombotic microangiopathy response. Median improvement in platelet count was 246 and 213 x109/L through week 26 and week 50, respectively. The median increase above baseline in estimated glomerular filtration rate was 80 and 94 mL/min/1.73m2 through week 26 and week 50, respectively. No unexpected adverse events, deaths, or meningococcal infections occurred. Thus, ravulizumab rapidly improved hematologic and kidney parameters with no unexpected safety concerns in complement inhibitor-naïve children with atypical hemolytic uremic syndrome.Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes kidney toxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced kidney toxicity is currently available. Here, based on a repositioning analysis of the Food and Drug Administration Adverse Events Reporting System, we found that a previously developed drug, diphenhydramine, may provide a novel treatment for cisplatin-induced kidney toxicity. To confirm this, the actual efficacy of diphenhydramine was evaluated in in vitro and in vivo experiments. Diphenhydramine inhibited cisplatin-induced cell death in kidney proximal tubular cells. Mice administered cisplatin developed kidney injury with significant dysfunction (mean plasma creatinine 0.43 vs 0.15 mg/dl) and showed augmented oxidative stress, increased apoptosis, elevated inflammatory cytokines, and MAPKs activation. However, most of these symptoms were suppressed by treatment with diphenhydramine. Furthermore, the concentration of cisplatin in the kidney was significantly attenuated in diphenhydramine-treated mice (mean platinum content 70.0 vs 53.4 μg/g dry kidney weight). Importantly, diphenhydramine did not influence or interfere with the anti-tumor effect of cisplatin in any of the in vitro or in vivo experiments. In a selected cohort of 98 11 matched patients from a retrospective database of 1467 patients showed that patients with malignant cancer who had used diphenhydramine before cisplatin treatment exhibited significantly less acute kidney injury compared to ones who did not (6.1 % vs 22.4 %, respectively). Thus, diphenhydramine demonstrated efficacy as a novel preventive medicine against cisplatin-induced kidney toxicity.Mind wandering has been associated with both adaptive outcomes and performance impairment, depending on the context. Recently, non-invasive brain stimulation has been applied in several studies with the aim to investigate the neural region(s) casually involved in mind wandering. However, to date there has been little definitive work assessing whether or not the stimulation of different brain regions leads to distinct mind wandering outcomes. The present preregistered study considered the role of the prefrontal cortex and inferior parietal lobule in mind wandering using two stimulation intensities (1mA and 2mA) and two stimulation polarity montages. One-hundred and fifty subjects were randomly allocated to one of the four active stimulation groups or a sham group. https://www.selleckchem.com/products/nlg919.html Participants' mind wandering propensity was measured via a task unrelated thought probe dispersed throughout an attention-based task completed directly after stimulation. Anodal stimulation to the prefrontal cortex, and cathodal stimulation to the inferior parietal lobule, increased mind wandering propensity and this effect was relatively unaffected by stimulation dosage. These findings support a causal role for these two regions in mind wandering, one that is polarity specific.We investigated the neural basis of newly learned words in Spanish as a mother tongue (L1) and English as a second language (L2). Participants acquired new names for real but unfamiliar concepts in both languages over the course of two days. On day 3, they completed a semantic categorization task during fMRI scanning. The results revealed largely overlapping brain regions for newly learned words in Spanish and English. However, Spanish showed a heightened BOLD response within prefrontal cortex (PFC), due to increased competition of existing lexical representations. In contrast, English displayed higher activity than Spanish within primary auditory cortex, which suggests increased phonological processing due to more irregular phonological-orthographic mappings. Overall, these results suggest that novel words are learned similarly in Spanish L1 and English L2, and that they are represented in largely overlapping brain regions. However, they differ in terms of cognitive control and phonological processes.