Discovery of a potent melatonin-based inhibitor of quinone reductase-2 with neuroprotective and neurogenic properties.

5-Methoxy-3-(5-methoxyindolin-2-yl)-1H-indole (3), whose structure was unambiguously elucidated by X-ray analysis, was identified as a multi-target compound with potential application in neurodegenerative diseases. It is a low nanomolar inhibitor of QR2 (IC = 7.7 nM), with greater potency than melatonin and comparable efficacy to the most potent QR2 inhibitors described to date.

Brain vasculature accumulates tau and is spatially related to tau tangle pathology in Alzheimer's disease.

Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting cerebral homeostasis. In this work, we provide new evidence from three-dimensional human brain histology that tau protein, the main component of neurofibrillary tangles, can similarly accumulate along brain vascular segments. We quantitatively assessed n = 6 Alzheimer's disease (AD), and n = 6 normal aging control brains and saw that tau-positive blood vessel segments were present in all AD cases.

Brain Vasculature Accumulates Tau and Is Spatially Related to Tau Tangle Pathology in Alzheimer's Disease.

Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting cerebral homeostasis. In this work we provide new evidence from three-dimensional human brain histology that tau protein, the main component of neurofibrillary tangles, can similarly accumulate along brain vascular segments. We quantitatively assessed n=6 Alzheimer's disease (AD), and n=6 normal aging control brains and saw that tau-positive blood vessel segments were present in all AD cases.

Increasing Gram-Negative Catheter-Related Bloodstream Infection in Cancer Patients.

: We aimed to assess the incidence, etiology and outcomes of catheter-related bloodstream infection (CRBSI) in onco-hematological patients, to assess the differences between patients with hematological malignancies (HMs) and solid tumors (STs) and to identify the risk factors for Gram-negative (GN) CRBSI. : All consecutive episodes of BSI in adult cancer patients were prospectively collected (2006-2020). The etiology of CRBSI was analyzed in three different 5-year periods.

Microglial Hemoxygenase-1 Deletion Reduces Inflammation in the Retina of Old Mice with Tauopathy.

Tauopathies such as Alzheimer's disease are characterized by the accumulation of neurotoxic aggregates of tau protein. With aging and, especially, in Alzheimer's patients, the inducible enzyme heme oxygenase 1 (HO-1) progressively increases in microglia, causing iron accumulation, neuroinflammation, and neurodegeneration. The retina is an organ that can be readily accessed and can reflect changes that occur in the brain.

Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades.

By replacing a phenolic ring of ()-resveratrol with an 1,3,4-oxadiazol-2(3)-one heterocycle, new resveratrol-based multitarget-directed ligands (MTDLs) were obtained. They were evaluated in several assays related to oxidative stress and inflammation (monoamine oxidases, nuclear erythroid 2-related factor, quinone reductase-2, and oxygen radical trapping) and then in experiments of increasing complexity (neurogenic properties and neuroprotection okadaic acid). 5-[()-2-(4-Methoxyphenyl)ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2(3)-one () showed a well-balanced MTDL profile: cellular activation of the NRF2-ARE pathway (CD = 9.

Impact of Empirical Antibiotic Regimens on Mortality in Neutropenic Patients with Bloodstream Infection Presenting with Septic Shock.

We analyzed risk factors for mortality in febrile neutropenic patients with bloodstream infections (BSI) presenting with septic shock and assessed the impact of empirical antibiotic regimens. A multicenter retrospective study (2010 to 2019) of two prospective cohorts compared BSI episodes in patients with or without septic shock. Multivariate analysis was performed to identify independent risk factors for mortality in episodes with septic shock.

Intracellular calcium and inflammatory markers, mediated by purinergic stimulation, are differentially regulated in monocytes of patients with major depressive disorder.

The P2X7 receptor (P2X7R) is a ligand-gated ion channel that is being recognized as a major player in neuropsychiatric disorders such as Major Depressive Disorder (MDD). P2X7R activation is triggered by high extracellular ATP concentrations, leading to channel opening and inducing an increase in cytosolic calcium concentration ([Ca]), that activates the inflammatory pathway. Those receptors are expressed not only in CNS cells but also in peripheral blood cells, where they are activated in response to inflammatory molecules such as bacterial lipopolysaccharide (LPS).

Hepatic Encephalopathy-Associated Cerebral Vasculopathy in Acute-on-Chronic Liver Failure: Alterations on Endothelial Factor Release and Influence on Cerebrovascular Function.

The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts.

Do high MICs predict the outcome in invasive fusariosis?

Background: Invasive fusariosis (IF) affects mostly severely immunocompromised hosts and is associated with poor outcome. Since Fusarium species exhibit high MICs for most antifungal agents, this could explain the poor prognosis. However, a clear-cut correlation between MIC and outcome has not been established.

Nicotianamine Synthase 2 Is Required for Symbiotic Nitrogen Fixation in Nodules.

Symbiotic nitrogen fixation carried out by the interaction between legumes and diazotrophic bacteria known as rhizobia requires relatively large levels of transition metals. These elements are cofactors of many key enzymes involved in this process. Metallic micronutrients are obtained from soil by the roots and directed to sink organs by the vasculature, in a process mediated by a number of metal transporters and small organic molecules that facilitate metal delivery in the plant fluids.

Acute-on-chronic liver disease enhances phenylephrine-induced endothelial nitric oxide release in rat mesenteric resistance arteries through enhanced PKA, PI3K/AKT and cGMP signalling pathways.

Acute-on-chronic liver disease is a clinical syndrome characterized by decompensated liver fibrosis, portal hypertension and splanchnic hyperdynamic circulation. We aimed to determine whether the alpha-1 agonist phenylephrine (Phe) facilitates endothelial nitric oxide (NO) release by mesenteric resistance arteries (MRA) in rats subjected to an experimental microsurgical obstructive liver cholestasis model (LC). Sham-operated (SO) and LC rats were maintained for eight postoperative weeks.

Misdiagnosis of resistant hypertension: Real frequency of true resistant hypertension in patients with suspected resistance to treatment.

Introduction: Resistant hypertension(RH) has been defined as failure to control office blood pressure (BP) despite the use of≥3 different antihypertensive agents at optimal doses, including, ideally, a diuretic. Apparent RH, defines patients with an incorrect diagnosis of RH due to different causes. The objective was to determine whether most patients with RH in fact have apparent but not true RH.

Decompensated liver cirrhosis and neural regulation of mesenteric vascular tone in rats: role of sympathetic, nitrergic and sensory innervations.

We evaluated the possible alterations produced by liver cholestasis (LC), a model of decompensated liver cirrhosis in sympathetic, sensory and nitrergic nerve function in rat superior mesenteric arteries (SMA). The vasoconstrictor response to electrical field stimulation (EFS) was greater in LC animals. Alpha-adrenoceptor antagonist phentolamine and P2 purinoceptor antagonist suramin decreased this response in LC animals more than in control animals.

Biphasic Effect of Diabetes on Neuronal Nitric Oxide Release in Rat Mesenteric Arteries.

Introduction: We analysed possible time-dependent changes in nitrergic perivascular innervation function from diabetic rats and mechanisms implicated.

Materials And Methods: In endothelium-denuded mesenteric arteries from control and four- (4W) and eight-week (8W) streptozotocin-induced diabetic rats the vasoconstriction to EFS (electrical field stimulation) was analysed before and after preincubation with L-NAME. Neuronal NO release was analysed in the absence and presence of L-arginine, tetrahydrobiopterine (BH4) and L-arginine plus BH4.

Alterations in perivascular innervation function in mesenteric arteries from offspring of diabetic rats.

Background And Purpose: We have reported that exposure to a diabetic intrauterine environment during pregnancy increases blood pressure in adult offspring, but the mechanisms involved are not completely understood. This study was designed to analyse a possible role of perivascular sympathetic and nitrergic innervation in the superior mesenteric artery (SMA) in this effect.

Experimental Approach: Diabetes was induced in pregnant Wistar rats by a single injection of streptozotocin.

Aerobic exercise training increases nitrergic innervation function and decreases sympathetic innervation function in mesenteric artery from rats fed a high-fat diet.

Introduction: We investigated whether high-fat diet (HFD)-induced obesity was associated with modifications in mesenteric innervation function, the mechanisms involved, and the possible effects of aerobic exercise training on these changes.

Materials And Methods: Male Wistar rats were divided into three groups: rats fed a standard diet (control group); rats fed a HFD (35% fat) for 8 weeks; and HFD rats submitted to aerobic exercise training (8 weeks, 5 times per week for 50  min). Segments of isolated mesenteric arteries were exposed to electric field stimulation (EFS) with or without phentolamine, suramin, or Nω nitro-L-arginine methyl ester.

Alterations in perivascular sympathetic and nitrergic innervation function induced by late pregnancy in rat mesenteric arteries.

Background And Purpose: We investigated whether pregnancy was associated with changed function in components of perivascular mesenteric innervation and the mechanism/s involved.

Experimental Approach: We used superior mesenteric arteries from female Sprague-Dawley rats divided into two groups: control rats (in oestrous phase) and pregnant rats (20 days of pregnancy). Modifications in the vasoconstrictor response to electrical field stimulation (EFS) were analysed in the presence/absence of phentolamine (alpha-adrenoceptor antagonist) or L-NAME (nitric oxide synthase-NOS- non-specific inhibitor).

Prenatal and Perinatal Morbidity in Children with Tic Disorders: A Mainstream School-based Population Study in Central Spain.

Background: While current research suggests that genetic factors confer the greatest risk for the development of tic disorders, studies of environmental factors are relatively few, with a lack of consistent risk factors across studies. Our aim is to analyze the association of tic disorders with exposure to prenatal and perinatal morbidity.

Methods: This was a nested case-control study design.

Tranilast increases vasodilator response to acetylcholine in rat mesenteric resistance arteries through increased EDHF participation.

Background And Purpose: Tranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA).

Experimental Approach: Acetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats.

Opposite effect of mast cell stabilizers ketotifen and tranilast on the vasoconstrictor response to electrical field stimulation in rat mesenteric artery.

Objectives: We analyzed whether mast cell stabilization by either ketotifen or tranilast could alter either sympathetic or nitrergic innervation function in rat mesenteric arteries.

Methods: Electrical field stimulation (EFS)-induced contraction was analyzed in mesenteric segments from 6-month-old Wistar rats in three experimental groups: control, 3-hour ketotifen incubated (0.1 αmol/L), and 3-hour tranilast incubated (0.

Aerobic exercise training increases neuronal nitric oxide release and bioavailability and decreases noradrenaline release in mesenteric artery from spontaneously hypertensive rats.

Objective: To study the effect of aerobic exercise training on sympathetic, nitrergic and sensory innervation function in superior mesenteric artery from spontaneously hypertensive rats (SHRs).

Methods: De-endothelized vascular rings from sedentary and trained SHRs (treadmill 12 weeks) were used. Vasomotor responses to electrical field stimulation (EFS), noradrenaline, nitric oxide donor DEA-NO and calcitonin gene-related peptide (CGRP) were studied.

Breast feeding increases vasoconstriction induced by electrical field stimulation in rat mesenteric artery. Role of neuronal nitric oxide and ATP.

Objectives: The aim of this study was to investigate in rat mesenteric artery whether breast feeding (BF) affects the vasomotor response induced by electrical field stimulation (EFS), participation by different innervations in the EFS-induced response and the mechanism/s underlying these possible modifications.

Methods: Experiments were performed in female Sprague-Dawley rats (3 months old), divided into three groups: Control (in oestrous phase), mothers after 21 days of BF, and mothers that had recovered their oestral cycle (After BF, in oestrous phase). Vasomotor response to EFS, noradrenaline (NA) and nitric oxide (NO) donor DEA-NO were studied.

Evaluation of pre-treatment processes for increasing biodegradability of agro-food wastes.

Anaerobic digestion (AD) technology can be employed for treating sewage sludge, livestock waste or food waste. Generally, the hydrolysis stage is the rate-limiting step of the AD processes for solid waste degradation. Therefore, physical, chemical and biological pre-treatment methods or their combination are required, in order to reduce the rate of such a limiting step.