Efficacy of high doses of intravenous fosfomycin for treatment of urinary tract infection caused by KPC carbapenemase-producing Klebsiella pneumoniae. An observational study.

Objectives: To evaluate the efficacy of high-dose intravenous fosfomycin for the treatment of urinary tract infections (UTI) caused by KPC carbapenemase-producing Klebsiella pneumoniae (KPC-Kp). A secondary objective was to evaluate the impact of the results of fosfomycin susceptibility testing on prognosis.

Methods: This is an observational and retrospective study.

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.

TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation.

It has remained unknown how cells reduce cystine taken up from the extracellular space, which is a required step for further utilization of cysteine in key processes such as protein or glutathione synthesis. Here, we show that the thioredoxin-related protein of 14 kDa (TRP14, encoded by TXNDC17) is the rate-limiting enzyme for intracellular cystine reduction. When TRP14 is genetically knocked out, cysteine synthesis through the transsulfuration pathway becomes the major source of cysteine in human cells, and knockout of both pathways becomes lethal in C.

Innovative pathological network-based multitarget approaches for Alzheimer's disease treatment.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is a major health threat globally. Its prevalence is forecasted to exponentially increase during the next 30 years due to the global aging population. Currently, approved drugs are merely symptomatic, being ineffective in delaying or blocking the relentless disease advance.

The Melatonin Derivative ITH13001 Prevents Hypertension and Cardiovascular Alterations in Angiotensin II-Infused Mice.

Inflammatory mechanisms and oxidative stress seem to contribute to the pathogenesis of hypertension. ITH13001 is a melatonin-phenyl-acrylate hybrid that moderately induces the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) and has a potent oxidant scavenging effect compared with other derivatives of its family. Here we investigated the effect of ITH13001 on hypertension and the associated cardiovascular alterations.

High-resolution temporal monitoring of rare earth elements in acidic drainages from an abandoned sulphide mine (iberian pyrite belt, Spain).

Rare earth elements (REE) are strategic elements due to their economic importance. However, the studies dedicated to the distribution and behaviour of REE in aquatic systems have been scarce until a few decades ago. This work studies the seasonal variations of REE concentrations in acid mine drainage (AMD) affected water courses and the factors controlling their mobility under different hydrological conditions.

Wildfire effects on the hydrogeochemistry of a river severely polluted by acid mine drainage.

This study evaluates for the first time the impact of a large wildfire on the hydrogeochemistry of a deeply AMD-affected river at the beginning of the wet season. To accomplish this, a high-resolution water monitoring campaign was performed within the basin coinciding with the first rainfalls after summer. Unlike similar events recorded in AMD-affected areas, where dramatic increases in most dissolved element concentrations, and decreases in pH values are observed as a result of evaporitic salts flushing and the transport of sulfide oxidation products from mine sites, a slight increase in pH values (from 2.

KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is considered the master regulator of the phase II antioxidant response. It controls a plethora of cytoprotective genes related to oxidative stress, inflammation, and protein homeostasis, among other processes. Activation of these pathways has been described in numerous pathologies including cancer, cardiovascular, respiratory, renal, digestive, metabolic, autoimmune, and neurodegenerative diseases.

Stream-pit lake interactions in an abandoned mining area affected by acid drainage (Iberian Pyrite Belt).

Opencast mining of sulfide ore deposits may lead to the formation of anthropogenic acidic lakes with highly polluted waters. In these systems, it is crucial to understand the hydrological connections between surface and groundwater and their contribution to the pollutant load delivered to the downgradient streams. This study characterizes the interactions between surface and groundwater in an acidic pit lake using different geochemical tracers (i.

Climate vulnerability assessment of key fishery resources in the Northern Humboldt Current System.

The Northern Humboldt Current System sustains one of the most productive fisheries in the world. However, climate change is anticipated to negatively affect fish production in this region over the next few decades, and detailed analyses for many fishery resources are unavailable. We implemented a trait-based Climate Vulnerability Assessment based on expert elicitation to estimate the relative vulnerability of 28 fishery resources (benthic, demersal, and pelagic) to the impacts of climate change by 2055; ten exposure factors (e.

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.

Novel Series of Dual NRF2 Inducers and Selective MAO-B Inhibitors for the Treatment of Parkinson's Disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. It is characterized by a complex network of physiopathological events where oxidative stress plays a central role among other factors such as neuroinflammation and protein homeostasis. Nuclear factor-erythroid 2 p45-related factor 2 (NRF2) has a multitarget profile itself as it controls a plethora of cellular processes involved in the progression of the disease.

Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157-Lipoic Acid Hybrids for the Treatment of Alzheimer's Disease.

Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na/Ca exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman's chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood-brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity.

Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation.

Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer's disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species.

Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation.

The use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with β-cyclodextrin and hydroxypropyl-β-cyclodextrin. These cyclodextrin complexes were characterized by nuclear magnetic resonance spectroscopy (NMR).

Bisavenathramide Analogues as Nrf2 Inductors and Neuroprotectors in In Vitro Models of Oxidative Stress and Hyperphosphorylation.

Oxidative stress is crucial to the outbreak and advancement of neurodegenerative diseases and is a common factor to many of them. We describe the synthesis of a library of derivatives of the 4-arylmethylen-2-pyrrolin-5-one framework by sequential application of a three-component reaction of primary amines, β-dicarbonyl compounds, and α-haloketones and a Knoevenagel condensation. These compounds can be viewed as cyclic amides of caffeic and ferulic acids, and are also structurally related to the bisavenanthramide family of natural antioxidants.

Inflammatory Biomarkers in the Pathogenesis of Respiratory Dysfunction in People Living with HIV.

Background: Although the association between HIV infection and airways obstruction is well known, its etiopathogenesis is not clear.

Objectives: Our aim was to analyze the association between biomarkers of systemic inflammation and bacterial translocation and pulmonary function tests in HIV infected patients and compare it between smokers and non-smokers.

Methods: Cross-sectional, observational study.

Large scale use of SARS-CoV-2 antigen-based detection tests: a three-month experience in Guatemala, June-August 2020.

Objectives: To measure protocol adherence and antigen-based detection tests (AgDT) negative predictive value after 3 months of massive use as a diagnostic tool for COVID-19 in Guatemala.

Methods: The study period included nasopharyngeal swabs taken between March 12 and August 31, 2020, which results were entered in the national COVID-19 information system. Proportional increase in testing between one month before and one month after the introduction of AgDT (May 9-June 8 vs.

Monoamine Oxidase Inhibitors: From Classic to New Clinical Approaches.

Monoamine oxidases (MAOs) are involved in the oxidative deamination of different amines and neurotransmitters. This pointed them as potential targets for several disorders and along the last 70 years a wide variety of MAO inhibitors have been developed as successful drugs for the treatment of complex diseases, being the first drugs approved for depression in the late 1950s. The discovery of two MAO isozymes (MAO-A and B) with different substrate selectivity and tissue expression patterns led to novel therapeutic approaches and to the development of new classes of inhibitors, such as selective irreversible and reversible MAO-B inhibitors and reversible MAO-A inhibitors.

When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration.

Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions.

Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer's Disease.

Alzheimer's disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein.