Naunyn-Schmiedebergs Archiv fur experimentelle Pathologie und Pharmakologie最新文献

Background: Sickle-cell diseases (SCD) are a group of hereditary disorders in which a specific mutation in the gene that encodes the hemoglobin ß chain leads to formation of an anomalous hemoglobin molecule (HbS) with high polymerization power. This leads to sickling of erythrocytes in situations of low oxygen tension, such as in microcirculation, resulting in peripheral microvasculature occlusion, chronic hemolysis, inflammation, and damage to several target organs. Malleolar ulcers are among the most-debilitating complications of the disease, as they are associated with significant pain, secondary infections, and social impact due to their aesthetic impairment. There are no completely satisfactory therapeutic options for this complication; local healing agents, antibiotics, and dressings are used, with high rates of recurrence and complications, such as osteomyelitis and even limb amputation.

Case: This case study evaluated the effect of Traditional Chinese Medicine techniques on chronic malleolar ulcers in a 49-year-old male patient. Ten sessions of systemic acupuncture (combinations involving Source, Master, Energetic Action, and Extraordinary Vessels points), auriculotherapy, and dressing with magnets were conducted.

Results: Although the primary outcome sought was not reached (decrease in ulcer diameters), this patient had great reduction of local pain, a decrease in limb edema, and important reduction of his inflammatory condition, reflected in his decreasing blood levels of C-reactive protein.

Conclusions: These results show that acupuncture should be considered as an important auxiliary treatment for SCD complications.

Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer's disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-to-cell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

In Peru, nearly half of children aged 6-36 months were diagnosed with anaemia in 2017. To address this disease, the Peruvian Ministry of Health implemented a national programme in 2014, distributing free micronutrient powders (MNPs) to all children of this age. However, rates of childhood anaemia remain high. The aim of this study was to explore factors at all levels of the Social-Ecological Model that affect MNP use and adherence in Arequipa, an Andean city with childhood anaemia rates higher than the national average. We conducted in-depth interviews with 20 health personnel and 24 caregivers and 12 focus group discussions with 105 caregivers. We identified numerous barriers, including negative side effects (constipation, vomiting, and diarrhoea), poor taste of MNP, lack of familial and peer support for its use, insufficient informational resources provided by the health system, and limited human resources that constricted health personnel abilities to implement MNP programming successfully. Facilitators identified included concern about the long-term effects of anaemia, support from organizations external to the health system, well-coordinated care within the health system, and provision of resources by the Ministry of Health. We found that community or organizational and societal factors were key to limited MNP use and adherence, specifically the limited time health personnel have to address caregivers' doubts during appointments and the lack of informational resources outside of these appointments. Potential policy implications could be to increase informational resources available outside of individualized counselling by strengthening existing collaborations with community organizations, increasing media coverage, and providing group counselling.

Background: Neonatal herpes simplex virus (HSV) disease results in unacceptable morbidity and mortality. The primary humoral immune response to natural infection is neutralizing antibodies (Abs). However, Abs that activate Fc gama receptors (FcγRs) and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) may play a dominant role in protection. In adult mice, a single-cycle HSV candidate vaccine deleted in glycoprotein-D (ΔgD-2) that induces ADCC provided complete protection against HSV disease and prevented the establishment of latency. Passive transfer studies showed that Abs were sufficient for protection. The current study tested the hypothesis that maternal immunization with ΔgD-2 would protect neonates.

Methods: C57BL/6 female mice were vaccinated 3 weeks apart with ΔgD-2, and pups were challenged at different times postnatally with lethal doses of HSV-1 or HSV-2. Concentration and functionality of Abs and immune cells were assessed.

Results: Maternal ΔgD-2 immunization provided significant protection and reduced viral dissemination after lethal challenge with HSV-1 or HSV-2. Protection correlated with Abs acquired transplacentally or from breastmilk that mediated ADCC. Protection was reduced when pups were challenged on Day 1 of life, and this was associated with decreased ability of newborn cells to mediate Ab-dependent cell killing.

Conclusions: Antibodies mediating ADCC provide significant protection against neonatal HSV.

Background: High intensity interval training (HIIT) is a robust and time-efficient approach to improve multiple health indices including maximal oxygen uptake (VO₂max). Despite the intense nature of HIIT, data in untrained adults report greater enjoyment of HIIT versus continuous exercise (CEX). However, this has yet to be investigated in persons with spinal cord injury (SCI).

Objective: To examine differences in enjoyment in response to CEX and HIIT in persons with SCI.

Design: Repeated measures, within-subjects design.

Setting: University laboratory in San Diego, CA.

Participants: Nine habitually active men and women (age = 33.3 ± 10.5 years) with chronic SCI.

Intervention: Participants performed progressive arm ergometry to volitional exhaustion to determine VO₂peak. During subsequent sessions, they completed CEX, sprint interval training (SIT), or HIIT in randomized order.

Outcome measures: Physical activity enjoyment (PACES), affect, rating of perceived exertion (RPE), VO₂, and blood lactate concentration (BLa) were measured.

Results: Despite a higher VO₂, RPE, and BLa consequent with HIIT and SIT (P < 0.05), PACES was significantly higher (P = 0.03) in response to HIIT (107.4 ± 13.4) and SIT (103.7 ± 12.5) compared to CEX (81.6 ± 25.4). Fifty-five percent of participants preferred HIIT and 45% preferred SIT, with none identifying CEX as their preferred exercise mode.

Conclusion: Compared to CEX, brief sessions of submaximal or supramaximal interval training elicit higher enjoyment despite higher metabolic strain. The long-term efficacy and feasibility of HIIT in this population should be explored considering that it is not viewed as more aversive than CEX.

Triterpenoids produced by plants play important roles in the protection against biotic stress. Roots of Arabidopsis thaliana produce different triterpenoids, which include the tricyclic triterpene diol, arabidiol. In a degradation reaction induced by infection with the oomycete pathogen, Pythium irregulare, arabidiol is cleaved to the 11-carbon volatile homoterpene, (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT), and the 19-carbon ketone, apo-arabidiol. The arabidiol pathway and its volatile breakdown product DMNT have been implicated in the defense against P. irregulare infection. Here we show that the non-volatile breakdown product apo-arabidiol is further converted to the acetylated derivative α-14-acetyl-apo-arabidiol via a presumed epimerization and subsequent acetylation reaction. α-14-acetyl-apo-arabidiol and the detected intermediates in the derivatization pathway are partially exuded from the root indicating possible defensive activities of these molecules in the rhizosphere. The conversion steps of apo-arabidiol vary among different Arabidopsis accessions and are present in only rudimentary form in the close relative Arabidopsis lyrata, which supports an intra- and inter-specific modularity in triterpenoid metabolism.

Purpose: The currently held mechanistic understanding of microsomal cytochrome P450s (CYPs) seeks that diverse drug molecules bind within the deep-seated distal heme pocket and subsequently react at the heme centre. To explain a bevy of experimental observations and meta-analyses, we indulge a hypothesis that involves a "diffusible radical mediated" mechanism. This new hypothesis posits that many substrates could also bind at alternate loci on/within the enzyme and be reacted without the pertinent moiety accessing a bonding proximity to the purported catalytic Fe-O enzyme intermediate.

Methods: Through blind and heme-distal pocket centered dockings of various substrates and non-substrates (drug molecules of diverse sizes, classes, topographies etc.) of microsomal CYPs, we explored the possibility of access of substrates via the distal channels, its binding energies, docking orientations, distance of reactive moieties (or molecule per se) to/from the heme centre, etc. We investigated specific cases like- (a) large drug molecules as substrates, (b) classical marker drug substrates, (c) class of drugs as substrates (Sartans, Statins etc.), (d) substrate preferences between related and unrelated CYPs, (e) man-made site-directed mutants' and naturally occurring mutants' reactivity and metabolic disposition, (f) drug-drug interactions, (g) overall affinities of drug substrate versus oxidized product, (h) meta-analysis of in silico versus experimental binding constants and reaction/residence times etc.

Results: It was found that heme-centered dockings of the substrate/modulator drug molecules with the available CYP crystal structures gave poor docking geometries and distances from Fe-heme centre. In conjunction with several other arguments, the findings discount the relevance of erstwhile hypothesis in many CYP systems. Consequently, the newly proposed hypothesis is deemed a viable alternate, as it satisfies Occam's razor.

Conclusions: The new proposal affords expanded scope for explaining the mechanism, kinetics and overall phenomenology of CYP mediated drug metabolism. It is now understood that the heme-iron and the hydrophobic distal pocket of CYPs serve primarily to stabilize the reactive intermediate (diffusible radical) and the surface or crypts of the apoprotein bind to the xenobiotic substrate (and in some cases, the heme distal pocket could also serve the latter function). Thus, CYPs enhance reaction rates and selectivity/specificity via a hitherto unrecognized modality.

Endothelial dysfunction involves deregulation of the key extracellular matrix (ECM) enzyme lysyl oxidase (LOX) and the vasoconstrictor protein, endothelin-1 (ET-1), whose gene expression can be modulated by the transcriptional activators nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). Advanced glycation end products (AGEs) present an aggravating factor of endothelial dysfunction which upon engagement to their receptor RAGE induce upregulation of mitogen-activated protein kinases (MAPKs), leading to NF-κB and AP-1 potentiation. We hypothesized that AGEs could induce NF-κΒ- and AP-1-dependent regulation of LOX and ET-1 expression via the AGE/RAGE/MAPK signaling axis. Western blot, real-time qRT-PCR, FACS analysis and electrophoretic mobility-shift assays were employed in human aortic endothelial cells (HAECs) following treatment with AGE-bovine serum albumin (AGE-BSA) to investigate the signaling pathway towards this hypothesis. Furthermore, immunohistochemical analysis of AGEs, RAGE, LOX and ET-1 expression was conducted in aortic endothelium of a rat experimental model exposed to high- or low-AGE content diet. HAECs exposed to AGE-BSA for various time points exhibited upregulation of LOX and ET-1 mRNA levels in a dose- and time-dependent manner. Exposure of HAECs to AGE-BSA also showed specific elevation of phospho(p)-ERK1/2 and p-JNK levels in a dose- and time-dependent fashion. AGE administration significantly increased NF-κΒ- and AP-1-binding activity to both LOX and ET-1 cognate promoter regions. Moreover, LOX and ET-1 overexpression in rat aortic endothelium upon high-AGE content diet confirmed the functional interrelation of these molecules. Our findings demonstrate that AGEs trigger NF-κΒ- and AP-1-mediated upregulation of LOX and ET-1 via the AGE/RAGE/MAPK signaling cascade in human endothelial cells, thus contributing to distorted endothelial homeostasis by impairing endothelial barrier function, altering ECM biomechanical properties and cell proliferation.