Background
Prenatal stress is associated with increased susceptibility to psychiatric and metabolic disorders later in life. Prenatal exposure to stress mediators may have sex‐dependent effects on ...offspring brain and metabolic function, promoting a sex‐specific vulnerability to psychopathology and metabolic alterations at adulthood. In this work, the impact of prenatal stress on glucose homeostasis and peripheral metabolism of male and female offspring was investigated in a chronic anxiety animal model.
Methods
Pregnant Wistar rats were injected with saline or glucocorticoid (dexamethasone: 1 mg/kg, subcutaneous) at gestational days 18 and 19. Male and female offspring weight was monitored, and anxious‐like behaviour and peripheral insulin‐sensitive tissues were analysed at adulthood.
Results
At birth, females and males prenatally exposed to stress presented decreased body weight which remained low in females. At adulthood, a morphological disorganization of the Langerhans islets was observed in both sexes prenatally exposed to stress, yet not changes in insulin levels were detected. Also, prenatal stress increased glucose transporter 4 (GLUT‐4) levels in female and male adipose tissues and decreased insulin receptor levels in the liver and skeleton muscle but only in females.
Conclusions
Exposure to stress mediators in critical periods of development negatively affects behaviour and metabolism. Prenatal stress programmes offspring peripheral metabolism in a sex‐specific manner, emphasizing that the response to stress in critical periods of development may be sex‐specific having each sex different vulnerabilities to psychiatric and metabolic disorders. Considering sex‐specificities may provide critical clues for the design of preventive strategies and for early therapeutic intervention.
During infections, the host redistributes iron in order to starve pathogens from this nutrient. Several proteins are involved in iron absorption, transport, and storage. Ferritin is the most ...important iron storage protein. It is composed of variable proportions of two peptides, the L- and H-ferritins (FTL and FTH). We previously showed that macrophages increase their expression of FTH1 when they are infected in vitro with
, without a significant increase in FTL. In this work, we investigated the role of macrophage FTH1 in
infection in vivo. We found that mice deficient in FTH1 in myeloid cells are more resistant to
infection, presenting lower bacterial loads and lower levels of proinflammatory cytokines than wild-type littermates, due to the lower levels of available iron in the tissues. Importantly, we also found that FTH1 produced by myeloid cells in response to infection may be found in circulation and that it plays a key role in iron redistribution. Specifically, in the absence of FTH1 in myeloid cells, increased expression of ferroportin is observed in liver granulomas and increased iron accumulation occurs in hepatocytes. These results highlight the importance of FTH1 expression in myeloid cells for iron redistribution during infection.
Trypanosomiasis is a parasitic disease affecting both humans and animals
in the form of Human African Trypanosomiasis and Nagana disease,
respectively. Anemia is one of the most common symptoms of
...trypanosomiasis, and if left unchecked can cause severe complications and
even death. Several factors have been associated with the development of
this anemia, including dysregulation of iron homeostasis, but little is known
about the molecular mechanisms involved. Here, using murine models, we
study the involvement of hepcidin, the key regulator of iron metabolism and
an important player in the development of anemia of inflammation. Our
data show two stages for the progression of anemia, to which hepcidin contributes
a first stage when anemia develops, with a likely cytokine-mediated
stimulation of hepcidin and subsequent limitation in iron availability and
erythropoiesis, and a second stage of recovery, where the increase in hepcidin
then declines due to the reduced inflammatory signal and increased
production of erythroid regulators by the kidney, spleen and bone marrow,
thus leading to an increase in iron release and availability, and enhanced erythropoiesis.
In agreement with this, in hepcidin knockout mice, anemia is
much milder and its recovery is complete, in contrast to wild-type animals
which have not fully recovered from anemia after 21 days. Besides all other
factors known to be involved in the development of anemia during trypanosomiasis,
hepcidin clearly makes an important contribution to both its
development and recovery.
Alzheimer's disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are ...responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown that the retina can also be affected in AD, presenting some molecular and cellular changes in the brain, such as microglia activation. However, there are only a few studies assessing such changes in the retinal microglia in animal models of AD. These studies use retinal sections, which have some limitations. In this study, we performed, for the first time in a triple-transgenic AD mouse model (3xTg-AD), a quantitative morphometric analysis of microglia activation (using the anti-Iba-1 antibody) in retinal whole-mounts, allowing visualization of the entire microglial cell, as well as its localization along the extension of the retina in different layers. Compared to age-matched animals, the retina of 3xTg-AD mice presents a higher number of microglial cells and a thicker microglial cell body area. Moreover, the microglia migrate, reorient, and retract their processes, changing their localization from a parallel to a perpendicular position relative to the retinal surface. These findings demonstrate clear microglia remodeling in the retina of 3xTg-AD mice.
Anemia is a frequent and challenging complication of mycobacterial infections. We used a model of disseminated
infection in mice to investigate the mechanisms of mycobacteria-induced anemia. We found ...increased formation of RBC in the bone marrow and spleen of infected mice. Infection induced reticulocytosis and the premature egress of immature progenitors to the systemic circulation in an IFN-γ (IFNG)-dependent way. The newly formed RBC had reduced CD47 surface expression and a reduced life span and were phagocytosed in the liver of infected mice, increasing iron recycling in this organ. The increased engulfment and degradation of RBC was independent of IFNG sensing by macrophages. Together, our findings demonstrate that mycobacterial infection alters the formation of erythrocytes, leading to their accelerated removal from circulation and hemolytic anemia. This comprehensive elucidation of the mechanisms underlying mycobacteria-induced anemia has important implications for its efficient clinical management.
During bacterial infection, the pathogenic agent and the host battle for iron, due to its importance for fundamental cellular processes. However, iron redistribution and sequestration during ...infection can culminate in anemia. Although hepcidin has been recognized as the key regulator of iron metabolism, in some infections its levels remain unaffected, suggesting the involvement of other players in iron metabolism deregulation. In this work, we use a mouse model to elucidate the main cellular and molecular mechanisms that lead to iron redistribution during infection with two different pathogens:
and
serovar Typhimurium. Both infections clearly impacted iron metabolism, causing iron redistribution, decreasing serum iron levels, decreasing the saturation of transferrin, and increasing iron accumulation in the liver. Both infections were accompanied by the release of proinflammatory cytokines. However, when analyzing iron-related gene expression in the liver, we observed that hepcidin was induced by
Typhimurium but not by
In the latter model, the downregulation of hepatic ferroportin mRNA and protein levels suggested that ferroportin plays a major role in iron redistribution. On the other hand,
Typhimurium infection induced the expression of hepcidin mRNA, and we show here, for the first time
, that this induction is Toll-like receptor 4 (TLR4) dependent. In this work, we compare several aspects of iron metabolism alterations induced by two different pathogens and suggest that hepcidin-(in)dependent mechanisms contribute to iron redistribution upon infection.
Alzheimer’s disease is the most frequent cause of dementia worldwide, representing a global health challenge, with a massive impact on the quality of life of Alzheimer’s disease patients and their ...relatives. The diagnosis of Alzheimer’s disease constitutes a real challenge, because the symptoms manifest years after the first degenerative changes occurring in the brain and the diagnosis is based on invasive and/or expensive techniques. Therefore, there is an urgent need to identify new reliable biomarkers to detect Alzheimer’s disease at an early stage. Taking into account the evidence for visual deficits in Alzheimer’s disease patients, sometimes even before the appearance of the first disease symptoms, and that the retina is an extension of the brain, the concept of the retina as a window to look into the brain or a mirror of the brain has received increasing interest in recent years. However, only a few studies have assessed the changes occurring in the retina and the brain at the same time points. Unlike previous reviews on this subject, which are mainly focused on brain changes, we organized this review by comprehensively summarizing findings related with structural, functional, cellular, and molecular parameters in the retina reported in both Alzheimer’s disease patients and animal models. Moreover, we separated the studies that assessed only the retina, and those that assessed both the retina and brain, which are few but allow establishing correlations between the retina and brain. This review also highlights some inconsistent results in the literature as well as relevant missing gaps in this field.
Acute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide ...triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TG- and 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin, as a target for TG and 22-HTG. The application of N-acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin.
•TG and 22-HTG induce caspase-mediated apoptotic cell death.•TG and 22-HTG target oxidative stress through downregulation of thioredoxin.•TG and 22-HTG cause DNA damage.•TG and 22-HTG cause JNK/p38-mediated apoptosis.
Hepcidin is a small cysteine rich peptide that regulates the sole known cellular iron exporter, ferroportin, effectively controlling iron metabolism. Contrary to humans, where a single hepcidin ...exists, many fish have two functionally distinct hepcidin types, despite having a single ferroportin gene. This raises the question of whether ferroportin is similarly regulated by the iron regulator Hamp1 and the antimicrobial Hamp2. In sea bass (Dicentrarchus labrax), iron overload prompted a downregulation of ferroportin, associated with an upregulation of hamp1, whereas an opposite response was observed during anemia, with no changes in hamp2 in either situation. During infection, ferroportin expression decreased, indicating iron withholding to avoid microbial proliferation. In vivo administration of Hamp1 but not Hamp2 synthetic peptides caused significant reduction in ferroportin expression, indicating that in teleost fish with two hepcidin types, ferroportin activity is mediated through the iron-regulator Hamp1, and not through the dedicated antimicrobial Hamp2. Additionally, in vitro treatment of mouse macrophages with fish Hamp1 but not Hamp2 caused a decrease in ferroportin levels. These results raise questions on the evolution of hepcidin and ferroportin functional partnership and open new possibilities for the pharmaceutical use of selected fish Hamp2 hepcidins during infections, with no impact on iron homeostasis.
Abstract
The understanding of the natural history of Alzheimer’s disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal ...imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Molecular characterization evaluated hippocampal levels of amyloid β (Aβ) and hyperphosphorylated tau. Magnetic resonance imaging (MRI) included assessment of hippocampal structural integrity, blood–brain barrier (BBB) permeability and neurospectroscopy to determine levels of the endogenous neuroprotector taurine. Longitudinal brain amyloid accumulation was assessed using 11C Pittsburgh compound B positron emission tomography (PET), and neuroinflammation/microglia activation was investigated using 11C-PK1195. We found altered locomotor activity at months 4/8 and 16 months and recognition memory impairment at all time points. Substantial early reduction of hippocampal volume started at month 4 and progressed over 8/12 and 16 months. Hippocampal taurine levels were significantly decreased in the hippocampus at months 4/8 and 16. No differences were found for amyloid and neuroinflammation with PET, and BBB was disrupted only at month 16. In summary, 3xTg-AD mice showed exploratory and recognition memory impairments, early hippocampal structural loss, increased Aβ and hyperphosphorylated tau and decreased levels of taurine. In sum, the 3xTg-AD animal model mimics pathological and neurobehavioral features of AD, with early-onset recognition memory loss and MRI-documented hippocampal damage. The early-onset profile suggests temporal windows and opportunities for therapeutic intervention, targeting endogenous neuroprotectors such as taurine.