High-fat diet-induced metabolic changes are not restricted to the onset of cardiovascular diseases, but also include effects on brain functions related to learning and memory. This study aimed to ...evaluate mitochondrial markers and function, as well as cognitive function, in a rat model of metabolic dysfunction. Eight-week-old male
Wistar
rats were subjected to either a control diet or a two-hit protocol combining a high fat diet (HFD) with the nitric oxide synthase inhibitor L-NAME in the drinking water. HFD plus L-NAME induced obesity, hypertension, and increased serum cholesterol. These rats exhibited bioenergetic dysfunction in the hippocampus, characterized by decreased oxygen (O
2
) consumption related to ATP production, with no changes in H
2
O
2
production. Furthermore, OPA1 protein expression was upregulated in the hippocampus of HFD + L-NAME rats, with no alterations in other morphology-related proteins. Consistently, HFD + L-NAME rats showed disruption of performance in the Morris Water Maze Reference Memory test. The neocortex did not exhibit either bioenergetic changes or alterations in H
2
O
2
production. Calcium uptake rate and retention capacity in the neocortex of HFD + L-NAME rats were not altered. Our results indicate that hippocampal mitochondrial bioenergetic function is disturbed in rats exposed to a HFD plus L-NAME, thus disrupting spatial learning, whereas neocortical function remains unaffected.
Highlights
A two-hit protocol using HFD + L-NAME induces metabolic dysfunction in rats.
Spatial memory is impacted in HFD + L-NAME rats.
Hippocampal but not neocortex bioenergetics is affected in HFD + L-NAME rats.
OPA-1 expression is upregulated in the hippocampus of HFD + L-NAME rats.
Cortical calcium dynamics was not affected by HFD + L-NAME.
Graphical abstract
Abstract
Background and Aims
Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential ...treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure.
Methods
Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets.
Results
4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure.
Conclusions
4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.
High-fat diet-induced metabolic changes are not restricted to the onset of cardiovascular diseases, but also include effects on brain functions related to learning and memory. This study aimed to ...evaluate mitochondrial markers and function, as well as cognitive function, in a rat model of metabolic dysfunction. Eight-week-old male Wistar rats were subjected to either a control diet or a two-hit protocol combining a high fat diet (HFD) with the nitric oxide synthase inhibitor L-NAME in the drinking water. HFD plus L-NAME induced obesity, hypertension, and increased serum cholesterol. These rats exhibited bioenergetic dysfunction in the hippocampus, characterized by decreased oxygen (O2) consumption related to ATP production, with no changes in H2O2 production. Furthermore, OPA1 protein expression was upregulated in the hippocampus of HFD + L-NAME rats, with no alterations in other morphology-related proteins. Consistently, HFD + L-NAME rats showed disruption of performance in the Morris Water Maze Reference Memory test. The neocortex did not exhibit either bioenergetic changes or alterations in H2O2 production. Calcium uptake rate and retention capacity in the neocortex of HFD + L-NAME rats were not altered. Our results indicate that hippocampal mitochondrial bioenergetic function is disturbed in rats exposed to a HFD plus L-NAME, thus disrupting spatial learning, whereas neocortical function remains unaffected. A two-hit protocol using HFD + L-NAME induces metabolic dysfunction in rats.Spatial memory is impacted in HFD + L-NAME rats.Hippocampal but not neocortex bioenergetics is affected in HFD + L-NAME rats.OPA-1 expression is upregulated in the hippocampus of HFD + L-NAME rats.Cortical calcium dynamics was not affected by HFD + L-NAME.
Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients ...and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1−/−) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1−/− resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1−/− resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling.
Traditionally, humans have consumed nonhuman primates in many places, including throughout the Amazon region. However, primate consumption rates are changing with rising urbanization and market ...access. We characterize primate consumption in central Amazonia using 192 qualitative interviews with inhabitants in three rural villages and in the city of Tefé. We used a generalized linear model to investigate how individual consumer characteristics, such as age and gender, and livelihoods affected primate consumption. We also used principal coordinate analysis (PCoA), and word clouds and network text analyses, to describe reasons people gave for eating or avoiding primates. Our results show that men were more likely to say that they eat primates than women, and that the probability that a person said that they eat primates correlated positively with the percentage of their life lived in rural areas. People gave sentiment and ethical reasons not to eat primates. Custom influenced whether people said they eat primates both positively and negatively, while taste positively influenced whether people said they eat primates. A preference for other wild meats in rural areas, and for domestic meats in cities negatively influenced whether people said they eat primates. People also cited the perceptions that primates have a human-like appearance and that primate meat is unhealthy as reasons not to eat primates. People in urban areas also cited conservation attitudes as reasons for not eating primates. Our findings provide an understanding of factors influencing primate consumption in our study area and will be useful for designing tailored conservation initiatives by reducing hunting pressure on primates in rural settings and increasing the effectiveness of outreach campaigns in urban centers.
Cancer treatment: changes in hearing thresholds Ramalho Machado, Larissa Azevedo; Santos Amaral, Tarsila; Santos de Aguiar, Lisley Kelly ...
Oncology Research and Reviews,
2018, Letnik:
1, Številka:
2
Journal Article
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