scholarly journals Effect of Leptin Treatment in a Mouse Model of Tdp-43 Proteinopathy

2021 ◽  
Author(s):  
Agueda Ferrer-Donato ◽  
Ana Contreras ◽  
Paloma Fernandez ◽  
Carmen M. Fernandez-Martos
Keyword(s):  
Motor Performance ◽  
Motor Coordination ◽  
Disease Onset ◽  
Serum Levels ◽  
Mice Model ◽  
Progressive Decline ◽  
Beneficial Effects ◽  
Metabolic Component ◽  
Underlying Mechanisms ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is an irreversible neurodegenerative disease with no known cure. Recent studies suggest a strong metabolic component in ALS pathogenesis and have shown an inverse relationship between leptin levels and ALS progression, although the effects of leptin as a treatment have not yet been studied. Therefore, we aim to examine whether the acute treatment with leptin has beneficial effects on brain pathology and cognitive function in the transgenic TDP43A315T line of ALS. Mice were treated intranasally (IN) with 0.03mg/kg of leptin or vehicle (VH) daily for 7 days. Data showed a progressive decline in body weight and motor coordination in TDP43A315T mice. Moreover, Lep-treated TDP43A315T mice showed an earlier disease onset, along with an improvement in motor performance. Altered levels of some of the adipokines and metabolic proteins studied were found in TDP43A315T mice, which were differently expressed among Lep-treated and VH-treated animals. Furthermore, some correlations were found among the serum levels of this proteins in WT and TDP43A315T mice. As far as we know, this is the first pilot study to provide evidence of the therapeutic effect of leptin treatment in a mice model of ALS, although further studies are needed to expound on the underlying mechanisms.

scholarly journals Effect of ozone exposure on Amyotrophic Lateral Sclerosis (ALS) pathology using a mice model of TDP-43 proteinopathy

2021 ◽  
Author(s):  
Ana Rodriguez ◽  
Agueda Ferrer-Donato ◽  
Marta Cabrera-Pinto ◽  
Susana Seseña ◽  
Paloma Fernández ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Body Weight ◽  
Plasma Glucose ◽  
Motor Performance ◽  
Motor Coordination ◽  
Ozone Exposure ◽  
Mice Model ◽  
Inhibitory Peptide ◽  
Glucose Content ◽  
Lateral Sclerosis

AbstractBackgroundOzone (O3), one of the main photochemical pollutants in the atmosphere today, is a serious health risk factor. Although the effects of O3 exposure have been documented on many diseases, they have not yet been examined on Amyotrophic Lateral Sclerosis (ALS)- a fatal progressive and neurodegenerative disease.ObjectivesTo investigate the effect of the O3 exposure in a mice model of TDP-43 proteinopathy, exploring a possible association between the O3 exposure and the ALS pathogenesis.MethodsTDP-43A315T and wild-type (WT) mice were exposed to O3 (0.25 ppm) or filtered air (FA) for 15 days (4 hours/day). We assessed (1) weight loss (2) motor performance (3) plasma glucose content and (4) metabolic markers from plasma samples of the animals.ResultsThroughout the experiment, we observed a progressive decline in body weight and the motor coordination in TDP-43A315T mice compared to WT controls. Although there was a trend, there were no significant differences in the decline of body weight of TDP-43A315T mice when exposed to either FA or O3. In O3-TDP-43A315T mice, the disease duration lasted longer. In addition, O3-TDP-43A315T mice showed improvements in motor performance as well TDP-43A315T mice were hypoglycemic compared to WT mice. However, FA-TDP-43A315T mice showed lower plasma glucose levels at the disease end-stage. We found altered levels of adipokines and metabolic proteins in TDP-43A315T mice compared to WT controls. A positive correlation was found among GIP and glucagon compared to insulin concentrations in control mice. Interestingly, resistin, Gastric Inhibitory Peptide (GIP), Glucagon Like Peptide 1 (GIP-1) and insulin levels were higher in O3-TDP-43A315T mice.DiscussionWe provide new evidence about a mechanistic link between O3 exposure and the improvement of the metabolic disturbances present in TDP-43A315T mice. Further studies are needed to corroborate the obtained results as they warrant to understanding the underlying mechanisms.

scholarly journals Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1G93A female mice

2020 ◽  
Vol 13 (10) ◽  
pp. dmm045732
Author(s):  
Cristina Ruiz-Ruiz ◽  
Nuria García-Magro ◽  
Pilar Negredo ◽  
Carlos Avendaño ◽  
Anindya Bhattacharya ◽  
...  
Keyword(s):  
Body Weight ◽  
P2x7 Receptor ◽  
Motor Coordination ◽  
Disease Onset ◽  
Body Weight Loss ◽  
Chronic Administration ◽  
Study Endpoint ◽  
Reduced Body ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

ABSTRACTNeuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1G93A murine model. SOD1G93A mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age (here, postnatal day 60; P60) until study endpoint. Body weight, motor coordination, phenotypic score, disease onset and survival were measured throughout the study, and compared between vehicle- and drug-injected groups. Treatment with the P2X7R antagonist JNJ-47965567 delayed disease onset, reduced body weight loss and improved motor coordination and phenotypic score in female SOD1G93A mice, although it did not increase lifespan. Interestingly, neither beneficial nor detrimental effects were observed in males in any of the analyzed parameters. Treatment did not affect motor neuron survival or ChAT, Iba-1 and P2X7R protein expression in endpoint individuals of mixed sexes. Overall, chronic administration of JNJ-47965567 for 4 times per week to SOD1G93A mice from pre-onset stage altered disease progression in female individuals while it did not have any effect in males. Our results suggest a partial, yet important, effect of P2X7R in the development and progression of ALS.

scholarly journals Aldosterone directly affects apelin expression and secretion in adipocytes

2013 ◽  
Vol 51 (1) ◽  
pp. 37-48 ◽  
Author(s):  
He Jiang ◽  
Xiao-Ping Ye ◽  
Zhong-Yin Yang ◽  
Ming Zhan ◽  
Hai-Ning Wang ◽  
...  
Keyword(s):  
Target Genes ◽  
Direct Interaction ◽  
Serum Levels ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Beneficial Effects ◽  
Underlying Mechanisms ◽  
Plasma Apelin ◽  
Dose Dependent

There is a high incidence of metabolic syndrome among patients with primary aldosteronism (PA), which has recently been associated with an unfavorable cardiometabolic profile. However, the underlying mechanisms have not been clarified in detail. Characterizing aldosterone (Ald) target genes in adipocytes will help us to elucidate the deleterious effects associated with excess Ald. Apelin, a novel adipokine, exerts beneficial effects on obesity-associated disorders and cardiovascular homeostasis. The objective of this study was to investigate the effects of high Ald levels on apelin expression and secretion and the underlying mechanisms involved in adipocytes. In vivo, a single-dose Ald injection acutely decreased apelin serum levels and adipose tissue apelin production, which demonstrates a clear inverse relationship between the levels of plasma Ald and plasma apelin. Experiments using 3T3-L1 adipocytes showed that Ald decreased apelin expression and secretion in a time- and dose-dependent manner. This effect was reversed by glucocorticoid receptor (GR) antagonists or GR (NR3C1) knockdown; furthermore, putative HREs were identified in the apelin promoter. Subsequently, we verified that both glucocorticoids and mineralocorticoids regulated apelin expression through GR activation, although no synergistic effect was observed. Additionally, detailed potential mechanisms involved a p38 MAPK signaling pathway. In conclusion, our findings strengthen the fact that there is a direct interaction between Ald and apelin in adipocytes, which has important implications for hyperaldosteronism or PA-associated cardiometabolic syndrome and hoists apelin on the list of potent therapeutic targets for PA.

Excitotoxicity as a Target Against Neurodegenerative Processes

2020 ◽  
Vol 26 (12) ◽  
pp. 1251-1262 ◽  
Author(s):  
Octavio Binvignat ◽  
Jordi Olloquequi
Keyword(s):  
Neurodegenerative Diseases ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Prolonged Exposure ◽  
Mitochondrial Dysfunctions ◽  
Beneficial Effects ◽  
Clinical Investigations ◽  
Turn Over ◽  
Excitotoxic Cell Death ◽  
Lateral Sclerosis

: The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. : Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. : In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.

scholarly journals Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Estela Area-Gomez ◽  
D. Larrea ◽  
T. Yun ◽  
Y. Xu ◽  
J. Hupf ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Cell Structure ◽  
Disease Onset ◽  
Point Of View ◽  
Motor Dysfunction ◽  
Cellular Processes ◽  
Progressive Muscle Weakness ◽  
Human Pathology ◽  
Lateral Sclerosis

AbstractMotor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.

scholarly journals Dehulled Adlay Consumption Modulates Blood Pressure in Spontaneously Hypertensive Rats and Overweight and Obese Young Adults

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2305
Author(s):  
Wan-Ju Yeh ◽  
Jung Ko ◽  
Wei-Yi Cheng ◽  
Hsin-Yi Yang
Keyword(s):  
Blood Pressure ◽  
Daily Intake ◽  
Experimental Period ◽  
Overweight And Obesity ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Beneficial Effects ◽  
Underlying Mechanisms ◽  
Grain Foods

High blood pressure is a crucial risk factor for many cardiovascular diseases, and a diet rich in whole-grain foods may modulate blood pressure. This study investigated the effects of dehulled adlay consumption on blood pressure in vivo. We initially fed spontaneous hypertensive rats diets without (SHR group) or with 12 or 24% dehulled adlay (SHR + LA and SHR + HA groups), and discovered that it could limit blood pressure increases over a 12-week experimental period. Although we found no significant changes in plasma, heart, and kidney angiotensin-converting enzyme activities, both adlay-consuming groups had lower endothelin-1 and creatinine concentrations than the SHR group; the SHR + HA group also had lower aspartate aminotransferase and uric acid levels than the SHR group did. We later recruited 23 participants with overweight and obesity, and they consumed 60 g of dehulled adlay daily for a six-week experimental period. At the end of the study, we observed a significant decrease in the group’s systolic blood pressure (SBP), and the change in SBP was even more evident in participants with high baseline SBP. In conclusion, our results suggested that daily intake of dehulled adlay had beneficial effects in blood-pressure management. Future studies may further clarify the possible underlying mechanisms for the consuming of dehulled adlay as a beneficial dietary approach for people at risk of hypertension.

scholarly journals IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1686
Author(s):  
Adelaida M. Celaya ◽  
Lourdes Rodríguez-de la Rosa ◽  
Jose M. Bermúdez-Muñoz ◽  
José M. Zubeldia ◽  
Carlos Romá-Mateo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inflammatory Cytokines ◽  
Noise Exposure ◽  
Sensorineural Deafness ◽  
Serum Levels ◽  
Genetic Syndromes ◽  
Expression Ratio ◽  
Postnatal Maturation ◽  
Age Related ◽  
Underlying Mechanisms

Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/− mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.

scholarly journals Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents

2021 ◽  
Vol 11 (2) ◽  
pp. 160
Author(s):  
Mor R. Alkaslasi ◽  
Noell E. Cho ◽  
Navpreet K. Dhillon ◽  
Oksana Shelest ◽  
Patricia S. Haro-Lopez ◽  
...  
Keyword(s):  
Risk Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Disease Onset ◽  
Poor Health ◽  
Disease Symptoms ◽  
Established Risk Factor ◽  
Early Injury ◽  
Corticospinal Motor Neurons ◽  
Lateral Sclerosis

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.

Beneficial effects of natural compounds on experimental liver ischemia-reperfusion injury

2021 ◽  
Author(s):  
Camila Dossi ◽  
Romina Vargas ◽  
Rodrigo Valenzuela ◽  
Luis Videla
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Natural Compounds ◽  
Liver Ischemia ◽  
Hepatic Surgery ◽  
Beneficial Effects ◽  
Underlying Mechanisms ◽  
Experimental Liver

Liver ischemia-reperfusion injury (IRI) is a phenomenon inherent to hepatic surgery that severely compromises the organ functionality, whose underlying mechanisms involve cellular and molecular interrelated processes leading to the development...

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