ABSTRACT
BACKGROUND: sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child's needs, as the splitting of the tablet into smaller portions or its dilution in water. It's essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients. MATERIALS AND METHODS: we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD. RESULTS: we documented the stability for 28â¯days at 25⯰C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance. CONCLUSIONS: in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.
ABSTRACT
Methylmalonyl-CoA epimerase enzyme (MCEE) is responsible for catalyzing the isomeric conversion between D- and L-methylmalonyl-CoA, an intermediate along the conversion of propionyl-CoA to succinyl-CoA. A dedicated test for MCEE deficiency is not included in the newborn screening (NBS) panels but it can be incidentally identified when investigating methylmalonic acidemia and propionic acidemia. Here, we report for the first time the biochemical description of a case detected by NBS. The NBS results showed increased levels of propionylcarnitine (C3) and 2-methylcitric acid (MCA), while methylmalonic acid (MMA) and homocysteine (Hcy) were within the reference limits. Confirmatory analyses revealed altered levels of metabolites, including MCA and MMA, suggesting a block in the propionate degradation pathway. The analysis of methylmalonic pathway genes by next-generation sequencing (NGS) allowed the identification of the known homozygous nonsense variation c.139C>T (p.R47X) in exon 2 of the MCE gene. Conclusions: Elevated concentrations of C3 with a slight increase in MCA and normal MMA and Hcy during NBS should prompt the consideration of MCEE deficiency in differential diagnosis. Increased MMA levels may be negligible at NBS as they may reach relevant values beyond the first days of life and thus could be identified only in confirmatory analyses.
ABSTRACT
Recessive mutations in the Parkin gene (PRKN) are the most common cause of young-onset inherited parkinsonism. Parkin is a multifunctional E3 ubiquitin ligase that plays a variety of roles in the cell including the degradation of proteins and the maintenance of mitochondrial homeostasis, integrity, and biogenesis. In 2001, the R275W mutation in the PRKN gene was identified in two unrelated families with a multigenerational history of postural tremor, dystonia and parkinsonism. Drosophila models of Parkin R275W showed selective and progressive degeneration of dopaminergic neuronal clusters, mitochondrial abnormalities, and prominent climbing defects. In the Prkn mouse orthologue, the amino acid R274 corresponds to human R275. Here we described an age-related motor impairment and a muscle phenotype in R274W +/+ mice. In vitro, Parkin R274W mutation correlates with abnormal myoblast differentiation, mitochondrial defects, and alteration in mitochondrial mRNA and protein levels. Our data suggest that the Parkin R274W mutation may impact mitochondrial physiology and eventually myoblast proliferation and differentiation.
ABSTRACT
Background: Rating of perceived exertion (RPE) is considered a valid method for prescribing prolonged aerobic steady-state exercise (SSE) intensity due to its association with physiological indicators of exercise intensity, such as oxygen uptake (VÌO2) or heart rate (HR). However, these associations between psychological and physiological indicators of exercise intensity were found during graded exercise tests (GXT) but are currently used to prescribe SSE intensity even though the transferability and validity of the relationships found during GXT to SSE were not investigated. The present study aims to verify whether (a) RPE-HR or RPE-VÌO2 relations found during GXTs are valid during SSEs, and (b) the duration and intensity of SSE affect these relations. Methods: Eight healthy and physically active males (age 22.6 ± 1.2 years) were enrolled. On the first visit, pre-exercise (during 20 min standing) and maximal (during a GXT) HR and VÌO2 values were measured. Then, on separate days, participants performed 4 SSEs on the treadmill by running at 60% and 80% of the HR reserve (HRR) for 15 and 45 min (random order). Individual linear regressions between GXTs' RPE (dependent variable) and HRR and VÌO2 reserve (VÌO2R) values (computed as the difference between maximal and pre-exercise values) were used to predict the RPE associated with %HRR (RPEHRR) and %VÌO2R (RPEVÌO2R) during the SSEs. For each relation (RPE-%HRR and RPE-%VÌO2R), a three-way factorial repeated measures ANOVA (α = 0.05) was used to assess if RPE (dependent variable) was affected by exercise modality (i.e., RPE recorded during SSE [RPESSE] or GXT-predicted), duration (i.e., 15 or 45 min), and intensity (i.e., 60% or 80% of HRR). Results: The differences between RPESSE and GXT-predicted RPE, which were assessed by evaluating the effect of modality and its interactions with SSE intensity and duration, showed no significant differences between RPESSE and RPEHRR. However, when RPESSE was compared with RPEVÌO2R, although modality or its interactions with intensity were not significant, there was a significant (p = 0.020) interaction effect of modality and duration yielding a dissociation between changes of RPESSE and RPEVÌO2R over time. Indeed, RPESSE did not change significantly (p = 0.054) from SSE of 15 min (12.1 ± 2.0) to SSE of 45 min (13.5 ± 2.1), with a mean change of 1.4 ± 1.8, whereas RPEVÌO2R decreased significantly (p = 0.022) from SSE of 15 min (13.7 ± 3.2) to SSE of 45 min (12.4 ± 2.8), with a mean change of -1.3 ± 1.5. Conclusion: The transferability of the individual relationships between RPE and physiological parameters found during GXT to SSE should not be assumed as shown by the results of this study. Therefore, future studies modelling how the exercise prescription method used (e.g., RPE, HR, or VÌO2) and SSE characteristics (e.g., exercise intensity, duration, or modality) affect the relationships between RPE and physiological parameters are warranted.
Subject(s)
Exercise Test , Exercise , Heart Rate , Oxygen Consumption , Physical Exertion , Humans , Male , Heart Rate/physiology , Physical Exertion/physiology , Oxygen Consumption/physiology , Young Adult , Exercise Test/methods , Exercise/physiology , Exercise/psychology , Adult , Perception/physiologyABSTRACT
The immunoglobulin LAMP/OBCAM/NTM (IgLON) family of cell adhesion molecules comprises five members known for their involvement in establishing neural circuit connectivity, fine-tuning, and maintenance. Mutations in IgLON genes result in alterations in these processes and can lead to neuropsychiatric disorders. The two IgLON family members NEGR1 and OPCML share common links with several of them, such as schizophrenia, autism, and major depressive disorder. However, the onset and the underlying molecular mechanisms have remained largely unresolved, hampering progress in developing therapies. NEGR1 and OPCML are evolutionarily conserved in teleosts like the zebrafish (Danio rerio), which is excellently suited for disease modelling and large-scale screening for disease-ameliorating compounds. To explore the potential applicability of zebrafish for extending our knowledge on NEGR1- and OPCML-linked disorders and to develop new therapeutic strategies, we investigated the spatio-temporal expression of the two genes during early stages of development. negr1 and opcml are expressed maternally and subsequently in partially distinct domains of conserved brain regions. Other areas of expression in zebrafish have not been reported in mammals to date. Our results indicate that NEGR1 and OPCML may play roles in neural circuit development and function at stages earlier than previously anticipated. A detailed functional analysis of the two genes based on our findings could contribute to understanding the mechanistic basis of related psychiatric disorders.
Subject(s)
Depressive Disorder, Major , Schizophrenia , Animals , Humans , Zebrafish/genetics , Zebrafish/metabolism , Cell Adhesion Molecules/genetics , Brain/metabolism , Immunoglobulins/genetics , Mammals/metabolism , GPI-Linked Proteins/metabolismABSTRACT
In the brain, cell adhesion molecules (CAMs) are critical for neurite outgrowth, axonal fasciculation, neuronal survival and migration, and synapse formation and maintenance. Among CAMs, the IgLON family comprises five members: Opioid Binding Protein/Cell Adhesion Molecule Like (OPCML or OBCAM), Limbic System Associated Membrane Protein (LSAMP), neurotrimin (NTM), Neuronal Growth Regulator 1 (NEGR1), and IgLON5. IgLONs exhibit three N-terminal C2 immunoglobulin domains; several glycosylation sites; and a glycosylphosphatidylinositol anchoring to the membrane. Interactions as homo- or heterodimers in cis and in trans, as well as binding to other molecules, appear critical for their functions. Shedding by metalloproteases generates soluble factors interacting with cellular receptors and activating signal transduction. The aim of this review was to analyse the available data implicating a role for IgLONs in neuropsychiatric disorders. Starting from the identification of a pathological role for antibodies against IgLON5 in an autoimmune neurodegenerative disease with a poorly understood mechanism of action, accumulating evidence links IgLONs to neuropsychiatric disorders, albeit with still undefined mechanisms which will require future thorough investigations.
Subject(s)
Neurodegenerative Diseases , Humans , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurons/metabolism , Cell Adhesion Molecules/metabolism , Immunoglobulins/genetics , Brain/metabolism , GPI-Linked Proteins/metabolism , Cell Adhesion Molecules, Neuronal/geneticsABSTRACT
The prompt identification of at-risk newborns for drug-induced hypoglycemia can minimize the risk for adverse side effects, inappropriate investigations, and considerable unnecessary costs. Existing literature discusses drug-induced hypoglycemia, but a systematic description of neonatal hypoglycemia induced or exacerbated by maternal medications is missing. We reviewed the association between neonatal hypoglycemia and maternal medications. We systematically searched the literature according to the PICOS model on drug-induced hypoglycemia in neonates born to nondiabetic women treated with medications during the pregnancy or the labor. The main outcomes of the review were: (1) prevalence of hypoglycemia, (2) risk factors and potential confounders, (3) time at onset and severity of hypoglycemia, (4) dose-response gradient, (5) metabolic features of hypoglycemia, (6) modalities to treat hypoglycemia, and (7) quality of the studies. We included 69 studies in this review and we identified 11 groups of maternal drugs related to neonatal hypoglycemia. Results were classified for each outcome. Our review aims at supporting clinicians in the identification of the newborn at risk for hypoglycemia and in the differential diagnosis of neonatal hypoglycemia. Further studies are necessary to assess the risk of neonatal hypoglycemia associated with common maternal medications. KEY POINTS: · A systematic description of neonatal hypoglycemia induced or exacerbated by maternal medications is missing.. · In our review we identified 11 groups of maternal drugs related to neonatal hypoglycemia.. · Our review aims at supporting clinicians in the identification of the newborn at risk for hypoglycemia..
ABSTRACT
Nucleoporins (NUPs) are proteins that comprise the nuclear pore complexes (NPCs). The NPC spans the nuclear envelope of a cell and provides a channel through which RNA and proteins move between the nucleus and the cytoplasm and vice versa. NUP and NPC disruptions have a great impact on the pathophysiology of neurodegenerative diseases (NDDs). Although the downregulation of Nup358 leads to a reduction in the scaffold protein ankyrin-G at the axon initial segment (AIS) of mature neurons, the function of Nup358 in the cytoplasm of neurons remains elusive. To investigate whether Nup358 plays any role in neuronal activity, we downregulated Nup358 in non-pathological mouse cortical neurons and measured their active and passive bioelectrical properties. We identified that Nup358 downregulation is able to produce significant modifications of cell-membrane excitability via voltage-gated sodium channel kinetics. Our findings suggest that Nup358 contributes to neuronal excitability through a functional stabilization of the electrical properties of the neuronal membrane. Hypotheses will be discussed regarding the alteration of this active regulation as putatively occurring in the pathophysiology of NDDs.
ABSTRACT
Neuroblastoma is among the most common childhood cancers. Neuroblastoma in advanced stages is one of the most intractable pediatric cancers, notwithstanding the recent therapeutic advances. ALK mutations are among the leading cause of hereditary neuroblastoma and account for more than 14% of the somatically acquired alterations. ALK kinase activity is currently one of the main targets for pharmacological strategies. However, evidence from ALK fusion-positive lung cancer studies has shown that resistance to ALK inhibition arises during the therapy, causing a relapse within several years. IgLONs are membrane-bound proteins involved in cell-to-cell adhesion. The expression of the IgLON family results altered in different cancers. We found that the IgLON member Negr1 is downregulated in neuroblastoma. The ectopic overexpression of Negr1 impairs neuroblastoma growth in vitro and in vivo. Negr1 exists as a GPI-anchored membrane-bound protein and as a soluble protein released upon metalloprotease cleavage. We generated and characterized a panel of Negr1-derived peptides. The treatment with Negr1 protein and derived peptides induce ALK downregulation and halt neuroblastoma progression in vitro and in vivo.
ABSTRACT
Background: Breast cancer (BC) is the second-leading cause of cancer-related death worldwide. This study aimed to investigate the effects of a 12-week home-based lifestyle intervention (based on nutrition and exercise) on gut microbial composition in twenty BC survivors of the MoviS clinical trial (protocol: NCT04818359). Methods: Gut microbiota analysis through 16S rRNA gene sequencing, anthropometrics, Mediterranean Diet (MD) adherence, and cardiometabolic parameters were evaluated before (Pre) and after (Post) the lifestyle intervention (LI). Results: Beneficial effects of the LI were observed on MD adherence, and cardiometabolic parameters (pre vs post). A robust reduction of Proteobacteria was observed after LI, which is able to reshape the gut microbiota by modulating microorganisms capable of decreasing inflammation and others involved in improving the lipid and glycemic assets of the host. A significant negative correlation between fasting glucose and Clostridia_vadinBB60 (r = -0.62), insulin and homeostatic model assessment (HOMA) index and Butyricicoccus genera (r = -0.72 and -0.66, respectively), and HDL cholesterol and Escherichia/Shigella (r = -0.59) have been reported. Moreover, positive correlations were found between MD adherence and Lachnospiraceae_ND3007 (r = 0.50), Faecalibacterium (r = 0.38) and Butyricimonas (r = 0.39). Conclusion: These data suggest that adopting a healthy lifestyle, may contribute to ameliorate several biological parameters that could be involved in the prevention of cancer relapses through the modulation of gut microbiota.
ABSTRACT
The initial step for the differential diagnosis of hypoglycemia is to determine whether it is hyperinsulinemic or non hyperinsulinemic. Existing literature discusses drug-related hypoglycemia, but it misses a focus on drug-induced hyperinsulinemic hypoglycemia (DHH). Here we reviewed the association existing between drugs and hyperinsulinemic hypoglycemia. We primarily selected on the main electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) the reviews on drug-induced hypoglycemia. Among the drugs listed in the reviews, we selected the ones linked to an increase in insulin secretion. For the drugs missing a clear association with insulin secretion, we investigated the putative mechanism underlying hypoglycemia referring to the original papers. Our review provides a list of the most common agents associated with hyperinsulinemic hypoglycemia (HH), in order to facilitate both the recognition and the prevention of DHH. We also collected data about the responsiveness of DHH to diazoxide or octreotide.
Subject(s)
Hyperinsulinism , Hypoglycemia , Humans , Hypoglycemia/chemically induced , Hypoglycemia/complications , Hypoglycemia/drug therapy , Hyperinsulinism/chemically induced , Hyperinsulinism/complications , Hyperinsulinism/diagnosis , Diazoxide/adverse effects , Insulin SecretionABSTRACT
Objective. Kabuki syndrome (KS) is associated with hyperinsulinemic hypoglycemia (HH) in 0.3-4% of patients, thus exceeding the prevalence in the general population. HH association is stronger for KS type 2 (KDM6A-KS, OMIM #300867) than KS type 1 (KMT2D-KS, OMIM #147920). Both the disease-associated genes, KMD6A and KMT2D, modulate the chromatin dynamic. As such, KS is considered to be the best characterized pediatric chromatinopathy. However, the exact pathogenetic mechanisms leading to HH in this syndrome remain still unclear. Methods. We selected on the electronic database PubMed all articles describing or hypothesizing the mechanisms underlying the dysregulated insulin secretion in KS. Results. The impact on the gene expression due to the KDM6A or KMT2D function loss may lead to a deregulated pancreatic ß-cell differentiation during embryogenesis. Moreover, both KMT2D gene and KDM6A gene are implicated in promoting the transcription of essential pancreatic ß-cell genes and in regulating the metabolic pathways instrumental for insulin release. Somatic KMT2D or KDM6A mutations have also been described in several tumor types, including insulinoma, and have been associated with metabolic pathways promoting pancreatic cell proliferation. Conclusions. The impact of pathogenic variants in KDM6A and KDM2D genes on ß-cell insulin release remains to be fully clarified. Understanding this phenomenon may provide valuable insight into the physiological mechanisms of insulin release and into the pathological cascade causing hyperinsulinism in KS. The identification of these molecular targets may open new therapeutic opportunities based on epigenetic modifiers.
Subject(s)
Hyperinsulinism , Hypoglycemia , Humans , Child , Mutation , Hyperinsulinism/complications , Hyperinsulinism/genetics , Histone Demethylases/genetics , Insulin , Hypoglycemia/geneticsABSTRACT
The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. A recent revision questioned the impact of high doses of coenzyme Q10 on cardiac function in patients with cardiomyopathy (CM). Liver transplantation is a therapeutic option for several patients since it may stabilize or reverse CM. Both the patients waiting for liver transplantation and, even more, the ones not eligible for transplant programs urgently need therapies to improve cardiac function. To this aim, the identification of the pathogenetic mechanisms represents a key point. Aims: This review summarizes: (1) the current knowledge of the pathogenetic mechanisms underlying cardiac complications in PA and (2) the available and potential pharmacological options for the prevention or the treatment of cardiac complications in PA. To select articles, we searched the electronic database PubMed using the Mesh terms "propionic acidemia" OR "propionate" AND "cardiomyopathy" OR "Long QT syndrome". We selected 77 studies, enlightening 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration, genetics, epigenetics, microRNAs, micronutrients deficiencies, renin-angiotensin-aldosterone system activation, and increased sympathetic activation. We provide a critical discussion of the related therapeutic options. Current literature supports the involvement of multiple cellular pathways in cardiac complications of PA, indicating the growing complexity of their pathophysiology. Elucidating the mechanisms responsible for such abnormalities is essential to identify therapeutic strategies going beyond the correction of the enzymatic defect rather than engaging the dysregulated mechanisms. Although these approaches are not expected to be resolutive, they may improve the quality of life and slow the disease progression. Available pharmacological options are limited and tested in small cohorts. Indeed, a multicenter approach is mandatory to strengthen the efficacy of therapeutic options.
ABSTRACT
A decline in muscle mass and function represents one of the most problematic changes associated with aging, and has dramatic effects on autonomy and quality of life. Several factors contribute to the inexorable process of sarcopenia, such as mitochondrial and autophagy dysfunction, and the lack of regeneration capacity of satellite cells. The physiologic decline in muscle mass and in motoneuron functionality associated with aging is exacerbated by the sedentary lifestyle that accompanies elderly people. Regular physical activity is beneficial to most people, but the elderly need well-designed and carefully administered training programs that improve muscle mass and, consequently, both functional ability and quality of life. Aging also causes alteration in the gut microbiota composition associated with sarcopenia, and some advances in research have elucidated that interventions via the gut microbiota-muscle axis have the potential to ameliorate the sarcopenic phenotype. Several mechanisms are involved in vitamin D muscle atrophy protection, as demonstrated by the decreased muscular function related to vitamin D deficiency. Malnutrition, chronic inflammation, vitamin deficiencies, and an imbalance in the muscle-gut axis are just a few of the factors that can lead to sarcopenia. Supplementing the diet with antioxidants, polyunsaturated fatty acids, vitamins, probiotics, prebiotics, proteins, kefir, and short-chain fatty acids could be potential nutritional therapies against sarcopenia. Finally, a personalized integrated strategy to counteract sarcopenia and maintain the health of skeletal muscles is suggested in this review.
Subject(s)
Sarcopenia , Humans , Sarcopenia/prevention & control , Sarcopenia/metabolism , Quality of Life , Muscle, Skeletal/metabolism , Antioxidants/metabolism , Vitamins/metabolismABSTRACT
BACKGROUND: Breast cancer (BC) is the most common invasive cancer in women, and exercise can significantly improve the outcomes of BC survivors. MoviS (Movement and Health Beyond Care) is a randomized controlled trial aimed to evaluate the potential health benefits of exercise and proper nutritional habits. This study aims to assess the efficacy of aerobic exercise training in improving quality of life (QoL) and health-related factors in high-risk BC. METHODS: One hundred seventy-two BC survivor women, aged 30-70 years, non-metastatic, stage 0-III, non-physically active, 6-12 months post-surgery, and post chemo- or radiotherapy, will be recruited in this study. Women will be randomly allocated to the intervention arm (lifestyle recommendations and MoviS Training) or control arm (lifestyle recommendations). The MoviS training consists of 12 weeks of aerobic exercise training (2 days/week of supervised and 1 day/week of unsupervised exercise) with a progressive increase in exercise intensity (40-70% of heart rate reserve) and duration (20-60 min). Both arms will receive counseling on healthy lifestyle habits (nutrition and exercise) based on the World Cancer Research Fund International (WCRF) 2018 guidelines. The primary outcome is the improvement of the QoL. The secondary outcomes are improvement of health-related parameters such as Mediterranean diet adherence, physical activity level, flexibility, muscular fitness, fatigue, cardiorespiratory fitness (estimated maximal oxygen uptake), echocardiographic parameters, heart rate variability (average of the standard deviations of all 5 min normal to normal intervals (ASDNN/5 min) and 24 h very low and low frequency), and metabolic, endocrine, and inflammatory serum biomarkers (glycemia, insulin resistance, progesterone, testosterone, and high-sensitivity C-reactive protein). DISCUSSION: This trial aims to evaluate if supervised exercise may improve QoL and health-related factors of BC survivors with a high risk of recurrence. Findings from this project could provide knowledge improvement in the field of exercise oncology through the participation of a multidisciplinary team that will provide a coordinated program of cancer care to improve healthcare quality, improve prognosis, increase survival times and QoL, and reduce the risk of BC recurrence. TRIAL REGISTRATION: ClinicalTrials.gov NCT04818359 . Retrospectively registered on March 26, 2021.
Subject(s)
Breast Neoplasms , Cancer Survivors , Female , Humans , Quality of Life , Breast Neoplasms/pathology , Neoplasm Recurrence, Local , Exercise/physiology , Survivors , Randomized Controlled Trials as TopicABSTRACT
This study aimed to assess if, during incremental exercise, considering individual characteristics can make the relationship between the percentages of heart rate (HRR) and oxygen uptake (VÌO2R) reserve either 1:1 or more accurate. Cycle ergometer data of the maximal incremental exercise tests performed by 450 healthy and sedentary participants (17-66 years) of the HERITAGE Family Study, grouped for sex, ethnicity, age, body fat, resting HR, and VÌO2max, were used to calculate the individual linear regressions between %HRR and %VÌO2R. The mean slope and intercept of the individual linear regressions of each subgroup were compared with 1 and 0 (identity line), respectively, using Hotelling tests followed by post-hoc one-sample t-tests. Two multiple linear regressions were also performed, using either the slopes or intercepts of the individual linear regressions as dependent variables and sex, age, resting HR, and VÌO2max as independent variables. The mean %HRR-%VÌO2R relationships of all subgroups differed from the identity line. Moreover, individual linear regression intercepts (8.9 ± 16.0) and slopes (0.971 ± 0.190) changed (p < 0.001) after 20 weeks of aerobic training (13.1 ± 11.1 and 0.891 ± 0.122). The multiple linear regressions could explain only 3.8% and 1.3% of the variance in the intercepts and slopes, whose variability remained high (standard error of estimate of 15.8 and 0.189). In conclusion, the %HRR-%VÌO2R relationship differs from the identity line regardless of individual characteristics and their difference increased after aerobic training. Moreover, due to the high interindividual variability, using a single equation for the whole population seems not suitable for representing the %HRR-%VÌO2R relationship of a given subject, even when several individual characteristics are considered.HighlightsThe association between %HRR and %VÌO2R is not 1:1 even when individuals are grouped by age, sex, ethnicity, body composition, HRrest, and VÌO2max.Using several subject characteristics to identify the individual's %HRR-%VÌO2R relationship does not meaningfully increase its prediction accuracy or reduce the interindividual variability of %HRR-%VÌO2R relationshipsUsing a single equation for the whole population is not suitable for representing the relationship of a given subject; hence, individual relationships should be preferred when prescribing the intensity of aerobic exercise.The individual %HRR-%VÌO2R relationship should be periodically assessed due to the potential training induced changes in the relationship.
Subject(s)
Exercise , Oxygen Consumption , Humans , Oxygen Consumption/physiology , Heart Rate/physiology , Exercise/physiology , Exercise Test , ErgometryABSTRACT
The Excitatory Amino Acid Transporter 2 (EAAT2) accounts for 80% of brain glutamate clearance and is mainly expressed in astrocytic perisynaptic processes. EAAT2 function is finely regulated by endocytic events, recycling to the plasma membrane and degradation. Noteworthy, deficits in EAAT2 have been associated with neuronal excitotoxicity and neurodegeneration. In this study, we show that EAAT2 trafficking is impaired by the leucine-rich repeat kinase 2 (LRRK2) pathogenic variant G2019S, a common cause of late-onset familial Parkinson's disease (PD). In LRRK2 G2019S human brains and experimental animal models, EAAT2 protein levels are significantly decreased, which is associated with elevated gliosis. The decreased expression of the transporter correlates with its reduced functionality in mouse LRRK2 G2019S purified astrocytic terminals and in Xenopus laevis oocytes expressing human LRRK2 G2019S. In LRRK2 G2019S knock-in mouse brain, the correct surface localization of the endogenous transporter is impaired, resulting in its interaction with a plethora of endo-vesicular proteins. Mechanistically, we report that pathogenic LRRK2 kinase activity delays the recycling of the transporter to the plasma membrane via Rabs inactivation, causing its intracellular re-localization and degradation. Taken together, our results demonstrate that pathogenic LRRK2 interferes with the physiology of EAAT2, pointing to extracellular glutamate overload as a possible contributor to neurodegeneration in PD.
Subject(s)
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Parkinson Disease , Amino Acid Transport System X-AG , Animals , Glutamates , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics , Mice , Mutation , Neurons/pathology , Parkinson Disease/pathologyABSTRACT
Background: The percentages of heart rate (%HRR) or oxygen uptake (%VÌO2R) reserve are used interchangeably for prescribing aerobic exercise intensity due to their assumed 1:1 relationship, although its validity is debated. This study aimed to assess if %HRR and %VÌO2R show a 1:1 relationship during steady-state exercise (SSE) and if exercise intensity and duration affect their relationship. Methods: Eight physically active males (age 22.6 ± 1.2 years) were enrolled. Pre-exercise and maximal HR and VÌO2 were assessed on the first day. In the following 4 days, different SSEs were performed (running) combining the following randomly assigned durations and intensities: 15 min, 45 min, 60% HRR, 80% HRR. Post-exercise maximal HR and VÌO2 were assessed after each SSE. Using pre-exercise and post-exercise maximal values, the average HR and VÌO2 of the last 5 min of each SSE were converted into percentages of the reserves (%RES), which were computed in a 3-way RM-ANOVA (α = 0.05) to assess if they were affected by the prescription parameter (HRR or VÌO2R), exercise intensity (60% or 80% HRR), and duration (15 or 45 min). Results: The %RES values were not affected by the prescription parameter (p = 0.056) or its interactions with intensity (p = 0.319) or duration and intensity (p = 0.117), while parameter and duration interaction was significant (p = 0.009). %HRRs and %VÌO2Rs did not differ in the 15-min SSEs (mean difference [MD] = 0.7 percentage points, p = 0.717), whereas %HRR was higher than %VÌO2R in the 45-min SSEs (MD = 6.7 percentage points, p = 0.009). Conclusion: SSE duration affects the %HRR-%VÌO2R relationship, with %HRRs higher than %VÌO2Rs in SSEs of longer duration.
Subject(s)
Exercise Test , Oxygen Consumption , Male , Humans , Young Adult , Adult , Heart Rate/physiology , Oxygen Consumption/physiology , Exercise/physiology , OxygenABSTRACT
The disaccharide trehalose is a well-established autophagy inducer, but its therapeutic application is severely hampered by its low potency and poor pharmacokinetic profile. Thus, we targeted the rational design and synthesis of trehalose-based small molecules and nano objects to overcome such issues. Among several rationally designed trehalose-centered putative autophagy inducers, we coupled trehalose via suitable spacers with known self-assembly inducer squalene to yield two nanolipid-trehalose conjugates. Squalene is known for its propensity, once linked to a bioactive compound, to assemble in aqueous media in controlled conditions, internalizing its payload and forming nanoassemblies with better pharmacokinetics. We assembled squalene conjugates to produce the corresponding nanoassemblies, characterized by a hydrodynamic diameter of 188 and 184 nm and a high stability in aqueous media as demonstrated by the measured Z-potential. Moreover, the nanoassemblies were characterized for their toxicity and capability to induce autophagy in vitro.
ABSTRACT
Major depressive disorder (MDD) is a common mental illness. Evidence suggests that the gut microbiota play an essential role in regulating brain functions and the pathogenesis of neuropsychiatric diseases, including MDD. There are numerous mechanisms through which the gut microbiota and brain can exchange information in a continuous, bidirectional communication. Current research emphasizes the interexchange of signals influenced by the gut microbiota that are detected and transduced in information from the gut to the nervous system involving neural, endocrine, and inflammatory mechanisms, suggesting a relationship between oxidative stress and the pathophysiology of MDD via the hyperactivation of inflammatory responses. Potential sources of inflammation in the plasma and hippocampus of depressed individuals could stem from increases in intestinal permeability. Some nutraceuticals, such as specific probiotics, namely psychobiotics, polyphenols, carotenoids, butyrate, and prebiotics, have been demonstrated to exert an antidepressant activity, but most of them need to be metabolized and activated by gut microorganisms. By inducing changes in the gut microbiota composition, physical exercise might also exert a role in alleviating depression-like symptoms. The mutual relationships among nutraceuticals, exercise, and depression will be discussed, and the potential role of the gut microbiota as a therapeutic target to treat depression will be explored.