Search Results (5)

The intestinal microbiota and its metabolites are essential for the health and growth development of animals. Current research indicates that sex has a certain impact on the structure and function of the intestinal microbiota, but there are few reports on sex differences in intestinal microbiota metabolites, including those of castrated male animals. This study aimed to explore the impact of sex on the intestinal microbial metabolites of Hainan special wild boars (10 entire male pigs, 10 female pigs, and 10 castrated male pigs, denoted EM, FE, and CM, respectively) by employing non-targeted metabolomics and gas chromatography. A total of 1086 metabolites were detected, with the greatest number of differential metabolites observed between EM and FE (54 differential metabolites, including 18 upregulated and 36 downregulated metabolites), the fewest between CM and FE (7 differential metabolites, including 1 upregulated and 6 downregulated metabolites), and an intermediate number between CM and EM (47 differential metabolites, including 35 upregulated and 12 downregulated metabolites). Differential metabolites were involved in more pathways between EM and FE and between CM and EM, including amino acid metabolism and digestive system pathways, whereas differential metabolites were involved in the fewest pathways between CM and FE. Correlation analysis showed Ruminococcaceae UCG-009, uncultured_bacterium_o_SAR324_cladeMarine_group_B, and Candidatus Saccharimonas contributed to the production of metabolites such as trehalose, docosatrienoic acid, D(−)-beta-hydroxy butyric acid, and acetyl-DL-leucine. The levels of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid were significantly higher in EM than in FE, with CM falling between the two. Streptococcus, Lachnospiraceae_NK4A136_group and Rikenellaceae_RC9_gut_group showed a significant positive correlation with the production of short-chain fatty acids (SCFAs), while [Eubacterium]_coprostanoligenes_group, uncultured_bacterium_f_p–251–o5 and Ruminococcaceae_UCG–005 showed a significant negative correlation with the generation of SCFAs. This study provides foundational data and significant insights into precision feeding strategies for Hainan special wild boars of different sexes, as well as the study of sex differences in intestinal microbial metabolites in animals. Full article

A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic ataxias summarized by disease, highlighting novel clinical trials and emerging therapies with a particular emphasis on first-in-human gene therapies. We present disease-specific treatments if they exist and review the current evidence for symptomatic treatments of these highly heterogeneous diseases (where cerebellar ataxia is part of their phenotype) that aim to improve the disease burden and enhance quality of life. In general, a multimodal and holistic approach to the treatment of cerebellar ataxia, irrespective of etiology, is necessary to offer the best medical care. Physical therapy and speech and occupational therapy are obligatory. Genetic counseling is essential for making informed decisions about family planning. Full article

We have previously reported in a feline model of acute peripheral vestibulopathy (APV) that the sudden, unilateral, and irreversible loss of vestibular inputs induces selective overexpression of small conductance calcium-activated potassium (SK) channels in the brain stem vestibular nuclei. Pharmacological blockade of these ion channels by the selective antagonist apamin significantly alleviated the evoked vestibular syndrome and accelerated vestibular compensation. In this follow-up study, we aimed at testing, using a behavioral approach, whether the antivertigo (AV) effect resulting from the antagonization of SK channels was species-dependent or whether it could be reproduced in a rodent APV model, whether other SK channel antagonists reproduced similar functional effects on the vestibular syndrome expression, and whether administration of SK agonist could also alter the vestibular syndrome. We also compared the AV effects of apamin and acetyl-DL-leucine, a reference AV compound used in human clinic. We demonstrate that the AV effect of apamin is also found in a rodent model of APV. Other SK antagonists also produce a trend of AV effect when administrated during the acute phase of the vertigo syndrome. Conversely, the vertigo syndrome is worsened upon administration of SK channel agonist. It is noteworthy that the AV effect of apamin is superior to that of acetyl-DL-leucine. Taken together, these data reinforce SK channels as a pharmacological target for modulating the manifestation of the vertigo syndrome during APV. Full article

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a multisystem hereditary ataxia associated with mutations in SACS, which encodes sacsin, a protein of still only partially understood function. Although mouse models of ARSACS mimic largely the disease progression seen in humans, their use in the validation of effective therapies has not yet been proposed. Recently, the teleost Danio rerio has attracted increasing attention as a vertebrate model that allows rapid and economical screening, of candidate molecules, and thus combines the advantages of whole-organism phenotypic assays and in vitro high-throughput screening assays. Through CRISPR/Cas9-based mutagenesis, we generated and characterized a zebrafish sacs-null mutant line that replicates the main features of ARSACS. The sacs-null fish showed motor impairment, hindbrain atrophy, mitochondrial dysfunction, and reactive oxygen species accumulation. As proof of principle for using these mutant fish in high-throughput screening studies, we showed that both acetyl-DL-leucine and tauroursodeoxycholic acid improved locomotor and biochemical phenotypes in sacs^−/− larvae treated with these neuroprotective agents, by mediating significant rescue of the molecular functions altered by sacsin loss. Taken together, the evidence here reported shows the zebrafish to be a valuable model organism for the identification of novel molecular mechanisms and for efficient and rapid in vivo optimization and screening of potential therapeutic compounds. These findings may pave the way for new interventions targeting the earliest phases of Purkinje cell degeneration in ARSACS. Full article

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb^-/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL. Full article