Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders.
Polyglutamine (polyQ) diseases are incurable neurological disorders caused by CAG repeat expansion in the open reading frames (ORFs) of specific genes. This type of mutation in the HTT gene is responsible for Huntington’s disease (HD). CAG repeat-targeting artificial miRNAs (art-miRNAs) were shown as attractive therapeutic approach for polyQ disorders as they caused allele-selective decrease in the level of mutant proteins. Here, using polyQ disease models, we aimed to demonstrate how miRNA-based gene expression regulation is dependent on target sequence features. We show that the silencing efficiency and selectivity of art-miRNAs is influenced by the localization of the CAG repeat tract within transcript and the specific sequence context. Furthermore, we aimed to reveal the events leading to downregulation of mutant polyQ proteins and found very rapid activation of translational repression and HTT transcript deadenylation. Slicer-activity of AGO2 was dispensable in this process, as determined in AGO2 knockout cells generated with CRISPR-Cas9 technology. We also showed highly allele-selective downregulation of huntingtin in human HD neural progenitors (NPs). Taken together, art-miRNA activity may serve as a model of the cooperative activity and targeting of ORF regions by endogenous miRNAs.
Background Cystic endometrial hyperplasia-pyometra complex (CEH-P) is one of the most common uteropathies in bitches. In diseases with mild or obscure clinical signs and normal uterine size, a diagnosis based on a clinical assessment might be incorrect. The main aim of the research was to determine the morphological variables accompanying uterine diseases in bitches in microscopic evaluation. Consequently, the obtained results can be used to create a new classification system for uterine pathological changes during the development of the CEH-P, diagnosed by microscopic examination in bitches. Material for the study consisted of the uteri of 120 female dogs, aged 1–16 years, obtained during routine ovariohysterectomies. Macroscopic observation after a longitudinal incision of the uterine horns, allowed a preliminary classification of the uteri into research groups: control group (physiological uteri), and groups GI-III uteri collected form bitches with varying degrees of endometrial pathology. These preliminary classifications were then verified by histological analysis (H&E stain). Results The obtained results made it possible to determine and describe the prevalence (%) of pathological changes characteristic of the analyzed uterine diseases in the examined bitches. Histopathological analyses that were conducted have confirmed preliminary macroscopic evaluation for the control group, group GII (CEH), and group GIII (pyometra). In the uteri of the GI group, a severe congestion of the endometrium has been observed – this is typical of inflammation – which was not confirmed during histopathological examinations. However, these examinations revealed acute endometrial haemorrhage of varying severity. Conclusions Early reproduction disorders in bitches are, in general, not confirmed by clinical signs in the examined animals. The results show that during classification of typical morphological changes in the endometrium over the development of the CEH-P complex in bitches microscopic examinations are required. The obtained results indicate a frequent lack of consistency in the macroscopic assessment and histological analysis of the endometrium, observed in the analyzed uterine diseases, which in most cases is not followed by clinical symptoms. The presented classification of uterine diseases may be useful as a diagnostic tool in reproductive disorders in bitches and in examination in the field of basic research.
Background The aim of the analysis was to designate the morphological symptoms that appear during the Cystic Endometrial Hyperplasia - Pyometra complex (CEH-P), diagnosed by microscopic examination. The investigation were conducted on the uteri of 120 bitches in age between 1–16. The microscopic examinations were based on histological stainings. The aim of examinations was to find the differences in morphology of endometrium in the specimens of the uteri wall (H&E stain). All of the uteri were divided into three pathological groups (GI – GIII), created on the basis of clinically symptoms of analyzed diseases. Uteri without symptoms were classified as a control group (C).Results Histopathological analysis that were conducted have confirmed preliminary macroscopic evaluation for control group with unchanged uteri, group GII with cystic endometrial hyperplasia of uteri (CEH), and group GIII with uteri with pyometra. The confirmation of compatibility of both macroscopic and microscopic evaluation of the uteri were observed in groups GII and GIII. In the uteri of the group GI a severe congestion of endometrium have been observed – it is typical for the inflammation – which was not confirmed during histopathological examinations. Those examinations revealed only endometrial haemorrhage.Conclusions The results are showing that during classification of research material microscopic examinations are required. The diagnose based on the macroscopic changes in typical for CEH-P symptoms might be incorrect, if it is not supported by detailed research. More than that, in all uteri with the closed pyometra the CEH was also observed. It suggest that pyometra may occur as a consequence of cystic endometrial hyperplasia and bacterial infections ended with inflammation. The results obtained can be used to create a basis for pathologic classification of endometrial hyperplasia, including CEH-P complex in bitches.
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