Background New noninvasive and affordable molecular approaches that will complement current practices and increase the accuracy of Parkinson's disease (PD) diagnosis are urgently needed. Circular RNAs (circRNAs) are stable noncoding RNAs that accumulate with aging in neurons and are increasingly shown to regulate all aspects of neuronal development and function. Objectives Τhe aims of this study were to identify differentially expressed circRNAs in blood mononuclear cells of patients with idiopathic PD and explore the competing endogenous RNA networks affected. Methods Eighty‐seven circRNAs were initially selected based on relatively high gene expression in the human brain. More than half of these were readily detectable in blood mononuclear cells using real‐time reverse transcription‐polymerase chain reaction. Comparative expression analysis was then performed in blood mononuclear cells from 60 control subjects and 60 idiopathic subjects with PD. Results Six circRNAs were significantly down‐regulated in patients with PD. The classifier that best distinguished PD consisted of four circRNAs with an area under the curve of 0.84. Cross‐linking immunoprecipitation‐sequencing data revealed that the RNA‐binding proteins bound by most of the deregulated circRNAs include the neurodegeneration‐associated FUS, TDP43, FMR1, and ATXN2. MicroRNAs predicted to be sequestered by most deregulated circRNAs have the Gene Ontology categories “protein modification” and “transcription factor activity” mostly enriched. Conclusions This is the first study that identifies specific circRNAs that may serve as diagnostic biomarkers for PD. Because they are highly expressed in the brain and are derived from genes with essential brain functions, they may also hint on the PD pathways affected. © 2021 Biomedical Research Foundation, Academy of Athens. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Total number of figures: 6 Supporting files: 1 (containing 3 figures) DECLARATIONS AVAILABILITY OF DATA AND MATERIALSThe data that support the findings of this study are available from the corresponding author upon reasonable request.
Background Post-stroke functional recovery is severely impaired by type 2 diabetes (T2D). This is an important clinical problem since T2D is one of the most common diseases. Because weight loss-based strategies have been shown to decrease stroke risk in people with T2D, we aimed to investigate whether diet-induced weight loss can also improve post-stroke functional recovery and identify some of the underlying mechanisms. Methods T2D/obesity was induced by 6 months of high-fat diet (HFD). Weight loss was achieved by a short- or long-term dietary change, replacing HFD with standard diet for 2 or 4 months, respectively. Stroke was induced by middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Mechanisms involved in neurovascular damage in the post-stroke recovery phase, i.e. neuroinflammation, impaired angiogenesis and cellular atrophy of GABAergic parvalbumin (PV)+ interneurons were assessed by immunohistochemistry/quantitative microscopy. Results Both short- and long-term dietary change led to similar weight loss. However, only the latter enhanced functional recovery after stroke. This effect was associated with pre-stroke normalization of fasting glucose and insulin resistance, and with the reduction of T2D-induced cellular atrophy of PV+ interneurons. Moreover, stroke recovery was associated with decreased T2D-induced neuroinflammation and reduced astrocyte reactivity in the contralateral striatum. Conclusion The global diabetes epidemic will dramatically increase the number of people in need of post-stroke treatment and care. Our results suggest that diet-induced weight loss leading to pre-stroke normalization of glucose metabolism has great potential to reduce the sequelae of stroke in the diabetic population.
BackgroundNew noninvasive and affordable molecular approaches that will complement current practices and increase the accuracy of PD diagnosis are urgently needed. CircRNAs are highly stable non-coding RNAs that accumulate with aging in neurons and are increasingly shown to regulate all aspects of neuronal development and function.ObjectivesThe aims of the present study were to identify differentially expressed circRNAs in PBMCs of idiopathic PD patients and explore the competing endogenous RNA networks affected.MethodsEighty-seven circRNAs were initially selected based on relatively high gene expression in the human brain. Over half of these were readily detectable in PBMCs using RT-qPCR. Comparative expression analysis was then performed in PBMCs from sixty controls and sixty idiopathic subjects with PD.ResultsSix circRNAs derived from MAPK9, HOMER1, SLAIN1, DOP1B, REPS1, and PSEN1 transcripts were significantly downregulated in PD patients. The classifier that best distinguished PD consisted of four circRNAs with an AUC of 0.84. CLIP-Seq data revealed that the RNA binding proteins bound by most of the deregulated circRNAs include the neurodegeneration-associated FUS, TDP43, FMR1 and ATXN2. MicroRNAs predicted to be sequestered by most deregulated circRNAs had the GOslim categories ‘Protein modification’, ‘Transcription factor activity’ and ‘Cytoskeletal protein binding’ mostly enriched.ConclusionsThis is the first study that identifies circRNAs deregulated in the peripheral blood of PD patients. They may serve as diagnostic biomarkers and since they are highly expressed in the brain and are derived from genes with essential brain functions, they may also hint on the PD pathways affected.
Background Glucagon-like peptide-1 receptor (GLP-1R) activation can decrease stroke risk in people with type 2 diabetes (T2D). Moreover, animal studies have shown the efficacy of GLP-1R agonists to counteract stroke-induced acute brain damage. Whether GLP-1R activation can also improve stroke recovery during the post-acute, chronic phase after stroke, however, remains to be determined. We investigated whether post-acute, chronic administration of the GLP-1R agonist Exendin-4 improves poststroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice. Methods We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered daily for 8 weeks from day 3 after tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests, while insulin sensitivity and glycemia were evaluated at 4 and 8 weeks after tMCAO. Neuronal cell death, stroke-induced neurogenesis, neuroinflammation, potential atrophy of GABAergic, parvalbumin + interneurons, poststroke vascular remodeling and fibrotic scar formation were investigated by immunohistochemistry. Results Exendin-4 entirely normalized the T2D-induced impairment of forepaw grip strength recovery. The recovery correlated with the normalization of glycemia and insulin sensitivity. We also show that Exendin-4 counteracted the T2D-induced atrophy of parvalbumin + interneurons and decreased microglia activation. In addition, Exendin-4 normalized density and pericyte coverage of microvessels and restored fibrotic scar formation in T2D mice. In non-T2D mice the recovery effect of Exendin-4 was minor. Conclusion This study demonstrates that post-acute, chronic GLP-1R activation mediates neurological recovery after stroke in T2D mice likely through the normalization of glucose metabolism and neuroplasticity mechanisms as well as improved vascular remodeling in the recovery phase. The results promote launching clinical trials investigating whether GLP-1R agonists improve the efficacy of rehabilitation after stroke in people with T2D.
<p>Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). While accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. </p> <p>Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitors (DPP-4i) linagliptin and the sulfonylurea glimepiride, restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before the sacrifice. </p> <p>We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalised T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial-vascular interaction, and increased collagen IV density. </p> <p>This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage which may contribute to the antidiabetic neurorestorative effects. </p>
<p>Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). While accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. </p> <p>Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitors (DPP-4i) linagliptin and the sulfonylurea glimepiride, restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before the sacrifice. </p> <p>We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalised T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial-vascular interaction, and increased collagen IV density. </p> <p>This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage which may contribute to the antidiabetic neurorestorative effects. </p>
Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). While accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitors (DPP-4i) linagliptin and the sulfonylurea glimepiride, restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before the sacrifice. We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalised T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial-vascular interaction, and increased collagen IV density. This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage which may contribute to the antidiabetic neurorestorative effects.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.