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- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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- Chen, Y, et al.
(författare)
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miR-124/VAMP3 is a novel therapeutic target for mitigation of surgical trauma-induced microglial activation
- 2019
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Ingår i: Signal transduction and targeted therapy. - : Springer Science and Business Media LLC. - 2059-3635. ; 4, s. 27-
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Tidskriftsartikel (refereegranskat)abstract
- Activation of microglia and the subsequently elevated inflammatory cytokine release in the brain during surgery predispose individuals to cognitive dysfunction, also known as postoperative cognitive dysfunction (POCD). miR-124 is one of the most abundant microRNAs in the brain that regulates microglial function. Elucidating the role of miR-124 in microglial activation in the context of surgery may therefore promote understanding of as well as therapeutic development for post-surgical disorders involving microglial activation. The downstream targets of miR-124 were investigated using bioinformatic screening and dual-luciferase reporter assay validation, and vesicle-associated membrane protein 3 (VAMP3) was identified as a potential target. The kinetics of miR-124/VAMP3 expression was first examined in vitro in microglial cells (primary microglia and BV2 microglial cells) following lipopolysaccharide (LPS) stimulation. LPS induced a time-dependent decrease of miR-124 and upregulated the expression of VAMP3. Manipulating miR-124/VAMP3 expression by using miR-124 mimics or VAMP3-specific siRNA in LPS-stimulated BV2 microglial cells inhibited BV2 microglial activation-associated inflammatory cytokine release. To further examine the role of miR-124/VAMP3 in a surgical setting, we employed a rat surgical trauma model. Significant microglial activation and altered miR-124/VAMP3 expression were observed following surgical trauma. We also altered miR-124/VAMP3 expression in the rat surgical trauma model by administration of exogenous miR-124 and by using electroacupuncture, which is a clinically applicable treatment that modulates microglial function and minimizes postoperative disorders. We determined that electroacupuncture treatment specifically increases the expression of miR-124 in the hypothalamus and hippocampus. Increased miR-124 expression with a concomitant decrease in VAMP3 expression resulted in decreased inflammatory cytokine release related to microglial activation post-surgery. Our study indicates that miR-124/VAMP3 is involved in surgery-induced microglial activation and that targeting miR-124/VAMP3 could be a potential therapeutic strategy for postoperative disorders involving microglial activation.
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- Kuo, TT, et al.
(författare)
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PT320, a Sustained-Release GLP-1 Receptor Agonist, Ameliorates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease
- 2023
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 24:5
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Tidskriftsartikel (refereegranskat)abstract
- To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson’s disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks. The late treatment group was given L-DOPA starting at 28 weeks of age and longitudinally observed up to 29 weeks. To explore dopaminergic transmission, fast scan cyclic voltammetry (FSCV) was utilized to measure presynaptic dopamine (DA) dynamics in striatal slices following drug treatments. Early administration of PT320 significantly mitigated the severity L-DOPA-induced abnormal involuntary movements; PT320 particularly improved excessive numbers of standing as well as abnormal paw movements, while it did not affect L-DOPA-induced locomotor hyperactivity. In contrast, late administration of PT320 did not attenuate any L-DOPA-induced dyskinesia measurements. Moreover, early treatment with PT320 was shown to not only increase tonic and phasic release of DA in striatal slices in L-DOPA-naïve MitoPark mice, but also in L-DOPA-primed animals. Early treatment with PT320 ameliorated L-DOPA-induced dyskinesia in MitoPark mice, which may be related to the progressive level of DA denervation in PD.
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- Muehlenbein, MP, et al.
(författare)
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Traveller exposures to animals: a GeoSentinel analysis
- 2020
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Ingår i: Journal of travel medicine. - : Oxford University Press (OUP). - 1708-8305 .- 1195-1982. ; 27:7
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundHuman coexistence with other animals can result in both intentional and unintentional contact with a variety of mammalian and non-mammalian species. International travellers are at risk for such encounters; travellers risk injury, infection and possibly death from domestic and wild animal bites, scratches, licks and other exposures. The aim of the present analysis was to understand the diversity and distribution of animal-related exposures among international travellers.MethodsData from January 2007 through December 2018 from the GeoSentinel Surveillance Network were reviewed. Records were included if the exposure was non-migration travel with a diagnosis of an animal (dog, cat, monkey, snake or other) bite or other exposure (non-bite); records were excluded if the region of exposure was not ascertainable or if another, unrelated acute diagnosis was reported.ResultsA total of 6470 animal exposures (bite or non-bite) were included. The majority (71%) occurred in Asia. Travellers to 167 countries had at least one report of an animal bite or non-bite exposure. The majority (76%) involved dogs, monkeys and cats, although a wide range of wild and domestic species were involved. Almost two-thirds (62.6%) of 4395 travellers with information available did not report a pretravel consultation with a healthcare provider.ConclusionsMinimizing bites and other animal exposures requires education (particularly during pretravel consultations) and behavioral modification. These should be supplemented by the use of pre-exposure rabies vaccination for travellers to high-risk countries (especially to those with limited access to rabies immunoglobulin), as well as encouragement of timely (in-country) post-exposure prophylaxis for rabies and Macacine alphaherpesvirus 1 (herpesvirus B) when warranted.
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