ABSTRACT
Parkinson's disease (PD) is a common disorder attributed to the loss of midbrain dopamine (mDA) neurons and reduced dopamine secretion. Currently, the treatment regimes for PD comprise deep brain stimulations, however, it attenuates the PD progression marginally and does not improve neuronal cell death. We investigated the function of Ginkgolide A (GA) to reinforce Wharton's Jelly-derived mesenchymal stem cells (WJMSCs) for treating the in vitro model of PD. GA enhanced the self-renewal, proliferation, and cell homing function of WJMSCs as assessed by MTT and transwell co-culture assay with a neuroblastoma cell line. GA pre-treated WJMSCs can restore 6-hydroxydopamine (6-OHDA)-induced cell death in a co-culture assay. Furthermore, exosomes isolated from GA pre-treated WJMSCs significantly rescued 6-OHDA-induced cell death as determined by MTT assay, flow cytometry, and TUNEL assay. Western blotting showed that apoptosis-related proteins were decreased following GA-WJMSCs exosomal treatment which further improved mitochondrial dysfunction. We further demonstrated that exosomes isolated from GA-WJMSCs could restore autophagy using immunofluorescence staining and immunoblotting assay. Finally, we used the alpha-synuclein recombinant protein and found that exosomes derived from GA-WJMSCs led to the reduced aggregation of alpha-synuclein compared to that in control. Our results suggested that GA could be a potential candidate for strengthening stem cell and exosome therapy for PD.
Subject(s)
Exosomes , Mesenchymal Stem Cells , Neuroprotective Agents , Parkinson Disease , Humans , Oxidopamine/toxicity , alpha-Synuclein/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Dopamine/metabolism , Mesenchymal Stem Cells/metabolismABSTRACT
Diabetes-related brain complications have been reported in clinical patients and experimental models. The objective of the present study was to investigate the neuroprotective mechanisms of Lactobacillus reuteri GMNL-263 in streptozotocin (STZ)-induced diabetic rats. In this study, three different groups, namely control group, STZ-induced (55 mg/kg streptozotocin intraperitoneally) diabetic rats (DM), and DM rats treated with Lactobacillus reuteri GMNL-263 (1 × 109 CFU/rat/day), were utilized to study the protective effect of GMNL-263 in the hippocampus of STZ-induced diabetic rats. The results demonstrated that GMNL-263 attenuated diabetes-induced hippocampal damage by enhancing the cell survival pathways and repressing both inflammatory and apoptotic pathways. Histopathological analysis revealed that GMNL-263 prevented structural changes in the hippocampus in the DM group and decreased the level of inflammation and apoptosis in the hippocampus of DM rats. The IGF1R cell survival signaling pathway also improved after GMNL-263 treatment. These results indicate that probiotic GMNL-263 exerts beneficial effects in the brain of diabetic rats and has potential ability for clinical application.
Subject(s)
Diabetes Mellitus, Experimental , Limosilactobacillus reuteri , Neuroprotective Agents , Probiotics , Rats , Animals , Neuroprotective Agents/pharmacology , Streptozocin/adverse effects , Streptozocin/metabolism , HippocampusABSTRACT
To date, few studies have investigated the toxicological effects of the combined use of amphetamine and heroin in the heart. Hence, the aim of this study was to identify indicators for clinical evaluation and prevention of cardiac injury induced by the combined use of amphetamine and heroin. Four different groups were analyzed: (1) normal group (nï¼25ï¼average ageï¼35 ± 6.8); (2) heart disease group (nï¼25ï¼average ageï¼58 ± 17.2); (3) drug abusers (n = 27; average age = 37 ± 7.7); (4) drug abstainers (previous amphetamine-heroin users who had been drug-free for more than two weeks; n = 22; average age = 35 ± 5.6). The activity of MMPs, and levels of TNF-α, IL-6, GH, IGF-I, and several serum biomarkers were examined to evaluate the impact of drug abuse on the heart. The selected plasma biomarkers and classic cardiac biomarkers were significantly increased compared to the normal group. The zymography data showed the changes in cardiac-remodeling enzymes MMP-9 and MMP-2 among combined users of amphetamine and heroin. The levels of TNF-α and IL-6 only increased in the heart disease group. Growth hormone was increased; however, IGF-I level decreased with drug abuse and the level was not restored by abstinence. We speculated that the amphetamine-heroin users might pose risk to initiate heart disease even though the users abstained for more than two weeks. The activity change of MMP-9 and MMP-2 can be a direct reason affecting heart function. The indirect reason may be related to liver damage by drug abuse reduce IGF-1 production to protect heart function.
Subject(s)
Heart Diseases , Heart Injuries , Heroin Dependence , Humans , Adult , Middle Aged , Aged , Insulin-Like Growth Factor I , Matrix Metalloproteinase 2 , Matrix Metalloproteinase 9 , Heroin , Heroin Dependence/complications , Interleukin-6 , Tumor Necrosis Factor-alpha , Amphetamine , BiomarkersABSTRACT
Some clinical studies have indicated the patients with Alzheimer's disease (AD) display an increased risk of cardiovascular disease (CVD). Here, to examine the relationship between AD and CVDs, we investigated the changes in heart function in triple-transgenic late-stage AD model mice (3× Tg-AD; APPSwe, PS1M146V, and tauP301L). We fed the AD mice folic acid (FA) or folinic acid (FN) and analyzed the protective effects of the compounds on the heart; specifically, 20-month-old triple-transgenic AD mice, weighing 34-55 g, were randomly allocated into three groups-the AD, AD + FA, and AD + FN groups-and subject to gastric feeding with FA or FN once daily at 12 mg/kg body weight (BW) for 3 months. Mouse BWs were assessed throughout the trial, at the end of which the animals were sacrificed using carbon dioxide suffocation. We found that BW, whole-heart weight, and left-ventricle weight were reduced in the AD + FA and AD + FN groups as compared with the measurements in the AD group. Furthermore, western blotting of excised heart tissue revealed that the levels of the hypertrophy-related protein markers phospho(p)-p38 and p-c-Jun were markedly decreased in the AD + FA group, whereas p-GATA4, and ANP were strongly reduced in the AD + FN group. Moreover, the fibrosis-related proteins uPA, MMP-2, MEK1/2 and SP-1 were decreased in the heart in both AD + FN group. In summary, our results indicate that FA and FN can exert anti-cardiac hypertrophy and fibrosis effects to protect the heart in aged triple-transgenic AD model mice, particular in FN.
Subject(s)
Alzheimer Disease , Aged , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Animals , Cardiomegaly , Disease Models, Animal , Fibrosis , Folic Acid/pharmacology , Folic Acid/therapeutic use , Humans , Leucovorin , Mice , Mice, TransgenicABSTRACT
Ageing is a complex biological process that increases the probability of disease and death, which affects the organs of all species. The accumulation of oxidative damage in the brain contributes to a progressive loss of cognitive functions or even declined the energy metabolism. In this study, we tested the effects of exercise training on the apoptosis, survival, and antioxidant signaling pathways in the cerebral cortex of three age groups of male rats; 3, 12, and 18 months. We observed that H2S and the expression of Nrf2-related antioxidant pathways declined with age and increased after exercise training. IGF1R survival pathway was less increased in middle-aged rats; however, significantly increased after exercise training. The expression of mitochondrial-dependent apoptotic pathway components, such as Bak, cytochrome C, and caspase 3 in the ageing control group, were much higher than those of the exercise training groups. This study demonstrated that exercise training could reduce the apoptosis and oxidative stress that accrues throughout ageing, which causes brain damage.
Subject(s)
Antioxidants , NF-E2-Related Factor 2 , Aging , Animals , Apoptosis , Cerebral Cortex/metabolism , Male , NF-E2-Related Factor 2/metabolism , RatsABSTRACT
INTRODUCTION: Indigenous communities in Taiwan shoulder a disproportionate burden of unintentional injury fatalities. We compare unintentional injury mortality rate trends among Taiwan's indigenous communities and the general population from 2002 to 2013, and evaluate potential impact of a community-based injury prevention programme on indigenous unintentional injury death rates. METHODS: Standardised and crude unintentional injury mortality rates were obtained from Taiwan government reports. Segmented linear regression was used to estimate and compare unintentional injury mortality rate trends before and after the intervention. RESULTS: Between 2002 and 2013, unintentional injury mortality rates among Taiwan's indigenous population significantly declined by about 4.5 deaths per 100 000 each year (p<0.0001). During that time, the unintentional injury mortality rate ratio between indigenous Taiwanese and the general population significantly decreased by approximately 1% each successive year (p=0.02). However, we were unable to detect evidence that the 'Healthy and Safe Tribe' programme was associated with a statistically significant decrease in the unintentional injury mortality rate trend among indigenous persons (p=0.81). CONCLUSION: Taiwanese indigenous communities remain at significantly higher risk of unintentional injury death, though the gap may be slowly narrowing. We found no evidence that the 'Healthy and Safe Tribe' indigenous injury-prevention programme significantly contributed to the nationwide decline in unintentional injury mortality among indigenous Taiwanese communities from 2009 to 2013. Future interventions to address the disproportionate burden of unintentional injury fatalities among indigenous Taiwanese should consider interventions with wider coverage of the indigenous population, and complementing grass roots led community-based interventions with structural policy interventions as well.
Subject(s)
Accident Prevention , Accidents/mortality , Health Promotion/organization & administration , Health Services, Indigenous/organization & administration , Population Groups/statistics & numerical data , Wounds and Injuries/mortality , Cause of Death , Community Health Planning , Health Knowledge, Attitudes, Practice , Health Status Disparities , Health Surveys , Humans , Taiwan , Wounds and Injuries/prevention & controlABSTRACT
BACKGROUND: Sleep disorders, especially chronic insomnia, have become major health problem worldwide and, as a result, the use of hypnotics is steadily increasing. However, few studies with a large sample size and long-term observation have been conducted to investigate the relationship between specific hypnotics and mortality. METHODS: We conducted this retrospective cohort study using data from the National Health Insurance Research Database in Taiwan. Information from claims data including basic characteristics, the use of hypnotics, and survival from 2000 to 2009 for 1,320,322 individuals were included. The use of hypnotics was divided into groups using the defined daily dose and the cumulative length of use. Hazard ratios (HRs) were calculated from a Cox proportional hazards model, with two different matching techniques to examine the associations. RESULTS: Compared to the non-users, both users of benzodiazepines (HR = 1.81; 95% confidence interval [CI] = 1.78-1.85) and mixed users (HR = 1.44; 95% CI = 1.42-1.47) had a higher risk of death, whereas the users of other non-benzodiazepines users showed no differences. Zolpidem users (HR = 0.73; 95% CI = 0.71-0.75) exhibited a lower risk of mortality in the adjusted models. This pattern remained similar in both matching techniques. Secondary analysis indicated that zolpidem users had a reduced risk of major cause-specific mortality except cancer, and that this protective effect was dose-responsive, with those using for more than 1 year having the lowest risk. CONCLUSIONS: The effects of different types of hypnotics on mortality were diverse in this large cohort with long-term follow-up based on representative claims data in Taiwan. The use of zolpidem was associated with a reduced risk of mortality.