Manganese (Mn) overexposure is frequently associated with the development of a neurodegenerative disorder known as Manganism. The Mn-mediated generation of reactive oxygen species (ROS) promotes ...cellular damage, finally leading to apoptotic cell death in rat astrocytoma C6 cells. In this scenario, the autophagic pathway could play an important role in preventing cytotoxicity. In the present study, we found that Mn induced an increase in the amount and total volume of acidic vesicular organelles (AVOs), a process usually related to the activation of the autophagic pathway. Particularly, the generation of enlarged AVOs was a ROS- dependent event. In this report we demonstrated for the first time that Mn induces autophagy in glial cells. This conclusion emerged from the results obtained employing a battery of autophagy markers: a) the increase in LC3-II expression levels, b) the formation of autophagic vesicles labeled with monodansylcadaverine (MDC) or LC3 and, c) the increase in Beclin 1/ Bcl-2 and Beclin 1/ Bcl-XL ratio. Autophagy inhibition employing 3-MA and mAtg5K130R resulted in decreased cell viability indicating that this event plays a protective role in Mn- induced cell death. In addition, mitophagy was demonstrated by an increase in LC3 and TOM-20 colocalization. On the other hand, we proposed the occurrence of lysosomal membrane permeabilization (LMP) based in the fact that cathepsins B and D activities are essential for cell death. Both cathepsin B inhibitor (Ca-074 Me) or cathepsin D inhibitor (Pepstatin A) completely prevented Mn- induced cytotoxicity. In addition, low dose of Bafilomycin A1 showed a similar effect, a finding that adds evidence about the lysosomal role in Mn cytotoxicity. Finally, in vivo experiments demonstrated that Mn induces injury and alters LC3 expression levels in rat striatal astrocytes. In summary, our results demonstrated that autophagy is activated to counteract the harmful effect caused by Mn. These data is valuable to be considered in future research concerning Manganism therapies.
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•Manganese (Mn) increases the number and size of acidic vesicular organelles.•Mn induces autophagy in astrocytoma C6 cells.•Autophagy is a cytoprotective response towards Mn toxicity.•Mitophagy is one of the autophagic mechanisms operating.•Cathepsins B and D play a pivotal role in cell death.
Manganese (Mn) is an essential trace metal which plays a critical role in brain physiology by acting as a cofactor for several enzymes. However, upon overexposure, Mn preferentially accumulates ...within the basal ganglia leading to the development of a Parkinsonism known as Manganism. Data from our group have proved that Mn induces oxidative stress-mediated apoptosis in astrocytoma C6 cells. In the present study we described how cathepsins impact on different steps of each apoptotic cascade. Evidence obtained demonstrated that Mn generates lysosomal membrane permeabilization (LMP) and cathepsin release. Both cathepsins B (Ca-074 Me) and D (Pepstatin A) inhibitors as well as Bafilomycin A1 prevented caspases-3, -7, -8 and -9 activation, FasL upregulation, Bid cleavage, Δ
φm
disruption and cytochrome c release. Results from in vivo studies showed that intrastriatal Mn injection increased cathepsin D levels from corpus striatum and substantia nigra pars compacta. Our results point to LMP and lysosomal cathepsins as key mediators in the apoptotic process triggered by Mn. These findings highlight the relevance of targeting the lysosomal pathway for Manganism therapy.
Systematic Review Briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each ...Systematic Review Brief summarizes the evidence on a theme related to a systematic review topic. This Systematic Review Brief presents findings for task-oriented/occupation-based approaches and augmenting task-oriented training with cognitive strategies to support performance in instrumental activities of daily living among adult stroke survivors.
Systematic Review Briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each ...Systematic Review Brief summarizes the evidence on a theme and/or subthemes, related to a specific topic. This Systematic Review Brief summarizes findings from the systematic review on interventions to improve performance and participation in instrumental activities of daily living among adult stroke survivors. This theme reports on the effectiveness of virtual reality, exercise, vision rehabilitation, and community-based stroke empowerment group interventions.
Koi herpesvirus (KHV) causes KHV disease (KHVD). The virus is highly contagious in carp or koi and can induce a high mortality. Latency and, in some cases, a lack of signs presents a challenge for ...virus detection. Appropriate immunological detection methods for anti‐KHV antibodies have not yet been fully validated for KHV. Therefore, it was developed and validated an enzyme‐linked immunosorbent assay (ELISA) to detect KHV antibodies. The assay was optimized with respect to plates, buffers, antigens and assay conditions. It demonstrated high diagnostic and analytical sensitivity and specificity and was particularly useful at the pond or farm levels. Considering the scale of the carp and koi industry worldwide, this assay represents an important practical tool for the indirect detection of KHV, also in the absence of clinical signs.
Antipsychotic medications cause a wide range of adverse effects and have been associated with sudden death in psychiatric patients.
To supply power spectral analysis of heart rate variability as a ...tool to examine the arrythmogenic effects of neuroleptics.
Heart rate analysis was carried out in patients with schizophrenia on standard doses of neuroleptic monotherapy -- 21 were on clozapine, 18 on haloperidol and 17 on olanzapine -- and in 53 healthy subjects.
Patients with schizophrenia on clozapine had significantly higher heart rate, lower heart rate variability and lower high-frequency and higher low-frequency components compared with patients on haloperidol or olanzapine and matched control subjects. Prolonged QTc intervals were more common in patients than controls.
Patients treated with neuroleptic medications, especially clozapine, showed autonomic dysregulation and cardiac repolarisation changes. Physicians should be aware of this adverse reaction.
The Hsp40, Hsp70, and Hsp90 chaperone families are ancient, highly conserved, and critical to cellular protein homeostasis. Hsp40 chaperones can transfer their protein clients to Hsp70, and Hsp70 can ...transfer clients to Hsp90, but the functional benefits of these transfers are unclear. Recent structural and mechanistic work has opened up the possibility of uncovering how Hsp40, Hsp70, and Hsp90 work together as unified system. In this review, we compile mechanistic data on the ER J-domain protein 3 (ERdj3) (an Hsp40), BiP (an Hsp70), and Grp94 (an Hsp90) chaperones within the endoplasmic reticulum; what is known about how these chaperones work together; and gaps in this understanding. Using calculations, we examine how client transfer could impact the solubilization of aggregates, the folding of soluble proteins, and the triage decisions by which proteins are targeted for degradation. The proposed roles of client transfer among Hsp40-Hsp70-Hsp90 chaperones are new hypotheses, and we discuss potential experimental tests of these ideas.
Deep transcranial magnetic stimulation (DTMS) is an emerging and promising treatment for major depression. In our study, we explored the effectiveness of a second antidepressant course of deep TMS in ...major depression. We enrolled eight patients who had previously responded well to DTMS but relapsed within 1
year in order to evaluate whether a second course of DTMS would still be effective.
Eight depressive patients who relapsed after a previous successful deep TMS course expressed their wish to be treated again. Upon their request, they were recruited and treated with 20 daily sessions of DTMS at 20
Hz using the Brainsway's H1 coil. The Hamilton depression rating scale (HDRS), Hamilton anxiety rating scale (HARS) and the Beck depression inventory (BDI) were used weekly to evaluate the response to treatment.
Similar to the results obtained in the first course of treatment, the second course of treatment (after relapse) induced significant reductions in HDRS, HARS and BDI scores, compared to the ratings measured prior to treatment. The magnitude of response in the second course was smaller relative to that obtained in the first course of treatment.
Our results suggest that depressive patients who previously responded well to deep TMS treatment are likely to respond again. However, the slight reduction in the magnitude of the response in the second treatment raises the question of whether tolerance or resistance to this treatment may eventually develop.
► A second course of deep TMS in major depression relapse is a feasible option. ► Deep transcranial magnetic stimulation is an emerging and promising treatment. ► Deep TMS was shown to be an effective treatment for major depression.
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