The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, and life span. mTOR signaling is a central regulator of autophagy by ...modulating multiple aspects of the autophagy process, such as initiation, process, and termination through controlling the activity of the unc51-like kinase 1 (ULK1) complex and vacuolar protein sorting 34 (VPS34) complex, and the intracellular distribution of TFEB/TFE3 and proto-lysosome tubule reformation. Parkinson's disease (PD) is a serious, common neurodegenerative disease characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies. An increasing amount of evidence indicates that mTOR and autophagy are critical for the pathogenesis of PD. In this review, we will summarize recent advances regarding the roles of mTOR and autophagy in PD pathogenesis and treatment. Further characterizing the dysregulation of mTOR pathway and the clinical translation of mTOR modulators in PD may offer exciting new avenues for future drug development.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy‐lysosomal pathway (ALP), is promising for the treatment of neurodegenerative ...disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta‐amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg‐AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C‐terminal fragments (CTF‐β/α), β‐amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.
A small molecule activator of transcription factor EB (TFEB) promotes the degradation of beta‐amyloid precursor protein (APP) fragments, β‐amyloid peptides (Aβ), and phosphorylated MAPT/Tau aggregates in three transgenic mice models of Alzheimer's disease (P301S, 5xFAD, and 3xTg) and prevents memory impairments.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
A progressive approach to quitting smoking has been a popular strategy for motivating smokers who are reluctant to quit. However, whether this strategy can effectively achieve complete cessation or ...is as successful as quitting immediately remains unresolved. This study aimed to determine whether quitting immediately or progressively was more effective in achieving complete cessation among smokers in Hong Kong who presented at emergency departments.
A posteriori analysis of a single-blinded, multicenter, randomized controlled trial was performed. The original trials was conducted at emergency departments of four major acute hospitals in different districts of Hong Kong. In total, 1571 smokers 18 years or older who presented at 4 major emergency departments between July 4, 2015 and March 17, 2017 were randomized into an intervention group (n = 787) and a control group (n = 784). The intervention group received brief advice (about 1 minute) and could choose their own quit schedules (immediate or progressive, labeled QI and QP, respectively). The control group received a smoking cessation leaflet. Follow-ups were conducted at 1, 3, 6 and 12 months. The primary outcomes, by intention-to-treat, were biochemically validated abstinence between the QI subgroup and control group; between the QP subgroup and control group, and between the QI subgroup and QP subgroup at 6 months. After the propensity sore matching, the biochemically validated abstinence was statistically significantly higher in the QI subgroup than the control group at 6 months (12.1% vs 3.4%, P = 0.003; adjusted odds ratio aOR 4.34, 95% CI 1.63-11.52) and higher in the QP subgroup than the control group at 6 months (9.8% vs 3.4%, P = 0.02; aORs 2.95, 95% CI: 1.04-8.39). No statistically significant differences of biochemically validated abstinence at both 6 month (12.1% vs 9.8%, P = 0.49; aORs 1.50, 95% CI: 0.71-3.19) were found in the comparison between QI and QP subgroups.
This study demonstrates that the strategy of quitting progressively is effective, especially for smokers who lack motivation or find it difficult to quit. If adopted routinely, such an approach can help achieve a greater level of smoking abstinence in the community.
ClinicalTrials.gov: NCT02660957.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
4.
Calcium signaling in Alzheimer's disease & therapies Tong, Benjamin Chun-Kit; Wu, Aston Jiaxi; Li, Min ...
Biochimica et biophysica acta. Molecular cell research,
11/2018, Volume:
1865, Issue:
11
Journal Article
Peer reviewed
Open access
Alzheimer's disease (AD) is the most common type of dementia and is characterized by the accumulation of amyloid (Aβ) plaques and neurofibrillary tangles in the brain. Much attention has been given ...to develop AD treatments based on the amyloid cascade hypothesis; however, none of these drugs had good efficacy at improving cognitive functions in AD patients suggesting that Aβ might not be the disease origin. Thus, there are urgent needs for the development of new therapies that target on the proximal cause of AD. Cellular calcium (Ca2+) signals regulate important facets of neuronal physiology. An increasing body of evidence suggests that age-related dysregulation of neuronal Ca2+ homeostasis may play a proximal role in the pathogenesis of AD as disrupted Ca2+ could induce synaptic deficits and promote the accumulation of Aβ plaques and neurofibrillary tangles. Given that Ca2+ disruption is ubiquitously involved in all AD pathologies, it is likely that using chemical agents or small molecules specific to Ca2+ channels or handling proteins on the plasma membrane and membranes of intracellular organelles to correct neuronal Ca2+ dysregulation could open up a new approach to AD prevention and treatment. This review summarizes current knowledge on the molecular mechanisms linking Ca2+ dysregulation with AD pathologies and discusses the possibility of correcting neuronal Ca2+ disruption as a therapeutic approach for AD.
•Ca2+ dysregulation occurs prior other Alzheimer pathologies including plaques, tangles, and synaptic deficits•Ca2+ dysregulation may be the proximal cause of Alzheimer's disease•Targeting deranged Ca2+ signaling may serve as therapeutic approaches to treat AD
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor ...functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated.
Methods
Novel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca
2+
) imaging and flow cytometry were used to delineate the role of pathological tau and tetrandrine in lysosomal Ca
2+
and pH homeostasis. Biochemical BiFC fluorescence, Western blotting and immunofluorescence staining were used to evaluate degradation of hyperphosphorylated tau in vitro, whereas coculture of brain slices with isolated microglia was used to evaluate tau clearance ex vivo.
Results
We observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca
2+
release, thereby contributing to lysosome alkalinization. Tetrandrine inhibits TPC2, thereby restoring the lysosomal pH, promotes tau degradation via autophagy, and ameliorates tau aggregation. Furthermore, in an ex vivo assay, we demonstrated that tetrandrine treatment promotes pathological tau clearance by microglia.
Conclusions
Together, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca
2+
homeostasis, thereby restoring ALP function, could be an effective general strategy for the development of novel therapies for tauopathies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This is a prospective study to establish prediction models that map the refined Scoliosis Research Society 22-item (SRS-22r) onto EuroQoL-5 dimension 5-level (EQ-5D-5L) utility scores in adolescent ...idiopathic scoliosis (AIS) patients. Comparison of treatment outcomes in AIS can be determined by cost-utility analysis. However, the mainstay spine-specific health-related quality of life outcome measure, the SRS-22r questionnaire does not provide utility assessment. In this study, AIS patients were prospectively recruited to complete both the EQ-5D-5L and SRS-22r questionnaires by trained interviewers. Ordinary least squares regression was undertaken to develop mapping models, which the validity and robustness were assessed by using the 10-fold cross-validation procedure. EQ-5D-5L utility scores were regressed on demographics, Cobb angle, curve types, treatment modalities, and five domains of the SRS-22r questionnaire. Three models were developed using stepwise selection method. EQ-5D-5L scores were regressed on 1) main effects of SRS-22r subscale scores, 2) as per 1 plus squared and interaction terms, and 3) as per 2 plus demographic and clinical characteristics. Model goodness-of-fit was assessed using R-square, adjusted R-square, and information criteria; whereas the predictive performance was evaluated using root mean square error (RMSE), mean absolute error (MAE), and the proportion of absolute error within the threshold of 0.05 and 0.10. A total of 227 AIS patients with mean age of 15.6 years were recruited. The EQ-5D-5L scores were predicted by four domains of SRS-22r (main effects of 'Function', 'Pain', 'Appearance' and 'Mental Health', and squared term of 'Function' and 'Pain'), and Cobb angle in Model 3 with the best goodness-of-fit (R-square/adjusted R-square: 62.1%/60.9%). Three models demonstrated an acceptance predictive performance in error analysis applying 10-fold cross-validation to three models where RMSE and MAE were between 0.063-0.065 and between 0.039-0.044, respectively. Model 3 was therefore recommended out of three mapping models established in this paper. To our knowledge, this is the first study to map a spine-specific health-related quality of life measure onto EQ-5D-5L for AIS patients. With the consideration and incorporation of demographic and clinical characteristics, over 60% variance explained by mapping model 3 enabled the satisfactory prediction of EQ-5D-5L utility scores from existing SRS-22r data for health economic appraisal of different treatment options.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
bstract
TFEB (transcription factor EB), which is a master regulator of autophagy and lysosome biogenesis, is considered to be a new therapeutic target for Parkinson's disease (PD). However, only ...several small-molecule TFEB activators have been discovered and their neuroprotective effects in PD are unclear. In this study, a curcumin derivative, named E4, was identified as a potent TFEB activator. Compound E4 promoted the translocation of TFEB from cytoplasm into nucleus, accompanied by enhanced autophagy and lysosomal biogenesis. Moreover, TFEB knockdown effectively attenuated E4-induced autophagy and lysosomal biogenesis. Mechanistically, E4-induced TFEB activation is mainly through AKT-MTORC1 inhibition. In the PD cell models, E4 promoted the degradation of α-synuclein and protected against the cytotoxicity of MPP
(1-methyl-4-phenylpyridinium ion) in neuronal cells. Overall, the TFEB activator E4 deserves further study in animal models of neurodegenerative diseases, including PD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Eukaryotic cells possess a plethora of regulatory mechanisms to maintain homeostasis and ensure proper biochemical functionality. Autophagy, a central, conserved self-consuming process of the cell, ...ensures the timely degradation of damaged cellular components. Several studies have demonstrated the important roles of autophagy activation in mitigating neurodegenerative diseases, especially Alzheimer's disease (AD). However, surprisingly, activation of macroautophagy has not shown clinical efficacy. Hence, alternative strategies are urgently needed for AD therapy. In recent years, selective autophagy has been reported to be involved in AD pathology, and different subtypes have been identified, such as aggrephagy, mitophagy, reticulophagy, lipophagy, pexophagy, nucleophagy, lysophagy and ribophagy. By clarifying the underlying mechanisms governing these various subtypes, we may come to understand how to control autophagy to treat AD. In this review, we summarize the latest findings concerning the role of selective autophagy in the pathogenesis of AD. The evidence overwhelmingly suggests that selective autophagy is an active mechanism in AD pathology, and that regulating selective autophagy would be an effective strategy for controlling this pathogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neuroinflammation is the precursor for several neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Targeting neuroinflammation ...has emerged as a promising strategy to address a wide range of CNS pathologies. These NDDs still present significant challenges in terms of limited and ineffective diagnosis and treatment options, driving the need to explore innovative and novel therapeutic alternatives. Aptamers are single-stranded nucleic acids that offer the potential for addressing these challenges through diagnostic and therapeutic applications. In this review, we summarize diagnostic and therapeutic aptamers for inflammatory biomolecules, as well as the inflammatory cells in NDDs. We also discussed the potential of short nucleotides for Aptamer-Based Targeted Brain Delivery through their unique features and modifications, as well as their ability to penetrate the blood-brain barrier. Moreover, the unprecedented opportunities and substantial challenges of using aptamers as therapeutic agents, such as drug efficacy, safety considerations, and pharmacokinetics, are also discussed. Taken together, this review assesses the potential of aptamers as a pioneering approach for target delivery to the CNS and the treatment of neuroinflammation and NDDs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Spondyloarthritis (SpA) has a significant impact on patients' quality of life due to functional impairments. Generic health instruments like the EuroQoL 5-dimension (EQ-5D) is important for the ...cost-utility analysis of health care interventions and calculation of quality-adjusted life years. However, the applicability of the EQ-5D health measure in Chinese patients with SpA is currently unknown. Hence, the aim of the study is to test the psychometric properties and to validate the use of the EQ-5D health measure for utility analyses in Chinese patients with SpA.
Prospective and consecutive recruitment of 220 Chinese patients with SpA was conducted. Demographic data including smoking and drinking habits, education level, income, and occupation was collected. Disease-associated data including disease duration, the presence of back pain, peripheral arthritis, dactylitis, enthesitis, uveitis, psoriasis, and inflammatory bowel disease was also recorded. Questionnaires regarding disease activity and functional disability (BASDAI, BASFI, BASGI, BASMI, ASDAS, ODI), mental health (HADS depression and anxiety), and the EQ-5D scores were recorded. SF-36 scores were used to verify the findings. Baseline correlations were performed along with test-retest reliability, validity, and internal consistency tests. Specifically, the relationship between EQ-5D and disease activity and functional scores was studied.
EQ-5D scores achieved acceptable internal consistency and reliability. A ceiling effect was observed for all domains of the EQ-5D except for pain/discomfort. No floor effect was observed. Significant negative correlations were observed between ODI, HADS, BASFI, BASMI, BASDAI, and ASDAS-CRP and with EQ-5D. A higher disease activity was well-differentiated by EQ-5D, as with the disability and mental health scores.
The EQ-5D demonstrates satisfactory psychometric properties for assessment of SpA patients. It has high utility for demonstrating changes in disease activity and disability.
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