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Liang Ouyang, Lan Zhang, Shouyue Zhang, Dahong Yao, Yuqian Zhao, Guan Wang, Leilei Fu, Peng Lei, Bo Liu
UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). Herein, we discovered a small molecule 33i (BL-918) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg18, Lys50, Asn86 and Tyr89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, we found that 33i induced autophagy via the ULK complex in SH-SY5Y cells...
March 21, 2018: Journal of Medicinal Chemistry
Yongchul Jang, Insu Kwon, Wankeun Song, Ludmila M Cosio-Lima, Youngil Lee
Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction. Growing evidence has demonstrated that endurance exercise (EE) confers neuroprotection against PD; However, the exact molecular mechanisms responsible for exercise-induced protection of dopaminergic neurons in PD remain unclear. Since oxidative stress plays a key role in the degenerative process of PD. We investigated whether EE-induced neuroprotection is associated with enhanced antioxidative capacity and autophagy, using a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration...
March 17, 2018: Neuroscience
Pennapa Chonpathompikunlert, Phetcharat Boonruamkaew, Wanida Sukketsiri, Pilaiwanwadee Hutamekalin, Morakot Sroyraya
BACKGROUND: Apium graveolens L. is a traditional Chinese medicine prescribed as a treatment for hypertension, gout, and diabetes. This study aimed to determine the neuroprotective effects of A. graveolens extract against a Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6 mice. METHODS: Male C57BL/6 mice treated with MPTP were orally dosed with A. graveolens extract daily for 21 days. Behavioral tests, including a rotarod apparatus, a narrow beam test, a drag test, a grid walk test, a swimming test, and a resting tremor evaluation, were performed...
March 20, 2018: BMC Complementary and Alternative Medicine
Toshiyuki Yano, Koki Abe, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Tetsuji Miura, Charles Steenbergen
p53 is well known as a regulator of apoptosis and autophagy. In addition, a recent study showed that p53 is a modulator of the opening of the mitochondrial permeability transition pore (mPTP), a trigger event of necrosis, but the role of p53 in necrosis induced by myocardial ischemia-reperfusion (I/R) remains unclear. The aim of this study was to determine the role of p53 in acute myocardial I/R injury in perfused mouse hearts. In male C57BL6 mice between 12 and 15 weeks of age, 2 types of p53 inhibitors were used to suppress p53 function during I/R: pifithrin-α, an inhibitor of transcriptional functions of p53, and pifithrin-μ, an inhibitor of p53 translocation from the cytosol to mitochondria...
January 1, 2018: Journal of Cardiovascular Pharmacology and Therapeutics
Rosalia Crupi, Daniela Impellizzeri, Marika Cordaro, Rosalba Siracusa, Giovanna Casili, Maurizio Evangelista, Salvatore Cuzzocrea
Parkinson's disease (PD) is a neurodegenerative disease characterized by degeneration of dopaminergic neurons. Aging is a major risk factor for idiopathic PD. Several prior studies examined the neuroprotective effects of palmitoylethanolamide (PEA), alone or combined with antioxidants, in a model of PD induced by the dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here, we analyzed the pretreatment effect of micronized PEA (PEAm) on neuroinflammation and neuronal cell death in the MPTP model...
March 19, 2018: Molecular Neurobiology
Hao Zhou, Pingjun Zhu, Jin Wang, Hong Zhu, Jun Ren, Yundai Chen
Disturbed mitochondrial homeostasis contributes to the pathogenesis of cardiac ischemia reperfusion (IR) injury, although the underlying mechanism remains elusive. Here, we demonstrated that casein kinase 2α (CK2α) was upregulated following acute cardiac IR injury. Increased CK2α was shown to be instrumental to mitochondrial damage, cardiomyocyte death, infarction area expansion and cardiac dysfunction, whereas cardiac-specific CK2α knockout (CK2αCKO ) mice were protected against IR injury and mitochondrial damage...
March 14, 2018: Cell Death and Differentiation
Danh T Tran, Scott Esckilsen, Jennifer Mulligan, Shikhar Mehrotra, Carl Atkinson, Satish N Nadig
BACKGROUND: Microvascular endothelial cells (ECs) are central to an allograft's immunogenicity. Cold ischemia and reperfusion injury associated with static cold storage and warm reperfusion activates ECs and increases the immunogenicity of the allograft. Following reperfusion, mitochondrial permeability transition pore (mPTP) opening contributes to mitochondrial dysfunction in the allograft, which correlates to alloimmune rejection. Current understanding of this relationship, however, centers on the whole allograft instead of ECs...
March 10, 2018: Transplantation
Beth Grimmig, Lauren Daly, Meena Subbarayan, Ched Hudson, Robert Williamson, Kevin Nash, Paula C Bickford
Parkinson's disease (PD) is the second most common neurodegenerative disorder and prevalence increases with age. Normal physiological changes that occur during the aging process reflect the pathological characteristics of Parkinson's disease. It is also recognized that age related changes significantly interact with the pathological mechanisms that underlie the neurodegeneration in PD and perpetuate the disease process. Despite the fact that aging is considered to be a primary risk factor for developing PD, the use of aged animal models are still under-utilized in pre-clinical research, thus reducing the translatability of experimental findings...
February 13, 2018: Oncotarget
Petter Z Marki, Jon Fjeldså, Martin Irestedt, Knud A Jønsson
Detailed knowledge of species limits is an essential component of the study of biodiversity. Although accurate species delimitation usually requires detailed knowledge of both genetic and phenotypic variation, such variation may be limited or unavailable for some groups. In this study, we reconstruct a molecular phylogeny for all currently recognized species and subspecies of Australasian shrikethrushes (Colluricincla), including the first sequences of the poorly known C. tenebrosa. Using a novel method for species delimitation, the multi-rate Poisson Tree Process (mPTP), in concordance with the phylogenetic data, we estimate species limits in this genetically diverse, but phenotypically subtly differentiated complex of birds...
March 8, 2018: Molecular Phylogenetics and Evolution
Xu Chen, Xuan Li, Wenyan Zhang, Jie He, Bo Xu, Bin Lei, Zhenhua Wang, Courtney Cates, Thomas Rousselle, Ji Li
BACKGROUND: AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-κB is an important transcription factor involved in ischemia and reperfusion injury. METHODS AND RESULTS: The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-κB signaling pathway...
March 8, 2018: Metabolism: Clinical and Experimental
Nicolas Veyres, Adjia Hamadjida, Philippe Huot
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate is the gold-standard animal model of Parkinson's disease (PD) and has been used to assess the effectiveness of experimental drugs on dyskinesia, parkinsonism and psychosis. Three species have been used in the majority of studies, the macaque, marmoset and squirrel monkey, the latter much less so than the first 2 species. However, the predictive rate of each species at forecasting clinical efficacy, or lack thereof, is poorly documented...
March 9, 2018: Journal of Pharmacology and Experimental Therapeutics
Matthew L Neal, Alexa M Boyle, Kevin M Budge, Fayez F Safadi, Jason R Richardson
BACKGROUND: Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson's disease (PD). Activation of glial cells, including microglia and astrocytes, is a characteristic of the inflammatory response. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that releases a soluble signaling peptide when cleaved by ADAM10 or other extracellular proteases. GPNMB has demonstrated a neuroprotective role in animal models of ALS and ischemia...
March 8, 2018: Journal of Neuroinflammation
Vachirapong Sompakdee, Auemduan Prawan, Laddawan Senggunprai, Upa Kukongviriyapan, Papavee Samathiwat, Jaroon Wandee, Veerapol Kukongviriyapan
AIMS: Transcription factor Nrf2, which regulates the expression of cytoprotective and antioxidant enzymes, contributes to proliferation and resistance to chemotherapy in cancer. The inhibition of Nrf2 can sensitize cholangiocarcinoma (CCA) cells to the cytotoxicity of several chemotherapeutic agents. In this study, we investigated the mechanism of this chemosensitizing effect. MAIN METHODS: KKU-100 cells were used in the study. Nrf2 expression was knocked down by siRNA and expression was validated by reverse transcription and polymerase chain reaction...
March 5, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Yi Lu, Xiaoxia Zhang, Liangcai Zhao, Changwei Yang, Linlin Pan, Chen Li, Kun Liu, Guanghui Bai, Hongchang Gao, Zhihan Yan
Metabolic confusion has been linked to the pathogenesis of Parkinson's disease (PD), while the dynamic changes associated with the onset and progression of PD remain unclear. Herein, dynamic changes in metabolites were detected from the initiation to the development of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -induced Parkinsonism model to elucidate its potential metabolic mechanism. Ex vivo 1 H nuclear magnetic resonance (NMR) spectroscopy was used to measure metabolite changes in the striatum and substantia nigra (SN) of mice at 1, 7, and 21 days after injection of MPTP...
2018: Frontiers in Neuroscience
José Teixeira, Catarina Oliveira, Fernando Cagide, Ricardo Amorim, Jorge Garrido, Fernanda Borges, Paulo J Oliveira
Pharmacological interventions targeting mitochondria present several barriers for a complete efficacy. Therefore, a new mitochondriotropic antioxidant (AntiOxBEN3 ) based on the dietary antioxidant gallic acid was developed. AntiOxBEN3 accumulated several thousand-fold inside isolated rat liver mitochondria, without causing disruption of the oxidative phosphorylation apparatus, as seen by the unchanged respiratory control ratio, phosphorylation efficiency, and transmembrane electric potential. AntiOxBEN3 showed also limited toxicity on human hepatocarcinoma cells...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Qin Chen, Xiaoyan Huang, Renjie Li
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), as a long chain non-coding RNA (lncRNA), has been reported to be upregulated in Parkinson's disease (PD). However, the mechanisms underlying this process remain unknown. Hence, to investigate the role of MALAT1 in PD, N-methyl-4-phenylpyridinium (MPP+ ) was used to induce PD in vitro in the MN9D dopaminergic neuronal cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce PD in vivo in C57BL/6 mice. Quantitative Real-Time PCR (qRT-PCR) and western blot assay showed that the expression levels of MALAT1 and leucine-rich repeat kinase (LRRK2) were increased, and that of miR-205-5p was decreased in the midbrains of mice in which PD was induced by MPTP...
2018: American Journal of Translational Research
Hannah J Whittington, Philip J Ostrowski, Debra J McAndrew, Fang Cao, Andrew Shaw, Thomas R Eykyn, Hannah Lake, Jack Tyler, Jurgen E Schneider, Stefan Neubauer, Sevasti Zervou, Craig A Lygate
Aims: Mitochondrial creatine kinase (MtCK) couples ATP production via oxidative phosphorylation to phosphocreatine in the cytosol, which acts as a mobile energy store available for regeneration of ATP at times of high demand. We hypothesised that elevating MtCK would be beneficial in ischaemia-reperfusion (I/R) injury. Methods and Results: Mice were created overexpressing the sarcomeric MtCK gene with αMHC promoter at the Rosa26 locus (MtCK-OE) and compared with wild-type (WT) littermates...
March 2, 2018: Cardiovascular Research
Yingjuan Liu, Lihua Geng, Jingjing Zhang, Jing Wang, Qi Zhang, Delin Duan, Quanbin Zhang
Parkinson's disease (PD) is a neurodegenerative movement disorder that is caused by a selective loss of dopaminergic neurons. Current PD treatments provide symptomatic relief but do not prevent or decelerate disease progression. Previous studies have suggested that acetylated and phosphorylated porphyran, derived from Porphyra , produces a neuroprotective effect against 6-OHDA-induced damage. Due to its antioxidant and neuroprotective potential, this study evaluates whether oligo-porphyran (OP) could be beneficial in an experimental model of PD in mice...
March 6, 2018: Marine Drugs
Goichi Beck, Shunsuke Maehara, Phat Ly Chang, Stella M Papa
BACKGROUND: Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia...
March 6, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
Carola Stockburger, Schamim Eckert, Gunter P Eckert, Kristina Friedland-Leuner, Walter E Müller
Because of the failure of all amyloid-β directed treatment strategies for Alzheimer's disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development...
February 28, 2018: Journal of Alzheimer's Disease: JAD
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