The alternative initiation factor eIF2A plays key role in RAN translation of myotonic dystrophy type 2 CCUG•CAGG repeats.

Repeat-associated non-ATG (RAN) proteins have been reported in 11 microsatellite expansion disorders but the factors that allow RAN translation to occur and the effects of different repeat motifs and alternative AUG-like initiation codons are unclear. We studied the mechanisms of RAN translation across myotonic dystrophy type 2 (DM2) expansion transcripts with (CCUG) or without (CAGG) efficient alternative AUG-like codons. To better understand how DM2 LPAC and QAGR RAN proteins are expressed, we generated a series of CRISPR/Cas9-edited HEK293T cell lines.

Metformin inhibits RAN translation through PKR pathway and mitigates disease in ALS/FTD mice.

Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). In cells, structured CAG, CCUG, CAGG, and GC expansion RNAs activate PKR, which leads to increased levels of multiple RAN proteins.

Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model.

The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice.

RAN Translation in Huntington Disease.

Huntington disease (HD) is caused by a CAG ⋅ CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum.

Salvia macilenta exhibits antiglycating activity and protects PC12 cells against H2O 2-induced apoptosis.

Salvia macilenta is a member of the genus Salvia (Laminaceae) whose antioxidant activity and neuroprotective effect has been shown previously. The present study aimed to examine the antiglycating and antiapoptotic abilities of methanolic extract of this plant. Moreover, the effect of S.

3-Thiomethyl-5,6-(dimethoxyphenyl)-1,2,4-triazine improves neurite outgrowth and modulates MAPK phosphorylation and HSPs expression in H2O2-exposed PC12 cells.

Neurite outgrowth is an important aspect of neuronal plasticity and regeneration after neuronal injury. In this study we aimed to investigate the possible effect of 3-thiomethyl-5,6-dimethoxyphenyl-1,2,4-triazine (TDMT) on H(2)O(2)-induced impairment of neurite outgrowth. We found that TDMT could improve neurite outgrowth and neurite complexity in H(2)O(2)-exposed PC12 cells.

Involvement of molecular chaperones and the transcription factor Nrf2 in neuroprotection mediated by para-substituted-4,5-diaryl-3-thiomethyl-1,2,4-triazines.

Much evidence supports that oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease. Herein, we studied the compensatory/adaptive mechanisms involved in 3-thiomethyl-5,6-(diphenyl)-1,2,4-triazine and 3-thiomethyl-5,6-(dichlorophenyl)-1,2,4-triazine neuroprotection. We found that these compounds could counteract H(2)O(2)-induced rupture of neurite outgrowth in differentiated PC12 cells.

S. choloroleuca, S. mirzayanii and S. santolinifolia protect PC12 cells from H(2)O (2)-induced apoptosis by blocking the intrinsic pathway.

Several studies have shown that neuronal cell death due to apoptosis is the major reason for cognitive decline in Alzheimer's disease. In this study, we report the anti-apoptotic effects of three Salvia species from Iran-S. choloroleuca, S.

The interaction between intrathecal administration of low doses of palmitoylethanolamide and AM251 in formalin-induced pain related behavior and spinal cord IL1-β expression in rats.

Most of the modulating effects of cannabinoids on pain are through putative cannabinoid CB1 and CB2 receptors. However, the involvement of other receptors is also suggested. Cannabinoid compounds with analgesic activity such as palmitoylethanolamide (PEA) show low affinity to CB1 and CB2 receptors, yet selectively activate GPR55 receptors.

Chemical composition analysis, antioxidant, antiglycating activities and neuroprotective effects of S. choloroleuca, S. mirzayanii and S. santolinifolia from Iran.

This study was designed to examine antioxidant activities, antiglycating abilities and neuroprotective effects of methanolic extracts of Salvia choloroleuca, Salvia santolinifolia and Salvia mirzayanii from Iran. The extracts were screened for their possible antioxidant activities by several biochemical assays such as DPPH, FRAP, β-carotene bleaching and TEAC assays. HPLC analysis of these extracts led to the separation of a number of components such as catechine and rosmarinic acid.

Alginate oligosaccharide protects against endoplasmic reticulum- and mitochondrial-mediated apoptotic cell death and oxidative stress.

Oxidative stress is a major component of harmful cascades activated in neurodegenerative disorders. We sought to elucidate possible effects of alginate oligosaccharide (AOS) on H(2)O(2)-induced cell death and to determine the underlying molecular mechanisms in neuron-like PC12 cells. We found that AOS treatment protected PC12 cells against H(2)O(2)-induced endoplasmic reticulum (ER) and mitochondrial-dependent apoptotic cell death.

Stabilization of Nrf2 by tBHQ prevents LPS-induced apoptosis in differentiated PC12 cells.

The inflammatory reaction plays an important role in the pathogenesis of the neurodegenerative disorders. tert-butylhydroquinone (tBHQ) exhibits a wide range of pharmacological activities including anti-oxidative and anti-inflammatory action. In this study, we tried to elucidate possible effects of tBHQ on lipopolysaccharide (LPS)-induced inflammatory reaction and its underlying mechanism in neuron-like PC12 cells.

Antioxidant and antiglycating activities of Salvia sahendica and its protective effect against oxidative stress in neuron-like PC12 cells.

Increased oxidative stress is widely accepted to be a factor in the development and progression of Alzheimer's disease (AD). Here we introduced Salvia sahendica as a protective agent in differentiated PC12 cells, which are commonly considered to be a reliable model of neuronal cells. Our results demonstrated that S.

Dietary supplementation with tBHQ, an Nrf2 stabilizer molecule, confers neuroprotection against apoptosis in amyloid β-injected rat.

Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). There is significant evidence that oxidative stress is a critical event in the pathogenesis of AD. Considering the protective role of Nrf2 against oxidative injury, we studied to determine whether in vivo toxicity of amyloid β (Aβ) can be attenuated by tBHQ, an Nrf2 stabilizer, Using an Aβ injection model.

Designing a highly efficient chemical chaperone system using chitosan-coated alginate.

In the present work we prepared chitosan-coated alginate beads, to use as a chemical chaperone based on the electrostatic interaction between the carboxylate groups of alginate and the ammonium groups of chitosan. This procedure was an attempt for designing a highly efficient chemical chaperone to improve protein stability and refolding. Based on enzyme recovered activity, turbidity, far-UV CD and fluorescence data, alkaline phosphatase can be stabilized and refolded to a higher degree in the presence of alginate capsules compared with unassisted form and was further improved by including chitosan.

Synthesis and in vitro evaluation of novel 1,2,4-triazine derivatives as neuroprotective agents.

The role of novel triazine derivatives against oxidative stress exerted by hydrogen peroxide on differentiated rat pheochromocytoma (PC12) cell line was examined and a consistent protection from H(2)O(2)-induced cell death, associated with a marked reduction in caspase-3 activation, was observed. Moreover, activation of NF-kappaB, a known regulator of a host of genes that involves in specific stress and inflammatory responses by H(2)O(2), was greatly impaired by triazine pretreatment in differentiated PC12 cells. Neuroprotective effect of such compounds may represent a promising approach for treatment of neurodegenerative diseases.

Attenuation of NF-kappaB and activation of Nrf2 signaling by 1,2,4-triazine derivatives, protects neuron-like PC12 cells against apoptosis.

Oxidative stress has been implicated in the etiology of neurodegenerative diseases and aging. Indeed, accumulation of reactive oxygen species, such as hydrogen peroxide, generated by inflammatory cells, leads to oxidative stress, which may contribute to the neuronal degeneration observed in a wide variety of neurodegenerative disorders of the central nervous system, such as Alzheimer's disease. The present study indicates that H(2)O(2)-induced cell death can be inhibited in the presence of 1,2,4-triazine derivatives, as measured by MTT and caspase-3 activity.