Gold Nanocage-Incorporated Poly(ε-Caprolactone) (PCL) Fibers for Chemophotothermal Synergistic Cancer Therapy.

This paper introduces a new fibrous system for synergistic cancer therapy, which consists of gold nanocage (AuNC)-loaded poly(ε-caprolactone) (PCL) fibers with encapsulation of a chemotherapeutic anticancer drug in their core and loading of a phase-changeable fatty acid in their sheath. Under on⁻off switching of near-infrared (NIR) light irradiation, the excellent photothermal ability and photostability of AuNCs allows repeated, significant heating of the fibers to a temperature available to hyperthermia. Simultaneously, the NIR light-induced heat generation enables the melting out of the loaded fatty acid, leading to a rapid release of the drug molecules from the fibers.

Poly(d,l-lactic-co-glycolic acid) (PLGA) hollow fiber with segmental switchability of its chains sensitive to NIR light for synergistic cancer therapy.

This work introduces a new fibrous system for synergistic cancer therapy. The system consists of poly(d,l-lactic-co-glycolic acid) (PLGA) fibers with a core encapsulating an anticancer drug and a shell entrapping gold nanorods (AuNRs) as a photothermal agent. On exposure to NIR light, the photothermal agent generates heat to raise the local temperature of the fibers.

Isocitrate protects DJ-1 null dopaminergic cells from oxidative stress through NADP+-dependent isocitrate dehydrogenase (IDH).

DJ-1 is one of the causative genes for early onset familiar Parkinson's disease (PD) and is also considered to influence the pathogenesis of sporadic PD. DJ-1 has various physiological functions which converge on controlling intracellular reactive oxygen species (ROS) levels. In RNA-sequencing analyses searching for novel anti-oxidant genes downstream of DJ-1, a gene encoding NADP+-dependent isocitrate dehydrogenase (IDH), which converts isocitrate into α-ketoglutarate, was detected.

The Tnfaip8-PE complex is a novel upstream effector in the anti-autophagic action of insulin.

Defective hepatic autophagy is observed in obesity and diabetes, whereas autophagy is inhibited by insulin in hepatocytes. Insulin-induced anti-autophagy is mediated by non-canonical Gαi3 signaling via an unknown mechanism. Previously, we identified the anti-autophagic activity of Tnfaip8 via activation of mammalian target of rapamycin (mTOR) in the nervous system.

A Novel Non-Apoptotic Role of Procaspase-3 in the Regulation of Mitochondrial Biogenesis Activators.

The executioner caspase-3 has been proposed as a pharmacological intervention target to preserve degenerating dopaminergic (DA) neurons because apoptotic mechanisms involving caspase-3 contribute, at least in part, to the loss of DA neurons in patients and experimental models of Parkinson's disease (PD). Here, we determined that genetic intervention of caspase-3 was sufficient to prevent cell death against oxidative stress (OS), accompanied by unexpected severe mitochondrial dysfunction. Specifically, as we expected, caspase-3-deficient DA neuronal cells were very significantly resistant to OS-induced cell death, while the activation of the initiator caspase-9 by OS was preserved.

Nitric oxide induction of Parkin translocation in PTEN-induced putative kinase 1 (PINK1) deficiency: functional role of neuronal nitric oxide synthase during mitophagy.

The failure to trigger mitophagy is implicated in the pathogenesis of familial Parkinson disease that is caused by PINK1 or Parkin mutations. According to the prevailing PINK1-Parkin signaling model, mitophagy is promoted by the mitochondrial translocation of Parkin, an essential PINK1-dependent step that occurs via a previously unknown mechanism. Here we determined that critical concentrations of NO was sufficient to induce the mitochondrial translocation of Parkin even in PINK1 deficiency, with apparent increased interaction of full-length PINK1 accumulated during mitophagy, with neuronal nitric oxide synthase (nNOS).

Mitochondrial homeostasis molecules: regulation by a trio of recessive Parkinson's disease genes.

Mitochondria are small organelles that produce the majority of cellular energy as ATP. Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD), and rare familial forms of PD provide valuable insight into the pathogenic mechanism underlying mitochondrial impairment, even though the majority of PD cases are sporadic. The regulation of mitochondria is crucial for the maintenance of energy-demanding neuronal functions in the brain.

Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy.

CHDH (choline dehydrogenase) is an enzyme catalyzing the dehydrogenation of choline to betaine aldehyde in mitochondria. Apart from this well-known activity, we report here a pivotal role of CHDH in mitophagy. Knockdown of CHDH expression impairs CCCP-induced mitophagy and PARK2/parkin-mediated clearance of mitochondria in mammalian cells, including HeLa cells and SN4741 dopaminergic neuronal cells.

A preliminary X-ray study of murine Tnfaip8/Oxi-α.

Tnfaip8/oxidative stress regulated gene-α (Oxi-α) is a novel protein expressed specifically in brain dopaminergic neurons and its over-expression has been reported to protect dopaminergic cells against OS-induced cell death. In this study, murine C165S mutant Tnfaip8/Oxi-α has been crystallized and X-ray data have been collected to 1.8 Å using synchrotron radiation.

Tnfaip8 l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model.

Abnormal autophagy may contribute to neurodegeneration in Parkinson's disease (PD). However, it is largely unknown how autophagy is dysregulated by oxidative stress (OS), one of major pathogenic causes of PD. We recently discovered the potential autophagy regulator gene family including Tnfaip8/Oxi-α, which is a mammalian target of rapamycin (mTOR) activator down-regulated by OS in dopaminergic neurons (J.

Simultaneous activation of mitophagy and autophagy by staurosporine protects against dopaminergic neuronal cell death.

Abnormal autophagy is frequently observed during dopaminergic neurodegeneration in Parkinson's disease (PD). However, it is not yet firmly established whether active autophagy is beneficial or pathogenic with respect to dopaminergic cell loss. Staurosporine, a common inducer of apoptosis, is often used in mechanistic studies of dopaminergic cell death.

Tnfaip8l1/Oxi-β binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model.

Abnormal autophagy may contribute to neurodegeneration in Parkinson's disease (PD). However, it is largely unknown how autophagy is dysregulated by oxidative stress (OS), one of major pathogenic causes of PD. We recently discovered the potential autophagy regulator gene family including Tnfaip8/Oxi-α, which is an mTOR activator downregulated by OS in dopaminergic neurons (Choi et al.

Hybrid scaffold composed of hydrogel/3D-framework and its application as a dopamine delivery system.

Cell-based drug delivery systems (DDSs) have been increasingly exploited because cells can be utilized as a continuous drug delivering system to produce therapeutic molecules over a more extended period compared to the simple drug carriers. Although hydrogels have many advantages for this application, their mechanical properties are generally not desirable to structurally protect implanted cells. Here, we present a three-dimensional (3D) hybrid scaffold with a combination of a 3D framework and a hydrogel to enhance the mechanical properties without chemically altering the transport properties of the hydrogel.

Rescue of PINK1 protein null-specific mitochondrial complex IV deficits by ginsenoside Re activation of nitric oxide signaling.

PINK1, linked to familial Parkinson's disease, is known to affect mitochondrial function. Here we identified a novel regulatory role of PINK1 in the maintenance of complex IV activity and characterized a novel mechanism by which NO signaling restored complex IV deficiency in PINK1 null dopaminergic neuronal cells. In PINK1 null cells, levels of specific chaperones, including Hsp60, leucine-rich pentatricopeptide repeat-containing (LRPPRC), and Hsp90, were severely decreased.

Neuronal autophagy and neurodegenerative diseases.

Autophagy is a dynamic cellular pathway involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. The integrity of postmitotic neurons is heavily dependent on high basal autophagy compared to non-neuronal cells as misfolded proteins and damaged organelles cannot be diluted through cell division. Moreover, neurons contain the specialized structures for intercellular communication, such as axons, dendrites and synapses, which require the reciprocal transport of proteins, organelles and autophagosomes over significant distances from the soma.

The antioxidant Trolox helps recovery from the familial Parkinson's disease-specific mitochondrial deficits caused by PINK1- and DJ-1-deficiency in dopaminergic neuronal cells.

The nature of mitochondrial dysfunction in dopaminergic neurons in familial Parkinson's disease (PD) is unknown. We characterized the pathophenotypes of dopaminergic neuronal cells that were deficient in PINK1 or DJ-1, genes with mutations linked to familial PD. Both PINK1- and DJ-1-deficient dopaminergic neurons had the increased production of ROS, severe mitochondrial structural damages and complex I deficits.

DJ-1 mediates paraquat-induced dopaminergic neuronal cell death.

There are two causes of Parkinson's disease (PD): environmental insults and genetic mutations of PD-associated genes. Environmental insults and genetic mutations lead to mitochondrial dysfunction, and a combination of mitochondrial dysfunction and increased oxidative stress in dopaminergic neurons is thought to contribute to the pathogenesis of PD. Among the PD-associated genes, DJ-1 acts as a redox sensor for oxidative stress and has been also proposed to maintain mitochondrial complex I activity.

Primary culture of central neurocytoma: a case report.

A seventeen-year-old female patient was admitted with sudden-onset of headache and vomiting. Brain magnetic resonance imaging demonstrated a heterogeneously enhancing tumour in the left lateral ventricle. The tumour was removed and confirmed as a central neurocytoma (CN).

PINK1 gene knockdown leads to increased binding of parkin with actin filament.

Mutations in the PINK1 gene are known to cause early onset familial Parkinson's disease (PD). Genetic fruit fly model studies and rescue experiments with parkin overexpression suggest that PINK1 and parkin are associated via an unidentified mechanism. To gain additional insight into this interaction, we have investigated the impact of PINK1 deficiency on the biological function of parkin using actin filament dynamics.

A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death.

Our previous microarray analysis identified a neuroprotective protein Oxi-alpha, that was down-regulated during oxidative stress (OS)-induced cell death in dopamine neurons [Neurochem. Res. (2004) vol.

Neurotoxicity and behavioral deficits associated with Septin 5 accumulation in dopaminergic neurons.

Septin 5, a parkin substrate, is a vesicle- and membrane-associated protein that plays a significant role in inhibiting exocytosis. The regulatory function of Septin 5 in dopaminergic (DAergic) neurons of substantia nigra (SN), maintained at relatively low levels, has not yet been delineated. As loss of function mutations of parkin are the principal cause of a familial Parkinson's disease, a prevailing hypothesis is that the loss of parkin activity results in accumulation of Septin 5 which confers neuron-specific toxicity in SN-DAergic neurons.

Heme oxygenase-1 induction by dieldrin in dopaminergic cells.

We investigated the transcriptional events and signaling pathways involved in the induction of heme oxygenase-1 (HO-1) by dieldrin, an environmental risk factor of Parkinson's disease, in a dopaminergic neuronal cells (SN4741). Dieldrin exposure caused dose-dependent and time-dependent induction of heme oxygenase activity and HO-1 protein expression. Deletional and mutational analyses showed that the 5' distal enhancers, E1 and E2, mediate dieldrin-induced HO-1 gene transcription, and the AP-1 DNA binding sites in the E2 enhancer are critical for E2-mediated HO-1 gene activation.

Experimental strategy to identify genes susceptible to oxidative stress in nigral dopaminergic neurons.

Neuropathological evidence from both human and experimental models of Parkinson's disease (PD) firmly supports a significant role for oxidative stress (OS) in the death of dopaminergic (DA) neurons in substantia nigra. Largely unknown are the genes underlying selective susceptibility of nigral DA neuron to OS and how they effect nigral DA cell death. The major barriers to high-throughput identification of candidate genes are the paucity of nigral DA neurons as well as the dilution effect of non-DA cells both in primary cultures and brain tissues.