The Role of PPARs in Cancer

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARα is mainly expressed in the liver, where it activates fatty acid catabolism. PPARα activators have been used to treat dyslipidemia, causing a reduction in plasma triglyceride and elevation of high-density lipoprotein cholesterol. PPARδ is expressed ubiquitously and is implicated in fatty acid oxidation and keratinocyte differentiation. PPARδ activators have been proposed for the treatment of metabolic disease. PPARγ2 is expressed exclusively in adipose tissue and plays a pivotal role in adipocyte differentiation. PPARγ is involved in glucose metabolism through the improvement of insulin sensitivity and represents a potential therapeutic target of type 2 diabetes. Thus PPARs are molecular targets for the development of drugs treating metabolic syndrome. However, PPARs also play a role in the regulation of cancer cell growth. Here, we review the function of PPARs in tumor growth

Cryopreservation of Induced Pluripotent Stem Cell-Derived Dopaminergic Neurospheres for Clinical Application

[Background:] Pluripotent stem cell (PSC)-derived dopaminergic (DA) neurons are an expected source of cell therapy for Parkinson’s disease. The transplantation of cell aggregates or neurospheres, instead of a single cell suspension has several advantages, such as keeping the 3D structure of the donor cells and ease of handling. For this PSC-based therapy to become a widely available treatment, cryopreservation of the final product is critical in the manufacturing process. However, cryopreserving cell aggregates is more complicated than cryopreserving single cell suspensions. Previous studies showed poor survival of the DA neurons after the transplantation of cryopreserved fetal ventral-mesencephalic tissues. [Objective:] To achieve the cryopreservation of induced pluripotent stem cell (iPSC)-derived DA neurospheres toward clinical application. [Methods:] We cryopreserved iPSC-derived DA neurospheres in various clinically applicable cryopreservation media and freezing protocols and assessed viability and neurite extension. We evaluated the population and neuronal function of cryopreserved cells by the selected method in vitro. We also injected the cells into 6-hydroxydopamine (6-OHDA) lesioned rats, and assessed their survival, maturation and function in vivo. [Results:] The iPSC-derived DA neurospheres cryopreserved by Proton Freezer in the cryopreservation medium Bambanker hRM (BBK) showed favorable viability after thawing and had equivalent expression of DA-specific markers, dopamine secretion, and electrophysiological activity as fresh spheres. When transplanted into 6-OHDA-lesioned rats, the cryopreserved cells survived and differentiated into mature DA neurons, resulting in improved abnormal rotational behavior. [Conclusion:] These results show that the combination of BBK and Proton Freezer is suitable for the cryopreservation of iPSC-derived DA neurospheres

Evaluation of vascular quality of life questionnaire in dialysis patients with peripheral arterial disease treated by low-density lipoprotein apheresis

Background: Peripheral arterial disease (PAD) is a common complication in dialysis patients. Early diagnosis and treatment are recommended. Low-density lipoprotein apheresis (LDL-A) is a potential therapy to improve PAD. However, the mechanism has yet to be fully clarified due to lack of established quantitative methods to assess the therapeutic effects of LDL-A treatment. Improvement of skin perfusion pressure (SPP) or ankle brachial index (ABI) is a representative therapy goal, but clinical symptoms were not always consistent with the values of SPP/ABI. Vascular quality of life questionnaire (VascuQOL) was proposed as a disease-specific QOL score, getting validated recently. The possibility of VascuQOL to reflect the severity of PAD in dialysis patients and evaluate the therapeutic effects of LDL-A has yet to be elucidated. Methods: This is an observational study. LDL-A treatment was performed in 32 dialysis patients with PAD. They were divided to critical limb ischemia (CLI) group (17 subjects) and non-CLI group (15 subjects) according to their clinical manifestations. We examined the relationship of PAD severity with SPP, ABI, VascuQOL, and lipid profile such as apoB/apoA-I ratio, malondialdehyde-modified LDL, and remnant-like particles cholesterol. Furthermore, we evaluated these parameters successively to find out a suitable therapeutic marker just after the first LDL-A, at tenth LDL-A, and 1 month after completion of LDL-A treatment. Results: All of the lipid markers were higher in CLI patients, but not significantly different from those in the non-CLI group. They decreased significantly just after LDL-A, although no changes were observed 1 month after completion of LDL-A treatment. ABI was significantly different between the CLI and non-CLI groups, but did not improve by LDL-A treatment. By contrast, SPP was ameliorated significantly and the peak was at tenth LDL-A. Among VascuQOL domains, “Symptom” and “Emotional” domains were significantly different between the CLI and non-CLI groups. The average score of VascuQOL increased successively until 1 month after completion of LDL-A treatment. Conclusions: Several domains of VascuQOL can reflect the severity of PAD in dialysis patients. VascuQOL was a useful marker to show the prolonged therapeutic effects of LDL-A treatment in dialysis patients with PAD, independent of SPP

Rheology of hexagonal close-packed(hcp) iron

The viscosity of hexagonal close-packed (hcp) Fe is a fundamental property controlling the dynamics of the Earth’s inner core. We studied the rheology of hcp-Fe using high-pressure and -temperature deformation experiments with in situ stress and strain measurements. Experiments were conducted using D111-type and deformation-DIA apparatuses at pressures of 16.3–22.6 GPa, temperatures of 423–923 K, and uniaxial strain rates of 1.52 × 10−6 to 8.81 × 10−5 s−1 in conjunction with synchrotron radiation. Experimental results showed that power-law dislocation creep with a stress exponent of n = 4.0 ± 0.3, activation energy of E* = 240 ± 20 kJ/mol, and activation volume of V* = 1.4 ± 0.2 cm3/mol is dominant deformation mechanism at >∼800 K, whereas a mechanism with power-law breakdown prevails at lower temperatures. An extrapolation of the power-law dislocation creep flow law based on homologous temperature scaling suggests the viscosity of hcp-Fe under inner core conditions is ≥∼1019 Pa s. If this power-law dislocation creep mechanism is assumed to be the dominant mechanism in the Earth’s inner core, the equatorial growth or translation mode mechanism may be the dominant geodynamical mechanism causing the observed inner core structure