6‐Dihydroparadol,a Ginger Constituent,Enhances Cholesterol Efflux from THP‐1‐Derived Macrophages

1 Scope

Ginger is reported to be used for the prevention and treatment of cardiovascular diseases (CVD). Cholesterol efflux from macrophage foam cells is an important process in reverse cholesterol transport, whose increase may help to prevent or treat CVD. In this study, we investigated the effects of 6‐dihydroparadol from ginger on macrophage cholesterol efflux.

2 Methods and results

We show that 6‐dihydroparadol concentration‐dependently enhances both apolipoprotein A1‐ and human plasma–mediated cholesterol efflux from cholesterol‐loaded THP‐1‐derived macrophages using macrophage cholesterol efflux assay. 6‐Dihydroparadol increases protein levels of both ATP‐binding cassette transporters A1 and G1 (ATP‐binding cassette transporter A1 [ABCA1] and ATP‐binding cassette transporter G1 [ABCG1]) according to Western blot analysis. The ABCA1 inhibitor probucol completely abolishes 6‐dihydroparadol‐enhanced cholesterol efflux. Furthermore, increased ABCA1 protein levels in the presence of 6‐dihydroparadol were associated with both increased ABCA1 mRNA levels and increased ABCA1 protein stability. Enhanced ABCG1 protein levels were only associated with increased protein stability. Increased ABCA1 protein stability appeared to be the result of a reduced proteasomal degradation of the transporter in the presence of 6‐dihydroparadol.

3 Conclusion

We identified 6‐dihydroparadol from ginger as a novel promoter of cholesterol efflux from macrophages that increases both ABCA1 and ABCG1 protein abundance. This newly identified bioactivity might contribute to the antiatherogenic effects of ginger.     

Lessons learned from studying public initiatives to support energy efficiency finance in Thailand from 1992 to 2014

Despite the huge technical and market potential for cost-effective energy efficiency investments in Southeast Asian markets, only a small fraction of this potential has been realised. Given that the major share of global future energy demand, and associated greenhouse gas emissions, will come from emerging economies, it is important to understand the barriers to mainstreaming energy efficiency into the financial sector. This paper focuses on public initiatives that support one of the main barriers: access to capital. The researchers chose Thailand as a case study because of the range of energy efficiency finance programmes that have been designed and implemented since the early 1990s. Interviews with 21 experts from government, the private sector and academia provided the core data for this research. The analysis employed a multi-level perspective and focused on the historical evolution of public support of energy efficiency finance in the country. We identified three distinct phases of public policy development over the past two decades. Despite an impressive variety of ambitious and creative programmes, the initiatives have not yet succeeded in integrating energy efficiency into the financial sector in a meaningful way. Some of the key lessons found are that (a) it is better to treat energy efficiency and renewable energy in separate financing initiatives, (b) governments find it challenging to design effective mechanisms to de-risk financial investments, and (c) international organisations play an important role in testing and facilitating the introduction of new financing approaches and mechanisms. In emerging economies, cost-effective implementation of energy efficiency measures is a promising alternative that can reduce the need for investment in large-scale power generation capacity. The researchers hope that this paper will contribute to more effective design of programmes to incentivise energy efficiency financing in Thailand and in other economies in Southeast Asia.     

Metal Ion‐Terpyridine‐Functionalized L‐Tyrosinamide Aptamers: Nucleoapzymes for Oxygen Insertion into C?H Bonds and the Transformation of L‐Tyrosinamide into Amidodopachrome

A series of metal ion‐terpyridine‐modified L‐tyrosinamide aptamers (M^{n +} = Cu²⁺ or Fe³⁺) act as enzyme‐mimicking catalysts (nucleoapzymes) for oxygen‐insertion into C? H bonds and the transformation of L‐tyrosinamide into amidodopachrome. The reaction proceeds in the presence of H₂O₂ and coadded L‐ascorbic acid. In one series of experiments, the catalyzed oxidation of L‐tyrosinamide to amidodopachrome by a set of nucleoapzymes consisting of Fe³⁺‐ or Cu²⁺‐terpyridine complexes tethered directly or through a 4 × thymidine (4 × T) bridge, to the 5′‐ or 3′‐end of the 49‐mer L‐tyrosinamide aptamer or to a shorter 23‐mer L‐tyrosinamide aptamer is examined. All nucleoapzymes reveal catalytic Michaelis–Menten enzyme‐like activities and the separated Fe³⁺‐ or Cu²⁺‐terpyridine and L‐tyrosinamide aptamer units show only minute catalytic properties. The catalytic activities of the nucleoapzymes are attributed to the concentration of the L‐tyrosinamide substrate by the aptamer units in proximity to the catalytic sites (K_d = (14 ± 0.1) × 10^?6 m for all 49‐mer catalysts and K_d = (2.5 ± 0.1) × 10^?6 m and K_d = (0.8 ± 0.04) × 10^?6 m for the 23‐mer catalysts). Electron spin resonance experiments reveal that ?OH radicals and ascorbate radicals participate in the transformation of tyrosine derivatives to catechol products. An autocatalytic feedback mechanism for the amplified generation of the two radicals is suggested.     

Roles for Selenoprotein I and Ethanolamine Phospholipid Synthesis in T Cell Activation

The selenoprotein family includes 25 members, many of which are antioxidant or redox regulating enzymes. A unique member of this family is Selenoprotein I (SELENOI), which does not catalyze redox reactions, but instead is an ethanolamine phosphotransferase (Ept). In fact, the characteristic selenocysteine residue that defines selenoproteins lies far outside of the catalytic domain of SELENOI. Furthermore, data using recombinant SELENOI lacking the selenocysteine residue have suggested that the selenocysteine amino acid is not directly involved in the Ept reaction. SELENOI is involved in two different pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, which are constituents of cellular membranes. Ethanolamine phospholipid synthesis has emerged as an important process for metabolic reprogramming that occurs in pluripotent stem cells and proliferating tumor cells, and this review discusses roles for upregulation of SELENOI during T cell activation, proliferation, and differentiation. SELENOI deficiency lowers but does not completely diminish de novo synthesis of PE and plasmenyl PE during T cell activation. Interestingly, metabolic reprogramming in activated SELENOI deficient T cells is impaired and this reduces proliferative capacity while favoring tolerogenic to pathogenic phenotypes that arise from differentiation. The implications of these findings are discussed related to vaccine responses, autoimmunity, and cell-based therapeutic approaches.     

SiC ceramic micropatterns from polycarbosilanes

Micropatterned SiC ceramics were fabricated from polycarbosilanes applying a softlithographic replication technique. A polydimethylsiloxane mould replicated from a photolithographic microstructured silicon wafer was used as master structure. The polydimethylsiloxane mould was coated with a solution containing a mixture of two different polycarbosilanes in n-octane. After treatment at 200–400 °C the cross-linked polycarbosilane films were debonded and pyrolysed at 900 °C in nitrogen and subsequently crystallised at temperatures up to 1500 °C in argon. The cross-linking and thermal degradation behaviour of the polycarbosilanes was investigated by Fourier-transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. X-ray diffractrometry showed the expected development of a nanocrystalline β-SiC (3 nm) as the main phase with increasing temperature. However, traces of α-SiO₂ derived from the polycarbosilane precursors were also detected by X-ray analysis. Removal of the α-SiO₂ dioxide with hydrofluoric acid in the pyrolysed samples and subsequent increased the crystallite size to 7 nm. The Young's modulus determined by nanoindentation was increased from 3 GPa after cross-linking to 110 GPa after crystallisation. Scanning electron microscopy revealed, that the initial micropatterns were fully retained in the pyrolysed and crystallised SiC ceramics. The micropatterned cross-linked and crystallised β-SiC based substrates exhibited light scattering characteristics, which qualify them as promising candidates for diffractive optical elements in microoptical applications.     

Biological evaluation and structural determinants of p38α mitogen-activated-protein kinase and c-Jun-N-terminal kinase 3 inhibition by flavonoids

A series of 42 naturally occurring flavonoids and one flavonoid glucuronide were tested for their ability to inhibit p38α mitogen-activated protein kinase (p38α) and c-Jun-N-terminal kinase 3 (JNK3). Potent inhibitors with IC(50) values in the low micromolar range were identified. Structure-activity relationships were evaluated and the most promising compounds were docked into the ATP binding site of these kinases. Among the different classes of flavonoids, the flavonol group showed better inhibition of p38α. Of this class, kaempferol-7,4'-dimethylether was a potent p38α inhibitor, displaying 13-fold selectivity for p38α over JNK3. The flavone compounds without a 6-methoxy group preferentially inhibited JNK3. The flavone glycoside, luteolin-7-O-glycoside, was identified as a potent inhibitor with the greatest selectivity toward JNK3. In contrast, the flavanol compounds displayed similar inhibitory activities toward both kinases.     

The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases

The mitogen-activated protein (MAP) kinase family includes extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38/RK/CSBP (p38) as structurally and functionally distinct enzyme classes. Here we describe two new dual specificity phosphatases of the CL100/MKP-1 family that are selective for inactivating ERK or JNK/SAPK and p38 MAP kinases when expressed in COS-7 cells. M3/6 is the first phosphatase of this family to display highly specific inactivation of JNK/SAPK and p38 MAP kinases. Although stress-induced activation of p54 SAPKbeta, p46 SAPKgamma (JNK1) or p38 MAP kinases is abolished upon co-transfection with increasing amounts of M3/6 plasmid, epidermal growth factor-stimulated ERK1 is remarkably insensitive even to the highest levels of M3/6 expression obtained. In contrast to M3/6, the dual specificity phosphatase MKP-3 is selective for inactivation of ERK family MAP kinases. Low level expression of MKP-3 blocks totally epidermal growth factor-stimulated ERK1, whereas stress-induced activation of p54 SAPKbeta and p38 MAP kinases is inhibited only partially under identical conditions. Selective regulation by M3/6 and MKP-3 was also observed upon chronic MAP kinase activation by constitutive p21(ras) GTPases. Hence, although M3/6 expression effectively blocked p54 SAPKbeta activation by p21(rac) (G12V), ERK1 activated by p21(ras) (G12V) was insensitive to this phosphatase. ERK1 activation by oncogenic p21(ras) was, however, blocked totally by co-expression of MKP-3. This is the first report demonstrating reciprocally selective inhibition of different MAP kinases by two distinct dual specificity phosphatases.