DDAH1 deficiency promotes intracellular oxidative stress and cell apoptosis via a miR-21-dependent pathway in mouse embryonic fibroblasts

Publication date: Available online 21 January 2016
Source:Free Radical Biology and Medicine
Author(s): Chenyang Zhao, Tianhe Li, Bingxing Han, Wenhui Yue, Linlin Shi, Hongyun Wang, Yuting Guo, Zhongbing Lu
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is degraded by dimethylarginine dimethylaminohydrolase 1 (DDAH1). Emerging evidence suggests that plasma ADMA accumulation, DDAH1 activity/expression reduction, and microRNA-21 (miR-21) upregulation are linked to disease pathology, but the mechanisms remain largely unknown. In the present study, we assessed the potential role of the ADMA–DDAH1–miR-21 pathway in the regulation of the cellular redox state and apoptosis using wild-type (WT) and DDAH1-knockout (KO) immortalized mouse embryonic fibroblasts (MEFs). DDAH1 deficiency significantly increased ADMA levels, enhanced cellular oxidative stress, and rendered cells more vulnerable to apoptosis induced by tert-butyl hydroperoxide (tBHP) or A23187. However, treatment with exogenous ADMA (1–80μM) for 24h or for a prolonged period (10μM, 10 passages) in WT MEFs had no marked effect on intracellular reactive oxygen species (ROS) and apoptosis sensitivity. Interestingly, miR-21 expression was significantly increased, by 4 fold, in DDAH1^-/- MEFs, and the induction of miR-21 by DDAH1 deficiency was dependent on oxidative stress and NF-κB activation. Inhibition of DDAH1 activity by PD 404182 also increased miR-21 expression. Furthermore, inhibition of miR-21 with a lentiviral vector in DDAH1^-/- MEFs significantly upregulated SOD2 expression and the attenuated oxidative stress and apoptosis induced by tBHP or A23187. Taken together, our results suggest that DDAH1 not only acts as an enzyme degrading ADMA but also controls cellular oxidative stress and apoptosis via a miR-21-dependent pathway.

Graphical abstract

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“Cold training” affects rat liver responses to continuous cold exposure

Publication date: Available online 22 January 2016
Source:Free Radical Biology and Medicine
Author(s): Paola Venditti, Gaetana Napolitano, Daniela Barone, Sergio Di Meo
Continuous exposure of homeothermic animals to low environmental temperatures elicits physiological adaptations necessary for animal survival, which are associated to higher generation of pro-oxidants in thermogenic tissues. It is not known whether intermittent cold exposure (cold training) is able to affect tissue responses to continuous cold exposure. Therefore, we investigated whether rat liver responses to continuous cold exposure of 2 days are modified by cold training (1hour daily for 5day per week for 3 consecutive weeks). Continuous cold increased liver oxidative metabolism by increasing tissue content of mitochondrial proteins and mitochondrial aerobic capacity. Cold training did not affect such parameters, but attenuated or prevented the changes elicited by continuous cold exposure. Two-day cold exposure increased lipid hydroperoxide and protein-bound carbonyl levels in homogenates and mitochondria, whereas cold training decreased such effects although it decreased only homogenate protein damage in control rats. The activities of the antioxidant enzymes GPX and GR and H2O2 production were increased by continuous cold exposure. Despite the increase in GPX and GR activities, livers from cold-exposed rats showed increased susceptibility to in vitro oxidative challenge. Such cold effects were decreased by cold training, which in control rats reduced only H2O2 production and susceptibility to stress. The changes of PGC-1, NRF-1, and NRF-2 expression levels were consistent with those induced by cold exposure and cold training in mitochondrial protein content and antioxidant enzyme activities. However, the mechanisms by which cold training attenuates the effects of the continuous cold exposure remain to be elucidated.



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Finger-vein authentication based on deformation-tolerant feature-point matching

Abstract

A novel method for finger-vein authentication based on feature-point matching is proposed and evaluated. A finger-vein image captured by infrared light contains artifacts such as irregular shading and vein posture deformation that can degrade accuracy of finger-vein authentication. Therefore, a method is proposed for extracting features from vein patterns and for matching feature points that is robust against irregular shading and vein deformation. In the proposed method, curvature of image-intensity profiles is used for feature point extraction because such image profiles are a robust feature against irregular shading. To increase the number of feature points, these points are extracted from any positions where vein shape is non-linear. Moreover, a finger-shape model and non-rigid registration method are proposed. Both the model and the registration method correct a deformation caused by the finger-posture change. It is experimentally shown that the proposed method achieves more robust matching than conventional methods. Furthermore, experiments on finger-vein identification show that the proposed method provides higher identification accuracy than conventional methods.

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Interaction between left ventricular twist mechanics and arterial haemodynamics during localised, non-metabolic hyperaemia with and without blood flow restriction

Whether left ventricular twist and untwisting rate (LV twist mechanics) respond to localised, peripheral, non-metabolic changes in arterial haemodynamics within an individual's normal afterload-range is presently unknown. Furthermore, previous studies indicate that LV twist mechanics may override the provision of cardiac output, but this hypothesis has not been examined purposefully. Therefore, we acutely altered local peripheral arterial haemodynamics in eleven healthy humans (Women/men: n = 3/8; age: 26±5 years) by bilateral arm heating (BAH). Ultrasonography was used to examine arterial haemodynamics, LV twist mechanics and the twist-to-shortening ratio (TSR). To further determine the arterial function-dependent contribution of LV twist mechanics to cardiac output, partial blood flow restriction to the arms was applied during BAH (BAH_BFR). BAH increased arm skin temperatures (Δ+6.4±0.9°C, P<0.0001) but not core temperature (-0.0±0.1°C, P>0.05), concomitant to increases in brachial artery blood flow (Δ 212±77 mL, P<0.0001), cardiac output (Δ 495±487 L min⁻¹, P<0.05), LV twist mechanics (Δ 15.2±5.2 degrees, P<0.05) and TSR (Δ 3.3±1.3, P<0.05) but maintained carotid artery blood flow (Δ 18±147 mL, P>0.05). Subsequently, BAH_BFR reduced all parameters to pre-heating levels, except for TSR and heart rate which remained at BAH levels. In conclusion, LV twist mechanics responded to local peripheral arterial haemodynamics within the normal afterload-range in part independent of TSR and heart rate. The findings suggest that LV twist mechanics may be more closely associated with intrinsic sensing of excessive pressure-stress rather than being associated with the delivery of adequate cardiac output.

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Synthesis and Dynamic Behavior of Chiral NNO-Scorpionate Zinc Initiators for the Ring-Opening Polymerization of Cyclic Esters

Abstract

The reaction of chiral alcohol–scorpionate compounds bpzbeH [bpzbeH = 1,1-bis(3,5-dimethylpyrazol-1-yl)-3,3-dimethyl-2-butanol] or bpzteH [bpzteH = 2,2-bis(3,5-dimethylpyrazol-1-yl)-1-para-tolylethanol] with [ZnR₂] (R = Me, Et, CH₂SiMe₃) in a 1:2 molar ratio afforded the dinuclear chiral zinc alkyls [Zn(R)(κ²-NNµ-O)Zn(R)₂] (1–4) [κ²-NNµ-O = bpzbe, R = Me (1), Et (2), CH₂SiMe₃ (3); bpzte, R = Et (4)]. Subsequent alcoholysis or thioalcoholysis reaction with ArEH (1 equiv.; E = O, S; Ar = 2,6-C₆H₃Me₂) yielded the chiral dinuclear mixed alkyl–alryl oxides/thioaryl oxides [(ZnR)₂(κN:κN-µ-O)(µ-EAr)] (5–12) [κN:κN-µ-O = bpzbe, E = O, R = Me (5), Et (6), CH₂SiMe₃ (7); bpzte, E = O, R = Et (8); bpzbe, E = S, R = Me (9), Et (10), CH₂SiMe₃ (11); bpzte, E = S, R = Et (12)]. The alcoholysis reaction of the previously reported monoalkyls [Zn(Me)(κ³-NNO)] or [Zn(R)(κ-NNµ-O)]₂ with ArOH (1 equiv., Ar = 2,6-C₆H₃Me₂) afforded the chiral aryl oxides [Zn(OAr)(κ²-NNµ-O)]₂ (13–14) [κ²-NNµ-O = bpzbe (13); bpzte (14)]. The X-ray crystal structures of 3, 5, 6, and 14 confirmed a dinuclear structure in all cases with the alkoxide of the heteroscorpionates in a µ-bridging mode between the Zn^II centers. Variable-temperature NMR spectroscopic studies were carried out to study their dynamic behavior in solution. Complexes 1–9 and 12 can act as single-component initiators for the ROP of ϵ-CL and L-/rac-LA, and afforded materials with low molecular weights and narrow monomodal molecular weight distributions. MALDI-TOF mass spectra confirmed that for 5–8 the initiation occurred through nucleophilic attack by the alkoxide group, rather than the alkyl group, on the lactide monomer. Furthermore, inspection of the kinetic parameters showed propagations with a pseudo-first-order dependence on monomer and catalyst concentrations. Microstructural analysis of poly(rac-lactide) revealed that the mixed alkyl/aryl oxide-substituted initiators exert a moderate level of heteroselectivity (P_s = 0.66).

A new series of chiral dinuclear trisalkyl- and alkyl–aryl oxide-containing zinc heteroscorpionates complexes, namely, [Zn(R)(κ²-NNµ-O)Zn(R)₂] and [(ZnR)₂(κN:κN-µ-O)(µ-OAr)], respectively, has been synthesized. Their dynamic behavior has been studied. Both families act as single-component living initiators for the ring-opening polymerization of ϵ-CL and L-/rac-LA.

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Controlled Synthesis of Pnicogen–Chalcogen Polycations in Ionic Li­quids

Abstract

Three new pnicogen–chalcogen polycations were synthesized under specific conditions in the Lewis-acidic ionic liquids (ILs) [EMIm]X·nAlX₃ and [BMIm]X·nAlX₃ (X = Cl, Br; [EMIm]: 1-ethyl-3-methylimidazolium, [BMIm]: 1-butyl-3-methylimidazolium) and crystallized as their tetrahalogenidoaluminate salts. Single-crystal X-ray diffraction revealed the new polycation [Bi₆Te₄Br₂]⁴⁺ in triclinic [Bi₆Te₄Br₂](AlBr₄)₄ as the reaction product of bismuth, tellurium, and bismuth tribromide. Substitution of the elements with Bi₂Te₃ yielded the heterocubane [Bi₄Te₄]⁴⁺ in tetragonal [Bi₄Te₄](AlBr₄)₄, which crystallizes isotypically to its known chlorine counterpart. The latter is also accessible from ILs. The interactions between cations and anions were evaluated by quantum-chemical calculations. Bi₂S₃, which is insoluble in most media, readily dissolves in the employed IL and forms the new augmented heterocubane [Bi₃S₄AlCl]³⁺, which crystallizes with the complex anion [S(AlCl₃)₃]^2– as triclinic [Bi₃S₄AlCl][S(AlCl₃)₃]AlCl₄. Quantum-chemical calculations support the assignment of elements in this compound. The monoclinic crystal structure of [Sb₁₃Se₁₆](AlCl₄)₆(Al₂Cl₇) contains a new member of the small family of pnicogen–chalcogen spiro-heterocubanes.

Heteropolycations: Three new pnicogen–chalcogen polycations were synthesized in imidazolium-based Lewis-acidic ionic liquids (IL) at moderate temperatures. Bi₂S₃, usually soluble only under harsh conditions, readily dissolves and reacts in the employed IL to give a quaternary polycation. The choice of starting materials and the reaction temperature were identified as important control parameters.

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Rare-Earth Metal Oxo/Hydroxo Clusters – Synthesis, Structures, and Applications

Abstract

Multinuclear rare-earth metal coordination clusters bridged by oxo/hydroxo units have emerged from being lab curiosities to become a readily accessible class of compounds. New synthetic strategies for accessing these compounds on reasonable scales have been established. Clusters of different sizes have been investigated in terms of their magnetic and photophysical properties. Some preliminary biological applications have also been established.

The synthesis and the structures of rare-earth metal oxo/hydroxo clusters are reviewed. The clusters are very robust, which makes them ideal materials for further chemical, physical, and biological studies.

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