ALDH2, a novel protector against stroke?

In a recent paper published in Cell Research, an association between expression of mitochondrial aldehyde dehydrogenase (ALDH2), a mitochondrial chaperon expressed in the brain, and the prevalence of stroke is revealed. This finding indicates that ALDH2 may serve as a potential endogenous neuroprotective target and a promising therapeutic strategy for the management of stroke.Stroke is one of the leading causes of death and a major reason of adult chronic disability as well as age-related cognitive decline and dementia¹. Ischemic stroke represents > 80% of all stroke incidences with the remaining 20% due to primary hemorrhage. Proper management of the conventional risk factors for stroke, such as high blood pressure, elevated blood cholesterol, cigarette smoking, carotid stenosis, diabetes mellitus and heart failure, may reduce the incidence of stroke only to a certain degree, suggesting the existence of undiscovered or undefined risk factors^1,2. The unidentified risk factors for stroke, in conjunction with unsatisfactory control of known risk factors (e.g., high cholesterol and hypertension), may explain the intimate clinical challenge or failure for stroke management. To this end, identification of novel risk factors may hold promises in the development of strategies for prevention and treatment of stroke. Ample evidence has implicated the importance of genetic predisposition in the onset and progression of stroke². More recently, genome-wide association study (GWAS) approach has transformed the genetics of many complex chronic diseases and is just beginning to impact the field of stroke³. Genetic variants predisposing to ischemic stroke have been revealed by GWAS, such as two loci associated with atrial fibrillation (PITX2 and ZFHX3) linked to cardioembolic stroke and a locus on chromosome 9p21 tied to large-vessel stroke^1,4,5. Nonetheless, the precise contribution of genetics to the etiology of stroke, in particular various stroke subtypes, remains somewhat elusive. Gene candidates that have been identified to be associated with stoke warrant further validation in a large independent data set to consolidate their causative role in the pathogenesis of stroke.In a recent paper published in Cell Research, Guo and colleagues performed an unbiased proteomic examination and unveiled a unique role of deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), the so-called “facial flash gene” responsible for detoxification of toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE), in the pathogenesis of stroke⁶. In their study, overexpression or activation of ALDH2 conferred neuroprotection through clearance of 4-HNE whereas ALDH2 knockdown mitigated the neuroprotective property of PKCɛ. The PKCɛ-ALDH2 pathway was shown to mediate neuroprotection offered by moderate ethanol intake. Serum 4-HNE levels were inversely correlated with lifespan and elevated plasma 4-HNE levels were observed for at least 6 months following stroke onset. Perhaps the most intriguing evidence is that much higher initial plasma 4-HNE levels were associated with development of stroke in an 8-year follow-up study. These findings favor a likely role of ALDH2 in the prevalence of stroke or stroke-prone subjects, and furthermore, its therapeutic potential as a target in the management of stroke (Figure 1).Open in a separate windowFigure 1Schematic diagram depicting the possible interplay between ischemic stroke and elevated serum 4-HNE levels. Serum 4-HNE levels positively correlates with stroke injury and remains elevated after stroke. Deficiency and activation of ALDH2 significantly accentuates and attenuates stroke-associated cerebral ischemia injury, respectively.ALDH2 is a human gene found on chromosome 12. All Caucasians are homozygous for ALDH2 while approximately 50% of Asians are heterozygous and possess only one normal copy of the ALDH2 gene and one mutant copy encoding an inactive mitochondrial isozyme⁷. A recent meta-analysis of GWAS identified a tight association between ALDH2 genetic mutation and elevated blood pressure, a known risk factor for stroke, in Asian decedents⁸. This is supported by the recent observation favoring a crucial role for ALDH2 in the regulation of cardiovascular homeostasis in diabetes, alcoholism, endoplasmic reticulum stress, arrhythmias and ischemia-reperfusion injury^9,10,11. Stroke is known to interrupt mitochondrial function and promote mitochondrial swelling and depolarization, leading to ultimate neuronal cell death¹². ALDH2 exerts a major role in aldehyde detoxification in mitochondria, and attenuates or ablates neuronal mitochondrial damage. Reactive aldehydes, including MDA, 4-HNE and 1-palmitoyl-2-oxovaleroyl phosphatidyl choline (POVPC), all of which are potential substrates for ALDH2, are elevated in ischemic stroke injury^1,12. Higher levels of 4-HNE and MDA were found in the serum of stroke-prone hypertensive rats compared with normotensive WKY rats⁶. Interestingly, only 4-HNE, but not MDA, was elevated in stroke-prone hypertensive rats compared with hypertensive rats, suggesting a role of 4-HNE as a possible biomarker for stroke.Given that approximately 40% of the East Asian population carries an ALDH2*2 mutant allele with dramatic reduction in ALDH2 enzymatic activity, the current observation suggest that ALDH2 mutation serves as a risk factor for stroke⁶. Unlike its reported role in the heart, little information is available for ALDH2 in the brain and cerebrovascular function. Like all animal studies, caution needs to be taken to translate experimental findings to a clinical setting. It is noteworthy that the animal outcome studies were performed at a relatively short period after stroke. A longer time window should be essential to the ultimate assessment of stroke injury. Further studies are needed to uncover the precise mechanism behind the regulation of ALDH2 in stroke.     

米诺环素对不完全脊髓损伤大鼠脊髓BDNF和NT-3表达的影响

目的观察腹腔注射米诺环素对改良Allen’s法造成的不完全脊髓损伤大鼠脊髓中脑源性神经营养因子以及神经营养因子3表达的影响,探讨米诺环素治疗脊髓损伤的作用机制。方法成年雌性Sprague-Dawley(SD)大鼠54只,改良Allen’s法造成不完全脊髓损伤,根据实验需要可以分为3组,空白组,只打开脊柱椎板,不损伤;治疗组,大鼠脊髓损伤,并腹腔注射米诺环素;损伤组,大鼠脊髓损伤,腹腔注射等剂量的生理盐水。观察各组大鼠的后肢能力Basso-Beattie-Bresnahan评分,并于不同时段(3d、7d,14d)取大鼠脊髓T8-9段采用逆转录PCR,以及免疫化学组织染色法测定脑源性神经营养因子以及神经营养因子3的表达。结果米诺环素能够明显改善不完全脊髓损伤大鼠的功能,逆转录PCR和脊髓组织冰冻切片免疫组织化学染色DAB都能证实米诺环素治疗组脑源性神经营养因子以及神经营养因子3表达显著增多。结论米诺环素在治疗不完全脊髓损伤大鼠的机制还应与其上调了大鼠体内的脑源性神经营养因子以及神经营养因子3表达有关。     

Influence of gestational overfeeding on myocardial proinflammatory mediators in fetal sheep heart

Maternal overnutrition is associated with predisposition of offspring to cardiovascular disease in later life. Since maternal overnutrition may promote fetal and placental inflammatory responses, we hypothesized that maternal overnutrition/obesity increases expression of fetal cardiac proinflammatory mediators and alter cardiac morphometry. Multiparous ewes were fed either 150% of National Research Council (NRC) nutrient recommendations (overfed) or 100% of NRC requirement (control) from 60 days prior to mating to gestation Day 75 (D75), when ewes were euthanized. An additional cohort of overfed and control ewes were necropsied on D135. Cardiac morphometry, histology, mRNA and protein expression of toll-like receptor 4, iNOS, IL-1a, IL-1b, IL-6, IL-18, CD-14, CD-68, M-CSF and protein levels of phosphorylated I-κB and nuclear factor κB (NF-κB) were examined. Immunohistochemistry was performed to assess neutrophil and monocyte infiltration. Crown rump length, left and right ventricular free wall weights as well as left and right ventricular wall thickness were significantly increased in D75 fetuses of overfed mothers. Hematoxylin and eosin staining revealed irregular myofiber orientation and increased interstitial space in fetal ventricular tissues born to overfed mothers. Oil red O staining exhibited marked lipid droplet accumulation in the overfed fetuses. Overfeeding significantly enhanced TLR4, IL-1a, IL-1b IL-6 expression, promoted phosphorylation of IκB, decreased cytoplasmic NF-κB levels and increased neutrophil and monocyte infiltration. Collectively, these data suggest that maternal overfeeding prior to and throughout gestation leads to inflammation in the fetal heart and alters fetal cardiac morphometry.     

(L)-(Trimethylsilyl)alanine synthesis exploiting hydroxypinanone-induced diastereoselective alkylation

A new and efficient synthesis of (L)-(trimethylsilyl)alanine (TMSAla) with suitable protection for use in Solid Phase Peptide Synthesis (SPPS) has been accomplished starting from glycine tert-butyl ester and using hydroxypinanone as chiral inductor. The silylated side chain was introduced by alkylation of the Schiff base intermediate with iodomethyl(trimethylsilane) at ?78 °C. Among the different synthetic routes that were tested including several chiral inductors and different Schiff bases, this strategy was selected and afforded (L)-TMSAla in good chemical overall yield with 98 % ee.     

Enantiomer-specific selection of amino acids

Dietary intake of l-amino acids impacts on several physiological functions, including the control of gastrointestinal motility, pancreatic secretion, and appetite. However, the biological mechanisms regulating behavioral predilections for certain amino acid types remain poorly understood. We tested the hypothesis that, in mice, the potency with which a given glucogenic amino acid increases glucose utilization reflects its rewarding properties. We have found that: (1) during long-, but not short-, term preference tests, l-alanine and l-serine were preferred over their d-enantiomer counterparts, while no such effect was observed for l-threonine vs. d-threonine; (2) these behavioral patterns were closely associated with the ability of l-amino acids to promote increases in respiratory exchange ratios such that those, and only those, l-amino acids able to promote increases in respiratory exchange ratios were preferred over their d-isomers; (3) these behavioral preferences were independent of gustatory influences, since taste-deficient Trpm5 knockout mice displayed ingestive responses very similar to those of their wild-type counterparts. We conclude that the ability to promote increases in respiratory exchange ratios enhances the reward value of nutritionally relevant amino acids and suggest a mechanistic link between substrate utilization and amino acid preferences.     

Supplementation with branched-chain amino acids to a low-protein diet regulates intestinal expression of amino acid and peptide transporters in weanling pigs

This study determined the effects of dietary branched-chain amino acids (AA) (BCAA) on growth performance, expression of jejunal AA and peptide transporters, and the colonic microflora of weanling piglets fed a low-protein (LP) diet. One hundred and eight Large White × Landrace × Duroc piglets (weaned at 28 days of age) were fed a normal protein diet (NP, 20.9 % crude protein), an LP diet (LP, 17.1 % crude protein), or an LP diet supplemented with BCAA (LP + BCAA, 17.9 % crude protein) for 14 days. Dietary protein restriction reduced piglet growth performance and small-intestinal villous height, which were restored by BCAA supplementation to the LP diet to values for the NP diet. Serum concentrations of BCAA were reduced in piglets fed the LP diet while those in piglets fed the LP + BCAA diet were similar to values for the NP group. mRNA levels for Na⁺-neutral AA exchanger-2, cationic AA transporter-1, b^0,+ AA transporter, and 4F2 heavy chain were more abundant in piglets fed the LP + BCAA diet than the LP diet. However, mRNA and protein levels for peptide transporter-1 were lower in piglets fed the LP + BCAA diet as compared to the LP diet. The colonic microflora did not differ among the three groups of pigs. In conclusion, growth performance, intestinal development, and intestinal expression of AA transporters in weanling piglets are enhanced by BCAA supplementation to LP diets. Our findings provide a new molecular basis for further understanding of BCAA as functional AA in animal nutrition.     

Responses of a rice–wheat rotation agroecosystem to experimental warming

Climate change is likely to affect agroecosystems in many ways. This study was performed to investigate how a rice–winter wheat rotation agroecosystem in southeast China would respond to global warming. By using an infrared heater system, the soil surface temperature was maintained about 1.5 °C above ambient milieu over 3 years. In the third growing season (2009–2010), the evapotranspiration (ET) rate, crop production, soil respiration, and soil carbon pool were monitored. The ET rate was 23 % higher in the warmed plot as compared to the control plot during the rice paddy growing season, and the rice grain yield was 16.3 % lower, but there was no significant difference in these parameters between the plots during the winter wheat-growing season. The phenology of the winter wheat shifted under experimental warming, and ET may decrease late in the winter wheat-growing season. Experimental warming significantly enhanced soil respiration, with mean annual soil respiration rates of 2.57 ± 0.17 and 1.96 ± 0.06 μmol CO₂ m^?2 s^?1 observed in the warmed and control plots, respectively. After 3 years of warming, a significant decrease in the total organic carbon was observed, but only in the surface soil (0–5 cm). Warming also stimulated the belowground biomass, which may have compensated for any heat-induced loss of soil organic carbon. Paddy rice seemed to be more vulnerable to warming than winter wheat in terms of water-use efficiency and grain production.     

Growth and pigment accumulation in nutrient-depleted Isochrysis aff. galbana T-ISO

The effect of three different nutrient depletions (nitrogen, sulphur and magnesium) on the growth and pigment accumulation of the haptophyte Isochrysis aff. galbana (clone T-ISO) has been studied. Pigments were quantified based on RP-UHPLC-PDA-MSⁿ analysis. All nutrient depletions led to reduced maximal biomass concentrations. Besides, all nutrient-depleted cultures accumulated 3-hydroxyechinenone. To our knowledge, this is the first time that 3-hydroxyechinenone has been found in I. aff. galbana T-ISO. Most 3-hydroxyechinenone, as well as the most echinenone and diatoxanthin, were found in the nitrogen-limited culture in which a more severe limitation resulted in higher cellular contents. Similar to accumulation of diatoxanthin, accumulation of 3-hydroxyechinenone and echinenone may be part of a global (stress) response mechanism to oversaturating light conditions.