A novel mouse model for pyridoxine-dependent epilepsy due to antiquitin deficiency.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disease caused by mutations in the ALDH7A1 gene leading to blockade of the lysine catabolism pathway. PDE is characterized by recurrent seizures that are resistant to conventional anticonvulsant treatment but are well-controlled by pyridoxine (PN). Most PDE patients also suffer from neurodevelopmental deficits despite adequate seizure control with PN. To investigate potential pathophysiological mechanisms associated with ALDH7A1 deficiency, we generated a transgenic mouse strain with constitutive genetic ablation of Aldh7a1. We undertook extensive biochemical characterization of Aldh7a1-KO mice consuming a low lysine/high PN diet. Results showed that KO mice accumulated high concentrations of upstream lysine metabolites including ∆1-piperideine-6-carboxylic acid (P6C), α-aminoadipic semialdehyde (α-AASA) and pipecolic acid both in brain and liver tissues, similar to the biochemical picture in ALDH7A1-deficient patients. We also observed preliminary evidence of a widely deranged amino acid profile and increased levels of methionine sulfoxide, an oxidative stress biomarker, in the brains of KO mice, suggesting that increased oxidative stress may be a novel pathobiochemical mechanism in ALDH7A1 deficiency. KO mice lacked epileptic seizures when fed a low lysine/high PN diet. Switching mice to a high lysine/low PN diet led to vigorous seizures and a quick death in KO mice. Treatment with PN controlled seizures and improved survival of high-lysine/low PN fed KO mice. This study expands the spectrum of biochemical abnormalities that may be associated with ALDH7A1 deficiency and provides a proof-of-concept for the utility of the model to study PDE pathophysiology and to test new therapeutics.

Aldehyde dehydrogenase plays crucial roles in response to lower temperature stress in Solanum tuberosum and Nicotiana benthamiana.

The aim of this study is to elucidate the role of ALDH2B7a during the response to lower temperature in Solanum tuberosum. This gene was found to have altered intragenic DNA methylation status in our previous reports. A total of 18 orthologs of StALDH2B7a were identified in the S. tuberosum genome, which were then divided into 8 aldehyde dehydrogenase (ALDH) subfamilies. The methylation statuses of four intragenic cytosine sites in intron 5 and exon 6 of genomic StALDH2B7a were altered by lower temperature stress, resulting in changes in the expression of StALDH2B7a. Silencing of NbALDH2C4, a homolog of StALDH2B7a in Nicotiana benthamiana, resulted in plants which were sensitive to lower temperature and accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA). These data suggested that the expression of StALDH2B7a was upregulated by alteration of its intragenic cytosine methylation status during lower temperature stress, and additional StALDH2B7a enzymes scavenged excess aldehydes resulting from ROS in a response to cold stress in potato. Our study expands the understanding of the mechanisms involved in plant responses to lower temperature, and provides a new gene source to improve potato tolerance to cold stress in northern China, where lower temperature is one of the key limiting factors for crop production.

The role of aldehyde dehydrogenase 1A1 in B-cell non-Hodgkin's lymphoma.

Previously we showed that aldehyde dehydrogenase 1A1 (ALDH1A1) is a new mediator for resistance of DLBCL to CHOP and a facility predictor of clinical prognosis. In the present study, knockdown and inhibitor of ALDH1A1 were applied to identify the role of ALDH1A1 in Raji cells. CCK-8 and clone formation assay were applied to determine the CHOP sensitivity and clone formation ability. Caspase colorimetric assay and Annexin V/FITC staining was performed to determine the degree of apoptosis. Western blot analysis was used to detect the NF-κB/STAT3 signaling proteins and apoptotic-associated proteins. Real-time quantitative PCR (RT-PCR) was used to identify the differential expression of ALDH1A1 between NHL patients and healthy donors. We demonstrated that inhibition of ALDH1A1 increased the sensitivity of Raji cells to CHOP, as indicated by increased cytotoxicity, reduced clonogenicity, activated caspase-3/-9, decreased NF-κB/STAT3 signaling and increased pro-apoptosis signaling, ad increased apoptosis rate. Moreover, we found high ALDH1A1 expression was associated with poor prognosis in NHL patients. Our data revealed the critical role of ALDH1A1 in NHL and provides a theoretical basis for the use of ALDH1A1 inhibitors in NHL patients.

Induction of innervation by encapsulated adipocytes with engineered vitamin A metabolism.

Innervation is a fundamental basis for function and survival of tissues. In the peripheral tissues, degenerative diseases create a neurotoxic metabolic milieu that either causes neurodegeneration or fails to sustain regenerative growth and reinnervation of injured/diseased tissues. Encapsulation of cells producing neurotrophic factors can augment axon growth and neuron survival; however, sustained innervation in vivo requires a combination of factors promoting axon growth and guidance pathway that are released in a tissue-specific context. Using novel encapsulation techniques and genetic tools, we manipulated retinoic acid-generating enzyme aldehyde dehydrogenase 1a1 (Aldh1a1) in adipocytes that are capable of promoting growth and innervation of white adipose tissue by sympathetic neurons. Aldh1a1-/- adipocytes secrete molecules that regulate axon guidance and markedly stimulate neurite outgrowth in vitro and in vivo. Based on studies with natural and synthetic RAR agonists and antagonists, gene microarray and nanostring arrays, we concluded that ephrin A5/ephrin A4 is a downstream pathway regulated by Aldh1a1. Encapsulation of Aldh1a1-/- adipocytes into alginate poly-L-lysine microcapsules induced functional innervation of adipose tissue in obese wild-type mice. We propose that encapsulated Aldh1a1-/- adipocytes could provide a therapeutic solution for the reinnervation of damaged tissues.

Aldehyde dehydrogenase 1-positive nigrostriatal dopaminergic fibers exhibit distinct projection pattern and dopamine release dynamics at mouse dorsal striatum.

Aldehyde dehydrogenase 1 (ALDH1A1)-positive dopaminergic (DA) neurons at the ventral substantia nigra pars compacta (SNpc) preferentially degenerate in Parkinson's disease (PD). Their projection pattern and dopamine release properties, however, remains uncharacterized. Here we show that ALDH1A1-positive axons project predominantly to the rostral two-thirds of dorsal striatum. A portion of these axons converge on a small fraction of striosome compartments restricted to the dorsolateral striatum (DLS), where less dopamine release was measured compared to the adjacent matrix enriched with the ALDH1A1-negative axons. Genetic ablation of Aldh1a1 substantially increases the dopamine release in striosomes, but not in matrix. Additionally, the presence of PD-related human α-synuclein A53T mutant or dopamine transporter (DAT) blockers also differentially affects the dopamine output in striosomes and matrix. Together, these results demonstrate distinct dopamine release characteristics of ALDH1A1-positive DA fibers, supporting a regional specific function of ALDH1A1 in regulating dopamine availability/release in striatum.

Association Study of Gene Polymorphisms in GABA, Serotonin, Dopamine, and Alcohol Metabolism Pathways with Alcohol Dependence in Taiwanese Han Men.

BACKGROUND: The roles of GABA, serotonin, dopamine, and alcohol metabolism pathways in alcohol dependence (AD) are evident from animal models and human studies. Aims of this study were to investigate associations between genes in the 4 pathways and AD. METHODS: Male subjects from 2 independent samples of Taiwanese Han descent, a family sample of 179 trios and a case-control sample of 262 AD cases and 273 normal controls, were included in this study. The Schedules for Clinical Assessment in Neuropsychiatry was used for phenotype assessment of AD. We genotyped 282 single nucleotide polymorphisms (SNPs) located in 61 candidate genes involving alcohol metabolism, serotonin, and GABA systems among the family sample and replicated the top hits in the case-control sample. RESULTS: Fifteen SNPs located in 10 genes showed signals of associations (FBAT test p < 0.05) with AD in the family sample. Three SNPs, rs1229984 in ADH1B, rs671 in ALDH2, and rs2000292 in HTR1B, were significantly replicated in the case-control sample (p = 5.87 × 10(-14) , 5.12 × 10(-14) , and 0.0051, respectively). In the combined meta-analysis, these 3 SNPs and 1 additional SNP, rs698 in ADH1C, showed significant association after correcting for multiple comparisons, and rs1229984 and rs671 showed the strongest association (p < 10(-16) ). Logistic regression conditioning on rs1229984 and rs671 in the case-control sample showed that rs2000292 in HTR1B remained nominally significant. CONCLUSIONS: Genes in alcohol metabolism pathway, especially ADH1B and ALDH2, conferred the major genetic risk for AD in Taiwanese Han population. Some genes in GABA and serotonin pathways showed nominal association with AD.

ALDH3A1 Plays a Functional Role in Maintenance of Corneal Epithelial Homeostasis.

Aldehyde dehydrogenase 1A1 (ALDH1A1) and ALDH3A1 are corneal crystallins. They protect inner ocular tissues from ultraviolet radiation (UVR)-induced oxidative damage through catalytic and non-catalytic mechanisms. Additionally, ALDH3A1 has been postulated to play a regulatory role in the corneal epithelium based on several studies that report an inverse association between ALDH3A1 expression and corneal cell proliferation. The underlying molecular mechanisms and the physiological significance of such association remain poorly understood. In the current study, we established Tet-On human corneal epithelial cell (hTCEpi) lines, which express tetracycline-inducible wild-type (wt) or catalytically-inactive (mu) ALDH3A1. Utilizing this cellular model system, we confirmed that human ALDH3A1 decreases corneal cell proliferation; importantly, this effect appears to be partially mediated by its enzymatic activity. Mechanistically, wt-ALDH3A1, but not mu-ALDH3A1, promotes sequestering of tumor suppressor p53 in the nucleus. In the mouse cornea, however, augmented cell proliferation is noted only in Aldh1a1(-/-)/3a1(-/-) double knockout (DKO) mice, indicating in vivo the anti-proliferation effect of ALDH3A1 can be rescued by the presence of ALDH1A1. Interestingly, the hyper-proliferative epithelium of the DKO corneas display nearly complete loss of p53 expression, implying that p53 may be involved in ALDH3A1/1A1-mediated effect. In hTCEpi cells grown in high calcium concentration, mRNA levels of a panel of corneal differentiation markers were altered by ALDH3A1 expression and modulated by its enzyme activity. In conclusion, we show for the first time that: (i) ALDH3A1 decreases corneal epithelial proliferation through both non-enzymatic and enzymatic properties; (ii) ALDH1A1 contributes to the regulation of corneal cellular proliferation in vivo; and (iii) ALDH3A1 modulates corneal epithelial differentiation. Collectively, our studies indicate a functional role of ALDH3A1 in the maintenance of corneal epithelial homeostasis by simultaneously modulating proliferation and differentiation through both enzymatic and non-enzymatic mechanisms.

Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/ß-catenin signaling.

Development of resistance represents a major drawback in osteosarcoma treatment, despite improvements in overall survival. Treatment failure and tumor progression have been attributed to pre-existing drug-resistant clones commonly assigned to a cancer stem-like phenotype. Evidence suggests that non stem-like cells, when submitted to certain microenvironmental stimuli, can acquire a stemness phenotype thereby strengthening their capacity to handle with stressful conditions. Here, using osteosarcoma cell lines and a mouse xenograft model, we show that exposure to conventional chemotherapeutics induces a phenotypic cell transition toward a stem-like phenotype. This associates with activation of Wnt/ß-catenin signaling, up-regulation of pluripotency factors and detoxification systems (ABC transporters and Aldefluor activity) that ultimately leads to chemotherapy failure. Wnt/ß-catenin inhibition combined with doxorubicin, in the MNNG-HOS cells, prevented the up-regulation of factors linked to transition into a stem-like state and can be envisaged as a way to overcome adaptive resistance. Finally, the analysis of the public R2 database, containing microarray data information from diverse osteosarcoma tissues, revealed a correlation between expression of stemness markers and a worse response to chemotherapy, which provides evidence for drug-induced phenotypic stem cell state transitions in osteosarcoma.

Aldehyde dehydrogenase activity is necessary for beta cell development and functionality in mice.

AIMS/HYPOTHESIS: Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells. METHODS: We generated an Aldh1b1-knockout mouse line (Aldh1b1 (tm1lacZ)) and used this to study pancreatic development, beta cell functionality and glucose homeostasis in the absence of Aldh1b1 function. RESULTS: Differentiation in the developing pancreas of Aldh1b1 (tm1lacZ) null mice was accelerated. Transcriptome analyses of newborn and adult islets showed misregulation of key beta cell transcription factors and genes crucial for beta cell function. Functional analyses showed that glucose-stimulated insulin secretion was severely compromised in islets isolated from null mice. Several key features of beta cell functionality were affected, including control of oxidative stress, glucose sensing, stimulus-coupling secretion and secretory granule biogenesis. As a result of beta cell dysfunction, homozygous mice developed glucose intolerance and age-dependent hyperglycaemia. CONCLUSIONS/INTERPRETATION: These findings show that Aldh1b1 influences the timing of the transition from the pancreas endocrine progenitor to the committed beta cell and demonstrate that changes in the timing of this transition lead to beta cell dysfunction and thus constitute a diabetes risk factor later in life. Gene Expression Omnibus (GEO) accession: GSE58025.

Aldehyde dehydrogenases and cancer stem cells.

Aldehyde dehydrogenases (ALDHs), as essential regulators of aldehyde metabolism in the human body, protect organisms from damage induced by active aldehydes. Given their roles in different cancer types, ALDHs have been evaluated as potential prognostic markers of cancer. ALDHs exhibit high activity in cancer stem cells (CSCs) and may serve as markers of CSCs. Moreover, studies indicated that ALDHs and their regulated retinoic acid, reactive oxygen species and reactive aldehydes metabolism were strongly related with various properties of CSCs. Besides, recent research evidences have demonstrated the transcriptional and post-translational regulation of ALDH expression and activation in CSCs. Thus, this review focuses on the function and regulation of ALDHs in CSCs, particularly ALDH1A1 and ALDH1A3.

Promyelocytic leukemia protein induces arsenic trioxide resistance through regulation of aldehyde dehydrogenase 3 family member A1 in hepatocellular carcinoma.

Clinical response of hepatocellular carcinoma (HCC) to arsenic trioxide (ATO) has been poor. Promyelocytic leukemia protein (PML) is central to ATO treatment efficacy of acute promyelocytic leukemia. We examine impacts of PML expression on the effectiveness of ATO treatment in HCC. We show that increased PML expression predicts longer survival and lower cancer recurrence rates after HCC resection. However, high PML expression dampens the anti-tumor effects of ATO in HCC cells. Gene microarray analysis shows that reduced PML expression significantly down-regulates expression of aldehyde dehydrogenase 3 family member A1 (ALDH3A1). ALDH3A1 depression facilitates accumulation of ATO-induced reactive oxygen species. Chromatin immunoprecipitation analysis and promoter activity assays confirm that PML regulates ALDH3A1 expression through binding to the promoter region of ALDH3A1. Clinically, ATO treatment decreases the disease progression rate in advanced HCC patients with negative PML expression. In conclusion, PML confers a favorable prognosis in HCC patients, but it induces ATO resistance through ALDH3A1 up-regulation in HCC cells. ATO is effective for HCC patients with negative PML expression. Combined with an ALDH3A1 inhibitor, ATO may be efficacious in patients with positive PML expression.

Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans.

BACKGROUND AND PURPOSE: Hypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature. EXPERIMENTAL APPROACH: The role of ALDH2 in vascular responses to nitrite was studied using rat thoracic aorta and gluteal subcutaneous fat resistance vessels from patients with heart failure (HF; 16 patients) in vitro and by measurement of changes in forearm blood flow (FBF) during intra-arterial nitrite infusion (21 patients) in vivo. Specifically, we investigated the effects of (i) ALDH2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance-independent inactivation of ALDH2 by glyceryl trinitrate (GTN) on the vasodilator activity of nitrite. In each setting, nitrite effects were measured via evaluation of the concentration-response relationship under normoxic and hypoxic conditions in the absence or presence of ALDH2 inhibitors. KEY RESULTS: Both in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH2 inhibition, in particular under hypoxia. In humans there was a non-significant trend towards attenuation of nitrite-mediated increases in FBF. CONCLUSIONS AND IMPLICATIONS: In human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with HF in vivo, the role of this enzyme in nitrite bioactivation is at the most, modest, suggesting the involvement of other more important mechanisms.

The effects of alcohol and aldehyde dehydrogenases on disorders of hematopoiesis.

Hematopoiesis involves the orderly production of millions of blood cells per second from a small number of essential bone marrow cells termed hematopoietic stem cells (HSCs). Ethanol suppresses normal hematopoiesis resulting in leukopenia, anemia, and thrombocytopenia and may also predispose to the development of diseases such as myelodysplasia (MDS) and acute leukemia. Currently the exact mechanisms by which ethanol perturbs hematopoiesis are unclear. The aldehyde dehydrogenase (ALDH) gene family plays a major role in the metabolism of reactive aldehydes derived from ethanol in the liver and other organs. At least one of the ALDH isoforms, ALDH1A1, is expressed at high levels in HSCs in humans, mice, and other organisms. Recent data indicate that ALDH1A1 and possibly other ALDH isoforms may metabolize reactive aldehydes in HSCs and other hematopoietic cells as they do in the liver and elsewhere. In addition, loss of these ALDHs leads to perturbation of a variety of cell processes that may predispose HSCs to disorders in growth and leukemic transformation. From these findings, we suggest a hypothesis that the cytopenias and possible increased risk of MDS and acute leukemia in heavy alcohol users is due to polymorphisms in genes responsible for metabolism of alcohol derived reactive aldehydes and repair of their DNA adducts in HSCs and other hematopoietic cells. In the article, we will summarize the biological properties of hematopoietic cells and diseases related to ethanol consumption, discuss molecular characteristics of ethanol metabolism, and describe a model to explain how ethanol derived reactive aldehydes may promote HSC damage.

Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms as indicator of mental disorders in Japanese employees.

AIMS: Alcohol-related disorders (ARD) have been shown to be accompanied by a variety of other comorbid mental disorders. This study evaluated the associations between a variety of mental disorders and genetic alcohol sensitivity. METHODS: A total of 1944 Japanese workers were interviewed regarding their mental disorders by the Mini-International Neuropsychiatric Interview (M.I.N.I.). We investigated the relationship of ADH1B rs1229984 and ALDH2 rs671 polymorphisms' combination with mental disorder risks. Logistic regression analysis was used to evaluate the associations between those polymorphisms and mental disorders, adjusting for sex, age, and job rank. RESULTS: The degree of alcohol sensitivity was classified into five groups according to the combination of ADH1B and ALDH2 genotypes (Group I-V in order starting from the lowest alcohol sensitivity). Those with ALDH2 *1/*1 and ADH1B *1/*1 or with ALDH2 *1/*1 and ADH1B *1/*2,*2/*2 (low sensitivity) were significantly or nearly significantly associated with an increased risk of ARD compared with those with ALDH2 *1/*2 and ADH1B *1/*2,*2/*2 as a reference. Those with ALDH2 *1/*1 and ADH1B *1/*1 were also likely to be at an increased risk of any mental disorder except ARD, as well as disorders without comorbid ARD. This tendency was more apparent among women (OR 11.94, 95% CI 0.73-195.63) and non-drinkers (OR 5.43, 95% CI 1.05-28.23). CONCLUSION: The genotype combination of ALDH2 *1/*1 and ADH1B *1/*1 is significantly associated with an increased risk of any mental disorder, especially ARD. Non-drinkers or women with ALDH2 *1/*1 and ADH1B *1/*1 are likely to suffer from any mental disorder except ARD.

Remote ischemic conditioning: from experimental observation to clinical application: report from the 8th Biennial Hatter Cardiovascular Institute Workshop.

In 1993, Przyklenk and colleagues made the intriguing experimental observation that 'brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion' and that this effect'... may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion'. This seminal study laid the foundation for the discovery of 'remote ischemic conditioning' (RIC), a phenomenon in which the heart is protected from the detrimental effects of acute ischemia/reperfusion injury (IRI), by applying cycles of brief ischemia and reperfusion to an organ or tissue remote from the heart. The concept of RIC quickly evolved to extend beyond the heart, encompassing inter-organ protection against acute IRI. The crucial discovery that the protective RIC stimulus could be applied non-invasively, by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce cycles of brief ischemia and reperfusion, has facilitated the translation of RIC into the clinical setting. Despite intensive investigation over the last 20 years, the underlying mechanisms continue to elude researchers. In the 8th Biennial Hatter Cardiovascular Institute Workshop, recent developments in the field of RIC were discussed with a focus on new insights into the underlying mechanisms, the diversity of non-cardiac protection, new clinical applications, and large outcome studies. The scientific advances made in this field of research highlight the journey that RIC has made from being an intriguing experimental observation to a clinical application with patient benefit.

[Effects of activation of ALDH2 by ethanol on the expression of JNK in kidney of diabetic rats].

OBJECTIVE: To observe the effect of activation of aldehyde dehydrogenase 2 (ALDH2) by ethanol on the expression of c-Jun N-terminal kinase (JNK) in the kidney of diabetic rats. METHODS: Eightheen healthy male SD rats were randomly divided into 3 groups (n = 6): normal control group, diabetes group and ethanol + diabetes group. After 8 weeks, 24 h urine samples from rats were collected to detect urinary protein content. The kidney was isolated and the ratio of kidney weight/body weight (index of kidney weight) was detected. The levels of fasting blood glucose, glycosylated hemoglobin serum urea nitrogen and serum creatinine were measured. Morphological changes of renal tissue were observed by optical microscope. The protein expressions of ALDH2 and JNK in renal tissue were detected by Western blot. RESULTS: Compared with the normal control rats, the levels of fasting blood glucose, glycosylated hemoglobin, serum urea nitrogen, serum creatinine and the index of kidney weight were increased markedly in diabetic rats. The expression of ALDH2 protein was decreased, while p-JNK, JNK protein expressions and the ratio of p-JNK/JNK were increased. The morphological observation was shown that the amount of glomerular mesangial matrix were increased, basement membrane were thickened and capillary lumen were narrowed. However,in ethanol + diabetes group, renal function was improved and the damage of renal structure was attenuated. The expression of ALDH2 protein was increased, while p-JNK, JNK and the ratio of p-JNK/JNK were decreased. CONCLUSION: Enhanced ALDH2 expression can protect kidney in diabetic rats, which may be relevant with inhibitting the activity of JNK pathway.

Effect of membrane-bound aldehyde dehydrogenase-encoding gene disruption on glyceric acid production in Gluconobacter oxydans.

Gluconobacter oxydans IFO12528 is able to produce glyceric acid (GA) from glycerol through the action of a membrane-bound alcohol dehydrogenase (mADH), which is required for GA production. To determine whether membrane-bound aldehyde dehydrogenase (mALDH) also plays a role in GA production in G. oxydans, we constructed an aldH-disrupted mutant of G. oxydans (ΔaldH). ΔaldH was unable to produce acetic acid from ethanol, but was able to produce GA at a level approximately half that of the wildtype strain, suggesting the involvement of another ALDH in GA production. We also investigated the enantiomeric composition of GA produced by the IFO12528 and ΔaldH strains. No difference in GA composition was evident in the ΔaldH mutant, with ~73% D-GA enantiomeric excess observed in both strains.

Aldehyde dehydrogenases in acute myeloid leukemia.

Acute myeloid leukemia (AML) affects approximately 15,000 persons per year in the United States and is the sixth leading cause of cancer-related deaths. The treatment of AML has advanced little in the past thirty years, in part because of the biologic heterogeneity of the disease and the difficulty in targeting AML cells while sparing normal hematopoietic cells. Advances in preventing and treating AML are likely to occur once the cellular and molecular differences between leukemia and normal hematopoietic cells are better understood. Aldehyde dehydrogenase (ALDH) activity is highly expressed in hematopoietic stem cells (HSCs), while, in contrast, a subset of AMLs are lacking this activity. This difference may be relevant to the development of AML and may also provide a better avenue for treating this disease. In this review, we summarize what is known about the ALDHs in normal HSCs and AML and propose strategies for capitalizing on these differences in the treatment of acute leukemia, and possibly other cancers as well.

Aldehyde dehydrogenase 2 as a potential protective factor for renal insufficiency in Japanese subjects with heart failure: a pilot study.

The association between the aldehyde dehydrogenase 2 (ALDH2, rs671) genotypes and the estimated glomerular filtration rate (eGFR) was investigated in Japanese hypertensive patients with/without coronary artery disease or with ischemic heart failure (HF), and age/sex-matched normotensive healthy controls. The eGFRs were significantly lower in the HF subjects with the ALDH2 *2/*2 genotype than in those with the other genotypes. Multiple regression analyses adjusted by the potentially confounding factors showed the *2/*2 genotype to be significantly associated with the decreased eGFR, compared to the *1/*1 genotype (ß = 31.99 ml min1 per 1.73 m2, P < 0.01).

ALDH3A1 is overexpressed in a subset of hepatocellular carcinoma characterised by activation of the Wnt/ß-catenin pathway.

Aldehyde dehydrogenase isoforms, ALDH1A1 and ALDH3A1, are associated with poor clinical outcome and resistance to chemotherapy in a wide variety of human malignancies. So far, their expression and prognostic significance in hepatocellular carcinoma (HCC) remains unknown. The aim of our study was to investigate their expression in HCC, and to correlate this to clinical, pathological and molecular features. ALDH1A1 and ALDH3A1 expression was first evaluated by microarray analysis in a series of 60 HCCs and five tumour-free liver tissue samples. Our findings related to ALDH3A1 were further validated by immunohistochemistry in a series of 81 HCCs and 23 hepatocellular adenomas (HCA). Microarray analysis showed no difference in ALDH1A1 expression between HCCs and tumour-free liver tissue. In contrast, ALDH3A1 was strongly upregulated in a subset of HCCs characterised by activation of the Wnt/ß-catenin pathway and CTNNB1 mutations. Using immunohistochemistry, we confirmed that high ALDH3A1 expression is associated with nuclear staining for ß-catenin and strong homogeneous staining for glutamine synthetase, two classical Wnt/ß-catenin pathway activation markers. Consistent with this finding, in tumour-free liver tissue, ALDH3A1 expression was observed in centrilobular hepatocytes, in which the Wnt/ß-catenin pathway is known to be physiologically activated. We also observed higher ALDH3A1 expression in CTNNB1-mutated HCA when compared with other subtypes. No correlation between ALDH3A1 expression and patient survival or tumour recurrence was observed.In conclusion, ALDH3A1 is a marker of activation of the Wnt/ß-catenin pathway in HCC, HCA and tumour-free liver tissue. Further studies may help to elucidate the potential role of ALDH3A1 in HCC development and resistance to chemotherapy.