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Background 3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies. Methods Western blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays. Results BDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of Akt Ser473 and mTOR Ser2448 . Conclusions Our study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.

BDH2 is a short-chain dehydrogenase/reductase family member involved in several biological and pathological processes, including the utilization of cytosolic ketone bodies, immunocyte regulation and tumor progression. In this study, we first revealed that BDH2 was downregulated in HCC tissues by qRT-PCR and immunohistochemistry analysis and that low BHD2 expression was significantly associated with poor overall survival, poor tumor differentiation, increased tumor size, venous invasion and an advanced BCLC stage. Moreover, the results of a univariate analysis and multivariate analysis revealed that BDH2 may be regarded as an independent prognostic marker. As a member of a gene family involved in ketone metabolism, BDH2 upregulated the level of β-HB in liver cells as well as the level of H3 histone acetylation. Functional analysis showed that BDH2 expression inhibited tumor cell growth, proliferation and migration. The results of the mechanistic analysis revealed that BDH2 induced mitochondrial apoptosis and inhibited autophagy through the unfolded protein response. Therefore, BDH2 may be a new HCC prognostic marker and a useful treatment target.

Mitochondria are the site of iron utilization, wherein imported iron is incorporated into heme or iron–sulfur clusters. Previously, we showed that a cytosolic siderophore, which resembles a bacterial siderophore, facilitates mitochondrial iron import in eukaryotes, including zebrafish. An evolutionarily conserved 3-hydroxy butyrate dehydrogenase, 3-hydroxy butyrate dehydrogenase 2 (Bdh2), catalyzes a rate-limiting step in the biogenesis of the eukaryotic siderophore. We found that inactivation of bdh2 in developing zebrafish embryo results in heme deficiency and delays erythroid maturation. The basis for this erythroid maturation defect is not known. Here we show that bdh2 inactivation results in mitochondrial dysfunction and triggers their degradation by mitophagy. Thus, mitochondria are prematurely lost in bdh2-inactivated erythrocytes. Interestingly, bdh2-inactivated erythroid cells also exhibit genomic alterations as indicated by transcriptome analysis. Reestablishment of bdh2 restores mitochondrial function, prevents premature mitochondrial degradation, promotes erythroid development, and reverses altered gene expression. Thus, mitochondrial communication with the nucleus is critical for erythroid development.

Objective This study aimed to identify potential susceptibility loci for testicular germ cell tumors (TGCT) through a comprehensive multi-omics analysis. Methods A Mendelian randomization (MR) analysis was conducted to investigate the causal relationships between immune cell phenotypes and TGCT. Summary-based Mendelian Randomization (SMR) and colocalization analyses were subsequently performed to examine candidate phenotypes and TGCT using quantitative trait locis from multiple datasets. Differential gene expression analysis was employed to explore the immune landscape of the target gene in the TGCT tumor microenvironment using UCSC databases. Additionally, potential pathway mechanisms were investigated to elucidate the functional role of candidate genes. Results MR analysis identified a significant causal association between the immune cell phenotype HLA-DR on monocytes and TGCT ( p  = 0.02). SMR analysis revealed that BDH2 was significantly associated with TGCT susceptibility (OR = 0.597, p  = 2.21e-07). Colocalization analysis suggested shared genetic variation between BDH2 and TGCT (PP.H4 = 0.95). Immunohistochemistry staining confirmed that BDH2 mRNA levels were significantly lower in TGCT tissues than in normal controls ( p  < 0.001). In the TGCT tumor microenvironment, lower BDH2 expression was associated with higher immune scores, with T cells and B cells predominantly enriched in the low-expression group, whereas monocytes and endothelial cells were more abundant in the high-expression group. Furthermore, members of the HLA family, exhibited significant correlations between their methylation levels and low BDH2 expression groups. Pathway analysis indicated that BDH2 may influence TGCT progression through the RAS-MAPK signaling pathway. Conclusions Our findings support a significant susceptibility relationship between the phenotype HLA-DR on monocytes, BDH2, and TGCT.

Background Recent studies in animal models, based on the hypothesis that malignant glioma cells are more dependent on glycolysis for energy generation, have shown promising results using ketogenic diet (KD) therapy as an alternative treatment strategy for malignant glioma, effectively starving glioma cells while providing ketone bodies as an energy source for normal neurons and glial cells. In order to test this treatment strategy in humans, we investigated the relative expression of several key enzymes involved in ketolytic and glycolytic metabolism in human anaplastic glioma (WHO grade III) and glioblastoma (GBM, WHO grade IV). Methods Immunohistochemistry was performed on formalin fixed paraffin embedded sections from 22 brain biopsies (17 GBM, 3 anaplastic astrocytoma and 2 anaplastic oligoastrocytoma) using antibodies raised against glycolytic and ketolytic enzymes. The glycolytic enzymes included hexokinase-II (HK2) and pyruvate kinase M2 isoform (PKM2). The ketone body metabolic enzymes included: succinyl CoA: 3-oxoacid CoA transferase (OXCT1), 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and BDH2), and acetyl-CoA acetyltransferase 1 (ACAT1). The immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: POS (>20%), LOW (5-20%), and very low (VLOW) (<5%). Focal non-neoplastic “normal” brain tissue within the biopsy specimens served as internal controls. Results The rate limiting mitochondrial ketolytic enzymes (OXCT1 and BDH1) were either LOW or VLOW, concordantly in 14 of the 17 GBMs and in 1 of 5 anaplastic gliomas, whereas at least one of the glycolytic enzymes was POS in 13 of these 17 GBMs and all 5 anaplastic gliomas. Cytosolic BDH2 and mitochondrial ACTAT1 were, surprisingly, POS in most of these tumors. Conclusion Our results showing that malignant gliomas have differential expression of ketolytic and glycolytic enzymes are consistent with previous studies that have shown that these are genetically heterogeneous tumors. It seems reasonable to hypothesize that patients with low or very low expression of key ketolytic enzymes in their malignant gliomas may respond better to the KD therapy than those patients with positive expression of these enzymes. Further studies in animal models and/or a large-scale clinical trial would be needed to test this hypothesis.

Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.

As a byproduct of yeast valine metabolism during fermentation, diacetyl can produce a buttery aroma in wine. However, high diacetyl concentrations generate an aromatic off-flavor and poor quality in wine. 2,3-Butanediol dehydrogenase encoded by BDH1 can catalyze the two reactions of acetoin from diacetyl and 2,3-butanediol from acetoin. BDH2 is a gene adjacent to BDH1 , and these genes are regulated reciprocally. In this study, BDH1 and BDH2 were overexpressed in Saccharomyces uvarum to reduce the diacetyl production of wine either individually or in combination. Compared with those in the host strain WY1, the diacetyl concentrations in the recombinant strains WY1-1 with overexpressed BDH1 , WY1-2 with overexpressed BDH2 alone, and WY1-12 with co-overexpressed BDH1 and BDH2 were decreased by 39.87, 33.42, and 46.71%, respectively. BDH2 was only responsible for converting diacetyl into acetoin, but not for the metabolic pathway of acetoin to 2,3-butanediol in S. uvarum . This study provided valuable insights into diacetyl reduction in wine.

3-hydroxybutyrate dehydrogenase-2 ( Bdh2 ), a short-chain dehydrogenase, catalyzes a rate-limiting step in the biogenesis of the mammalian siderophore, playing a key role in iron homeostasis, energy metabolism and apoptosis. However, the function of Bdh2 in embryonic stem cells (ESCs) remains unknown. To gain insights into the role of Bdh2 on pluripotency and cell fate decisions of mouse ESCs, we generated Bdh2 homozygous knockout lines for both mouse advanced embryonic stem cell (ASC) and ESC using CRISPR/Cas9 genome editing technology. Bdh2 deficiency in both ASCs and ESCs had no effect on expression of core pluripotent transcription factors and alkaline phosphatase activity, suggesting dispensability of Bdh2 for self-renewal and pluripotency of ESCs. Interestingly, cells with Bdh2 deficiency exhibited potency of endoderm differentiation in vitro ; with upregulated endoderm associated genes revealed by RNA-seq and RT-qPCR. We further demonstrate that Bdh2 loss inhibited expression of multiple methyltransferases (DNMTs) at both RNA and protein level, suggesting that Bdh2 may be essentially required to maintain DNA methylation in ASCs and ESCs. Overall, this study provides valuable data and resources for understanding how Bdh2 regulate earliest cell fate decision and DNA methylation in ASCs/ESCs.

Diacetyl causes an unwanted buttery off-flavor in lager beer. The production of diacetyl is reduced by modifying the metabolic pathway of yeast in the beer fermentation process. In this study, BDH2 and ILV5 genes, coding diacetyl reductase and acetohydroxy acid reductoisomerase, respectively, were expressed using a PGK 1 promoter in Saccharomyces cerevisiae , which deleted one ILV2 allelic gene. Diacetyl contents and fermentation performances were examined and compared. Results showed that the diacetyl content in beer was remarkably reduced by 16.52% in QI2-KP (one ILV2 allelic gene deleted), 55.65% in QI2-B2Y (overexpressed BDH2 gene and one ILV2 allelic gene deleted), and 69.13% in QI2-I5Y (overexpressed ILV5 gene and one ILV2 allelic gene deleted) compared with the host strain S2. The fermentation ability of mutant strains was similar to that of S2. Results of the present study can lead to further advances in this technology and its broad application in scientific investigations and industrial beer production.

Background The relevance of recurrent molecular abnormalities in cytogenetically normal (CN) acute myeloid leukemia (AML) was recently acknowledged by the inclusion of molecular markers such as NPM1 , FLT3 , and CEBPA as a complement to cytogenetic information within both the World Health Organization and the European Leukemia Net classifications. Mitochondrial metabolism is different in cancer and normal cells. A novel cytosolic type 2-hydroxybutyrate dehydrogenase, BDH2, originally named DHRS6, plays a physiological role in the cytosolic utilization of ketone bodies, which can subsequently enter mitochondria and the tricarboxylic acid cycle. Moreover, BDH2 catalyzes the production of 2, 3-DHBA during enterobactin biosynthesis and participates in 24p3 (LCN2)-mediated iron transport and apoptosis. Results We observed that BDH2 expression is an independent poor prognostic factor for CN-AML, with an anti-apoptotic role. Patients with high BDH2 expression have relatively shorter overall survival ( P = 0.007) and a low complete response rate ( P = 0.032). BDH2 -knockdown ( BDH2 -KD) in THP1 and HL60 cells increased the apoptosis rate under reactive oxygen species stimulation. Decrease inducible survivin, a member of the inhibitors of apoptosis family, but not members of the Bcl-2 family, induced apoptosis via a caspase-3-independent pathway upon BDH2 -KD. Conclusions BDH2 is a novel independent poor prognostic marker for CN-AML, with the role of anti-apoptosis, through surviving.