-
Pharmacology & Therapeutics Jul 2024Acute myocardial infarction (AMI) remains a leading cause of death worldwide. Increased formation of reactive oxygen species (ROS) during the early reperfusion phase is... (Review)
Review
Acute myocardial infarction (AMI) remains a leading cause of death worldwide. Increased formation of reactive oxygen species (ROS) during the early reperfusion phase is thought to trigger lipid peroxidation and disrupt redox homeostasis, leading to myocardial injury. Whilst the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) is chiefly recognised for its central role in ethanol metabolism, substantial experimental evidence suggests an additional cardioprotective role for ALDH2 independent of alcohol intake, which mitigates myocardial injury by detoxifying breakdown products of lipid peroxidation including the reactive aldehydes, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Epidemiological evidence suggests that an ALDH2 mutant variant with reduced activity that is highly prevalent in the East Asian population increases AMI risk. Additional studies have uncovered a strong association between coronary heart disease and this ALDH2 mutant variant. It appears this enzyme polymorphism (in particular, in ALDH2*2/2 carriers) has the potential to have wide-ranging effects on thiol reactivity, redox tone and therefore numerous redox-related signaling processes, resilience of the heart to cope with lifestyle-related and environmental stressors, and the ability of the whole body to achieve redox balance. In this review, we summarize the journey of ALDH2 from a mitochondrial reductase linked to alcohol metabolism, via pre-clinical studies aimed at stimulating ALDH2 activity to reduce myocardial injury to clinical evidence for its protective role in the heart.
Topics: Humans; Aldehyde Dehydrogenase, Mitochondrial; Oxidation-Reduction; Myocardial Infarction; Animals; Ethanol; Polymorphism, Genetic; Aldehyde Dehydrogenase; Reactive Oxygen Species
PubMed: 38763322
DOI: 10.1016/j.pharmthera.2024.108666 -
Journal of Ethnopharmacology Oct 2024Berberine (BBR) is the main active component from Coptidis rhizome, a well-known Chinese herbal medicine used for metabolic diseases, especially diabetes for thousands...
ETHNOPHARMACOLOGICAL RELEVANCE
Berberine (BBR) is the main active component from Coptidis rhizome, a well-known Chinese herbal medicine used for metabolic diseases, especially diabetes for thousands of years. BBR has been reported to cure various metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD). However, the direct proteomic targets and underlying molecular mechanism of BBR against NAFLD remain less understood.
AIM OF THE STUDY
To investigate the direct target and corresponding molecular mechanism of BBR on NAFLD is the aim of the current study.
MATERIALS AND METHODS
High-fat diet (HFD)-fed mice and oleic acid (OA) stimulated HepG2 cells were utilized to verify the beneficial impacts of BBR on glycolipid metabolism profiles. The click chemistry in proteomics, DARTS, CETSA, SPR and fluorescence co-localization analysis were conducted to identify the targets of BBR for NAFLD. RNA-seq and shRNA/siRNA were used to investigate the downstream pathways of the target.
RESULTS
BBR improved hepatic steatosis, ameliorated insulin resistance, and reduced TG levels in the NAFLD models. Importantly, Aldo-keto reductase 1B10 (AKR1B10) was first proved as the target of BBR for NAFLD. The gene expression of AKR1B10 increased significantly in the NAFLD patients' liver tissue. We further demonstrated that HFD and OA increased AKR1B10 expression in the C57BL/6 mice's liver and HepG2 cells, respectively, whereas BBR decreased the expression and activities of AKR1B10. Moreover, the knockdown of AKR1B10 by applying shRNA/siRNA profoundly impacted the beneficial effects on the pathogenesis of NAFLD by BBR. Meanwhile, the changes in various proteins (ACC1, CPT-1, GLUT2, etc.) are responsible for hepatic lipogenesis, fatty acid oxidation, glucose uptake, etc. by BBR were reversed by the knockdown of AKR1B10. Additionally, RNA-seq was used to identify the downstream pathway of AKR1B10 by examining the gene expression of liver tissues from HFD-fed mice. Our findings revealed that BBR markedly increased the protein levels of PPARα while downregulating the expression of PPARγ. However, various proteins of PPAR signaling pathways remained unaffected post the knockdown of AKR1B10.
CONCLUSIONS
BBR alleviated NAFLD via mediating PPAR signaling pathways through targeting AKR1B10. This study proved that AKR1B10 is a novel target of BBR for NAFLD treatment and helps to find new targets for the treatment of NAFLD by using active natural compounds isolated from traditional herbal medicines as the probe.
Topics: Animals; Non-alcoholic Fatty Liver Disease; Humans; Berberine; Hep G2 Cells; Mice, Inbred C57BL; Male; Diet, High-Fat; Lipid Metabolism; Mice; Aldo-Keto Reductases; Aldehyde Reductase; Glucose; Liver; Insulin Resistance
PubMed: 38762210
DOI: 10.1016/j.jep.2024.118354 -
Biochemical and Biophysical Research... Jul 2024Protein S-nitrosylation, which is defined by the covalent attachment of nitric oxide (NO) to the thiol group of cysteine residues, is known to play critical roles in...
Protein S-nitrosylation, which is defined by the covalent attachment of nitric oxide (NO) to the thiol group of cysteine residues, is known to play critical roles in plant development and stress responses. NO promotes seedling photomorphogenesis and NO emission is enhanced by light. However, the function of protein S-nitrosylation in plant photomorphogenesis is largely unknown. E3 ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) and transcription factor ELONGATED HYPOCOTYL 5 (HY5) antagonistically regulate seedling photomorphogenesis. COP1 inhibits plant photomorphogenesis by targeting photomorphogenic promoters like HY5 for 26S proteasome degradation. Here, we report that COP1 is S-nitrosylated in vitro. Mass spectrometry analyses revealed that two evolutionarily well conserved residues, cysteine 425 and cysteine 607, in the WD40 domain of COP1 are S-nitrosylated. S-nitrosylated glutathione (GSNO) is an important physiological NO donor for protein S-nitrosylation. The Arabidopsis (Arabidopsis thaliana) gsnor1-3 mutant, which accumulates higher level of GSNO, accumulated higher HY5 levels than wildtype (WT), indicating that COP1 activity is inhibited. Protein S-nitrosylation can be reversed by Thioredoxin-h5 (TRXh5) in plants. Indeed, COP1 interacts directly with TRXh5 and its close homolog TRXh3. Moreover, catalase 3 (CAT3) acts as a transnitrosylase that transfers NO to its target proteins like GSNO reductase (GSNOR). We found that CAT3 interacts with COP1 in plants. Taken together, our data indicate that the activity of COP1 is likely inhibited by NO via S-nitrosylation to promote the accumulation of HY5 and photomorphogenesis.
Topics: Arabidopsis Proteins; Arabidopsis; Ubiquitin-Protein Ligases; Basic-Leucine Zipper Transcription Factors; Nitric Oxide; Light; Cysteine; Seedlings; Aldehyde Oxidoreductases; Gene Expression Regulation, Plant
PubMed: 38749091
DOI: 10.1016/j.bbrc.2024.150096 -
Biochimica Et Biophysica Acta.... Aug 2024Pancreatic ductal adenocarcinoma (PDAC), is characteristic by a heterogeneous tumor microenvironment and gene mutations, conveys a dismal prognosis and low response to...
Pancreatic ductal adenocarcinoma (PDAC), is characteristic by a heterogeneous tumor microenvironment and gene mutations, conveys a dismal prognosis and low response to chemotherapy and immunotherapy. Here, we found that checkpoint suppressor 1 (CHES1) served as a tumor repressor in PDAC and was associated with patient prognosis. Functional experiments indicated that CHES1 suppressed the proliferation and invasion of PDAC by modulating cellular senescence. To further identify the downstream factor of CHES1 in PDAC, label-free quantitative proteomics analysis was conducted, which showed that the oncogenic Aldo-keto reductase 1B10 (AKR1B10) was transcriptionally repressed by CHES1 in PDAC. And AKR1B10 facilitated the malignant activity and repressed senescent phenotype of PDAC cells. Moreover, pharmaceutical inhibition of AKR1B10 with Oleanolic acid (OA) significantly induced tumor regression and sensitized PDAC cells to gemcitabine, and this combined therapy did not cause obvious side effects. Rescued experiments revealed that CHES1 regulated the tumorigenesis and gemcitabine sensitivity through AKR1B10-mediated senescence in PDAC. In summary, this study revealed that the CHES1/AKR1B10 axis modulated the progression and cellular senescence in PDAC, which might provide revenues for drug-targeting and senescence-inducing therapies for PDAC.
Topics: Animals; Humans; Mice; Aldehyde Reductase; Aldo-Keto Reductases; Carcinogenesis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Deoxycytidine; Gemcitabine; Gene Expression Regulation, Neoplastic; Mice, Nude; Oleanolic Acid; Pancreatic Neoplasms
PubMed: 38718846
DOI: 10.1016/j.bbadis.2024.167214 -
Biotechnology For Biofuels and... May 2024Vanillin is a flavoring substance derived from vanilla. We are currently developing a biotransformation method for vanillin production using glucose. This report...
BACKGROUND
Vanillin is a flavoring substance derived from vanilla. We are currently developing a biotransformation method for vanillin production using glucose. This report describes the last step in vanillin production: the conversion of vanillic acid to vanillin. First, we selected Corynebacterium glutamicum as the host owing to its high vanillin resistance. The aromatic aldehyde reductase gene (NCgl0324) and vanillic acid demethylase protein subunits A and B gene (vanAB, NCgl2300-NCgl2301) were deleted in C. glutamicum genome to avoid vanillin degradation. Next, we searched for an aromatic carboxylic acid reductase (ACAR), which converts vanillic acid to vanillin. Seventeen ACAR homologs from various organisms were introduced into C. glutamicum.
RESULTS
In vivo conversion experiments showed that eight ACARs were successfully expressed and produced vanillin. In terms of conversion activity and substrate specificity, the ACARs from Gordonia effusa, Coccomyxa subellipsoidea, and Novosphingobium malaysiense are promising candidates for commercial production.
CONCLUSIONS
Corynebacterium glutamicum harboring Gordonia effusa ACAR produced 22 g/L vanillin, which is, to the best of our knowledge, the highest accumulation reported in the literature. At the same time, we discovered ACAR from Novosphingobium malaysiense and Coccomyxa subellipsoidea C-169 with high substrate specificity. These findings are useful for reducing the byproducts.
PubMed: 38693567
DOI: 10.1186/s13068-024-02507-3 -
Planta Apr 2024The identification of a functional cinnamoyl-CoA reductase enzyme from Cinnamomum cassia involved in trans-cinnamaldehyde biosynthesis offers the potential for enhancing...
The identification of a functional cinnamoyl-CoA reductase enzyme from Cinnamomum cassia involved in trans-cinnamaldehyde biosynthesis offers the potential for enhancing trans-cinnamaldehyde production through genetic engineering. A significant accumulation of trans-cinnamaldehyde has been found in the bark tissues of C. cassia, used in traditional Chinese medicine. trans-Cinnamaldehyde exhibits various pharmacological properties such as anti-inflammatory, analgesic, and protection of the stomach and the digestive tract. However, further elucidation and characterization of the biosynthetic pathway for trans-cinnamaldehyde is required. In this study, we conducted an integrated analysis of trans-cinnamaldehyde accumulation profiles and transcriptomic data from five different C. cassia tissues to identify the genes involved in its biosynthesis. The transcriptome data we obtained included nearly all genes associated with the trans-cinnamaldehyde pathway, with the majority demonstrating high abundance in branch barks and trunk barks. We successfully cloned four C. cassia cinnamoyl-CoA reductases (CcCCRs), a key gene in trans-cinnamaldehyde biosynthesis. We found that the recombinant CcCCR1 protein was the only one that more efficiently converted cinnamoyl-CoA into trans-cinnamaldehyde. CcCCR1 exhibited approximately 14.7-fold higher catalytic efficiency (k/K) compared to the Arabidopsis thaliana cinnamoyl-CoA reductase 1 (AtCCR1); therefore, it can be utilized for engineering higher trans-cinnamaldehyde production as previously reported. Molecular docking studies and mutagenesis experiments also validated the superior catalytic activity of CcCCR1 compared to AtCCR1. These findings provide valuable insights for the functional characterization of enzyme-coding genes and hold potential for future engineering of trans-cinnamaldehyde biosynthetic pathways.
Topics: Acrolein; Cinnamomum aromaticum; Aldehyde Oxidoreductases; Molecular Docking Simulation; Plant Proteins; Plant Bark; Gene Expression Regulation, Plant
PubMed: 38687380
DOI: 10.1007/s00425-024-04419-w -
Oncology Research 2024Bortezomib results in peripheral neuropathy (PN) in approximately 50% of patients, during multiple myeloma (MM) treatment, a complication known as Bortezomib-induced...
BACKGROUND
Bortezomib results in peripheral neuropathy (PN) in approximately 50% of patients, during multiple myeloma (MM) treatment, a complication known as Bortezomib-induced peripheral neuropathy (BIPN). The drug response varies among individuals. Genetic factor may play an important role in BIPN.
METHODS
A next-generation sequencing (NGS) panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy. mRNA expression of and in 62 peripheral blood samples was detected by real-time quantitative PCR (RT-qPCR). Serum homocysteine (Hcy) levels were detected in 40 samples by chemiluminescent microparticle immunoassay (CMIA).
RESULTS
Compared with the non-BIPN group (n = 89), a total of 8 significantly associated single nucleotide polymorphisms (SNPs) were identified in the BIPN group (n = 115): (rs1801131, rs1801133, rs17421511), (rs1051740), (rs2016848), (rs6151031), (rs1935349) and (rs8192720). The mRNA expression level of in newly diagnosed patients with peripheral neuritis after treatment (NP group) was lower than that of newly diagnosed patients without peripheral neuritis after treatment (NnP group) (1.70 ± 0.77 . 2.81 ± 0.97, = 0.009). Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group (11.66 ± 1.79 μmol/L . 8.52 ± 3.29 μmol/L, = 0.016) and healthy controls (11.66 ± 1.79 μmol/L . 8.55 ± 2.13 μmol/L, ≤ 0.001).
CONCLUSION
and BIPN are linked in Chinese MM patients. BIPN is more likely to occur in patients with lower mRNA expression, which might result in higher serum Hcy levels.
Topics: Humans; Bortezomib; Peripheral Nervous System Diseases; Male; Female; Middle Aged; Polymorphism, Single Nucleotide; Multiple Myeloma; Aged; Methylenetetrahydrofolate Reductase (NADPH2); Asian People; Aldehyde Dehydrogenase 1 Family; Antineoplastic Agents; Retinal Dehydrogenase; Genetic Predisposition to Disease; Adult; China; High-Throughput Nucleotide Sequencing; East Asian People
PubMed: 38686049
DOI: 10.32604/or.2023.043922 -
Diabetes, Obesity & Metabolism Jul 2024The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain...
AIM
The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain elusive, so we aimed to investigate these issues.
METHODS
A 3-year prospective cohort study of 126 Taiwanese patients with SLD treated with pioglitazone (15-30 mg/day) was conducted. Phospholipase domain-containing protein 3 I148M rs738409, methylenetetrahydrofolate reductase rs1801133, aldehyde dehydrogenase 2 (ALDH2) rs671 and lipoprotein lipase rs10099160 single nucleotide polymorphisms were assessed in the patients.
RESULTS
Of 126 patients, 78 (61.9%) were men, and the mean and median ages were 54.3 and 56.5 years, respectively. Pioglitazone responders were defined as those with decreased alanine aminotransferase (ALT) levels at 6 months post-treatment, and 105 (83.3%) patients were responders. Compared with non-responders, responders were more frequently women and had higher baseline ALT levels. The proportion of patients with the ALDH2 rs671 GG genotype was lower among responders (38.6% vs. 66.6%, p = .028). Female sex [odds ratio (OR): 4.514, p = .023] and baseline ALT level (OR: 1.015, p = .046; cut-off level: ≥82 U/L) were associated with pioglitazone response. Among responders, the liver biochemistry and homeostasis model assessment of insulin resistance improved from 6 to 24 months post-treatment. The total cholesterol levels decreased within 6 months, while increases in high-density lipoprotein cholesterol levels and decreases in triglyceride levels and fibrosis-4 scores were noted only at 24 months post-treatment. The 2-year cumulative incidences of cardiovascular events, cancers and hepatic events were similar between responders and non-responders.
CONCLUSIONS
Regarding liver biochemistry, over 80% of Taiwanese patients with SLD had a pioglitazone response, which was positively associated with female sex and baseline ALT levels. Insulin resistance improved as early as 6 months post-treatment, while liver fibrosis improvement was not observed until 24 months post-treatment. The link between the pioglitazone response and the ALDH2 genotype warrants further investigation.
Topics: Humans; Pioglitazone; Male; Female; Middle Aged; Prospective Studies; Polymorphism, Single Nucleotide; Hypoglycemic Agents; Treatment Outcome; Aldehyde Dehydrogenase, Mitochondrial; Taiwan; Alanine Transaminase; Thiazolidinediones; Fatty Liver; Aged; Lipoprotein Lipase; Liver; Diabetes Mellitus, Type 2; Genotype; Adult
PubMed: 38685616
DOI: 10.1111/dom.15622 -
FEMS Microbiology Letters Jan 2024Thermo-acidic pretreatment of lignocellulosic biomass is required to make it amenable to microbial metabolism and results in generation of furfural due to breakdown of...
Thermo-acidic pretreatment of lignocellulosic biomass is required to make it amenable to microbial metabolism and results in generation of furfural due to breakdown of pentose sugars. Furfural is toxic to microbial metabolism and results in reduced microbial productivity and increased production costs. This study asks if deletion of yghZ gene which encodes a NADPH-dependent aldehyde reductase enzyme results in improved furfural tolerance in Escherichia coli host. The ∆yghZ strain-SSK201-was tested for tolerance to furfural in presence of 5% xylose as a carbon source in AM1 minimal medium. At 96 h and in presence of 1.0 g/L furfural, the culture harboring strain SSK201 displayed 4.5-fold higher biomass, 2-fold lower furfural concentration and 15.75-fold higher specific growth rate (µ) as compared to the parent strain SSK42. The furfural tolerance advantage of SSK201 was retained when the carbon source was switched to glucose in AM1 medium and was lost in rich LB medium. The findings have potential to be scaled up to a hydrolysate culture medium, which contains furan inhibitors and lack nutritionally rich components, under bioreactor cultivation and observe growth advantage of the ∆yghZ host. It harbors potential to generate robust industrial strains which can convert lignocellulosic carbon into metabolites of interest in a cost-efficient manner.
Topics: Xylose; Furaldehyde; Escherichia coli; Carbon; Aldehyde Reductase; Escherichia coli Proteins; Culture Media; Gene Deletion; Biomass; Glucose
PubMed: 38664064
DOI: 10.1093/femsle/fnae028 -
ELife Apr 2024Metabolism and biological functions of the nitrogen-rich compound guanidine have long been neglected. The discovery of four classes of guanidine-sensing riboswitches and...
Metabolism and biological functions of the nitrogen-rich compound guanidine have long been neglected. The discovery of four classes of guanidine-sensing riboswitches and two pathways for guanidine degradation in bacteria hint at widespread sources of unconjugated guanidine in nature. So far, only three enzymes from a narrow range of bacteria and fungi have been shown to produce guanidine, with the ethylene-forming enzyme (EFE) as the most prominent example. Here, we show that a related class of Fe- and 2-oxoglutarate-dependent dioxygenases (2-ODD-C23) highly conserved among plants and algae catalyze the hydroxylation of homoarginine at the C6-position. Spontaneous decay of 6-hydroxyhomoarginine yields guanidine and 2-aminoadipate-6-semialdehyde. The latter can be reduced to pipecolate by pyrroline-5-carboxylate reductase but more likely is oxidized to aminoadipate by aldehyde dehydrogenase ALDH7B . Arabidopsis has three 2-ODD-C23 isoforms, among which Din11 is unusual because it also accepted arginine as substrate, which was not the case for the other 2-ODD-C23 isoforms from Arabidopsis or other plants. In contrast to EFE, none of the three Arabidopsis enzymes produced ethylene. Guanidine contents were typically between 10 and 20 nmol*(g fresh weight) in Arabidopsis but increased to 100 or 300 nmol*(g fresh weight) after homoarginine feeding or treatment with Din11-inducing methyljasmonate, respectively. In 2-ODD-C23 triple mutants, the guanidine content was strongly reduced, whereas it increased in overexpression plants. We discuss the implications of the finding of widespread guanidine-producing enzymes in photosynthetic eukaryotes as a so far underestimated branch of the bio-geochemical nitrogen cycle and propose possible functions of natural guanidine production.
Topics: Guanidine; Mixed Function Oxygenases; Homoarginine; Arabidopsis; Guanidines; Protein Isoforms; 2-Aminoadipic Acid
PubMed: 38619227
DOI: 10.7554/eLife.91458