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Journal of Hazardous Materials Jan 2024Neonicotinoids are widely used but environmentally hazardous insecticides. Constructed wetlands offer potential for neonicotinoid removal, but the corresponding...
Neonicotinoids are widely used but environmentally hazardous insecticides. Constructed wetlands offer potential for neonicotinoid removal, but the corresponding metabolic pathways and mechanisms in wetland plants are incompletely understood. This study investigated the fate of six neonicotinoids and their metabolites in Cyperus papyrus, a common wetland plant, and the underlying metabolic mechanisms through enzymatic and transcriptomic analyses. Neonicotinoids were absorbed by roots and translocated upward, causing high levels in shoots. Concentrations of neonicotinoids and their metabolites declined to their minimum at day 28 of exposure. Nitro reduction, hydroxylation, and demethylation were the major metabolic reactions with which C. papyrus responded to neonicotinoids. These reactions may be mediated by cytochrome P450 enzyme, aldehyde oxidase, glutathione-disulfide reductase, and glucuronate reductase. The toxicity of neonicotinoids in C. papyrus was evaluated according to the peroxidase and catalase enzymatic activities. Transcriptomic analysis revealed that differentially expressed genes (DEGs) mainly encoded proteins related to immune processes and cell growth regulation. Co-expression correlation analysis of DEGs revealed that the genes encoding P450s, peroxidase and glutathione S-transferase were the key functional genes. This study elucidates the stress response and degradation mechanism of neonicotinoids in wetland plants, providing new insights into the phytoremediation of organic contaminants in constructed wetlands.
Topics: Neonicotinoids; Transcriptome; Cyperus; Insecticides; Wetlands; Plants; Peroxidases; Nitro Compounds
PubMed: 37844494
DOI: 10.1016/j.jhazmat.2023.132715 -
American Journal of Physiology. Cell... Dec 2023Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative...
Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative cardiac performance and long-term outcomes. We addressed here whether cardioplegia essential for cardiopulmonary bypass surgery activates Nrf2, a transcription factor regulating the expression of antioxidant and detoxification genes. With commonly used cardioplegic solutions, high K, low K, Del Nido (DN), histidine-tryptophan-ketoglutarate (HTK), and Celsior (CS), we found that DN caused a significant increase of Nrf2 protein in AC16 human cardiomyocytes. Tracing the ingredients in DN led to the discovery of KCl at the concentration of 20-60 mM capable of significant Nrf2 protein induction. The antioxidant response element (ARE) luciferase reporter assays confirmed Nrf2 activation by DN or KCl. Transcriptomic profiling using RNA-seq revealed that oxidation-reduction as a main gene ontology group affected by KCl. KCl indeed elevated the expression of classical Nrf2 downstream targets, including TXNRD1, AKR1C, AKR1B1, SRXN1, and G6PD. DN or KCl-induced Nrf2 elevation is Ca concentration dependent. We found that KCl decreased Nrf2 protein ubiquitination and extended the half-life of Nrf2 from 17.8 to 25.1 mins. Knocking out Keap1 blocked Nrf2 induction by K. Nrf2 induction by DN or KCl correlates with the protection against reactive oxygen species generation or loss of viability by HO treatment. Our data support that high K concentration in DN cardioplegic solution can induce Nrf2 protein and protect cardiomyocytes against oxidative damage. Open heart surgery is often an unavoidable procedure for the treatment of coronary artery disease. The procedure-associated reperfusion injury affects postoperative cardiac performance and long-term outcomes. We report here that Del Nido cardioplegic solution or potassium is an effective inducer of Nrf2 transcription factor, which controls the antioxidant and detoxification response. This indicates that Del Nido solution is not only essential for open heart surgery but also exhibits cardiac protective activity.
Topics: Humans; Cardioplegic Solutions; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Myocytes, Cardiac; Potassium; Coronary Artery Disease; Antioxidants; Hydrogen Peroxide; Heart Arrest, Induced; Oxidative Stress; Reperfusion Injury; Aldehyde Reductase
PubMed: 37842750
DOI: 10.1152/ajpcell.00436.2022 -
Microbial Cell Factories Oct 2023Enantio-pure α-hydroxy amides are valuable intermediates for the synthesis of chiral pharmaceuticals. The asymmetric reduction of α-keto amides to generate chiral...
Enantio-pure α-hydroxy amides are valuable intermediates for the synthesis of chiral pharmaceuticals. The asymmetric reduction of α-keto amides to generate chiral α-hydroxy amides is a difficult and challenging task in biocatalysis. In this study, iolS, an aldo-keto reductase from Bacillus subtilis 168 was exhibited as a potential biocatalyst, which could catalyze the reduction of diaryl α-keto amide such as 2-oxo-N, 2-diphenyl-acetamide (ONDPA) with moderate S-selectivity (76.1%, ee) and 60.5% conversion. Through semi-rational engineering, two stereocomplementary variants (I57F/F126L and N21A/F126A) were obtained with ee value of 97.6% (S) and 99.9% (R) toward ONDPA (1a), respectively, delivering chiral α-hydroxy amide with > 98% conversions. Moreover, the excellent S- and R-preference variants displayed improved stereoselectivities toward the other α-keto amide compounds. Molecular dynamic and docking analysis revealed that the two key residues at 21 and 126 were identified as the "switch", which specifically controlled the stereopreference of iolS by regulating the shape of substrate binding pocket as well as the substrate orientation. Our results offer an effective strategy to obtain α-hydroxy amides with high optical purity and provide structural insights into altering the stereoselectivity of AKRs.
Topics: Aldo-Keto Reductases; Amides; Substrate Specificity; Biocatalysis; Catalysis; Aldehyde Reductase
PubMed: 37840127
DOI: 10.1186/s12934-023-02225-9 -
The Turkish Journal of Gastroenterology... Dec 2023Gastric cancer is a prevalent malignancy with unfavorable prognosis partially resulting from its high metastasis rate. Clarifying the molecular mechanism of gastric...
BACKGROUND/AIMS
Gastric cancer is a prevalent malignancy with unfavorable prognosis partially resulting from its high metastasis rate. Clarifying the molecular mechanism of gastric cancer occurrence and progression for improvement of therapeutic efficacy and prognosis is needed. The study tended to delineate the role and regulatory mechanism of aldo-keto reductase 1B10 (AKR1B10) in gastric cancer progression.
MATERIALS AND METHODS
The relationship of AKR1B10 expression with survival rate in gastric cancer was analyzed through Kaplan-Meier analysis. The mRNA levels of AKR1B10 and integrin subunit alpha 5 (ITGA5) in gastric cancer tissues and cell lines were measured by real-time quantitative polymerase chain reaction. Protein levels of AKR1B10 and integrin subunit alpha 5 were assayed via western blot. The molecular relationship between AKR1B10 and ITGA5 was analyzed by co-immunoprecipitation assay. Cell viability was assayed through Cell Counting Kit-8, invasion and migration of tumor cells was assessed through wound healing and transwell assays. Transwell assay was utilized to detect invasion. The adhesion of gastric cancer cells was detected using cell adhesion assays.
RESULTS
The results unveiled that integrin subunit alpha 5 was upregulated, while AKR1B10 was downregulated in gastric cancer tissues and cells. Overexpressing AKR1B10 hindered gastric cancer cell proliferation, migration, invasion and adhesion. It was striking that we certified the inhibitory effect of AKR1B10 on integrin subunit alpha 5 expression and their (AKR1B10 and ITGA5)) negative relationship via bioinformatics method, real-time quantitative polymerase chain reaction, and co-immunoprecipitation assays. Via rescue experiments, it was concluded that AKR1B10 served as tumor suppressor potentially by ITGA5 expression in gastric cancer.
CONCLUSION
Our results indicated that AKR1B10 inhibited migration, invasion, and adhesion of gastric cancer cells via modulation of ITGA5.
Topics: Humans; Aldehyde Reductase; Aldo-Keto Reductases; Cell Line, Tumor; Cell Movement; Cell Proliferation; Integrins; Stomach Neoplasms
PubMed: 37823316
DOI: 10.5152/tjg.2023.22555 -
Journal of Translational Medicine Oct 2023Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatocellular injury,...
BACKGROUND
Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatocellular injury, inflammation, and fibrosis in various stages. More than 20% of patients with NASH will progress to cirrhosis. Currently, there is a lack of clinically effective drugs for treating NASH, as improving liver histology in NASH is difficult to achieve and maintain through weight loss alone. Hence, the present study aimed to investigate potential therapeutic drugs for NASH.
METHODS
BMDMs and THP1 cells were used to construct an inflammasome activation model, and then we evaluated the effect of epalrestat on the NLRP3 inflammasome activation. Western blot, real-time qPCR, flow cytometry, and ELISA were used to evaluate the mechanism of epalrestat on NLRP3 inflammasome activation. Next, MCD-induced NASH models were used to evaluate the therapeutic effects of epalrestat in vivo. In addition, to evaluate the safety of epalrestat in vivo, mice were gavaged with epalrestat daily for 14 days.
RESULTS
Epalrestat, a clinically effective and safe drug, inhibits NLRP3 inflammasome activation by acting upstream of caspase-1 and inducing ASC oligomerization. Importantly, epalrestat exerts its inhibitory effect on NLRP3 inflammasome activation by inhibiting the activation of aldose reductase. Further investigation revealed that the administration of epalrestat inhibited NLRP3 inflammasome activation in vivo, alleviating liver inflammation and improving NASH pathology.
CONCLUSIONS
Our study indicated that epalrestat, an aldose reductase inhibitor, effectively suppressed NLRP3 inflammasome activation in vivo and in vitro and might be a new therapeutic approach for NASH.
Topics: Humans; Mice; Animals; Non-alcoholic Fatty Liver Disease; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Aldehyde Reductase; Inflammation; Fibrosis; Mice, Inbred C57BL
PubMed: 37805545
DOI: 10.1186/s12967-023-04380-4 -
Bioresource Technology Dec 20232,5-Dihydroxymethylfuran and furfuryl alcohol serve as versatile building-blocks in pharmaceuticals, polymers, and value-added intermediates. To develop an efficient and...
2,5-Dihydroxymethylfuran and furfuryl alcohol serve as versatile building-blocks in pharmaceuticals, polymers, and value-added intermediates. To develop an efficient and sustainable method for their production from biomass, a combined approach using deep eutectic solvent Citric acid:Betaine (CTA:BT) for bagasse catalysis and recombinant E. coli SCFD23 for bioreduction of bagasse-derived 5-hydroxymethylfurfural and furfural was devised. Bagasse was effectively transformed into 5-hydroxymethylfurfural (48 mM) and furfural (14 mM) in CTA:BT (8 wt%)-water at 170 °C for 30 min. Bioreduction of 5-hydroxymethylfurfural and furfural by SCFD23 cell co-expressing formate dehydrogenase and NAD(P)H-dependent aldehyde reductase (SsCR) yielded 2,5-dihydroxymethylfuran (90.0 % yield) and furfuryl alcohol (99.0 % yield) in 6 h, using biomass-derived formic acid, xylose and glucose as co-substrates. Molecular docking confirmed the stable binding and reductase activity of SsCR with the biomass-derived 5-hydroxymethylfurfural and furfural. An efficient and eco-friendly chemobiological approach was applied for co-production of 2,5-dihydroxymethylfuran and furfuryl alcohol from biomass in one-pot two-step reaction.
Topics: Cellulose; Furaldehyde; Escherichia coli; Saccharum; Molecular Docking Simulation
PubMed: 37797802
DOI: 10.1016/j.biortech.2023.129819 -
Journal of Chemical Information and... Oct 2023Aldose reductase (ALR2) is a notable enzyme of the polyol pathway responsible for aggravating diabetic neuropathy complications. The first step begins when it catalyzes...
Aldose reductase (ALR2) is a notable enzyme of the polyol pathway responsible for aggravating diabetic neuropathy complications. The first step begins when it catalyzes the reduction of glucose to sorbitol with NADPH as a coenzyme. Elevated concentrations of sorbitol damage the tissues, leading to complications like neuropathy. Though considerable effort has been pushed toward the successful discovery of potent inhibitors, its discovery still remains an elusive task. To this end, we present a 3D convolutional neural network (3D-CNN) based ALR2 inhibitor classification technique by dealing with snapshots of images captured from 3D chemical structures with multiple rotations as input data. The CNN-based architecture was trained on the 360 sets of image data along each axis and further prediction on the Maybridge library by each of the models. Subjecting the retrieved hits to molecular docking leads to the identification of the top 10 molecules with high binding affinity. The hits displayed a better blood-brain barrier penetration (BBB) score (90% with more than four scores) as compared to standard inhibitors (38%), reflecting the superior BBB penetrating efficiency of the hits. Followed by molecular docking, the biological evaluation spotlighted five compounds as promising ALR2 inhibitors and can be considered as a likely prospect for further structural optimization with medicinal chemistry efforts to improve their inhibition efficacy and consolidate them as new ALR2 antagonists in the future. In addition, the study also demonstrated the usefulness of scaffold analysis of the molecules as a method for investigating the significance of structurally diverse compounds in data-driven studies. For reproducibility and accessibility purposes, all of the source codes used in our study are publicly available.
Topics: Humans; Molecular Docking Simulation; Aldehyde Reductase; Reproducibility of Results; Enzyme Inhibitors; Diabetes Complications; Neural Networks, Computer; Sorbitol
PubMed: 37788831
DOI: 10.1021/acs.jcim.3c00547 -
Drug Metabolism and Disposition: the... Dec 2023Enzymes catalyzing the reduction reaction of xenobiotics are mainly members of the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) superfamilies....
Enzymes catalyzing the reduction reaction of xenobiotics are mainly members of the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) superfamilies. The intestine, together with the liver, is responsible for first-pass effects and is an organ that determines the bioavailability of orally administered drugs. In this study, we evaluated the mRNA and protein expression levels of 12 AKR isoforms (AKR1A1, AKR1B1, AKR1B10, AKR1B15, AKR1C1, AKR1C2, AKR1C3, AKR1C4, AKR1D1, AKR1E2, AKR7A2, and AKR7A3) and 7 SDR isoforms (CBR1, CBR3, CBR4, DCXR, DHRS4, HSD11B1, and HSD17B12) in each region of the human intestine using next-generation sequencing and data-independent acquisition proteomics. At both the mRNA and protein levels, most AKR isoforms were highly expressed in the upper regions of the intestine, namely the duodenum and jejunum, and then declined toward the rectum. Among the members in the SDR superfamily, CBR1 and DHRS4 were highly expressed in the upper regions, whereas the expression levels of the other isoforms were almost uniform in all regions. Significant positive correlations between mRNA and protein levels were observed in AKR1A1, AKR1B1, AKR1B10, AKR1C3, AKR7A2, AKR7A3, CBR1, and CBR3. The mRNA level of AKR1B10 was highest, followed by AKR7A3 and CBR1, each accounting for more than 10% of the sum of all AKR and SDR levels in the small intestine. This expression profile in the human intestine was greatly different from that in the human liver, where AKR1C isoforms are predominantly expressed. SIGNIFICANCE STATEMENT: In this study comprehensively determined the mRNA and protein expression profiles of aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase isoforms involved in xenobiotic metabolism in the human intestine and found that most of them are highly expressed in the upper region, where AKR1B10, AKR7A3, and CBR1 are predominantly expressed. Since the intestine is significantly involved in the metabolism of orally administered drugs, the information provided here is valuable for pharmacokinetic studies in drug development.
Topics: Humans; Aldo-Keto Reductases; RNA, Messenger; Short Chain Dehydrogenase-Reductases; Aldehyde Reductase; Protein Isoforms; Oxidoreductases; Intestines
PubMed: 37722844
DOI: 10.1124/dmd.123.001402 -
The Journal of Biological Chemistry Oct 2023Many microorganisms use both biological and nonbiological molecules as sources of carbon and energy. This resourcefulness means that some microorganisms have mechanisms...
Many microorganisms use both biological and nonbiological molecules as sources of carbon and energy. This resourcefulness means that some microorganisms have mechanisms to assimilate pollutants found in the environment. One such organism is Comamonas testosteroni, which metabolizes 4-methylbenzenesulfonate and 4-methylbenzoate using the TsaMBCD pathway. TsaM is a Rieske oxygenase, which in concert with the reductase TsaB consumes a molar equivalent of NADH. Following this step, the annotated short-chain dehydrogenase/reductase and aldehyde dehydrogenase enzymes TsaC and TsaD each regenerate a molar equivalent of NADH. This co-occurrence ameliorates the need for stoichiometric addition of reducing equivalents and thus represents an attractive strategy for integration of Rieske oxygenase chemistry into biocatalytic applications. Therefore, in this work, to overcome the lack of information regarding NADH recycling enzymes that function in partnership with Rieske non-heme iron oxygenases (Rieske oxygenases), we solved the X-ray crystal structure of TsaC to a resolution of 2.18 Å. Using this structure, a series of substrate analog and protein variant combination reactions, and differential scanning fluorimetry experiments, we identified active site features involved in binding NAD and controlling substrate specificity. Further in vitro enzyme cascade experiments demonstrated the efficient TsaC- and TsaD-mediated regeneration of NADH to support Rieske oxygenase chemistry. Finally, through in-depth bioinformatic analyses, we illustrate the widespread co-occurrence of Rieske oxygenases with TsaC-like enzymes. This work thus demonstrates the utility of these NADH recycling enzymes and identifies a library of short-chain dehydrogenase/reductase enzyme prospects that can be used in Rieske oxygenase pathways for in situ regeneration of NADH.
Topics: Aldehyde Dehydrogenase; NAD; Oxygenases; Substrate Specificity; Comamonas testosteroni; Bacterial Proteins; Nonheme Iron Proteins; Recombinant Proteins; Protein Structure, Tertiary; Models, Molecular; Protein Stability; Computational Biology
PubMed: 37673337
DOI: 10.1016/j.jbc.2023.105222 -
Current Pharmaceutical Biotechnology 2024The expression of aldose reductase leads to a variety of biological and pathological effects. It is a multifunctional enzyme which has a tendency to reduce aldehydes to... (Review)
Review
The expression of aldose reductase leads to a variety of biological and pathological effects. It is a multifunctional enzyme which has a tendency to reduce aldehydes to the corresponding sugar.alcohol. In diabetic conditions, the aldose reductase enzyme converts glucose into sorbitol using nicotinamide adenine dinucleotide phosphate as a cofactor. It is a key enzyme in polyol pathway which is a surrogate course of glucose metabolism. The polyol pathway has a significant impact on the aetiology of complications in individuals with end-stage diabetes. The exorbitant level of sorbitol leads to the accumulation of intracellular reactive oxygen species in diabetic heart, neurons, kidneys, eyes and other vasculatures, leading to many complications and pathogenesis. Recently, the pathophysiological role of aldose reductase has been explored with multifarious perspectives. Research on aldose reductase suggest that besides implying in diabetic complications, the enzyme also turns down the lipid-derived aldehydes as well as their glutathione conjugates. Although aldose reductase has certain lucrative role in detoxification of toxic lipid aldehydes, its overexpression leads to intracellular accumulation of sorbitol which is involved in secondary diabetic complications, such as neuropathy, cataractogenesis, nephropathy, retinopathy and cardiovascular pathogenesis. Osmotic upset and oxidative stress are produced by aldose reductase via the polyol pathway. The inhibition of aldose reductase alters the activation of transcription factors like NF-ƙB. Moreover, in many preclinical studies, aldose reductase inhibitors have been observed to reduce inflammation-related impediments, such as asthma, sepsis and colon cancer, in diabetic subjects. Targeting aldose reductase can bestow a novel cognizance for this primordial enzyme as an ingenious strategy to prevent diabetic complications and associated morbidities. In this review article, the significance of aldose reductase is briefly discussed along with their prospective applications in other afflictions.
Topics: Aldehyde Reductase; Humans; Animals; Diabetes Complications; Polymers; Oxidative Stress; Sorbitol
PubMed: 37649296
DOI: 10.2174/1389201025666230830125147