BACKGROUND: Enzymes involved in drug and xenobiotic metabolism have been considered to exist in two groups: phase I and phase II enzymes. Cytochrome P450 isoenzymes (CYPs) are the most important phase I enzymes in the...BACKGROUND: Enzymes involved in drug and xenobiotic metabolism have been considered to exist in two groups: phase I and phase II enzymes. Cytochrome P450 isoenzymes (CYPs) are the most important phase I enzymes in the metabolism of xenobiotics. The products of phase I metabolism are then acted upon by phase II enzymes, including glutathione S-transferases (GSTs). Herbs that inhibit CYPs such as CYP3A4 or that induce GSTs may have the potential to protect against chemical carcinogenesis since the mutagenic effects of carcinogens are often mediated through an excess of CYP-generated reactive intermediates. This study was designed to investigate the effects of salvianolic acid B (Sal B), a pure compound extracted from Radix Salviae Miltiorrhizae, a Chinese herb, on cell proliferation and CYP1A2 and CYP3A4 mRNA expression in the presence or absence of rifampicin, a potent inducer of CYPs and GST protein expression in HepG2 cells. METHODS: HepG2 cells were incubated with different concentrations of Sal B. Cell proliferation was determined by SYTOX-Green nucleic acid staining. CYP3A4 and CYP1A2 mRNA expression was assayed by real-time PCR. GST protein expression was analyzed by Western blotting. RESULTS: Low concentrations of Sal B (0-20 μmol/L) had no significant effects on cell proliferation, while higher concentrations (100-250 μmol/L) significantly inhibited proliferation in a concentration-dependent manner. Ten μmol/L Sal B, but not 1 μmol/L, down-regulated CYP3A4 and CYP1A2 mRNA expression after 24 hours of incubation, whereas both 1 and 10 μmol/L Sal B down-regulated CYP3A4mRNA expression after 96 hours of incubation; moreover, 1 and 10 μmol/L Sal B inhibited CYP3A4 mRNA expression induced by rifampicin. Both 1 μmol/L and 10 μmol/L Sal B increased GST expression. CONCLUSION: Sal B inhibits CYP3A4 and CYP1A2 mRNA expression and induces GST expression in HepG2 cells.展开更多
AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents. METHODS: Forty-eight Sprague...AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents. METHODS: Forty-eight Sprague-Dawley rats were fed with a diet containing 0%, 2% or 5% H. cordata powder and 15% fresh soybean oil or 24-h oxidized frying oil (OFO) for 28 d respectively. The level of microsomal protein, total cytochrome 450 content (CYP450) and enzyme activities including NADPH reductase, ethoxyresorufin 0-deethylase (EROD), pentoxyresorufin 0-dealkylase (PROD), aniline hydroxylase (ANH), aminopyrine demethylase (AMD), and quinone reductase (QR) were determined. QR represented phase Ⅱ enzymes, the rest of the enzymes tested represented phase Ⅰ enzymes. RESULTS: The oxidized frying oil feeding produced a significant increase in phase Ⅰ and Ⅱ enzyme systems, including the content of CYP450 and microsomal protein, and the activities of NADPH reductase, EROD, PROD, ANH, AMD and QR in rats (P<0.05). In addition, the activities of EROD, ANH and AMD decreased and QR increased after feeding with H. cordata in OFO-fed group (P<0.05). The feeding with 2% H. cordata diet showed the most significant effect. CONCLUSION: The OFO diet induces phases I and II enzyme activity, and the 2% H. cordata diet resulted in a better regulation of the xenobiotic-metabolizing enzyme system.展开更多
The dynamic changes of liver microsomal drug-metabolizing system (MDMS) andlipoperoxidation were studied in scalded rats. The effects of treatment with vitamin E and silybinwere also evaluated. The results showeed tha...The dynamic changes of liver microsomal drug-metabolizing system (MDMS) andlipoperoxidation were studied in scalded rats. The effects of treatment with vitamin E and silybinwere also evaluated. The results showeed that liver microsomal cytochrome P-450 content, and p-nitroanisole demethylase (P-NOD) and aniline hydroxylase (AH) activity decreased markedlypostburn. On the contrary, liver lipoperoxide and mierosomal lipoperoxidation increased significantlyafter scalding. Both the increase of liver lipoperoxide and mierosomal lipoperoxidation and the de-crease of MDMS activity were prevented by vitamin E and silybin treatments.展开更多
Curry leaves, scientifically termed Murraya koenigii, are renowned in South Asian cuisine for their flavor enhancement and potential health benefits, including antioxidative, anti-inflammatory, and antidiabetic proper...Curry leaves, scientifically termed Murraya koenigii, are renowned in South Asian cuisine for their flavor enhancement and potential health benefits, including antioxidative, anti-inflammatory, and antidiabetic properties. This study aimed to evaluate the impact of thermal processing methods on curry leaves by analysing Total Phenolic Content (TPC), Total Flavonoid Content (TFC), antioxidant activity, and metabolizing enzyme inhibition. Fresh curry leaves were subjected to thermal treatments: Oven-dried at 60˚C and Air-dried at 25˚C for 2 weeks. Extracts were prepared using Ethanol and water solvents. Results indicated that Air-dried leaves exhibited significantly higher TPC (5132.65 mg GAE/100 g) and TFC (243.13 mg CE/100 g) compared to Fresh and Oven-dried leaves. Antioxidant assays show that oven-dried curry leaves at 60˚C displayed higher results in NORS, FRAP, and TEAC assays compared to Fresh and Air-dried leaves. Ethanol extracts showed better extraction of bioactive compounds than aqueous extracts. Moreover, Lipase inhibition activity was notably high, indicating potential health benefits. This study provides valuable insights into the effects of processing methods on curry leaf extracts, emphasizing the importance of solvent selection for optimal extraction of bioactive compounds.展开更多
Changes in sucrose metabolism in response to salt （NaC1） and water （polyethylene glycol, PEG6000） iso-osmotic stresses were measured in tomato cultivar Liaoyuan Duoli （Solanum lycopersicum L.） and the objective ...Changes in sucrose metabolism in response to salt （NaC1） and water （polyethylene glycol, PEG6000） iso-osmotic stresses were measured in tomato cultivar Liaoyuan Duoli （Solanum lycopersicum L.） and the objective was to provide a new evidence for the relationship between salt and osmotic stresses. The carbohydrate contents, as well as sucrose metabolizing enzymes activities and transcript levels were determined. The results indicated that soluble sugar and hexoses accumulated to higher levels and the contents of sucrose and starch were lower in mature fruit under the two stress treatments. Salt and water stresses can enhance the invertase and sucrose synthase activities of tomato fruit in a long period of time （45-60 days after anthesis）, and elevate the expression of soluble acid invertase mRNA. It showed that two different stresses could also regulate the soluble acid invertase activity by controlling its gene expression. The activity of sucrose synthase was linked to the changes in soluble sugar levels but not with transcript levels. The effects of salt and water stress treatments on sucrose phosphate synthase activities were weak.展开更多
The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administratio...The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.展开更多
Objective To evaluate the association of known polymorphisms in the lipid metabolic pathway with body mass index （BMI）, and estimate their interactions with soybean food intake. Methods A community-based cross-secti...Objective To evaluate the association of known polymorphisms in the lipid metabolic pathway with body mass index （BMI）, and estimate their interactions with soybean food intake. Methods A community-based cross-sectional survey was conducted in a Chinese Han population. BMI, soybean food intake, and single nucleotide polymorphisms of rs599839, rs3846662, rs3846663, rs12916, rs174547, rs174570, rs4938303, and rs1558861 were measured in 944 subjects. A multivariate logistic regression was used to analyze the association of the studied polymorphisms with BMIs. The expectation-maximization algorithm was employed to evaluate the extent of linkage disequilibrium between pairwise polymorphisms. The gene-environment interaction was assessed in the general multifactor dimensionality reduction model. Results The polymorphisms of rs3846662 and rs3846663 were associated with 10% highest BMIs when comparing to the 10% lowest values both in individuals and haplotype-based association tests. Although no statistically significant gene-environment interactions were found, people with the haplotype composed of C allele in rs3846662 and T allele in rs3846663 and low frequency of soybean intake had significantly hisher risk to overweight and obesity as compared with those with the haplotype consisting of T allele in rs3846662 and C allele in rs3846663 and highly frequent soybean food intake, with an odds ratio of 1.64 （95% confidence interval： 1.15-2.34, P〈0.01） after adjusting for the common confounders. Conclusion Our study has sugsested that rs3846662 and rs3846663 may be the potential candidate polymorphisms for obesity, and their effect on the pathogenesis could be mediated by the frequency of soybean food intake.展开更多
In the context of global efforts to reduce carbon(C)emissions,several studies have examined the effects of agricultural practices such as straw returning and fertilization on C sequestration by microorganisms.However,...In the context of global efforts to reduce carbon(C)emissions,several studies have examined the effects of agricultural practices such as straw returning and fertilization on C sequestration by microorganisms.However,our understanding of the specific microbial groups and their roles in long-term C increase remains limited.In this study,a 36-year(1984-2020)farmland experiment was conducted to investigate the impact of bacterial C metabolism on the augmentation of organic C in a Typic Hapludoll(Mollisol)in the black soil region of Jilin Province,Northeast China.Our results demonstrated a noteworthy increase in the diversity of microorganisms in the farmland as a result of long-term straw returning and application of mixed chemical fertilizers.However,by examining the functions of microorganisms involved in C metabolism,it was observed that the effects of fertilization on C metabolism were relatively consistent.This consistency was attributed to a deterministic competitive exclusion process,which minimized the differences between treatment groups.On the other hand,the influence of straw addition on C metabolism appeared to follow a more random pattern.These changes in microbial activity were closely linked to the downregulation of core metabolic pathways related to C metabolism.Notably,long-term fertilization had a negative impact on soil organic C levels,while long-term straw returning plus fertilization resulted in a positive increase in soil organic C.These findings have important implications for enhancing soil organic C and grain yield in the regions with typical black soil.展开更多
Pathophysiological changes in human patients and in animal models of infection or inflammation are associated with alterations in the production of numerous liver-derived proteins including metabolizing enzymes. In th...Pathophysiological changes in human patients and in animal models of infection or inflammation are associated with alterations in the production of numerous liver-derived proteins including metabolizing enzymes. In this study, the effects of adjuvant-induced arthritis (AA) in rats on the levels of mRNA and activity of hepatic xenobiotic metabolizing enzymes were determined during the inflammatory response. The mRNA levels of cytochrome P450 (CYP) 1A2, CYP2C12, CYP2D1, CYP2D2, and CYP3A1 were significantly decreased compared with control levels in almost all phases of inflammation. A reduction in the activity of CYP2C and CYP3A, which are abundantly expressed in the liver, was also observed. For phase II metabolizing enzymes, mRNA levels of uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A1, UGT1A6, sulfotransferase (SULT) 2A1, and glutathione S-transferase 2 were significantly decreased compared with control levels. However, the mRNA levels of UGT2B and SULT1A1 returned to control levels during the subacute (7 d after adjuvant treatment) and chronic (21 d after adjuvant treatment) phases although these levels decreased during the acute (3 d after adjuvant treatment) phase. These results suggest that the effects of inflammation on the expression of xenobiotic metabolizing enzymes differ depending on the isoform of the enzyme and could affect the pharmacokinetics of each substrate.展开更多
Pharmacogenomics,therapeutic drug monitoring,and the assessments of hepatic and renal function have made significant contributions to the advancement of individualized medicine.However,their lack of direct correlation...Pharmacogenomics,therapeutic drug monitoring,and the assessments of hepatic and renal function have made significant contributions to the advancement of individualized medicine.However,their lack of direct correlation with protein abundance/non-genetic factors,target drug concentration,and drug metabolism/excretion significantly limits their application in precision drug therapy.The primary task of precision medicine is to accurately determine drug dosage,which depends on a precise assessment of the ability to handle drugs in vivo,and drug metabolizing enzymes and transporters are critical determinants of drug disposition in the body.Therefore,accurately evaluating the functions of these enzymes and transporters is key to assessing the capacity to handle drugs and predicting drug concentrations in target organs.Recent advancements in the evaluation of enzyme and transporter functions using exogenous probes and endogenous biomarkers show promise in advancing personalized medicine.This article aims to provide a comprehensive overview of the latest research on markers used for the functional evaluation of drug-metabolizing enzymes and transporters.It also explores the application of marker omics in systematically assessing their functions,thereby laying a foundation for advancing precision pharmacotherapy.展开更多
The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation.Farnesoid X receptor(FXR) is critical for bile acid and lipid homeostasis in liver.However,the role o...The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation.Farnesoid X receptor(FXR) is critical for bile acid and lipid homeostasis in liver.However,the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear.Hence,we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control(C57BL/6) mouse livers during development.Liver samples of male C57BL/6 and Fxr-null mice at6 different ages from prenatal to adult were used.The Fxr-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression,including cytochrome P450 s at neonatal ages.Among the 185 phase-I genes from 12 different families,136 were expressed,and differential expression during development occurred in genes from all 12 phase-I families,including hydrolysis: carboxylesterase(Ces),paraoxonase(Pon),and epoxide hydrolase(Ephx); reduction: aldoketo reductase(Akr),quinone oxidoreductase(Nqo),and dihydropyrimidine dehydrogenase(Dpyd); and oxidation: alcohol dehydrogenase(Adh),aldehyde dehydrogenase(Aldh),flavin monooxygenases(Fmo),molybdenum hydroxylase(Aox and Xdh),cytochrome P450(P450),and cytochrome P450 oxidoreductase(Por).The data also suggested new phase-I genes potentially targeted by FXR.These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.展开更多
Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein’s function and account for susceptibility to disease and altered drug/xenobiotic re...Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein’s function and account for susceptibility to disease and altered drug/xenobiotic response. Many nsSNPs have been found in genes encoding human phase II metabolizing enzymes; however, there is little known about the relationship between the genotype and phenotype of nsSNPs in these enzymes. We have identified 923 validated nsSNPs in 104 human phase II enzyme genes from the Ensembl genome database and the NCBI SNP database. Using PolyPhen, Panther, and SNAP algorithms, 44%?59% of nsSNPs in phase II enzyme genes were predicted to have functional impacts on protein function. Predictions largely agree with the available experimental annotations. 68% of deleterious nsSNPs were correctly predicted as damaging. This study also identified many amino acids that are likely to be functionally critical, but have not yet been studied experimentally. There was significant concordance between the predicted results of Panther and PolyPhen, and between SNAP non-neutral predictions and PolyPhen scores. Evolutionarily non-neutral (destabilizing) amino acid substitutions are thought to be the pathogenetic basis for the alteration of phase II enzyme activity and to be associated with disease susceptibility and drug/xenobiotic toxicity. Furthermore, the molecular evolutionary patterns of phase II enzymes were characterized with regards to the predicted deleterious nsSNPs.展开更多
In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quali...In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quality and stress tolerance of crops.Synthetic metabolic engineering presents innovative strategies for the precision modification and de novo design of metabolic pathways.This approach generally encompasses three essential steps:identifying key metabolites through metabolomics,integrating multi-omics technologies to investigate the synthesis and regulation of these metabolites,and utilizing gene editing or de novo design to modify crop metabolic pathways associated with desirable agronomic traits.This review underscores the vital role of plant metabolite diversity in enhancing crop nutritional quality and stress resilience.Integrated multi-omics analyses facilitate the metabolic engineering by identifying key genes,transporters,and transcription factors that regulate metabolite biosynthesis.Precision modification strategies employ genome editing tools to reprogram endogenous metabolic networks,while de novo design reconstructs metabolic pathways through the introduction of exogenous biological elements—thereby both approaches enable the targeted enhancement of desired traits.These strategies have been effectively implemented in major food crops.However,simultaneously enhancing nutritional quality and stress resilience remains challenging due to inherent trade-offs and resource competition in distinct metabolic pathways within plants.Future research should integrate AI-driven predictive models with multi-omics datasets to decipher dynamic metabolic homeostasis and engineer climate-smart crops that maximize yield while preserving quality and environmental adaptability.展开更多
Background Endogenous estrogen plays a very important role in the carcinogenesis and progression of breast cancer. The enzymes involved in the biosynthesis and metabolism of estrogen have been proposed to contribute t...Background Endogenous estrogen plays a very important role in the carcinogenesis and progression of breast cancer. The enzymes involved in the biosynthesis and metabolism of estrogen have been proposed to contribute to this effect. To examine this hypothesis, we conducted a case-control study to investigate the relationship between polymorphisms of genes responsible for estrogen biosynthesis （CYP17, cytochrome P450c17a and CYP19, aromatase cytochrome P450） and estrogen sulfation of inactivation （ SULT1 A1, sulfotransferasel A1 ） and the risk of breast cancer in Chinese women. Methods This study involved 213 breast cancer patients and 430 matched controls. PCR-based restriction fragment length polymorphism （RFLP） and short tandem repeat polymorphism （STRP） assays were used to detect the mononucleotide transition of CYP17 and SULT1A1 and tandem repeat polymorphism of CYP19. Logistic regression analyses were used to determine OR and 95% CI of each and all three high-risk genotypes, of all three genotypes combined, and of estrogen exposure factbrs. The relationship between each high-risk genotype and clinicalpathological characteristics were also assessed. Results The frequency of A2 allele of CYP17 was 49.8% in cases and 49. 1% in controls （P =0. 82）. The frequency of His allele of SULT1A1 was significantly higher in cases （ 13.6% ） than in controls （9. 5% ） （P 〈 0. 05 ）. There was also significant difference of the （TTTA）10 allele of CYP19 which was 12. 4% in cases and 8.2% in controls （P 〈0. 05）. When the CYP17 A2 allele, CYP19 （TITA）1o and SULT1A1 His allele were considered as the “putative high-risk” genotype, there was an increased risk of breast cancer with the number of high-risk genotypes in a dose-response effect （trend, P = 0. 05 ）. In multivariate analysis, the SULT1A1 genotype remained the most significant determinant for breast cancer, with OR =2. 37 （95% CI 1.23 - 4. 74） , followed by CYP19, with OR = 1.75 （95% CI 1.27 - 3.56）. The （TTTA）10 allele of CYP19 was associated with tumor size, and the His allele of SULT1 A1 associated with status of lymph node metastasis. Conclusions This study supports the hypothesis that breast cancer can be initiated by estrogen exposure and that estrogen metabolizing genes are involved in this mechanism. This multigenic model is useful for identifying individuals who are at higher risks of breast cancer.展开更多
A growing global population and the increasing prevalence of diet-related health issues such as“hidden hunger”,obesity,hypertension,and diabetes necessitate a fundamental rethinking of crop design and breeding.Synth...A growing global population and the increasing prevalence of diet-related health issues such as“hidden hunger”,obesity,hypertension,and diabetes necessitate a fundamental rethinking of crop design and breeding.Synthetic metabolic engineering offers a method to modify and redesign metabolic pathways to increase the nutritional value of crops.We summarize recent advances in the biofortification of key nutrients including provitamin A,vitamin C,vitamin B9,iron,zinc,anthocyanins,flavonoids,and unsaturated fatty acids.We discuss the potential of multi-gene stacking,gene editing,enzyme engineering,and artificial intelligence in synthetic metabolic engineering.We propose future research directions and potential solutions centered on leveraging AI-driven systems biology,precision gene editing,enzyme engineering,agrobacterium-mediated genotype-independent transformation,and modular metabolic engineering strategies to develop next-generation nutritionally enhanced super crops and transform global food systems.展开更多
Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications wit...Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most prevalent chronic liver disease worldwide,affecting approximately 32%-38%of the adult population and posing a growing public health bu...Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most prevalent chronic liver disease worldwide,affecting approximately 32%-38%of the adult population and posing a growing public health burden.MASLD represents a continuous disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis(MASH),progressive hepatic fibrosis,cirrhosis,and ultimately hepatocellular carcinoma(HCC).The pathological core of MASLD lies in disruption of hepatic lipid metabolic homeostasis,characterized by an imbalance among de novo lipogenesis,fatty acidβ-oxidation,and very-low-density lipoprotein(VLDL)-mediated lipid export.This metabolic disequilibrium subsequently drives inflammatory injury and fibrotic progression.Among the multiple regulatory pathways involved,thyroid hormone(TH)signaling has emerged as a central regulator of hepatic metabolic homeostasis.The liver is a major peripheral target organ of TH action,where TH predominantly exerts its metabolic effects through thyroid hormone receptorβ(TRβ).Large-scale epidemiological studies and metaanalyses have demonstrated that hypothyroidism is significantly associated with increased MASLD prevalence,more severe histological injury,and advanced hepatic fibrosis,suggesting that dysregulation of TH signaling may participate throughout the entire MASLD disease spectrum.At the molecular level,TH regulates hepatic lipid metabolism by coordinating suppression of lipogenesis,enhancement of mitochondrial fatty acid oxidation,and promotion of VLDL assembly and secretion through integrated genomic actions of the T3-TRβaxis and non-genomic signaling pathways.Across different stages of MASLD,TH signaling exerts stagedependent protective effects.In the steatosis stage,TH improves metabolic flexibility by modulating insulin sensitivity,glucose metabolism,and lipid droplet clearance,thereby alleviating early lipotoxic stress.During progression to MASH,TH attenuates inflammatory amplification by improving mitochondrial homeostasis,suppressing activation of the NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome,and modulating the gut-liver axis microenvironment.In advanced stages,TH signaling influences hepatic stellate cell activation and extracellular matrix deposition,partly through interaction with the transforming growth factor-β(TGF-β)/SMAD pathway,while alterations in intrahepatic TH availability,mediated by dynamic changes in iodothyronine deiodinase 1(DIO1),contribute to fibrosis progression and hepatocellular dedifferentiation.In hepatocellular carcinoma,coordinated downregulation of TRβand DIO1 establishes a tumor-associated hypothyroid state that promotes metabolic reprogramming and tumor progression.The clinical relevance of TH signaling in MASLD has been underscored by the recent approval of Resmetirom,a liver-targeted TRβ-selective agonist,for the treatment of non-cirrhotic MASH with moderate-to-severe fibrosis(F2-F3).This approval represents a landmark transition from mechanistic understanding to metabolismcentered precision therapy in MASLD.Clinical trials have demonstrated that Resmetirom not only improves key histological endpoints,including MASH resolution and fibrosis regression,but also favorably modulates atherogenic lipid profiles,highlighting the therapeutic potential of selectively targeting hepatic TH pathways.This review systematically summarizes the multidimensional regulatory roles of TH across the MASLD disease spectrum and discusses emerging diagnostic and therapeutic implications of THbased interventions,aiming to inform future mechanistic research and optimize clinical management strategies.展开更多
As oncologic therapies continue to advance,the overall survival of cancer patients has markedly increased.Nevertheless,virtually every anticancer treatment modality is accompanied by some degree of cardiotoxicity.Epid...As oncologic therapies continue to advance,the overall survival of cancer patients has markedly increased.Nevertheless,virtually every anticancer treatment modality is accompanied by some degree of cardiotoxicity.Epidemiological data indicate that approximately 30%of cancer survivors ultimately die from cardiovascular disease.Among the cardiotoxic agents,the anthracycline doxorubicin(DOX)is the most widely used.It effectively suppresses a variety of malignant tumors——including breast cancer,lymphoma,and acute leukemia——but its cardiac toxicity limits further escalation of clinical dosing.Literature reports identify a cumulative dose of≥250 mg/m²as the threshold of high risk,with roughly 25%of patients receiving DOX developing varying degrees of myocardial injury;severe cases progress to heart failure.Even at cumulative doses below the traditional safety limit,some patients exhibit cardiac dysfunction after the first administration,suggesting that cardiotoxicity is not solely a linear function of dose.DOX related cardiotoxicity can be classified as acute(hours to days after administration),sub acute(weeks to months),and chronic/late onset(years later).Most patients initially exhibit only mild reductions in left ventricular ejection fraction(LVEF)or subtle abnormalities in global longitudinal strain(GLS),often without symptoms.Recently,cardiac biomarkers(cTn,NT proBNP)combined with high sensitivity echocardiography(speckle tracking)have been recommended for monitoring high risk individuals,enabling detection of subclinical injury before overt LVEF decline.Currently,several preventive and therapeutic approaches are used in clinical practice,which can be summarized into the following four points.(1)Dose limitation and administration strategies:fractionated low dose regimens,liposomal encapsulation,or continuous infusion lower peak plasma concentrations,thereby reducing cardiac exposure.(2)Pharmacologic prophylaxis:βblockers(e.g.,carvedilol)and ACE inhibitors/ARBs have shown protective effects on LVEF in some randomized trials,though results remain inconsistent and require larger confirmatory studies.(3)Metabolic targeted interventions:animal experiments indicate that activation of PPARαor supplementation with L carnitine restores fatty acid oxidation and improves ATP generation,suggesting metabolic modulators as promising cardioprotective candidates.(4)Lifestyle modifications:regular aerobic exercise up regulates mitochondrial biogenesis genes(PGC-1α)and reduces reactive oxygen species(ROS)production;small clinical studies have demonstrated a potential benefit in attenuating cTnT elevation.However,DOX-induced cardiotoxicity has not been effectively controlled,indicating that the core mechanism underlying DOX‑related cardiac toxicity remains unidentified.Cardiomyocytes are high energy demand cells,and metabolic dysregulation is considered a central component of DOX induced cardiotoxicity.DOX disrupts myocardial metabolic balance through several interrelated pathways.(1)Oxidative stress and mitochondrial damage:DOX generates abundant ROS within cells,leading to mitochondrial membrane potential loss,lipid peroxidation,and iron accumulation,which suppress electron transport chain activity and markedly reduce ATP synthesis efficiency.(2)Autophagy dysregulation:DOX interferes with autophagic flux,preventing the clearance of damaged mitochondria and further aggravating apoptosis and inflammatory responses.(3)Inflammation and cytokine release:oxidative stress activates NF‑κB,up-regulating pro inflammatory cytokines such as TNF‑αand IL-6,creating a chronic inflammatory microenvironment that weakens myocardial contractility.(4)Epigenetic modifications:studies have shown that DOX alters DNA methylation and histone acetylation patterns in cardiomyocytes,affecting the expression of key metabolic genes(e.g.,PGC-1α,CPT-1)and further inhibiting fatty acidβoxidation.These mechanisms collectively lead to suppressed fatty acid oxidation and compensatory up regulation of glycolysis,manifested by an elevated lactate/pyruvate ratio,accumulation of medium chain acyl carnitines,and a pronounced decline in ATP production.The resulting energy deficit precipitates left ventricular contractile dysfunction and,ultimately,heart failure.Despite extensive basic and clinical research on DOX cardiotoxicity,a unified risk assessment model and precise interventions targeting metabolic disturbances remain lacking.This review systematically summarizes recent progress on DOX induced cardiotoxicity and highlights that impairment of myocardial energy metabolism is a central mechanism of injury,thereby deepened our understanding of how impaired myocardial energy metabolism drives DOX induced injury,we can move toward safer chemotherapy protocols that achieve“cure cancer without harming the heart”.展开更多
This study employed integrated multi-omics approaches to elucidate,from the perspective of amino acid metabolism,the adaptive mechanism of Penicillium digitatum under modified atmosphere packaging(MAP)conditions.Compa...This study employed integrated multi-omics approaches to elucidate,from the perspective of amino acid metabolism,the adaptive mechanism of Penicillium digitatum under modified atmosphere packaging(MAP)conditions.Comparative analysis of natural air(Air),controlled atmosphere(CA),and MAP treatments revealed that MAP upregulated the expression of the hercynylcysteine S-oxide synthase(HCSOS),aldehyde dehydrogenase(ALDH),and monoamine oxidase(MAO)genes,thereby enhancing histidine-derived ergothioneine and methionine levels,and subsequently boosting glutathione-mediated redox homeostasis.Meanwhile,MAP induced the expression of the dihydroxyacid dehydratase(DHAD),saccharopine dehydrogenase(SDH),and arginosuccinate lyase(ASL)genes,redirecting valine,lysine,and arginine into the tricarboxylic acid(TCA)cycle to fuel ATP production.MAP also enhanced ASL-mediated arginine degradation and urea cycle activity,reducing arginine accumulation when compared to CA treatment.In contrast,while MAP induced upregulated expression of the pyrroline-5-carboxylate dehydrogenase(P5CDH)and D-amino acid oxidase(DAAO)genes,CA treatment promoted proline accumulation,reflecting stress-specific metabolic flexibility.Collectively,these findings demonstrate that MAP triggers transcriptional reprogramming of amino acid metabolism to coordinate oxidative defense,energy generation,and osmotic balance.By modulating these metabolic pathways and regulatory genes under MAP conditions,fungal adaptability can be disrupted.Hence,this study provides a promising strategy for suppressing green mold development,extending the postharvest shelf life,and improving the quality of fruits and vegetables.展开更多
Nitrogen is essential for plant growth and development,with the ratio of ammonium(NH_(4)^(+))to nitrate(NO_(3)^(-))critically influencing physiological efficiency.This study investigated the effects of different NH_(4...Nitrogen is essential for plant growth and development,with the ratio of ammonium(NH_(4)^(+))to nitrate(NO_(3)^(-))critically influencing physiological efficiency.This study investigated the effects of different NH_(4)^(+)-N/NO_(3)^(-)-N mass ratios(0︰1,3︰7,1︰1,7︰3,1︰0)and a no-nitrogen control on Zanthoxylum planispinum var.dintanensis seedlings,using NH_(4)Cl and NaNO_(3) as nitrogen sources.Key results revealed that a 3︰7 NH_(4)^(+)︰NO_(3)^(-)ratio(T2)significantly enhanced stomatal conductance(G_(s)),amino acid content,root tip number,and the photochemical quenching parameters q_(P),q_(L),ETR,and F_(v)/F_(m).This treatment also maximized ground diameter increment,chlorophyll content,intercellular CO_(2)concentration(C_(i)),transpiration rate(T_(r)),ribulose-1,5-bisphosphate carboxylase(Rubisco)activity,nitrate reductase(NR)activity,and soluble protein content.Conversely,a 7︰3 ratio(T4)yielded the highest net photosynthetic rate(Pn)and fructose-1,6-bisphosphate aldolase(FBA)activity.Overall,the T4 treatment exhibited the second most effective promotion of Z.planispinum var.dintanensis seedling growth and development,after T2.In summary,mixed NH_(4)^(+)-N/NO_(3)^(-)-N nutrition markedly enhances seedling performance,with the 3︰7 ratio optimal for growth,photosynthesis,and nitrogen assimilation.Sole nitrogen sources,particularly pure NH_(4)^(+)-N,exert inhibitory effects.展开更多
基金supported by grants from the National Natural Science Foundation of China (30901943)the Program for New Century Excellent Talents in University (NCET-04-0437)+1 种基金the E-institute of Shanghai Municipal Education Commission (E03008)the Innovative Research Team in Universities of Shanghai Municipal Education Commission
文摘BACKGROUND: Enzymes involved in drug and xenobiotic metabolism have been considered to exist in two groups: phase I and phase II enzymes. Cytochrome P450 isoenzymes (CYPs) are the most important phase I enzymes in the metabolism of xenobiotics. The products of phase I metabolism are then acted upon by phase II enzymes, including glutathione S-transferases (GSTs). Herbs that inhibit CYPs such as CYP3A4 or that induce GSTs may have the potential to protect against chemical carcinogenesis since the mutagenic effects of carcinogens are often mediated through an excess of CYP-generated reactive intermediates. This study was designed to investigate the effects of salvianolic acid B (Sal B), a pure compound extracted from Radix Salviae Miltiorrhizae, a Chinese herb, on cell proliferation and CYP1A2 and CYP3A4 mRNA expression in the presence or absence of rifampicin, a potent inducer of CYPs and GST protein expression in HepG2 cells. METHODS: HepG2 cells were incubated with different concentrations of Sal B. Cell proliferation was determined by SYTOX-Green nucleic acid staining. CYP3A4 and CYP1A2 mRNA expression was assayed by real-time PCR. GST protein expression was analyzed by Western blotting. RESULTS: Low concentrations of Sal B (0-20 μmol/L) had no significant effects on cell proliferation, while higher concentrations (100-250 μmol/L) significantly inhibited proliferation in a concentration-dependent manner. Ten μmol/L Sal B, but not 1 μmol/L, down-regulated CYP3A4 and CYP1A2 mRNA expression after 24 hours of incubation, whereas both 1 and 10 μmol/L Sal B down-regulated CYP3A4mRNA expression after 96 hours of incubation; moreover, 1 and 10 μmol/L Sal B inhibited CYP3A4 mRNA expression induced by rifampicin. Both 1 μmol/L and 10 μmol/L Sal B increased GST expression. CONCLUSION: Sal B inhibits CYP3A4 and CYP1A2 mRNA expression and induces GST expression in HepG2 cells.
基金Supported by Grant From the National Science Council of Taiwan, No. NSC 90-2320-13-038-038
文摘AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents. METHODS: Forty-eight Sprague-Dawley rats were fed with a diet containing 0%, 2% or 5% H. cordata powder and 15% fresh soybean oil or 24-h oxidized frying oil (OFO) for 28 d respectively. The level of microsomal protein, total cytochrome 450 content (CYP450) and enzyme activities including NADPH reductase, ethoxyresorufin 0-deethylase (EROD), pentoxyresorufin 0-dealkylase (PROD), aniline hydroxylase (ANH), aminopyrine demethylase (AMD), and quinone reductase (QR) were determined. QR represented phase Ⅱ enzymes, the rest of the enzymes tested represented phase Ⅰ enzymes. RESULTS: The oxidized frying oil feeding produced a significant increase in phase Ⅰ and Ⅱ enzyme systems, including the content of CYP450 and microsomal protein, and the activities of NADPH reductase, EROD, PROD, ANH, AMD and QR in rats (P<0.05). In addition, the activities of EROD, ANH and AMD decreased and QR increased after feeding with H. cordata in OFO-fed group (P<0.05). The feeding with 2% H. cordata diet showed the most significant effect. CONCLUSION: The OFO diet induces phases I and II enzyme activity, and the 2% H. cordata diet resulted in a better regulation of the xenobiotic-metabolizing enzyme system.
文摘The dynamic changes of liver microsomal drug-metabolizing system (MDMS) andlipoperoxidation were studied in scalded rats. The effects of treatment with vitamin E and silybinwere also evaluated. The results showeed that liver microsomal cytochrome P-450 content, and p-nitroanisole demethylase (P-NOD) and aniline hydroxylase (AH) activity decreased markedlypostburn. On the contrary, liver lipoperoxide and mierosomal lipoperoxidation increased significantlyafter scalding. Both the increase of liver lipoperoxide and mierosomal lipoperoxidation and the de-crease of MDMS activity were prevented by vitamin E and silybin treatments.
文摘Curry leaves, scientifically termed Murraya koenigii, are renowned in South Asian cuisine for their flavor enhancement and potential health benefits, including antioxidative, anti-inflammatory, and antidiabetic properties. This study aimed to evaluate the impact of thermal processing methods on curry leaves by analysing Total Phenolic Content (TPC), Total Flavonoid Content (TFC), antioxidant activity, and metabolizing enzyme inhibition. Fresh curry leaves were subjected to thermal treatments: Oven-dried at 60˚C and Air-dried at 25˚C for 2 weeks. Extracts were prepared using Ethanol and water solvents. Results indicated that Air-dried leaves exhibited significantly higher TPC (5132.65 mg GAE/100 g) and TFC (243.13 mg CE/100 g) compared to Fresh and Oven-dried leaves. Antioxidant assays show that oven-dried curry leaves at 60˚C displayed higher results in NORS, FRAP, and TEAC assays compared to Fresh and Air-dried leaves. Ethanol extracts showed better extraction of bioactive compounds than aqueous extracts. Moreover, Lipase inhibition activity was notably high, indicating potential health benefits. This study provides valuable insights into the effects of processing methods on curry leaf extracts, emphasizing the importance of solvent selection for optimal extraction of bioactive compounds.
基金supported by the National Key Tech-nologies R&D Program of China (2008BADA6B05)
文摘Changes in sucrose metabolism in response to salt （NaC1） and water （polyethylene glycol, PEG6000） iso-osmotic stresses were measured in tomato cultivar Liaoyuan Duoli （Solanum lycopersicum L.） and the objective was to provide a new evidence for the relationship between salt and osmotic stresses. The carbohydrate contents, as well as sucrose metabolizing enzymes activities and transcript levels were determined. The results indicated that soluble sugar and hexoses accumulated to higher levels and the contents of sucrose and starch were lower in mature fruit under the two stress treatments. Salt and water stresses can enhance the invertase and sucrose synthase activities of tomato fruit in a long period of time （45-60 days after anthesis）, and elevate the expression of soluble acid invertase mRNA. It showed that two different stresses could also regulate the soluble acid invertase activity by controlling its gene expression. The activity of sucrose synthase was linked to the changes in soluble sugar levels but not with transcript levels. The effects of salt and water stress treatments on sucrose phosphate synthase activities were weak.
基金supported by the National Natural Science Foundation of China(Grant Nos.82073934,81872937,and 81673513).
文摘The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.
基金supported by the National Basic Research Program of China(973 Program)(2006CB503903)the National Natural Science Foundation of China(81172744,81230066)
文摘Objective To evaluate the association of known polymorphisms in the lipid metabolic pathway with body mass index （BMI）, and estimate their interactions with soybean food intake. Methods A community-based cross-sectional survey was conducted in a Chinese Han population. BMI, soybean food intake, and single nucleotide polymorphisms of rs599839, rs3846662, rs3846663, rs12916, rs174547, rs174570, rs4938303, and rs1558861 were measured in 944 subjects. A multivariate logistic regression was used to analyze the association of the studied polymorphisms with BMIs. The expectation-maximization algorithm was employed to evaluate the extent of linkage disequilibrium between pairwise polymorphisms. The gene-environment interaction was assessed in the general multifactor dimensionality reduction model. Results The polymorphisms of rs3846662 and rs3846663 were associated with 10% highest BMIs when comparing to the 10% lowest values both in individuals and haplotype-based association tests. Although no statistically significant gene-environment interactions were found, people with the haplotype composed of C allele in rs3846662 and T allele in rs3846663 and low frequency of soybean intake had significantly hisher risk to overweight and obesity as compared with those with the haplotype consisting of T allele in rs3846662 and C allele in rs3846663 and highly frequent soybean food intake, with an odds ratio of 1.64 （95% confidence interval： 1.15-2.34, P〈0.01） after adjusting for the common confounders. Conclusion Our study has sugsested that rs3846662 and rs3846663 may be the potential candidate polymorphisms for obesity, and their effect on the pathogenesis could be mediated by the frequency of soybean food intake.
基金funded by the Science and Technology Cooperation Project Between Jilin Province and Chinese Academy of Sciences(No.2022000170)the National Natural Science Foundation of China(Nos.41920104008 and U22A20593)the Strategic Priority Research Program of CAS(No.XDA28020400)。
文摘In the context of global efforts to reduce carbon(C)emissions,several studies have examined the effects of agricultural practices such as straw returning and fertilization on C sequestration by microorganisms.However,our understanding of the specific microbial groups and their roles in long-term C increase remains limited.In this study,a 36-year(1984-2020)farmland experiment was conducted to investigate the impact of bacterial C metabolism on the augmentation of organic C in a Typic Hapludoll(Mollisol)in the black soil region of Jilin Province,Northeast China.Our results demonstrated a noteworthy increase in the diversity of microorganisms in the farmland as a result of long-term straw returning and application of mixed chemical fertilizers.However,by examining the functions of microorganisms involved in C metabolism,it was observed that the effects of fertilization on C metabolism were relatively consistent.This consistency was attributed to a deterministic competitive exclusion process,which minimized the differences between treatment groups.On the other hand,the influence of straw addition on C metabolism appeared to follow a more random pattern.These changes in microbial activity were closely linked to the downregulation of core metabolic pathways related to C metabolism.Notably,long-term fertilization had a negative impact on soil organic C levels,while long-term straw returning plus fertilization resulted in a positive increase in soil organic C.These findings have important implications for enhancing soil organic C and grain yield in the regions with typical black soil.
文摘Pathophysiological changes in human patients and in animal models of infection or inflammation are associated with alterations in the production of numerous liver-derived proteins including metabolizing enzymes. In this study, the effects of adjuvant-induced arthritis (AA) in rats on the levels of mRNA and activity of hepatic xenobiotic metabolizing enzymes were determined during the inflammatory response. The mRNA levels of cytochrome P450 (CYP) 1A2, CYP2C12, CYP2D1, CYP2D2, and CYP3A1 were significantly decreased compared with control levels in almost all phases of inflammation. A reduction in the activity of CYP2C and CYP3A, which are abundantly expressed in the liver, was also observed. For phase II metabolizing enzymes, mRNA levels of uridine 5’-diphospho-glucuronosyltransferase (UGT) 1A1, UGT1A6, sulfotransferase (SULT) 2A1, and glutathione S-transferase 2 were significantly decreased compared with control levels. However, the mRNA levels of UGT2B and SULT1A1 returned to control levels during the subacute (7 d after adjuvant treatment) and chronic (21 d after adjuvant treatment) phases although these levels decreased during the acute (3 d after adjuvant treatment) phase. These results suggest that the effects of inflammation on the expression of xenobiotic metabolizing enzymes differ depending on the isoform of the enzyme and could affect the pharmacokinetics of each substrate.
基金supported by the National Natural Science Foundation of China(Grant No.U21A20424)the Natural Science Foundation of Gansu Province,China(Grant No.24JRRA912).
文摘Pharmacogenomics,therapeutic drug monitoring,and the assessments of hepatic and renal function have made significant contributions to the advancement of individualized medicine.However,their lack of direct correlation with protein abundance/non-genetic factors,target drug concentration,and drug metabolism/excretion significantly limits their application in precision drug therapy.The primary task of precision medicine is to accurately determine drug dosage,which depends on a precise assessment of the ability to handle drugs in vivo,and drug metabolizing enzymes and transporters are critical determinants of drug disposition in the body.Therefore,accurately evaluating the functions of these enzymes and transporters is key to assessing the capacity to handle drugs and predicting drug concentrations in target organs.Recent advancements in the evaluation of enzyme and transporter functions using exogenous probes and endogenous biomarkers show promise in advancing personalized medicine.This article aims to provide a comprehensive overview of the latest research on markers used for the functional evaluation of drug-metabolizing enzymes and transporters.It also explores the application of marker omics in systematically assessing their functions,thereby laying a foundation for advancing precision pharmacotherapy.
基金supported in the part by the U.S. National Institutes of Health National Institute for Environmental Health Sciences [Grant R01ES-019487 to Xiao-bo Zhong]U.S. National Institutes of Health National Institute of General Medical Sciences [Grants R01GM-087376 and R01GM118367 to Xiao-bo Zhong]
文摘The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation.Farnesoid X receptor(FXR) is critical for bile acid and lipid homeostasis in liver.However,the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear.Hence,we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both Fxr-null and control(C57BL/6) mouse livers during development.Liver samples of male C57BL/6 and Fxr-null mice at6 different ages from prenatal to adult were used.The Fxr-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression,including cytochrome P450 s at neonatal ages.Among the 185 phase-I genes from 12 different families,136 were expressed,and differential expression during development occurred in genes from all 12 phase-I families,including hydrolysis: carboxylesterase(Ces),paraoxonase(Pon),and epoxide hydrolase(Ephx); reduction: aldoketo reductase(Akr),quinone oxidoreductase(Nqo),and dihydropyrimidine dehydrogenase(Dpyd); and oxidation: alcohol dehydrogenase(Adh),aldehyde dehydrogenase(Aldh),flavin monooxygenases(Fmo),molybdenum hydroxylase(Aox and Xdh),cytochrome P450(P450),and cytochrome P450 oxidoreductase(Por).The data also suggested new phase-I genes potentially targeted by FXR.These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.
基金supported by the Major National Science and Technology Program (Grant No. 2008ZX10005-004)the Liaoning Education Depart-ment (Grant No. 2009A120)the China Postdoctoral Science Founda-tion (Grant Nos. 20080440019 and 200902069)
文摘Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein’s function and account for susceptibility to disease and altered drug/xenobiotic response. Many nsSNPs have been found in genes encoding human phase II metabolizing enzymes; however, there is little known about the relationship between the genotype and phenotype of nsSNPs in these enzymes. We have identified 923 validated nsSNPs in 104 human phase II enzyme genes from the Ensembl genome database and the NCBI SNP database. Using PolyPhen, Panther, and SNAP algorithms, 44%?59% of nsSNPs in phase II enzyme genes were predicted to have functional impacts on protein function. Predictions largely agree with the available experimental annotations. 68% of deleterious nsSNPs were correctly predicted as damaging. This study also identified many amino acids that are likely to be functionally critical, but have not yet been studied experimentally. There was significant concordance between the predicted results of Panther and PolyPhen, and between SNAP non-neutral predictions and PolyPhen scores. Evolutionarily non-neutral (destabilizing) amino acid substitutions are thought to be the pathogenetic basis for the alteration of phase II enzyme activity and to be associated with disease susceptibility and drug/xenobiotic toxicity. Furthermore, the molecular evolutionary patterns of phase II enzymes were characterized with regards to the predicted deleterious nsSNPs.
基金supported by the Project of Sanya Yazhou Bay Science and Technology City (SKJC-JYRC-2024-26)the National Natural Science Foundation of China (32460072)+4 种基金Hainan Provincial Natural Science Foundation of China (323RC421)the Hainan Province Science and Technology Special Fund (ZDYF2022XDNY144)the Hainan Provincial Academician Innovation Platform Project (HDYSZX-202004)the Collaborative Innovation Center of Nanfan and High-Efficiency Tropical Agriculture, Hainan University (XTCX2022NYB06)Hainan Postdoctoral Research Grant Project
文摘In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quality and stress tolerance of crops.Synthetic metabolic engineering presents innovative strategies for the precision modification and de novo design of metabolic pathways.This approach generally encompasses three essential steps:identifying key metabolites through metabolomics,integrating multi-omics technologies to investigate the synthesis and regulation of these metabolites,and utilizing gene editing or de novo design to modify crop metabolic pathways associated with desirable agronomic traits.This review underscores the vital role of plant metabolite diversity in enhancing crop nutritional quality and stress resilience.Integrated multi-omics analyses facilitate the metabolic engineering by identifying key genes,transporters,and transcription factors that regulate metabolite biosynthesis.Precision modification strategies employ genome editing tools to reprogram endogenous metabolic networks,while de novo design reconstructs metabolic pathways through the introduction of exogenous biological elements—thereby both approaches enable the targeted enhancement of desired traits.These strategies have been effectively implemented in major food crops.However,simultaneously enhancing nutritional quality and stress resilience remains challenging due to inherent trade-offs and resource competition in distinct metabolic pathways within plants.Future research should integrate AI-driven predictive models with multi-omics datasets to decipher dynamic metabolic homeostasis and engineer climate-smart crops that maximize yield while preserving quality and environmental adaptability.
文摘Background Endogenous estrogen plays a very important role in the carcinogenesis and progression of breast cancer. The enzymes involved in the biosynthesis and metabolism of estrogen have been proposed to contribute to this effect. To examine this hypothesis, we conducted a case-control study to investigate the relationship between polymorphisms of genes responsible for estrogen biosynthesis （CYP17, cytochrome P450c17a and CYP19, aromatase cytochrome P450） and estrogen sulfation of inactivation （ SULT1 A1, sulfotransferasel A1 ） and the risk of breast cancer in Chinese women. Methods This study involved 213 breast cancer patients and 430 matched controls. PCR-based restriction fragment length polymorphism （RFLP） and short tandem repeat polymorphism （STRP） assays were used to detect the mononucleotide transition of CYP17 and SULT1A1 and tandem repeat polymorphism of CYP19. Logistic regression analyses were used to determine OR and 95% CI of each and all three high-risk genotypes, of all three genotypes combined, and of estrogen exposure factbrs. The relationship between each high-risk genotype and clinicalpathological characteristics were also assessed. Results The frequency of A2 allele of CYP17 was 49.8% in cases and 49. 1% in controls （P =0. 82）. The frequency of His allele of SULT1A1 was significantly higher in cases （ 13.6% ） than in controls （9. 5% ） （P 〈 0. 05 ）. There was also significant difference of the （TTTA）10 allele of CYP19 which was 12. 4% in cases and 8.2% in controls （P 〈0. 05）. When the CYP17 A2 allele, CYP19 （TITA）1o and SULT1A1 His allele were considered as the “putative high-risk” genotype, there was an increased risk of breast cancer with the number of high-risk genotypes in a dose-response effect （trend, P = 0. 05 ）. In multivariate analysis, the SULT1A1 genotype remained the most significant determinant for breast cancer, with OR =2. 37 （95% CI 1.23 - 4. 74） , followed by CYP19, with OR = 1.75 （95% CI 1.27 - 3.56）. The （TTTA）10 allele of CYP19 was associated with tumor size, and the His allele of SULT1 A1 associated with status of lymph node metastasis. Conclusions This study supports the hypothesis that breast cancer can be initiated by estrogen exposure and that estrogen metabolizing genes are involved in this mechanism. This multigenic model is useful for identifying individuals who are at higher risks of breast cancer.
基金supported by grants from the Guangxi Science and Technology Major Project(GKAA24206023)the Biological Breeding-National Science and Technology Major Project(2024ZD04077)+2 种基金the National Natural Science Foundation of China(32272120)the National Key Research and Development Program of China(2024YFF1000800)the Guangdong Basic Research Center of Excellence for Precise Breeding of Future Crops Major Project(FCBRCE-202502,FCBRCE-202504).
文摘A growing global population and the increasing prevalence of diet-related health issues such as“hidden hunger”,obesity,hypertension,and diabetes necessitate a fundamental rethinking of crop design and breeding.Synthetic metabolic engineering offers a method to modify and redesign metabolic pathways to increase the nutritional value of crops.We summarize recent advances in the biofortification of key nutrients including provitamin A,vitamin C,vitamin B9,iron,zinc,anthocyanins,flavonoids,and unsaturated fatty acids.We discuss the potential of multi-gene stacking,gene editing,enzyme engineering,and artificial intelligence in synthetic metabolic engineering.We propose future research directions and potential solutions centered on leveraging AI-driven systems biology,precision gene editing,enzyme engineering,agrobacterium-mediated genotype-independent transformation,and modular metabolic engineering strategies to develop next-generation nutritionally enhanced super crops and transform global food systems.
基金supported by the National Natural Science Foundation of China,Nos.82071383,82371392(to BN)the Natural Science Foundation of Shandong Province of China(Key Project),No.ZR2020KH007(to BN)+1 种基金“Taishan Scholar Distinguished Expert Program”of Shandong Province,No.tstp20231257(to BN)Health Commission Science and Technology Plan Project of Jinan,No.2023-1-8(to YZ).
文摘Lactate serves as a key energy metabolite in the central nervous system,facilitating essential brain functions,including energy supply,signaling,and epigenetic modulation.Moreover,it links epigenetic modifications with metabolic reprogramming.Nonetheless,the specific mechanisms and roles of this connection in astrocytes remain unclear.Therefore,this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system.The close relationship between epigenetic modifications and metabolic reprogramming was discussed.Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases.In the nervous system,lactate plays an essential role.However,its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation.The involvement of lactate in epigenetic modifications is currently a hot research topic,especially in lactylation modification,a key determinant in this process.Lactate also indirectly regulates various epigenetic modifications,such as N6-methyladenosine,acetylation,ubiquitination,and phosphorylation modifications,which are closely linked to several neurological disorders.In addition,exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most prevalent chronic liver disease worldwide,affecting approximately 32%-38%of the adult population and posing a growing public health burden.MASLD represents a continuous disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis(MASH),progressive hepatic fibrosis,cirrhosis,and ultimately hepatocellular carcinoma(HCC).The pathological core of MASLD lies in disruption of hepatic lipid metabolic homeostasis,characterized by an imbalance among de novo lipogenesis,fatty acidβ-oxidation,and very-low-density lipoprotein(VLDL)-mediated lipid export.This metabolic disequilibrium subsequently drives inflammatory injury and fibrotic progression.Among the multiple regulatory pathways involved,thyroid hormone(TH)signaling has emerged as a central regulator of hepatic metabolic homeostasis.The liver is a major peripheral target organ of TH action,where TH predominantly exerts its metabolic effects through thyroid hormone receptorβ(TRβ).Large-scale epidemiological studies and metaanalyses have demonstrated that hypothyroidism is significantly associated with increased MASLD prevalence,more severe histological injury,and advanced hepatic fibrosis,suggesting that dysregulation of TH signaling may participate throughout the entire MASLD disease spectrum.At the molecular level,TH regulates hepatic lipid metabolism by coordinating suppression of lipogenesis,enhancement of mitochondrial fatty acid oxidation,and promotion of VLDL assembly and secretion through integrated genomic actions of the T3-TRβaxis and non-genomic signaling pathways.Across different stages of MASLD,TH signaling exerts stagedependent protective effects.In the steatosis stage,TH improves metabolic flexibility by modulating insulin sensitivity,glucose metabolism,and lipid droplet clearance,thereby alleviating early lipotoxic stress.During progression to MASH,TH attenuates inflammatory amplification by improving mitochondrial homeostasis,suppressing activation of the NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome,and modulating the gut-liver axis microenvironment.In advanced stages,TH signaling influences hepatic stellate cell activation and extracellular matrix deposition,partly through interaction with the transforming growth factor-β(TGF-β)/SMAD pathway,while alterations in intrahepatic TH availability,mediated by dynamic changes in iodothyronine deiodinase 1(DIO1),contribute to fibrosis progression and hepatocellular dedifferentiation.In hepatocellular carcinoma,coordinated downregulation of TRβand DIO1 establishes a tumor-associated hypothyroid state that promotes metabolic reprogramming and tumor progression.The clinical relevance of TH signaling in MASLD has been underscored by the recent approval of Resmetirom,a liver-targeted TRβ-selective agonist,for the treatment of non-cirrhotic MASH with moderate-to-severe fibrosis(F2-F3).This approval represents a landmark transition from mechanistic understanding to metabolismcentered precision therapy in MASLD.Clinical trials have demonstrated that Resmetirom not only improves key histological endpoints,including MASH resolution and fibrosis regression,but also favorably modulates atherogenic lipid profiles,highlighting the therapeutic potential of selectively targeting hepatic TH pathways.This review systematically summarizes the multidimensional regulatory roles of TH across the MASLD disease spectrum and discusses emerging diagnostic and therapeutic implications of THbased interventions,aiming to inform future mechanistic research and optimize clinical management strategies.
基金supported by grants from the Applied Basic Research Foundation of Yunnan Province(202301AT070095)the Candidate Talents Training Fund of Yunnan Province(H-2024069)。
文摘As oncologic therapies continue to advance,the overall survival of cancer patients has markedly increased.Nevertheless,virtually every anticancer treatment modality is accompanied by some degree of cardiotoxicity.Epidemiological data indicate that approximately 30%of cancer survivors ultimately die from cardiovascular disease.Among the cardiotoxic agents,the anthracycline doxorubicin(DOX)is the most widely used.It effectively suppresses a variety of malignant tumors——including breast cancer,lymphoma,and acute leukemia——but its cardiac toxicity limits further escalation of clinical dosing.Literature reports identify a cumulative dose of≥250 mg/m²as the threshold of high risk,with roughly 25%of patients receiving DOX developing varying degrees of myocardial injury;severe cases progress to heart failure.Even at cumulative doses below the traditional safety limit,some patients exhibit cardiac dysfunction after the first administration,suggesting that cardiotoxicity is not solely a linear function of dose.DOX related cardiotoxicity can be classified as acute(hours to days after administration),sub acute(weeks to months),and chronic/late onset(years later).Most patients initially exhibit only mild reductions in left ventricular ejection fraction(LVEF)or subtle abnormalities in global longitudinal strain(GLS),often without symptoms.Recently,cardiac biomarkers(cTn,NT proBNP)combined with high sensitivity echocardiography(speckle tracking)have been recommended for monitoring high risk individuals,enabling detection of subclinical injury before overt LVEF decline.Currently,several preventive and therapeutic approaches are used in clinical practice,which can be summarized into the following four points.(1)Dose limitation and administration strategies:fractionated low dose regimens,liposomal encapsulation,or continuous infusion lower peak plasma concentrations,thereby reducing cardiac exposure.(2)Pharmacologic prophylaxis:βblockers(e.g.,carvedilol)and ACE inhibitors/ARBs have shown protective effects on LVEF in some randomized trials,though results remain inconsistent and require larger confirmatory studies.(3)Metabolic targeted interventions:animal experiments indicate that activation of PPARαor supplementation with L carnitine restores fatty acid oxidation and improves ATP generation,suggesting metabolic modulators as promising cardioprotective candidates.(4)Lifestyle modifications:regular aerobic exercise up regulates mitochondrial biogenesis genes(PGC-1α)and reduces reactive oxygen species(ROS)production;small clinical studies have demonstrated a potential benefit in attenuating cTnT elevation.However,DOX-induced cardiotoxicity has not been effectively controlled,indicating that the core mechanism underlying DOX‑related cardiac toxicity remains unidentified.Cardiomyocytes are high energy demand cells,and metabolic dysregulation is considered a central component of DOX induced cardiotoxicity.DOX disrupts myocardial metabolic balance through several interrelated pathways.(1)Oxidative stress and mitochondrial damage:DOX generates abundant ROS within cells,leading to mitochondrial membrane potential loss,lipid peroxidation,and iron accumulation,which suppress electron transport chain activity and markedly reduce ATP synthesis efficiency.(2)Autophagy dysregulation:DOX interferes with autophagic flux,preventing the clearance of damaged mitochondria and further aggravating apoptosis and inflammatory responses.(3)Inflammation and cytokine release:oxidative stress activates NF‑κB,up-regulating pro inflammatory cytokines such as TNF‑αand IL-6,creating a chronic inflammatory microenvironment that weakens myocardial contractility.(4)Epigenetic modifications:studies have shown that DOX alters DNA methylation and histone acetylation patterns in cardiomyocytes,affecting the expression of key metabolic genes(e.g.,PGC-1α,CPT-1)and further inhibiting fatty acidβoxidation.These mechanisms collectively lead to suppressed fatty acid oxidation and compensatory up regulation of glycolysis,manifested by an elevated lactate/pyruvate ratio,accumulation of medium chain acyl carnitines,and a pronounced decline in ATP production.The resulting energy deficit precipitates left ventricular contractile dysfunction and,ultimately,heart failure.Despite extensive basic and clinical research on DOX cardiotoxicity,a unified risk assessment model and precise interventions targeting metabolic disturbances remain lacking.This review systematically summarizes recent progress on DOX induced cardiotoxicity and highlights that impairment of myocardial energy metabolism is a central mechanism of injury,thereby deepened our understanding of how impaired myocardial energy metabolism drives DOX induced injury,we can move toward safer chemotherapy protocols that achieve“cure cancer without harming the heart”.
文摘This study employed integrated multi-omics approaches to elucidate,from the perspective of amino acid metabolism,the adaptive mechanism of Penicillium digitatum under modified atmosphere packaging(MAP)conditions.Comparative analysis of natural air(Air),controlled atmosphere(CA),and MAP treatments revealed that MAP upregulated the expression of the hercynylcysteine S-oxide synthase(HCSOS),aldehyde dehydrogenase(ALDH),and monoamine oxidase(MAO)genes,thereby enhancing histidine-derived ergothioneine and methionine levels,and subsequently boosting glutathione-mediated redox homeostasis.Meanwhile,MAP induced the expression of the dihydroxyacid dehydratase(DHAD),saccharopine dehydrogenase(SDH),and arginosuccinate lyase(ASL)genes,redirecting valine,lysine,and arginine into the tricarboxylic acid(TCA)cycle to fuel ATP production.MAP also enhanced ASL-mediated arginine degradation and urea cycle activity,reducing arginine accumulation when compared to CA treatment.In contrast,while MAP induced upregulated expression of the pyrroline-5-carboxylate dehydrogenase(P5CDH)and D-amino acid oxidase(DAAO)genes,CA treatment promoted proline accumulation,reflecting stress-specific metabolic flexibility.Collectively,these findings demonstrate that MAP triggers transcriptional reprogramming of amino acid metabolism to coordinate oxidative defense,energy generation,and osmotic balance.By modulating these metabolic pathways and regulatory genes under MAP conditions,fungal adaptability can be disrupted.Hence,this study provides a promising strategy for suppressing green mold development,extending the postharvest shelf life,and improving the quality of fruits and vegetables.
文摘Nitrogen is essential for plant growth and development,with the ratio of ammonium(NH_(4)^(+))to nitrate(NO_(3)^(-))critically influencing physiological efficiency.This study investigated the effects of different NH_(4)^(+)-N/NO_(3)^(-)-N mass ratios(0︰1,3︰7,1︰1,7︰3,1︰0)and a no-nitrogen control on Zanthoxylum planispinum var.dintanensis seedlings,using NH_(4)Cl and NaNO_(3) as nitrogen sources.Key results revealed that a 3︰7 NH_(4)^(+)︰NO_(3)^(-)ratio(T2)significantly enhanced stomatal conductance(G_(s)),amino acid content,root tip number,and the photochemical quenching parameters q_(P),q_(L),ETR,and F_(v)/F_(m).This treatment also maximized ground diameter increment,chlorophyll content,intercellular CO_(2)concentration(C_(i)),transpiration rate(T_(r)),ribulose-1,5-bisphosphate carboxylase(Rubisco)activity,nitrate reductase(NR)activity,and soluble protein content.Conversely,a 7︰3 ratio(T4)yielded the highest net photosynthetic rate(Pn)and fructose-1,6-bisphosphate aldolase(FBA)activity.Overall,the T4 treatment exhibited the second most effective promotion of Z.planispinum var.dintanensis seedling growth and development,after T2.In summary,mixed NH_(4)^(+)-N/NO_(3)^(-)-N nutrition markedly enhances seedling performance,with the 3︰7 ratio optimal for growth,photosynthesis,and nitrogen assimilation.Sole nitrogen sources,particularly pure NH_(4)^(+)-N,exert inhibitory effects.
