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
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
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
Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,par...Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,particularly palmitic acid,are potent inducers of chronic low-grade inflammation,largely due to disruptions in glucose metabolism and the onset of insulin resistance(Qiu et al.,2022).While many organs are affected,the brain,specifically the hypothalamus,is among the first to exhibit inflammation in response to an unhealthy diet,suggesting that obesity may,in fact,be a brain-centered disease with neuroinflammation as a central factor(Thaler et al., 2012).展开更多
Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progre...Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progression and provide symptomatic improvement in patients with IEM.Each metabolic disorder is unique,with the missing enzyme or transporter protein causing substrate deficiency or toxic byproduct production.Knowledge about the distribution of deficient enzymes,the percentage of enzymes replaced by LT,and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period.Most patients have multisystem involvement and can be on complex dietary regimens.Metabolic decompensation can be triggered due to the stress response to surgery,fasting and other unanticipated complications perioperatively.Thus,a multidisciplinary team’s input including those from metabolic specialists is essential to develop disease and patient-specific strategies for the perioperative management of these patients during LT.In this review,we outline the classification of IEM,indications for LT along with potential benefits,basic metabolic defects and their implications,details of extrahepatic involvement and perioperative management strategies for LT in children with some of the commonly presenting IEM,to assist anesthesiologists handling this cohort of patients.展开更多
Background:Bone tumors represent a significant clinical challenge characterized by high morbidity and complex therapeutic requirements.Although Astragali Radix(Huangqi)is recognized for its potential pharmacological b...Background:Bone tumors represent a significant clinical challenge characterized by high morbidity and complex therapeutic requirements.Although Astragali Radix(Huangqi)is recognized for its potential pharmacological benefits in cancer therapy,the specific molecular mechanisms and their influence on vitamin metabolism pathways in bone malignancies are not well defined.Methods:We conducted an integrated analysis of prognostic genes and survival outcomes in osteosarcoma,focusing on the expression of GPC2 and its correlation with tumor progression and patient survival rates.In order to explore the therapeutic relevance of 20 bioactive compounds extracted from Huangqi,molecular docking was performed to quantify their binding free energies to the GPC2 receptor,shedding light on their potential affinity and biological activity.Furthermore,the expression levels of GPC2 in tumor cells compared to normal cells were analyzed using qRT-PCR.Additionally,the effects of GPC2 overexpression and silencing on cellular viability,apoptotic response,and migratory capacity were systematically investigated.Results:In our study,GPC2 emerged as a significant prognostic gene,where high expression levels correlated with reduced overall survival.The molecular interactions between Astragalus components and the GPC2 receptor reveal compounds with strong affinity,suggesting their potential as effective targets.Furthermore,the overexpression of GPC2 enhanced tumor cell viability and migration,while its knockdown resulted in decreased cell viability and expanded apoptosis.Conclusion:This study demonstrates that Huangqi-derived components may exert anticancer effects by regulating the expression of the GPC2 gene within the vitamin metabolism pathway.These findings offer new insights into the therapeutic potential of traditional herbal medicine for improving bone tumor prognosis and provide a scientific foundation for future translational research.展开更多
Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the ...Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.展开更多
The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes und...The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes under both physiological and pathological conditions.These immune cells communicate with intrinsic and systemic factors and contribute to the structural and functional compartmentalization of the cerebellum.In this review,we discuss the roles of microglia in the cerebellar microenvironment,neuroinflammation,cerebellar adaptation,and neuronal activity,the associated molecular and cellular mechanisms,and potential therapeutic strategies targeting cerebellar microglia in the context of neuroinflammation.Future directions and unresolved questions in this field are further highlighted,particularly regarding therapeutic interventions targeting cerebellar microglia,functional mechanisms and activities of microglia in the cerebellar circuitry,neuronal connectivity,and neurofunctional outcomes of their activity.Cerebellar morphology and neuronal performance are influenced by both intrinsic and systemic factors that are actively monitored by microglia in both healthy and diseased states.Under pathological conditions,local subsets of microglia exhibit diverse responses to the altered microenvironment that contribute to the structural and functional compartmentalization of the cerebellum.Microglia in the cerebellum undergo early maturation during the embryonic stage and display specialized,highly immunogenic phenotypes.In summary,cerebellar microglia have the capacity to serve as regulatory tools that influence outcomes across a wide range of neurological and systemic conditions,including neurodevelopmental,neurodegenerative,metabolic,and stress-related disorders.展开更多
BACKGROUND Organ transplantation has emerged as a globally prevalent therapeutic modality for end-stage organ failure,yet the post-transplantation trajectory is increasingly complicated by a spectrum of metabolic sequ...BACKGROUND Organ transplantation has emerged as a globally prevalent therapeutic modality for end-stage organ failure,yet the post-transplantation trajectory is increasingly complicated by a spectrum of metabolic sequelae,with obesity emerging as a critical clinical challenge.AIM To systematically review the multifactorial mechanisms underlying obesity following organ transplantation and to integrate evidence from pharmacological,behavioral,and molecular perspectives,thereby providing a foundation for targeted interventions.METHODS We conducted a systematic search in PubMed and Web of Science for literature published from 2020 to 15 July 2025.The search strategy incorporated terms including“obesity”,“overweight”and“post organ transplantation”.Only randomized controlled trials,meta-analyses,and systematic reviews were included.Non-empirical publications and irrelevant studies were excluded.Data extraction and quality assessment were performed by two independent reviewers,with disagreements resolved by a third researcher.RESULTS A total of 1457 articles were initially identified,of which 146 met the inclusion criteria.These studies encompassed liver,kidney,heart,and lung transplant recipients.Key findings indicate that immunosuppressive drugs-especially corticosteroids and calcineurin inhibitors-promote hyperphagia,insulin resistance,and dyslipidemia.Post-transplant sedentary behavior and hypercaloric diets further contribute to positive energy balance.At the molecular level,immunosuppressants disrupt adipokine signaling(e.g.,leptin and adiponectin),induce inflammatory and oxidative stress responses,and activate adipogenic pathways leading to lipid accumulation.CONCLUSION Post-transplant obesity arises from a complex interplay of pharmacological,behavioral,and molecular factors.A multidisciplinary approach-incorporating pharmacological modification,nutritional management,physical activity,and molecular-targeted therapies-is essential to mitigate obesity and improve transplant outcomes.Further large-scale and mechanistic studies are warranted to establish evidence-based preventive and treatment strategies.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.
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 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Obesity is widely recognized as a global epidemic,primarily driven by an imbalance between energy expenditure and caloric intake associated with a sedentary lifestyle.Diets high in carbohydrates and saturated fats,particularly palmitic acid,are potent inducers of chronic low-grade inflammation,largely due to disruptions in glucose metabolism and the onset of insulin resistance(Qiu et al.,2022).While many organs are affected,the brain,specifically the hypothalamus,is among the first to exhibit inflammation in response to an unhealthy diet,suggesting that obesity may,in fact,be a brain-centered disease with neuroinflammation as a central factor(Thaler et al., 2012).
文摘Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progression and provide symptomatic improvement in patients with IEM.Each metabolic disorder is unique,with the missing enzyme or transporter protein causing substrate deficiency or toxic byproduct production.Knowledge about the distribution of deficient enzymes,the percentage of enzymes replaced by LT,and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period.Most patients have multisystem involvement and can be on complex dietary regimens.Metabolic decompensation can be triggered due to the stress response to surgery,fasting and other unanticipated complications perioperatively.Thus,a multidisciplinary team’s input including those from metabolic specialists is essential to develop disease and patient-specific strategies for the perioperative management of these patients during LT.In this review,we outline the classification of IEM,indications for LT along with potential benefits,basic metabolic defects and their implications,details of extrahepatic involvement and perioperative management strategies for LT in children with some of the commonly presenting IEM,to assist anesthesiologists handling this cohort of patients.
文摘Background:Bone tumors represent a significant clinical challenge characterized by high morbidity and complex therapeutic requirements.Although Astragali Radix(Huangqi)is recognized for its potential pharmacological benefits in cancer therapy,the specific molecular mechanisms and their influence on vitamin metabolism pathways in bone malignancies are not well defined.Methods:We conducted an integrated analysis of prognostic genes and survival outcomes in osteosarcoma,focusing on the expression of GPC2 and its correlation with tumor progression and patient survival rates.In order to explore the therapeutic relevance of 20 bioactive compounds extracted from Huangqi,molecular docking was performed to quantify their binding free energies to the GPC2 receptor,shedding light on their potential affinity and biological activity.Furthermore,the expression levels of GPC2 in tumor cells compared to normal cells were analyzed using qRT-PCR.Additionally,the effects of GPC2 overexpression and silencing on cellular viability,apoptotic response,and migratory capacity were systematically investigated.Results:In our study,GPC2 emerged as a significant prognostic gene,where high expression levels correlated with reduced overall survival.The molecular interactions between Astragalus components and the GPC2 receptor reveal compounds with strong affinity,suggesting their potential as effective targets.Furthermore,the overexpression of GPC2 enhanced tumor cell viability and migration,while its knockdown resulted in decreased cell viability and expanded apoptosis.Conclusion:This study demonstrates that Huangqi-derived components may exert anticancer effects by regulating the expression of the GPC2 gene within the vitamin metabolism pathway.These findings offer new insights into the therapeutic potential of traditional herbal medicine for improving bone tumor prognosis and provide a scientific foundation for future translational research.
基金supported by the National Key Research and Development Program of China,No. 2023YFF0714200 (to CW)the National Natural Science Foundation of China,Nos. 82472038 and 82202224 (both to CW)+3 种基金the Shanghai Rising-Star Program,No. 23QA1407700 (to CW)the Construction Project of Shanghai Key Laboratory of Molecular Imaging,No. 18DZ2260400 (to CW)the National Science Foundation for Distinguished Young Scholars,No. 82025019 (to CL)the Greater Bay Area Institute of Precision Medicine (Guangzhou)(to CW)。
文摘Epilepsy is a leading cause of disability and mortality worldwide. However, despite the availability of more than 20 antiseizure medications, more than one-third of patients continue to experience seizures. Given the urgent need to explore new treatment strategies for epilepsy, recent research has highlighted the potential of targeting gliosis, metabolic disturbances, and neural circuit abnormalities as therapeutic strategies. Astrocytes, the largest group of nonneuronal cells in the central nervous system, play several crucial roles in maintaining ionic and energy metabolic homeostasis in neurons, regulating neurotransmitter levels, and modulating synaptic plasticity. This article briefly reviews the critical role of astrocytes in maintaining balance within the central nervous system. Building on previous research, we discuss how astrocyte dysfunction contributes to the onset and progression of epilepsy through four key aspects: the imbalance between excitatory and inhibitory neuronal signaling, dysregulation of metabolic homeostasis in the neuronal microenvironment, neuroinflammation, and the formation of abnormal neural circuits. We summarize relevant basic research conducted over the past 5 years that has focused on modulating astrocytes as a therapeutic approach for epilepsy. We categorize the therapeutic targets proposed by these studies into four areas: restoration of the excitation–inhibition balance, reestablishment of metabolic homeostasis, modulation of immune and inflammatory responses, and reconstruction of abnormal neural circuits. These targets correspond to the pathophysiological mechanisms by which astrocytes contribute to epilepsy. Additionally, we need to consider the potential challenges and limitations of translating these identified therapeutic targets into clinical treatments. These limitations arise from interspecies differences between humans and animal models, as well as the complex comorbidities associated with epilepsy in humans. We also highlight valuable future research directions worth exploring in the treatment of epilepsy and the regulation of astrocytes, such as gene therapy and imaging strategies. The findings presented in this review may help open new therapeutic avenues for patients with drugresistant epilepsy and for those suffering from other central nervous system disorders associated with astrocytic dysfunction.
基金supported by grants from STI2030-Major Projects,No.2021ZD0204000(to YS)Key Strategic Science and Technology Cooperation Project of the Ministry of Science and Technology of China,No.SQ2023YFE0201430(to YS)+1 种基金the National Natural Science Foundation of China,Nos.31820103005(to YS),32200620(to LW)the Natural Science Foundation of Zhejiang Province of China,No.LZ24C090003(to YS)。
文摘The cerebellum is receiving increasing attention for its cognitive,emotional,and social functions,as well as its unique metabolic profiles.Cerebellar microglia exhibit specialized and highly immunogenic phenotypes under both physiological and pathological conditions.These immune cells communicate with intrinsic and systemic factors and contribute to the structural and functional compartmentalization of the cerebellum.In this review,we discuss the roles of microglia in the cerebellar microenvironment,neuroinflammation,cerebellar adaptation,and neuronal activity,the associated molecular and cellular mechanisms,and potential therapeutic strategies targeting cerebellar microglia in the context of neuroinflammation.Future directions and unresolved questions in this field are further highlighted,particularly regarding therapeutic interventions targeting cerebellar microglia,functional mechanisms and activities of microglia in the cerebellar circuitry,neuronal connectivity,and neurofunctional outcomes of their activity.Cerebellar morphology and neuronal performance are influenced by both intrinsic and systemic factors that are actively monitored by microglia in both healthy and diseased states.Under pathological conditions,local subsets of microglia exhibit diverse responses to the altered microenvironment that contribute to the structural and functional compartmentalization of the cerebellum.Microglia in the cerebellum undergo early maturation during the embryonic stage and display specialized,highly immunogenic phenotypes.In summary,cerebellar microglia have the capacity to serve as regulatory tools that influence outcomes across a wide range of neurological and systemic conditions,including neurodevelopmental,neurodegenerative,metabolic,and stress-related disorders.
基金Supported by the National Natural Science Foundation of China,No.82305376the Youth Talent Support Project of the China Acupuncture and Moxibustion Association,No.2024-2026ZGZJXH-QNRC005+2 种基金the 2024 Jiangsu Province Youth Science and Technology Talent Support Project,No.JSTJ-2024-3802025 Jiangsu Provincial Science and Technology Think Tank Program Project,No.JSKX0125035and 2025 College Student Innovation Training Program Project,No.X202510315373。
文摘BACKGROUND Organ transplantation has emerged as a globally prevalent therapeutic modality for end-stage organ failure,yet the post-transplantation trajectory is increasingly complicated by a spectrum of metabolic sequelae,with obesity emerging as a critical clinical challenge.AIM To systematically review the multifactorial mechanisms underlying obesity following organ transplantation and to integrate evidence from pharmacological,behavioral,and molecular perspectives,thereby providing a foundation for targeted interventions.METHODS We conducted a systematic search in PubMed and Web of Science for literature published from 2020 to 15 July 2025.The search strategy incorporated terms including“obesity”,“overweight”and“post organ transplantation”.Only randomized controlled trials,meta-analyses,and systematic reviews were included.Non-empirical publications and irrelevant studies were excluded.Data extraction and quality assessment were performed by two independent reviewers,with disagreements resolved by a third researcher.RESULTS A total of 1457 articles were initially identified,of which 146 met the inclusion criteria.These studies encompassed liver,kidney,heart,and lung transplant recipients.Key findings indicate that immunosuppressive drugs-especially corticosteroids and calcineurin inhibitors-promote hyperphagia,insulin resistance,and dyslipidemia.Post-transplant sedentary behavior and hypercaloric diets further contribute to positive energy balance.At the molecular level,immunosuppressants disrupt adipokine signaling(e.g.,leptin and adiponectin),induce inflammatory and oxidative stress responses,and activate adipogenic pathways leading to lipid accumulation.CONCLUSION Post-transplant obesity arises from a complex interplay of pharmacological,behavioral,and molecular factors.A multidisciplinary approach-incorporating pharmacological modification,nutritional management,physical activity,and molecular-targeted therapies-is essential to mitigate obesity and improve transplant outcomes.Further large-scale and mechanistic studies are warranted to establish evidence-based preventive and treatment strategies.
