Classifying self-management clusters of patients with mild cognitive impairment associated with diabetes: A cross-sectional study.

AIMS AND OBJECTIVES: This study aims to propose a self-management clusters classification method to determine the self-management ability of elderly patients with mild cognitive impairment (MCI) associated with diabetes mellitus (DM). BACKGROUND: MCI associated with DM is a common chronic disease in old adults. Self-management affects the disease progression of patients to a large extent. However, the comorbidity and patients' self-management ability are heterogeneous. DESIGN: A cross-sectional study based on cluster analysis is designed in this paper. METHOD: The study included 235 participants. The diabetes self-management scale is used to evaluate the self-management ability of patients. SPSS 21.0 was used to analyse the data, including descriptive statistics, agglomerative hierarchical clustering with Ward's method before k-means clustering, k-means clustering analysis, analysis of variance and chi-square test. RESULTS: Three clusters of self-management styles were classified as follows: Disease neglect type, life oriented type and medical dependence type. Among all participants, the percentages of the three clusters above are 9.78%, 32.77% and 57.45%, respectively. The difference between the six dimensions of each cluster is statistically significant. CONCLUSION(S): This study classified three groups of self-management styles, and each group has its own self-management characteristics. The characteristics of the three clusters may help to provide personalized self-management strategies and delay the disease progression of MCI associated with DM patients. RELEVANCE TO CLINICAL PRACTICE: Typological methods can be used to discover the characteristics of patient clusters and provide personalized care to improve the efficiency of patient self-management to delay the progress of the disease. PATIENT OR PUBLIC CONTRIBUTION: In our study, we invited patients and members of the public to participate in the research survey and conducted data collection.

Stratified support pattern-based internet-assisted self-management therapy for diabetes mellitus -mild cognitive impairment: a randomized controlled trial protocol.

BACKGROUND: Mild cognitive impairment (MCI) associated with diabetes mellitus (DM) is common among older adults, and self-management is critical to controlling disease progression. However, both MCI and DM are heterogeneous diseases, and existing integrated self-management interventions do not consider patient differences. Grouping patients by disease characteristics could help to individualize disease management and improve the use of available resources. The current study sought to explore the feasibility and effectiveness of a stratified support model for DM-MCI patients. METHODS: Eighty-four DM-MCI patients will be randomly divided into an intervention group and a control group in a 1:1 ratio. The intervention group will receive a self-management intervention using the stratified support pattern-based internet-assisted therapy (SISMT), while the control group will receive the health manual intervention (HMI). The study recruiter will be blinded to the group allocation and unable to foresee which group the next participant will be assigned to. At the same time, the allocation will be also hidden from the research evaluators and participants. After 12 weeks and 24 weeks, cognitive function, blood glucose, self-management ability, psychological status, health literacy, and self-management behavior of patients in both groups will be measured and compared. DISCUSSION: This study developed a stratified support pattern-based internet-assisted to provide self-management intervention for patients with DM-MCI. The impact of different models and forms of self-management intervention on cognitive function, blood glucose management, and psychological status health literacy and self-management behavior of patients will be assessed. The results of this study will inform related intervention research on the stratified support pattern-based internet-assisted self-management therapy, and help to slow the decline of cognitive function in patients with DM-MCI. TRIAL REGISTRATION: ChiCTR2200061991. Registered 16 July 2022.

Diastereoselective synthesis of polycyclic indolines via dearomative [4 + 2] cycloaddition of 3-nitroindoles with ortho-aminophenyl p-quinone methides.

A formal [4 + 2] cycloaddition of 3-nitroindoles with ortho-aminophenyl p-quinone methides via a dearomatization process was developed. This method provides a facile approach for preparing tetrahydro-5H-indolo[2,3-b]quinolones with good results. With the bifunctional Cinchona alkaloid-squaramide as the catalyst, the asymmetric version of the reaction successfully afforded the corresponding chiral products with moderate to good enantioselectivities. This work represents the first dearomative cycloaddition of electron-deficient heteroarenes triggered by aza-Michael addition from p-QMs.

Effects of an art-based intervention in older adults with mild cognitive impairment: a randomised controlled trial.

BACKGROUND: Art-based interventions may delay cognitive decline and improve health-related outcomes in older adults with mild cognitive impairment (MCI). OBJECTIVE: To examine the effects of the Creative Expressive Arts-based Storytelling (CrEAS) program compared to active and waitlist controls on neurocognitive and other health-related outcomes in older people with MCI. DESIGN: Three-arm parallel-group, randomised controlled design. PARTICIPANTS: One-hundred and thirty-five adults with MCI (mean age: 70.93 ± 6.91 years). METHODS: Participants were randomly assigned to intervention (CrEAS, n = 45), active control (n = 45) or waitlist control (n = 45) groups. Interventions were applied once per week for 24 weeks. The primary outcome was global cognitive function; secondary outcomes were specific cognition domains (memory, executive function, language and attention) and other health-related outcomes (anxiety, depression and quality of life [QoL]). All variables were measured at baseline (T0), 24-week follow-up (T1) and 48-week follow-up (T2). RESULTS: Participants in the CrEAS group showed significantly higher global cognitive function (adjusted mean difference [MD] = -0.905, 95% confidence interval [CI] -1.748 to -0.062; P = 0.038) and QoL (adjusted MD = -4.150, 95% CI -6.447 to -1.853; P = 0.001) and lower depression symptoms (adjusted MD = 2.902, 95% CI 0.699-5.104; P = 0.011) post-intervention at the 24-week follow-up compared with the active control group. At 48-week follow-up, only the Auditory Verbal Learning Test Immediate recall score was significantly improved compared with the active control group (adjusted MD = -2.941, 95% CI -5.262 to -0.620; P = 0.014). CONCLUSIONS: Older adults with MCI who participated in the CrEAS program improved their neuropsychological outcomes and QoL and reduced their rate of cognitive deterioration.

Associations of Parity With Change in Global Cognition and Incident Cognitive Impairment in Older Women.

Background: The evidence of the association between parity and risk of mild cognitive impairment (MCI) or dementia is mixed, and the relationship between parity and longitudinal cognitive changes is less clear. We investigated these issues in a large population of older women who were carefully monitored for development of MCI and probable dementia. Methods: Using the Women's Health Initiative Memory Study, 7,100 postmenopausal women (mean age 70.1 ± 3.8 years) with information on baseline parity (defined as the number of term pregnancies), measures of global cognition (Modified Mini-Mental State Examination score) from 1996-2007, and cognitive impairment (centrally adjudicated diagnoses of MCI and dementia) from 1996-2016 were included. Multivariable linear mixed-effects models were used to analyze the rate of changes in global cognition. Cox regression models were used to evaluate the risk of MCI/dementia across parity groups. Results: Over an average of 10.5 years, 465 new cases of MCI/dementia were identified. Compared with nulliparous women, those with a parity of 1-3 and ≥4 had a lower MCI/dementia risk. The HRs were 0.75 (0.56-0.99) and 0.71 (0.53-0.96), respectively (P < 0.01). Similarly, a parity of 1-3 and ≥4 was related to slower cognitive decline (ß = 0.164, 0.292, respectively, P < 0.05). Conclusion: Higher parity attenuated the future risk for MCI/dementia and slowed the rates of cognitive decline in elderly women. Future studies are needed to determine how parity affects late-life cognitive function in women.

Seroprevalence of IgM and IgG Antibodies against SARS-CoV-2 in Asymptomatic People in Wuhan: Data from a General Hospital Near South China Seafood Wholesale Market during March to April in 2020.

The aim of this study was to estimate the seroprevalence of immunoglobulin M (IgM) and G (IgG) antibodies against SARS-CoV-2 in asymptomatic people in Wuhan. This was a cross-sectional study, which enrolled 18,712 asymptomatic participants from 154 work units in Wuhan. Pearson Chi-square test, t-test, and Mann-Whitney test were used to compare the standardized seroprevalence of IgG and IgM for age and gender between different groups. The results indicated the standardized seroprevalence of IgG and IgM showed a downward trend and was significantly higher among females than males. Besides, different geographic areas and workplaces had different seroprevalence of IgG among asymptomatic people, and the number of abnormalities in CT imaging were higher in IgG antibody-positive cases than IgG-negative cases. We hope these findings can provide references for herd immunity investigation and provide basis for vaccine development.

TDP-43 proteolysis is associated with astrocyte reactivity after traumatic brain injury in rodents.

The aggregation and deposition of transactivation response DNA-binding protein 43 (TDP-43) in neurons and astrocytes is characteristic in a number of neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Nevertheless, the exact role of TDP-43 in astrocytes is unknown. Recently, TDP-43 was identified in neurons but not astrocytes after traumatic brain injury (TBI) in humans. In the present study, we evaluated TDP-43 expression and proteolysis in astrocytes in a rat model of TBI. We assessed TDP-43 fragment expression, astrocyte morphology, neuronal population numbers, and motor function after TBI with or without intracerebroventricular administration of a caspase-3 inhibitor. Motor dysfunction was observed after TBI in potential association astrocytic TDP-43 short fragment mislocalization and accumulation, astrogliosis, and neuronal loss. Notably, caspase-3 inhibition prevented these changes after TBI. Our findings suggest that TDP-43 proteolysis in astrocytes is related to astrogliosis and subsequent neuronal loss in TBI, and that TDP-43 may be an important therapeutic target for preventing motor dysfunction after TBI.

Saikosaponin a Induces Apoptosis through Mitochondria-Dependent Pathway in Hepatic Stellate Cells.

Saikosaponin a (SSa) is one of the main active components of Bupleurum falcatum. It is commonly used to treat liver injury and fibrosis in traditional Chinese medicine. Our previous study showed that SSa induces apoptosis and inhibits the proliferation of rat hepatic stellate cell (HSC) line HSC-T6. The aim of the present study was to elucidate the mechanism of SSa-mediated apoptosis. Rat HSC cell line HSC-T6 and human HSC cell line LX-2 were used in this study. SSa triggered cell death mainly by apoptosis, as indicated by the typical morphological changes, sub-G1 phase of cell cycle increase, and activation of the caspase-9/caspase-3 cascade. In addition, SSa-induced apoptosis was partially inhibited by the caspase-3 inhibitor Z-DEVD-FMK, suggesting an involvement of caspase-3 dependent and independent pathways. Moreover, SSa upregulated pro-apoptotic proteins [BAK, Bcl-2-associated death promoter (BAD), and p53 upregulated modulator of apoptosis (PUMA)] and downregulated anti-apoptotic proteins (Bcl-2). In the mitochondria, SSa triggered the translocation of BAX and BAK from the cytosol to the outer membrane, resulting in a reduction of mitochondrial functions and membrane potential and subsequent release of apoptotic factors. Therefore, this study demonstrates that SSa induces apoptosis through the intrinsic mitochondrial-dependent pathway in HSCs.

Identification of transcripts involved in digestion, detoxification and immune response from transcriptome of Empoasca vitis (Hemiptera: Cicadellidae) nymphs.

Tea production has been significantly impacted by the false-eye leafhopper, Empoasca vitis (Göthe), around Asia. To identify the key genes which are responsible for nutrition absorption, xenobiotic metabolism and immune response, the transcriptome of either alimentary tracts or bodies minus alimentary tract of E. vitis was sequenced and analyzed. Over 31 million reads were obtained from Illumina sequencing. De novo sequence assembly resulted in 52,182 unigenes with a mean size of 848nt. The assembled unigenes were then annotated using various databases. Transcripts of at least 566 digestion-, 224 detoxification-, and 288 immune-related putative genes in E. vitis were identified. In addition, relative expression of highly abundant transcripts was verified through quantitative real-time PCR. Results from this investigation provide genomic information about E. vitis, which will be helpful in further study of E. vitis biology and in the development of novel strategies to control this devastating pest.

Saikosaponin d induces cell death through caspase-3-dependent, caspase-3-independent and mitochondrial pathways in mammalian hepatic stellate cells.

BACKGROUND: Saikosaponin d (SSd) is one of the main active triterpene saponins in Bupleurum falcatum. It has a steroid-like structure, and is reported to have pharmacological activities, including liver protection in rat, cell cycle arrest and apoptosis induction in several cancer cell lines. However, the biological functions and molecular mechanisms of mammalian cells under SSd treatment are still unclear. METHODS: The cytotoxicity and apoptosis of hepatic stellate cells (HSCs) upon SSd treatment were discovered by MTT assay, colony formation assay and flow cytometry. The collage I/III, caspase activity and apoptotic related genes were examined by quantitative PCR, Western blotting, immunofluorescence and ELISA. The mitochondrial functions were monitored by flow cytometry, MitoTracker staining, ATP production and XF24 bioenergetic assay. RESULTS: This study found that SSd triggers cell death via an apoptosis path. An example of this path might be typical apoptotic morphology, increased sub-G1 phase cell population, inhibition of cell proliferation and activation of caspase-3 and caspase-9. However, the apoptotic effects induced by SSd are partially blocked by the caspase-3 inhibitor, Z-DEVD-FMK, suggesting that SSd may trigger both HSC-T6 and LX-2 cell apoptosis through caspase-3-dependent and independent pathways. We also found that SSd can trigger BAX and BAK translocation from the cytosol to the mitochondria, resulting in mitochondrial function inhibition, membrane potential disruption. Finally, SSd also increases the release of apoptotic factors. CONCLUSIONS: The overall analytical data indicate that SSd-elicited cell death may occur through caspase-3-dependent, caspase-3-independent and mitochondrial pathways in mammalian HSCs, and thus can delay the formation of liver fibrosis by reducing the level of HSCs.

Potential Association of Urinary N7-(2-Carbamoyl-2-hydroxyethyl) Guanine with Dietary Acrylamide Intake of Smokers and Nonsmokers.

Acrylamide (AA), a rodent carcinogen, is widely used in industry and present in cigarette smoke as well as in foods processed at high temperatures. The metabolic activation of AA to glycidamide (GA) could be critical for AA carcinogenicity since GA causes DNA adduct formation in vivo. N7-(2-carbamoyl-2-hydroxyethyl) guanine (N7-GAG), the most abundant DNA adduct of AA, is subjected to spontaneous and enzymatic depurination and excreted through urine. Urinary N7-GAG analysis can confirm AA genotoxicity and identify active species of AA metabolites in humans, thereby serving as a risk-associated biomarker for molecular epidemiology studies. This study aimed to develop an isotope-dilution solid-phase extraction liquid chromatography tandem mass spectrometry method to comparatively analyze urinary N7-GAG levels in nonsmokers and smokers. Urinary N-acetyl-S-(propionamide)-cysteine (AAMA), a metabolite of AA, was also analyzed as a biomarker for current AA exposure. Urinary N7-GAG was quantified by monitoring m/z 239 → 152 for N7-GAG and m/z 242 → 152 for (13)C3-labeled N7-GAG under positive electron spray ionization and multiple reaction mode. The median urinary N7-GAG level was 0.93 µg/g creatinine in nonsmokers (n = 33) and 1.41 µg/g creatinine in smokers (n = 30). Multiple linear regression analysis of data revealed that N7-GAG levels were only significantly associated with AAMA levels. These results demonstrate that urinary N7-GAG of nonsmokers and smokers is significantly associated with a very low level of dietary AA intake, assessed by analyzing urinary AAMA.

Vitamin C protects against cisplatin-induced nephrotoxicity and damage without reducing its effectiveness in C57BL/6 mice xenografted with Lewis lung carcinoma.

Vitamin C (vit C) has been shown to diminish cisplatin (CP)-induced nephrotoxicity and oxidative damage in healthy rats and mice. However, little is known whether vit C has similar actions and enhances the anticancer effect of CP in tumor-bearing mice. Herein, C57BL/6 mice were implanted (s.c.) with Lewis lung carcinoma (LLC) for 9 days before intraperitoneal administration with CP (5 mg/kg) in the presence or absence of low- (200 mg/kg) and high- (1000 mg/kg) dose vit C twice a week for an additional 28 days. Results reveal that vit C or CP treatment alone significantly inhibited tumor growth, although vit C in combination with CP did not further inhibit tumor growth, as compared to CP treatment alone. In addition, CP significantly induced nephrotoxicity and oxidative damage, as evidenced by increased plasma levels of blood urea nitrogen and creatinine as well as levels of lipid peroxidation and carbonyls, decreased ratios of GSH/GSSG in liver and kidney. Vit C significantly reversed these undesirable side effects induced by CP, and most of these actions of vit C were dose-dependent. Overall, we conclude that vit C can protect against CP-induced nephrotoxicity and damage without reducing CP's effectiveness in LLC-bearing mice.

Saikosaponin a and saikosaponin d inhibit proliferation and migratory activity of rat HSC-T6 cells.

The proliferation and migration of hepatic stellate cells (HSCs) profoundly impact the pathogenesis of liver inflammation and fibrogenesis. As a perennial herb native to China, Bupleurum falcatum is administered for its anti-inflammatory, antipyretic, and antihepatotoxic effects. Saikosaponin a (SSa) and Saikosaponin d (SSd) are the major active components of triterpene saponins in Bupleurum falcatum. This study analyzes how SSa and SSd affect rat HSC-T6 cell line proliferation and migration. Experimental results indicate that, in addition to suppressing HSC-T6 proliferation, wound healing activity and cell migration in a time- and dose-dependent manner, SSa and SSd significantly induce apoptosis. Additionally, SSa and SSd decreased the expressions of extracellular matrix-regulated kinase 1/2 (ERK1/2), platelet-derived growth factor receptor 1 (PDGFR1), and subsequently transforming growth factor-ß1 receptor (TGF-ß1R), α-smooth muscle actin, TGF-ß1 and connective tissue growth factor. They also decreased phosphorylation of p38 (p-p38) and ERK1/2 (p-ERK1/2) of HSC-T6. Furthermore, both SSa and SSd can block PDGF-BB and TGF-ß1-induced cell proliferation and migration of HSC-T6. These results suggest that SSa and SSd may inhibit proliferation and activation of HSC-T6, and the modulated mechanisms warrant further study.

The modifying effect of CYP2E1, GST, and mEH genotypes on the formation of hemoglobin adducts of acrylamide and glycidamide in workers exposed to acrylamide.

This study assesses the association of acrylamide (AA) and glycidamide (GA) hemoglobin adducts (AAVal and GAVal) and their ratios with genetic polymorphisms of the metabolic enzymes cytochrome P450 2E1 (CYP2E1), exon 3 and 4 of microsomal epoxide hydrolase (mEH3 and mEH4), glutathione transferase theta (GSTT1), and mu (GSTM1) or/and the combinations of these polymorphisms, involved in the activation and detoxification of AA in humans. Fifty-one AA-exposed workers and 34 controls were recruited and provided a post-shift blood sample. AAVal and GAVal were determined simultaneously using isotope-dilution liquid chromatography-electronspray ionization/tandem mass spectrometry (LC-ESI-MS/MS). Genetic polymorphisms of CYP2E1, mEH3 and 4, GSTT1, and GSTM1 were also analyzed. Our results reveal that the GAVal/AAVal ratio, potentially reflecting the proportion of AA metabolized to GA, ranged from 0.13 to 0.45 with a mean at 0.27. Multivariate regression analysis demonstrates that the joint effect of CYP2E1, GSTM1, and mEH4 genotypes was significantly associated with AAVal and GAVal levels after adjustment for AA exposures. These results suggest that mEH4 and the combined genotypes of CYP2E1, GSTM1 and mEH4 may be associated with the formation of AAVal and GAVal. Further studies may be needed to shed light on the roles that phase I and II enzymes play in AA metabolism.

Induction of apoptosis in human Hep3B hepatoma cells by norcantharidin through a p53 independent pathway via TRAIL/DR5 signal transduction.

OBJECTIVE: To investigate the inhibitory activities of norcantharidin (NCTD), a demethylated analogue of cantharidin, on Hep3B cells (a human hepatoma cell line) with deficiency of p53. METHODS: The survival rate of the Hep3B cells after treating with NCTD was measured by MTT assay. Cell cycle of treated cells was analyzed by flow cytometry, and DNA fragmentation was observed by electrophoresis. The influence of inhibitors for various caspases and anti-death receptors antibodies on the NCTD-induced apoptosis in the cells was determined. RESULTS: NCTD treatment resulted in growth inhibition of Hep3B cells in a dose- and time-dependent manner. Cell cycle analysis of the cells after treatment with NCTD for 48 h shows that NCTD induced G(2)M phase arrest occurs at low concentration ([Symbol: see text] 25 µmol/L) but G(0)G(1) phase arrest at high concentration (50 µmol/L). The addition of both caspase-3 and caspase-10 inhibitors completely inhibited DNA fragmentation. Addition of anti-TRAIL/DR5 antibody significantly inhibited DNA fragmentation. CONCLUSION: NCTD may inhibit the proliferation of Hep3B cells by arresting cell cycle at G(2)M or G(0)G(1) phase, and induce cells apoptosis via TRAIL/DR5 signal transduction through activation of caspase-3 and caspase-10 by a p53-independent pathway.

Fabrication, characterization, and kinetic study of vertical single-crystalline CuO nanowires on Si substrates.

We report here on the first study of the growth kinetics of high-yield, vertical CuO nanowires on silicon substrates produced by the process of thermal oxidation. The length of the CuO nanowires could be tuned from several to tens of micrometers by adjusting the oxidation temperature and time. The grown CuO nanowires were determined to be single-crystalline with different axial crystallographic orientations. After a series of scanning electron microscopy examinations, the average length of CuO nanowires produced at each temperature was found to follow a parabolic relationship with the oxidation time. The parabolic growth rate at different oxidation temperatures was measured. The activation energy for the growth of CuO nanowires calculated from an Arrhenius plot was found to be about 174.2 kJ/mole. In addition, the current-voltage characterization indicated that the sample with high-density CuO nanowires exhibited ohmic behavior, and its resistance was found to significantly decrease with increasing environmental temperature. The result can be attributed to an increase in the number of carriers at higher temperatures.

Time-dependent changes in BDNF expression of pentylenetetrazole-induced hippocampal astrocytes in vitro.

Pentylenetetrazole (PTZ), a γ-aminobutyric acid (GABA(A)) receptor antagonist, has been used extensively to induce seizures in animal models of epilepsy. The aim of the present study was to investigate the effects of PTZ on hippocampal astrocytes. Cells were incubated with 10, 20, or 40 mM PTZ for 24h and viability and apoptosis were examined using an MTT assay and Hoechst staining. The high concentration of PTZ (20 and 40 mM) resulted in a significant decrease in viability (MTT: 83.6 ± 7.8% and 69.3 ± 4.2%, respectively) (P<0.01), whereas the lower concentration of PTZ (10mM) did not induce cell apoptosis or reduce viability. When cells were treated with 10mM PTZ for 0, 0.5, 2, 4, 8, 12, or 24h, the level of brain-derived neurotrophic factor (BDNF), both protein and mRNA, was significantly reduced at 2 to 12h of culture (P<0.01), with maximal reduction detected at 8h; expression was restored to near control levels after 24h. Collectively, our results suggest that astrocytes may participate in epilepsy through a marked, but transient decrease in BDNF expression.

Inhibitory effect of vitamin C in combination with vitamin K3 on tumor growth and metastasis of Lewis lung carcinoma xenografted in C57BL/6 mice.

Vitamin C in combination with vitamin K3 (vit CK3) has been shown to inhibit tumor growth and lung metastasis in vivo, but the mechanism of action is poorly understood. Herein, C57BL/6 mice were implanted (s.c.) with Lewis lung carcinoma (LLC) for 9 days before injection (i.p.) with low-dose (100 mg vit C/kg + 1 mg vit K3/kg), high-dose (1,000 mg vit C/kg + 10 mg vit K3/kg) vit CK3 twice a week for an additional 28 days. As expected, vit CK3 or cisplatin (6 mg/kg, as a positive control) significantly and dose-dependently inhibited tumor growth and lung metastasis in LLC-bearing mice. Vit CK3 restored the body weight of tumor-bearing mice to the level of tumor-free mice. Vit CK3 significantly decreased activities of plasma metalloproteinase (MMP)-2, -9, and urokinase plasminogen activator (uPA). In lung tissues, vit CK3 1) increased protein expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, nonmetastatic protein 23 homolog 1 and plasminogen activator inhibitor-1; 2) reduced protein expression of MMP-2 and MMP-9; and 3) inhibited the proliferating cell nuclear antigen (PCNA). These results demonstrate that vit CK3 inhibits primary tumor growth and exhibits antimetastastic potential in vivo through attenuated tumor invasion and proliferation.

Association of CYP2E1, GST and mEH genetic polymorphisms with urinary acrylamide metabolites in workers exposed to acrylamide.

This study elucidates the association of acrylamide metabolites, N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA), N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-cysteine (GAMA2), and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-cysteine (GAMA3) in urine with genetic polymorphisms of the metabolic enzymes cytochrome P450 2E1 (CYP2E1), microsomal epoxide hydrolase (mEH) in exon 3 and exon 4, glutathione transferase theta (GSTT1) and mu (GSTM1), involved in the activation and detoxification of acrylamide (AA) in humans. Eighty-five workers were recruited, including 51 AA-exposed workers and 34 administrative staffs serve as controls. Personal air sampling was performed for the exposed workers. Each subject provided pre- and post-shift urine samples and blood samples. Urinary AAMA, GAMA2 and GAMA3 levels were simultaneously quantified using liquid chromatography-electronspray ionization/tandem mass spectrometry (LC-ESI-MS/MS). CYP2E1, mEH (in exon 3 and exon 4), GSTT1, and GSTM1 were analyzed using polymerase chain reaction (PCR). Our results reveal that AA personal exposures ranged from 4.37 × 10⁻³ to 113.61 µg/m³ with a mean at 15.36 µg/m³. The AAMA, GAMA2, and GAMA3 levels in the exposed group significantly exceeded those in controls. The GAMAs (the sum of GAMA2 and GAMA3)/AAMA ratios, potentially reflecting the proportion of AA metabolized to glycidamide (GA), varied from 0.003 to 0.456, and indicate high inter-individual variability in the metabolism of AA to GA in this study population. Multivariate regression analysis demonstrates that GSTM1 genotypes significantly modify the excretion of urinary AAMA and the GAMAs/AAMA ratio, exon 4 of mEH was significantly associated with the urinary GAMAs levels after adjustment for AA exposures. These results suggest that mEH and/or GSTM1 may be associated with the formation of urinary AAMA and GAMAs. Further study may be needed to shed light on the role of both enzymes in AA metabolism.

Comparative analysis of urinary N7-(2-hydroxyethyl)guanine for ethylene oxide- and non-exposed workers.

Ethylene oxide (EO), a direct alkylating agent and a carcinogen, can attack the nucleophilic sites of DNA bases to form a variety of DNA adducts. The most abundant adduct, N7-(2-hydroxyethyl)guanine (N7-HEG), can be depurinated spontaneously or enzymatically from DNA backbone to form abasic sites. Molecular dosimetry of the excised N7-HEG in urine can serve as an EO exposure and potential risk-associated biomarker. This study was to analyze N7-HEG in urine collected from 89 EO-exposed and 48 nonexposed hospital workers and 20 exposed and 10 nonexposed factory workers by using our newly developed on-line solid-phase extraction isotope-dilution LC-MS/MS method. Statistical analysis of data shows that the exposed factory workers excreted significantly greater concentrations of N7-HEG than both the nonexposed factory workers and hospital workers. Multiple linear regression analysis reveals that the EO-exposed factory workers had a significantly greater post-shift urinary N7-HEG than their nonexposed coworkers and hospital workers. These results demonstrate that analysis of urinary N7-HEG can serve as a biomarker of EO exposure for future molecular epidemiology studies to better understand the role of the EO-induced DNA adduct formation in EO carcinogenicity and certainly for routine surveillance of occupational EO exposure for the study of potential health impacts on workers.