Mediating Effects of Maternal Blood Triglycerides on the Relationship between Prepregnancy Body Mass Index and Fetal Macrosomia.

OBJECTIVE: To examine whether the association of prepregnancy body mass index (BMI) with fetal macrosomia is mediated through maternal circulating lipid concentrations during pregnancy. STUDY DESIGN: In this prospective cohort, 3011 eligible pregnant women were enrolled. Information on demographic characteristics were collected using questionnaires, and anthropometrics and laboratory tests were performed at 24 weeks of gestation and before delivery. Macrosomia was defined as birth weight ≥4000 g. Logistic regression and multivariable linear regression, adjusted for age, fetal sex, education, gestational weight gain, fasting blood glucose, gestational diabetes, gestational hypertension, gestational age at delivery, delivery mode, and parity, were used to assess the mediation path between prepregnancy BMI, maternal serum lipids, and fetal macrosomia. RESULTS: A total of 2454 participants with completed records were included in the final analyses. Among the maternal circulating lipid biomarkers, only triglyceride was significantly associated with both prepregnancy BMI and fetal macrosomia risk, adjusting for potential confounders. Mediation analyses demonstrated that the direct effect of prepregnancy BMI on fetal macrosomia was 0.0085 (95% CI, 0.0003-0.018; P < .05), the indirect effect mediated through maternal serum triglycerides was 0.0016 (95% CI, 0.0007-0.0029; P < .001), and the estimated proportion of mediated effect was 15.7% (P < .05). CONCLUSIONS: Maternal circulating triglycerides mediate the association of prepregnancy BMI with the risk of fetal macrosomia.

1, 25(OH)2D3-induced interaction of vitamin D receptor with p50 subunit of NF-κB suppresses the interaction between KLF5 and p50, contributing to inhibition of LPS-induced macrophage proliferation.

KLF5 and nuclear factor κB (NF-κB) regulate cell proliferation and inflammation. Vitamin D signaling through vitamin D receptor (VDR) exerts anti-proliferative and anti-inflammatory actions. However, an actual relationship between KLF5, NF-κB and VDR in the inflammation and proliferation of macrophages is still unclear. Here, we showed that LPS and proinflammatory cytokines stimulate KLF5 gene expression in macrophages, and that 1, 25(OH)2D3 suppresses LPS-induced KLF5 expression and cell proliferation via upregulation of VDR expression. Mechanistic studies suggested that KLF5 interacts with p50 subunit of NF-κB to cooperatively induce the expressions of positive cell cycle regulators cyclin B1 and Cdk1/Cdc2 in LPS-treated macrophages. Further studies revealed that 1, 25(OH)2D3-induced interaction of VDR with p50 decreases LPS-induced interaction of KLF5 with p50. Collectively, we identify a novel regulatory pathway in which 1, 25(OH)2D3 induces VDR expression and promotes VDR interaction with p50 subunit of NF-κB, which in turn attenuates the association of KLF5 with p50 subunit of NF-κB and thus exerts anti-inflammatory and anti-proliferative effects on macrophages.

Rat Testis Damage Caused by Lead Sulfide Nanoparticles After Oral Exposure.

Lead sulfide nanoparticals (PbS NPs) is an important semiconductor material due to its unique physical and chemical properties, but its potential health hazard to reproductive system is not clear. In the current study, we systematically explored the reproductive toxicity of PbS NPs in rats by measuring the body weight and testicular coefficient, testing serum testosterone levels, and studying the sperm survival rate and sperm abnormality rate. Furthermore, in order to study the toxic mechanism we performed lead contents measurements in testis, and investigated the pathology in testis. Our results confirmed that PbS NPs showed high reproductive toxicity due to PbS NPs in rats' testicular tissue by the establishment of PbS NPs chronic exposure model.

[Association between CCND1 polymorphisms and chromosomal damage among workers exposed to 1,3-butadiene].

OBJECTIVE: To investigate the association between CCND1 polymorphisms and the DNA and chromosome damage in peripheral blood lymphocytes among workers exposed to 1,3-butadiene(BD). METHODS: 171 workers exposed to 1,3-butadiene and 55 controls without occupational BD exposure were investigated. Cytokinesis-block micronucleus(CBMN) detection and comet assay were used to evaluate the chromosomal and DNA damage levels in peripheral blood lymphocyte. And the genotypes of CCND1 were detected by PCR-RFLP. Personal information including occupational history, age, sex, smoking and drinking status was collected by the questionnaire. RESULTS: The rate of CBMN and OTM of lymphocyte in BD exposed workers[(7. 17 ± 5. 09)% and 4. 65(95% CI 3. 49 - 5. 98), respectively] were higher than those in controls[(3. 82 ± 2. 37)% and 2. 38 (95% CI 0. 82 - 3. 98), P < 0. 01. Multivariate analysis of covariance revealed that in BD workers. The subjects with CCND1 A870G AA allele have significantly higher risk for DNA damage than subjects with GG allele (P < 0. 05). CONCLUSION: Under present BD exposure levels, both comet assay and cytokinesis-block micronucleus test could be sensitive group biomarkers to use to monitor the genotoxicity of BD occupational exposure. CCNDI A870G polymorphisms might influence the susceptibility of DNA damage in BD exposed workers.

[Effects of nano-lead exposure on learning and memory as well as iron homeostasis in brain of offspring rats].

OBJECTIVE: To investigate the effects of nano-lead exposure on learning and memory and iron homeostasis in the brain of the offspring rats on postnatal day 21 (PND21) and postnatal day 42 (PND42). METHODS: Twenty adult pregnant female Sprague-Dawley rats were randomly divided into control group and nano-lead group. Rats in the nano-lead group were orally administrated 10 mg/kg nano-lead, while rats in the control group were administrated an equal volume of normal saline until PND21. On PND21, the offspring rats were weaned and given the same treatment as the pregnant rats until 42 days after birth. The learning and memory ability of offspring rats on PND21 and PND42 was evaluated by Morris water maze test. The hippocampus and cortex s amples of offspring rats on PND21 and PND42 were collected to determine iron and lead levels in the hippocampus and cortex by inductively coupled plasma-mass spectrometry. The distributions of iron in the hippocampus and cortex were observed by Perl's iron staining. The expression levels of ferritin, ferroportin 1 (FPN1), hephaestin (HP), and ceruloplasmin (CP) were measured by enzyme-linked immunosorbent assay. RESULTS: After nano-lead exposure, the iron content in the cortex of offspring rats on PND21 and PND42 in the nano-lead group was significantly higher than those in the control group (32.63 ± 6.03 µg/g vs 27.04 ± 5.82 µg/g, P<0.05; 46.20 ±10.60 µg/g vs 36.61 ± 10.2µg/g, P<0.05). The iron content in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly higher than that in the control group (56.9 ± 4.37µg/g vs 37.71 ± 6.92µg/g, P<0.05). The Perl's staining showed massive iron deposition in the cortex and hippocampus in the nano-lead group. FPNl level in the cotfex of offspring rats on PND21 in the nano-lead group was significantly lower than that in the control group (3.64 ± 0.23 ng/g vs 4.99 ± 0.95 ng/g, P<0.05). FPN1 level in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly lower than that in the control group (2.28 ± 0.51 ng/g vs 3.69 ± 0.69 ng/g, P<0.05). The escape latencies of offspring rats on PND21 and PND42 in the nano-lead group were longer than those in the control group (15.54 ± 2.89 s vs 9.01 ± 4.66 s; 6.16 ± 1.42 s vs 4.26 ± 1.51 s). The numbers of platform crossings of offspring rats on PND21 and PND42 in the nano- lead group were significantly lower than those in the control group (7.77 ± 2.16 times vs 11.2 ± 1.61 times, P<0.05; 8.12 ± 1.51 times vs 13.0 ± 2.21 times, P<0.05). ONCLUSION: n Nano-lead exposure can result in iron homeostasis disorders in the hippocampus and cortex of offspring rats and affect their learning and memory ability.

[Determination of cyanamide in workplace air by high-performance liquid chromatography].

OBJECTIVE: To establish a method for determining cyanamide in workplace air by high-performance liquid chromatography (HPLC). METHODS: Air samples were collected from the workplace using the shock absorption tube containing water solution at a rate of 2.8∼3.0 ml/min for 60 min; dansyl chloride was used as a derivatization reagent to conduct pre-column derivatization, and the procedure was as follows: acetone solution (2.5 ml), mixed solution (1.0 ml) containing 0.016 mol/L Na2CO3 and 0.184 mol/L NaHCO3, and 10 mg/ml acetone solution of dansyl chloride (0.5 ml) were added into the samples, and reaction proceeded in a water bath (50 °C) for 1 h. HPLC was performed on an ODS C18 column (250 mm × 4.6 mm, 5 üm) with a mobile phase of acetonitrile-phosphate buffer (35:65) at a flow rate of 1.0 ml/min and a column temperature of 25°C; a fluorescence detector was used at an excitation wavelength of 360 nm and an emission wavelength of 495 nm. RESULTS: The minimum detectable concentration of cyanamide was 0.05 üg/ml; a good linear relationship was noted when the concentration of cyanamide was 0.2∼100.0 üg/ml; the intraday relative standard deviation (RSD) was 0.28%∼1.18%, and the interday RSD was 0.22∼2.16%; the recovery rate was 95.7%∼103.0%, and the sampling efficiency was 95.8%∼96.9%. Water solution of cyanamide (pH<6.5) could be stable in the dark at room temperature for 7 d. CONCLUSION: This method is stable, reliable, easy to operate, and highly sensitive and suitable for determination of cyanamide in workplace air.

Application of diversified and quantitative management model of exercise intervention in patients with gestational diabetes mellitus.

Objective: The study aims to explore the application of diversified and quantitative management model of exercise intervention in patients with gestational diabetes mellitus (GDM).Methods: From January 2018 to July 2018, 150 pregnant women with GDM were recruited from HangZhou Maternity Hospital, and were randomly divided into control group (n = 75) and experimental group (n = 75). All patients were registered pregnancy exercise self-efficacy scale (P-ESES), fasting blood glucose (FBG), and 2-hour postpranational blood glucose (2hPG). Patients in control group received conventional sports, while patients in experimental group added multiple quantitative exercise intervention management mode until delivery (accumulated at least 30 min per day, the time of not less than 150 min per week). After 4 weeks of intervention, patients in both groups were measured P-ESES, FBG, and 2hPG levels.Results: A total of 12 patients dropped out of the study, was lost to follow-up or was admitted to another hospital; therefore, 138 cases (68 vs. 70) were included in analysis. There was no significant difference of P-ESES, FBG, and 2hPG of patients in baseline. After four weeks intervention, compared with the control group, the P-ESES score was significantly increased (p<.05), the overcoming movement disorder, overcoming emotional disorder, and overcoming support disorder scores were significantly improved (p<.05), and the levels of FBG and 2hPG were significantly decreased (p<.05) in experimental group. Finally, the coincidence rate of weight gain during pregnancy was increased, the rate of macrosomia delivery and cesarean section were decreased in experimental group (p<.05).Conclusion: Quantitative management model of multiform exercise therapy improved patients with GDM.

Correction: Hierarchical microgroove/nanopore topography regulated cell adhesion to enhance osseointegration around intraosseous implants in vivo.

Correction for 'Hierarchical microgroove/nanopore topography regulated cell adhesion to enhance osseointegration around intraosseous implants in vivo' by Yujuan Tian et al., Biomater. Sci., 2022, 10, 560-580. DOI: 10.1039/D1BM01657A.

Hierarchical microgroove/nanopore topography regulated cell adhesion to enhance osseointegration around intraosseous implants in vivo.

Implant surface topography plays a crucial role in achieving successful implantation. Simple and controllable surface topographical modifications are considered a promising method to accelerate bone osseointegration for biomedical applications. Moreover, comprehension of the mechanism between surface topography and cell osteogenic differentiation is vital for the manipulation of these processes to promote bone tissue regeneration. In this study, we investigated the effects of implant surfaces with various sized hierarchical microgroove/nanopore topographies on cell adhesion, osteogenesis, and their underlying mechanism both in vitro and in vivo. Our findings reveal that a titanium surface with an appropriately sized microgroove/nanopore topography (SLM-1MAH) exhibits the more satisfactory adhesive and osteogenic efficiency than the clinically used sand-blasted, large-grit, and acid-etched (SLA) surface. The underlying molecular mechanism lies in the activation of the integrin α2-PI3K-Akt signaling pathway, where the SLM-1MAH surface increased the protein expressions of integrin α2 (Itga2), phosphatidylinositol 3-kinase (PI3K), and phosphorylated serine/threonine kinase Akt (p-Akt) to enhance osteogenesis and osseointegration. Furthermore, the SLM-1MAH surface also displays better osseointegration efficiency with stronger bonding strength than that on the SLA surface. This work provides a novel strategy for implant surface topography design to improve bone-implant osseointegration.

Granzyme B is recovered by natural killer cells via clathrin-dependent endocytosis.

When they recognize a target cell, natural killer (NK) cells mount an attack to kill the target by exerting their cytotoxicity via the exocytosis of cytotoxic granules. Although the details of this process (which includes the movement of cytotoxic granules in the immune synapse and their fusion with the plasma membrane, releasing granzymes and perforin into the synaptic cleft) are relatively better understood, the post-exocytosis regulation of the process is still largely unknown. Here we show that a clathrin-dependent endocytosis stimulated by target cell occurs in NK92 cell line, which is closely correlated with granzyme B recovery. Inhibition of the endocytosis significantly attenuates the cytotoxicity of NK92 cells. The NK cell recovery of its released effector molecules, in turn, suggests that endocytosis may well play a key role in the post exocytosis regulation of immune cells.

Toxic metals in outdoor/indoor airborne PM2.5 in port city of Northern, China: Characteristics, sources, and personal exposure risk assessment.

Outdoor and indoor PM2.5 samples were simultaneously collected over four seasons (2017-2018) in Caofeidian, China, and analyzed for 15 elements to investigate the characteristics, sources, and health risks of PM2.5-bound metals. Source-specific PM2.5-bound metals were analyzed using positive matrix factorization, combined with the conditional probability function and potential source contribution function model. The health risks were evaluated using the health risk assessment model, which included the exposure parameters of indoor and outdoor activities of Chinese residents. The annual median of PM2.5 concentrations (89.68 µg/m3) and total metals (2.67 µg/m3) from the outdoor samples significantly surpassed that of the indoor samples (51.56 µg/m3) and total metals (1.51 µg/m3) (P < 0.05). In addition, the indoor/outdoor concentration ratios indicated that most indoor metals mainly originated from outdoor emission sources. In the annual analysis of PM2.5-bound metal sources, this study identified five metal sources: coal combustion, resuspended dust, traffic emissions, fuel combustion sources, and industrial sources, among which industry sources (36.6%) contributed the most. The non-carcinogenic risks of metals for adults (2.81) and children (2.80) all exceed the acceptable non-carcinogenic risk level (1). The non-carcinogenic risk of Mn (1.46 for children, 1.48 for adults) was a key factor in the total non-carcinogenic risk. The total carcinogenic risk of metals for children (3.75 × 10-5) was above the acceptable level (1.0 × 10-6) but within the tolerant limit (1.0 × 10-4), and that for adults (1.48 × 10-4) was above the tolerant limit. The lifetime carcinogenic risk of Cr6+ had the highest proportion of the total carcinogenic risk for children (87.5%) and adults (87.8%). Our results revealed that both adults and children suffered carcinogenic and non-carcinogenic risks from the PM2.5-bound metals in Caofeidian. The corresponding emission control measures of metals in atmosphere should be considered.

The Role and Activation Mechanism of TAZ in Hierarchical Microgroove/Nanopore Topography-Mediated Regulation of Stem Cell Differentiation.

PURPOSE: To investigate the role and activation mechanism of TAZ in periodontal ligament stem cells (PDLSCs) perceiving hierarchical microgroove/nanopore topography. MATERIALS AND METHODS: Titanium surface with hierarchical microgroove/nanopore topography fabricated by selective laser melting combined with alkali heat treatment (SLM-AHT) was used as experimental group, smooth titanium surface (Ti) and sandblasted, large-grit, acid-etched (SLA) titanium surface were employed as control groups. Alkaline phosphatase (ALP) activity assays, qRT-PCR, Western blotting, and immunofluorescence were carried out to evaluate the effect of SLM-AHT surface on PDLSC differentiation. Moreover, TAZ activation was investigated from the perspective of nuclear localization to transcriptional activity. TAZ knockdown PDLSCs were seeded on three titanium surfaces to detect osteogenesis- and adipogenesis-related gene expression levels. Immunofluorescence and Western blotting were employed to investigate the effect of the SLM-AHT surface on actin cytoskeletal polymerization and MAPK signaling pathway. Cytochalasin D and MAPK signaling pathway inhibitors were used to determine whether actin cytoskeletal polymerization and the MAPK signaling pathway were indispensable for TAZ activation. RESULTS: Our results showed that SLM-AHT surface had a greater potential to promote PDLSC osteogenic differentiation while inhibiting adipogenic differentiation than the other two groups. The nuclear localization and transcriptional activity of TAZ were strongly enhanced on the SLM-AHT surface. Moreover, after TAZ knockdown, the enhanced osteogenesis and decreased adipogenesis in SLM-AHT group could not be observed. In addition, SLM-AHT surface could promote actin cytoskeletal polymerization and upregulate p-ERK and p-p38 protein levels. After treatment with cytochalasin D and MAPK signaling pathway inhibitors, differences in the TAZ subcellular localization and transcriptional activity were no longer observed among the different titanium surfaces. CONCLUSION: Our results demonstrated that actin cytoskeletal polymerization and MAPK signaling pathway activation triggered by SLM-AHT surface were essential for TAZ activation, which played a dominant role in SLM-AHT surface-induced stem cell fate decision.

Experimental observation of mitochondrial oxidative damage of liver cells induced by isonicotinic acid hydrazide.

The aim of the present study was to investigate the oxidative damage of liver mitochondria as an adverse effect of the anti-tuberculosis drug isonicotinic acid hydrazide (INH). The human hepatoblastoma cell line (HepG2) was exposed to INH at concentrations of 0, 1, 2 or 4 mg/ml for 24, 48, 72 or 96 h, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and 8-hydroxy-2-deoxyguanosine (8-OHdG) in mitochondria were detected. Changes in the mitochondrial ultrastructure were observed by electron microscopy. Along with the increase of incubation time and dose of INH, activities of mitochondrial SOD and GSH-Px decreased, MDA and 8-OHdG content increased, and the mitochondrial ultrastructure displayed varying degrees of pathological changes. In conclusion, INH was found to cause liver cell injury by inducing mitochondrial DNA damage.

SIRT1 alleviates isoniazid-induced hepatocyte injury by reducing histone acetylation in the IL-6 promoter region.

Silent information regulator 1 (SIRT1) is a type III histone deacetylase that is related to the inhibition of the inflammatory response. The aim of this study was to investigate the regulation of SIRT1 on isoniazid-induced hepatocyte injury and the possible mechanism of histone modification. We found that compared with the blank control group, expression of SIRT1 was decreased in the isoniazid group and that expression of NF-κB p65 was increased, leading to an increase of the expression of inflammatory cytokines Interleukin-6 (IL-6) and Tumour necrosis factor alpha (TNF-α). The level of histone H3K9 acetylation in the promoter region of IL-6 was increased as well. Addition of a SIRT1 agonist (SRT1720) alleviated the inflammatory reaction caused by isoniazid, while the use of a SIRT1 inhibitor (EX527) aggravated the inflammatory damage to cells. In conclusion, these findings indicated that during the period of isoniazid-induced hepatocyte injury, SIRT1 levels were decreased and inflammatory factor levels were increased. Activation of SIRT1 may reduce hepatocyte injury by reducing the level of histone H3K9 acetylation in the promoter region of the IL-6 gene.

Traditional Chinese medicine (Xiaoai Jiedu Decoction) as an adjuvant treatment for prevention new colorectal adenomatous polyp occurrence in post-polypectomy: Study protocol for a randomized controlled trial.

BACKGROUND: Colorectal Adenomatous Polyp (CAP) was one precursor of colorectal cancer (CRC) and having a high chance of developing into CRC. There was a lack of conclusive chemoprevention evidences to prevention new CAP occurrence in post-polypectomy. Xiaoai Jiedu Decoction, Chinese National Medical Professor (Zhou Zhongying)'s experience formula, has been used to treat new CAP occurrence in post-polypectomy from the 20th century in China. However, clinical research of Xiaoai Jiedu Decoction in the treatment of CAP recurrence was lack. We design this study to evaluate the efficacy and safety of Xiaoai Jiedu Decoction in the treatment of new CAP occurrence in post-polypectomy on colonoscopy. METHODS/DESIGN: A randomized, controlled, blind and multicenter trial to evaluate the efficacy and safety of Xiaoai Jiedu Decoction is proposed. CAP patients (after complete polypectomy under colonoscopy) will be randomly assigned into Xiaoai Jiedu Decoction group and Xiaoai Jiedu Decoction mimetic agent group. Patients will receive 6-course treatments and a 2-year follow-up. Follow-up colonoscopy will be anticipated to perform in 1 and 2 years after the baseline examinations. The primary outcome measure is the new CAP occurrence in 1 and 2 years. The secondary outcome measure is the occurrence of advanced adenoma in 1 and 2 years. DISCUSSION: This study will provide objective evidences to evaluate the efficacy and safety of Xiaoai Jiedu Decoction as an adjuvant treatment for new CAP occurrence in post-polypectomy. TRIAL REGISTRATION: NCT03616444.

Heme oxygenase-1 upregulation significantly inhibits TNF-alpha and Hmgb1 releasing and attenuates lipopolysaccharide-induced acute lung injury in mice.

The present study was designed to investigate whether administration of CoPPIX, an HO-1 inducer, could significantly inhibit TNF-alpha and Hmgb1 expression and thus attenuate the acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. Acute lung injury was induced successfully by intratracheal administration of LPS (0.5 mg/kg) in male BALB/c mice. CoPPIX or ZnPPIX (an HO-1 inhibitor) was administered to mice 24 h prior to LPS exposure. It was found that CoPPIX (5, 10 mg/kg, i.p.) caused a significant reduction in the total cells and neutrophils in BALF, a significant reduction in the W/D ratio and EBA leakage at 24 h after LPS challenge. Furthermore, the histopathologic findings indicated that alveolitis with leukocyte infiltration in the alveolar space was less severe in the CoPPIX-treated mice than in the mice treated with LPS alone. In addition, CoPPIX was also believed to have down-regulated the expression of LPS-induced proinflammatory cytokines, including early proinflammatory cytokine TNF-a, and late proinflammatory cytokine Hmgb1. In contrast, no obvious difference was observed between the ZnPPIX group and the LPS group. These findings demonstrate the significant protection of CoPPIX against LPS-induced ALI, and the effect mechanism of CoPPIX was associated with decreasing the expression of TNF-a and Hmgb1.

Genome Sequence of Corynebacterium pseudotuberculosis Strain KM01, Isolated from the Abscess of a Goat in Kunming, China.

Caseous lymphadenitis (CLA) is an acute, pyogenic, and contagious disease of goat that imposes considerable economic losses for farmers, and it is caused by Corynebacterium pseudotuberculosis Herein, we introduce the genome sequencing of C. pseudotuberculosis strain KM01, isolated from an abscess of a Saanen goat from Kunming, China. The genome contains 2,198 genes, the total length of the genes was 2,337,666 bp, and the GC content was 52.18%. The number of tandem repeat sequences was 44, the total length of the tandem repeat sequences was 1,970 bp (0.0772% of the genome), the number of minisatellite DNAs was 36, and there were 48 tRNAs and 12 rRNAs.

TNFR/TNF-α signaling pathway regulates apoptosis of alveolar macrophages in coal workers' pneumoconiosis.

We explored the role of TNFR/TNF-α signalingin apoptosis among alveolar macrophages (AM) and its relevance to the development of coal workers' pneumoconiosis (CWP). Purified alveolar macrophages (AMs) were prepared from bronchoalveolar lavage fluid harvested from 366 CWP patients and 120 healthy subjects enrolled inthe study. The purified AMs were then divided into control, SOD, anti-TNFR, TNFR and NFkB inhibitor groups and analyzed for apoptosis usingflow cytometry (sub-diploid peak) and western blotting (Bcl-2, Caspase-3 and Caspase-8 expression). We found thatAM apoptosis washigher amongCWP patients than thehealthycontrols. Expression ofBcl-2, Caspase-3 and Caspase-8 was higher inAMs from CWP patientsthan in those from the controlsand correlated with increased AM apoptosis. Univariate and multivariate analyses suggested that CWP grade, initial exposure time, exposure time inyears, and CWP onset agewereall associated with altered levels of Bcl-2, Caspase-3 and Caspase-8. Inhibition of TNFR/TNF-α signaling usinganti-TNFR antibody, SOD or NFkB inhibitionreduced AM apoptosisand decreased Bcl-2, Caspase-3 and Caspase-8 expression. These data suggestinhibition of a TNFR/TNF-α signaling pathway is a potentiallyeffective means ofalleviating CWP by inhibiting AM apoptosis.

Cytochrome P450 1A1 and 1B1 promoter CpG island methylation regulates rat liver injury induced by isoniazid.

DNA methylation is an important component of epigenetics that is involved in the occurrence and development of a variety of diseases. The present study aimed to clarify the relationship between cytochrome P450 (CYP)1A1 and CYP1B1 promoter CpG island methylation and isoniazid­induced liver injury in rats, and to explore the possible mechanism, rats were given an intragastric dose of isoniazid (55 mg·kg­1·d­1). High performance liquid chromatography was used to analyze the DNA methylation level of the whole genome in liver tissue. Methylation­specific polymerase chain reaction (PCR) was used to detect the methylation level of CpG islands in the promoter region of CYP1A1 and CYP1B1. Reverse transcription­quantitative PCR was used to determine the mRNA expression levels of CYP1A1, CYP1B1, toll­like receptor 4 (TLR4), extracellular signal­regulated kinase (ERK) 2, peroxisome proliferator­activated receptor (PPAR) ­Î³, interleukin (IL)­6 and tumor necrosis factor (TNF)­α. The expression levels of CYP1A1 and CYP1B1 proteins were measured by ELISA, and malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were analyzed by colorimetric method. Liver tissue pathology, an indicator of liver function, indicated rat liver injury at 10 days following isoniazid treatment. Whole­genome methylation levels were gradually reduced, and methylation at day 7 post­treatment was significantly lower than the control group. CYP1A1 and CYP1B1 promoter CpG island methylation level was significantly increased at 3 days post­treatment. CYP1A1 and CYP1B1 mRNA expression levels were significantly reduced from day 7 and 10, respectively. These results suggested that CpG island hypermethylation of the CYP1A1 and CYP1B1 promoters regulate the low expression of genes involved in the occurrence of isoniazid­induced liver injury. With the alterations of CYP1A1 and CYP1B1 expression, the mRNA expression levels of TLR4, ERK, MDA, IL­6 and TNF­α were upregulated, and the expression of SOD and PPAR­Î³ were downregulated. These data demonstrated that alterations in methylation patterns may involve changes in the TLR4­ERK signaling pathway and PPAR­Î³, which may alter the expression of MDA, SOD, IL­6 and TNF­α, leading to liver injury.