PM2.5 induces lung inflammation and fibrosis via airway smooth muscle cell expression of the Wnt5a/JNK pathway.

Background: In recent years, particulate matter 2.5 (PM2.5) exposure has been considered a key dangerous factor in chronic obstructive pulmonary disease (COPD). The dysfunction of airway smooth muscle cells (ASMCs) facilitates lung inflammation and fibrosis in COPD. Therefore, we explored whether PM2.5 could promote the inflammatory response and fibrosis in ASMCs in vivo and in vitro via the wingless-related integration site 5a (Wnt5a)/c-Jun N-terminal kinase (JNK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Methods: Wnt5a expression in the bronchoalveolar lavage fluid (BALF) of COPD patients exposed to PM2.5 was measured by enzyme-linked immunosorbent assay (ELISA). Mice were intratracheally injected with PM2.5 and a Wnt5a antagonist (BOX5). ASMCs were transfected with Wnt5a small interfering RNA (siRNA), BOX5 and the JNK inhibitor SP600125 before PM2.5 stimulation. Hematoxylin and eosin (H&E) staining was performed to measure the inflammatory response and airway fibrosis. The production of Wnt5a/JNK/NF-KB pathway factors was analyzed by Western blotting. The secretion of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-α (TNF-α) was measured by ELISA. The expression levels of alpha smooth muscle actin (α-SMA), collagen I and collagen III were assessed by quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting. Results: We found that the increase in Wnt5a expression in the BALF of COPD patients was positively correlated with the levels of PM2.5 exposure. The Wnt5a/JNK/NF-κB pathway was activated in the lung samples of PM2.5-induced model mice and PM2.5-exposed ASMCs, which promoted the production of α-SMA, collagen I and collagen III and increased the secretion of IL-6, IL-8 and TNF-α. Furthermore, our results showed that BOX5 could prevent these effects. Wnt5a siRNA blocked the activation of the Wnt5a/JNK/NF-κB pathway and inhibited the effects of PM2.5 on fibrosis and inflammation in ASMCs. SP600125 blocked the phosphorylation of NF-κB and inhibited inflammation and fibrosis in PM2.5-exposed ASMCs. Conclusions: These findings suggest that PM2.5 stimulation of ASMCs induces pulmonary inflammatory factor expression and collagen deposition during COPD via the Wnt5a/JNK pathway, which indicates that modulating the Wnt5a/JNK pathway could be a promising therapeutic strategy for PM2.5-induced COPD.

Effect of PRDX6 gene polymorphism on susceptibility to chronic obstructive pulmonary disease in the Chinese Han population.

BACKGROUND: To explore the relationship of peroxiredoxin6 (PRDX6) tag-single nucleotide polymorphisms (SNPs) with susceptibility to chronic obstructive pulmonary disease (COPD) in the Chinese Han population. METHODS: A total of 502 patients with COPD and 481 healthy controls from nine hospitals in China were enrolled in this study. The PRDX6 tag-SNPs were identified by linkage disequilibrium (LD) analysis in 30 healthy controls. The associations between identified tag-SNPs and COPD risk were further evaluated. RESULTS: Four PRDX6 tag-SNPs, including rs7314, rs34619706, rs33951697, and rs4382766, were identified in 30 healthy controls. Moreover, in the allele model, there was no statistical difference in locus in PRDX6 between patients with COPD and healthy controls (P > 0.05). However, in the recessive model, rs33951697 locus in PRDX6 gene carrier with T/T had an increased risk of COPD (odds ratio [OR] = 2.59, 95% CI = 1.06-6.33, P = 0.028). Furthermore, in the relevance analysis between genetic polymorphisms and smoking behavior and lung function indexes, we found that the number of smoked cigarettes per day and FEV1/FVC differed among different genotypes of PRDX6, rs4382766, and rs7314 (P < 0.05). CONCLUSION: PRDX6 gene polymorphism with smoking status may contribute to the etiology of COPD in the Chinese Han population.

Application of nursing intervention based on the IKAP model in self-management of patients with gastric cancer.

BACKGROUND: To explore the effect of IKAP nursing intervention on the self-management of patients with gastric cancer, so as to improve the patient's disease management ability and healthy behaviors. METHODS: In this retrospective study, a total of 124 patients with gastric cancer were included. The experimental group received the self-management intervention program for gastric cancer patients based on the IKAP model, and the control group only received routine nursing. The psychological status, quality of life, cancer-related symptoms, and self-management ability of the two groups were observed; moreover, multiple regression analysis was used to identify the risk factors of self-management. RESULTS: The nursing intervention based on the IKAP model had obvious effects on patients with gastric cancer. The SUPPH score was improved significantly after nursing intervention in the experimental group, and the improvement was more significant as compared to control group (both P < 0.05). The quality of life was significantly improved in the experimental group as compared with control group. The incidence of partial cancer-related symptoms, such as infection, fatigue and recurrent peptic ulcer in the experimental group was significantly lower after nursing intervention as compared with control group (all P < 0.05). Moreover, the regression analysis showed that being single, divorced or separated, widowed, as well as self-management nursing intervention, and quality of life showed significant correlation with self-management behavior. The multiple regression analysis demonstrated that psychological function (p = 0.003) and self-management nursing intervention (p < 0.0001) were the independent risk factors. CONCLUSIONS: Nursing intervention based on the IKAP model for patients with gastric cancer plays a positive role in improving the self-management ability of gastric cancer patients and improving their negative emotions.

Serine metabolism orchestrates macrophage polarization by regulating the IGF1-p38 axis.

Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK-STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.

Arsenic Trioxide Therapy During Pregnancy: ATO and Its Metabolites in Maternal Blood and Amniotic Fluid of Acute Promyelocytic Leukemia Patients.

Acute promyelocytic leukemia (APL) is extremely fatal if treatment is delayed. Management of APL in pregnancy is a challenging situation. Arsenic trioxide (ATO) is successfully applied to treat APL. ATO can be transformed into different arsenic species [arsenite (AsIII), monomethylated arsenic (MMA, consists of MMAIII and MMAV), dimethylated arsenic (DMA, consists of DMAIII and DMAV), and arsenate (AsV)], which produce different toxic effects. Investigating the maternal and fetal exposure to arsenic species is critical in terms of assessing maternal and fetal outcomes, choice of optimal treatment, and making decisions for attempting to preserve the obstetrical and fetal wellbeing. In this study, maternal blood and amniotic fluid (AF) from APL patients treated with ATO in pregnancy and blood samples of non-pregnant patients were collected. Concentrations of inorganic arsenic (iAs, iAs = AsIII+AsV), MMA, and DMA were analyzed by high-performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS). The difference in arsenic species of plasma between pregnant patients and non-pregnant patients, distribution of arsenic compounds in AF and maternal plasma, and arsenic penetration into AF were explored. The outcomes of pregnant women treated with ATO and their fetus were analyzed. No significant differences in arsenic concentration, percentage, and methylation index [PMI: primary methylation index (MMA/iAs); SMI: secondary methylation index (DMA/MMA)] between pregnant women and non-pregnant women (p > 0.05) were observed. The mean ratios of AF to maternal plasma were as follows: iAs, 2.09; DMA, 1.04; MMA, 0.49; and tAs, 0.98. Abortion rate is higher with the diagnosis at an earlier gestational age, with 0%, 67%, and 100% of pregnancies ending in abortion during the third, second, and first trimester, respectively. The age of the pregnant women, the dose of ATO, and the duration of fetal exposure in utero had no influence on fetal outcomes. All APL women achieved complete remission (CR). Collectively, ATO and its metabolites can easily cross the placenta. Levels and distribution of arsenic species in maternal plasma and AF gave evidence that arsenic species had a different ability to penetrate the placenta into AF (iAs > DMA > MMA) and indicated a relatively high fetal exposure to ATO and its metabolites in utero. Gestational age at diagnosis was more likely to be closely related to fetal outcomes, but had no effects on mother outcomes.

Kgp DNA Vaccine Prevents Experimental Periodontitis.

PURPOSE: To investigate the prophylactic effect of lysine-specific protease (Kgp) vaccine on experimental periodontitis in mice. MATERIALS AND METHODS: We constructed the eukaryotic expression plasmid pVAX1-kgp and immunised mice with the recombinant plasmid. Mice were divided into two groups and immunised with pVAX1-kgp or pVAX1 three times at 2-week intervals. Immunoglobulin (Ig)G, IgG1 and IgG2a antibodies were detected by enzyme-linked immunosorbent assay (ELISA) before and after immunisation. At the last immunisation, a silk ligature infiltrated with Porphyromonas gingivalis (P. gingivalis) was tied at the neck of the maxillary second molar to induce experimental periodontitis. Each group was euthanised after 10 days, and microcomputed tomography (micro-CT) and hematoxylin-eosin (HE) staining were used to detect the loss of alveolar bone. RESULTS: Comparison with the pVAX1 group indicated that mice immunised with Kgp had higher levels of IgG (P < 0.05); the levels of the IgG1 were statistically significantly different (p < 0.05), and the levels of the IgG2a subtype were not significantly different. The results of micro-CT and HE staining showed that the alveolar bone loss in the pVAX1-kgp group was statistically significantly less than that in the pVAX1 group (p < 0.05). The expression of the related inflammatory factors, including interleukin-1ß (IL-ß), tumour necrosis factor (TNF-α) and interleukin-6 (IL-6), was lower in the pVAX1-kgp group than in the pVAX1 group. CONCLUSION: The Kgp DNA vaccine can enhance IgG levels in a model of experimental periodontitis, effectively activate immunity, and mitigate alveolar bone loss.

PM2.5 Induces Airway Remodeling in Chronic Obstructive Pulmonary Diseases via the Wnt5a/ß-Catenin Pathway.

BACKGROUND: Fine-particulate matter ≤2.5 µm in diameter (PM2.5)-associated airway remodeling has recently been recognized as a central feature of COPD. Activation of the Wnt/ß-catenin pathway is closely related to the occurrence of airway remodeling. Accordingly, the goal of this study was to determine whether the Wnt5a/ß-Catenin pathway is involved in PM2.5-induced smooth muscle proliferation in vivo and in vitro, which promotes the development of airway remodeling in subjects with COPD. METHODS: The effect of Wnt5a on ß-Catenin-mediated airway remodeling was assessed using an in vivo model of PM2.5-induced COPD and PM2.5-exposed human bronchial smooth muscle cells (HBSMCs) in vitro. Small animal spirometry was used to measure lung function in mice. H&E staining and immunohistochemistry were performed to inspect emphysema and airway remodeling indices. Real-time PCR was used to detect Wnt5a, ß-Catenin, TGF-ß1, CyclinD1 and c-myc mRNA expression. The CCK8 assay was performed to detect cellular activity. Western blotting was performed to assess PCNA, α-SMA, Wnt5a, ß-Catenin, PDGFRß and TenascinC protein expression. ß-Catenin expression was detected using cellular immunofluorescence. RESULTS: Exposure to PM2.5 led to emphysema, airway wall thickening, an increased smooth muscle layer thickness, decreased lung function and increased expression of the Wnt5a, ß-Catenin, PDGFRß and Tenascin C proteins in the mouse lung tissue. BOX5 (a Wnt5a antagonist) alleviated these PM2.5-induced outcomes in mice. Moreover, PM2.5 induced the expression of the Wnt5a, ß-Catenin, TGF-ß1, CyclinD1 and c-myc mRNAs in HBSMCs. BOX5 also inhibited the PM2.5-induced increases in PCNA, α-SMA, Wnt5a, ß-Catenin, PDGFRß and Tenascin C protein expression in HBSMCs. CONCLUSION: Our findings suggest that PM2.5 exposure induces HBSMC proliferation, contributing to airway remodeling via the Wnt5a/ß-Catenin signaling pathway in vivo and in vitro, which might be a target for COPD treatment.

Effect of renal impairment on arsenic accumulation, methylation capacity, and safety in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide.

Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL).Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMAV%, DMAV%, primary methylation index (PMI, MMAV/iAs), and secondary methylated index (SMI, DMAV/MMAV). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed.Results: Compared with normal renal function, MMAV and DMAV concentrations increased 1.5-4 fold in moderate and severe renal impairment groups, iAs increased 1.3-1.7 fold. APL patients with renal impairment showed lower iAs%, but higher DMAV% and PMI in plasma than those with normal renal function (P < 0.05). MMAV, DMAV, and tAs apparently accumulated with administration frequency in moderate and severe renal dysfunction groups. The incidence of QTc interval prolongation and liver injury increased with the increasing severity of renal impairment.Conclusion: Renal dysfunction may increase exposure to arsenic and arsenic accumulation and affect methylation capacity, then the clinical safety in APL patients treated with ATO. Arsenic-level monitoring and dosing regimen adjustment should be considered in APL patients with moderate and severe renal dysfunction.

Evaluation of arsenic species in leukocytes and granulocytes of acute promyelocytic leukemia patients treated with arsenic trioxide.

Concentrations of arsenic metabolites were important to clarify the sensitivity and resistance of APL (acute promyelocytic leukemia) patients to arsenic trioxide (As2O3). Our purpose was to evaluate levels and distributions of arsenic species in leukocytes and granulocytes of APL patients. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were measured by high performance liquid chromatography coupled inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Leukocytes were collected from 21 patients treated with As2O3 during induction, consolidation, and drug-withdrawal period. The upregulation of granulocytes in induction period was closely related to the differentiation of promyelocytes. Therefore, granulocytes were collected during induction period from 4 APL patients and purified by flow cytometry sorting using a panel of monoclonal antibodies specific for CD45, CD3, CD14, and CD19. The developed HPLC-ICP-MS method was precise and accurate with the limit of quantification of 0.5 ng/mL. During induction, consolidation, and drug-withdrawal period, the general trend of arsenic species was iAs > MMA > DMA (P < 0.05) in leukocytes. iAs was predominant arsenic species with median concentration of 10.84 (6.03-14.62) ng/mL. MMA was major methylated metabolite with median concentration of 0.94 (0.60-2.50) ng/mL. Moreover, arsenicals were detected in leukocytes during drug-withdrawal. In granulocytes, iAs was found during induction period with median concentration of 1.08 ng/mL, while MMA and DMA were not detected. These results showed that iAs was the primary arsenic species in leukocytes and granulocytes from APL patients treated with As2O3. This study suggested that iAs might play a dominant therapeutic role during the whole treatment process of APL.

Monomethylated arsenic was the Major methylated arsenic in Red blood cells of acute promyelocytic leukemia patients treated with arsenic trioxide.

BACKGROUND: Arsenic trioxide (ATO) has been successfully applied in the treatment of acute promyelocytic leukemia (APL). Arsenic metabolites including inorganic arsenic and methylated arsenic could lead to different toxicity and curative effect. This study aims to establish a method to determine arsenic species in red blood cells (RBCs), clarify the distribution characteristics of arsenic species in RBCs. METHODS: Steady state blood samples were collected from 97 APL patients. H2O2 and HClO4 were used to release the hemoglobin bounding arsenic and precipitate protein. Arsenite (iAsIII), arsenate (iAsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in plasma and RBCs were detected by HPLC-HG-AFS. Free and bound arsenic species in RBCs were separated by 30 kDa molecular mass cutoff filters and determined to evaluate hemoglobin binding capacity of different arsenic species. RESULTS: The method was validated with accuracy ranged from 84.75% to 104.13%. Arsenic species in RBCs followed the trend iAs > MMA > DMA (p < 0.01), while the concentration of DMA was significantly higher than iAs and MMA in plasma (p < 0.01). The correlation between iAs concentration in plasma and corresponding RBCs arsenic level was weak. And the concentrations of DMA and MMA in plasma were moderately positive correlated with those in RBCs. Hemoglobin-binding ratios of iAs, MMA and DMA were all over 70 %. CONCLUSIONS: In this study, we provided a reliable method to determine arsenic species in RBCs of APL patients treated with ATO by HPLC-HG-AFS. It was confirmed that the concentration of DMA is the highest in plasma, while MMA is the most predominant methylated arsenic in RBCs. High affinity of MMA with human Hb was responsible for the accumulation of arsenic in RBCs of APL patients.

Characteristics and clinical influence factors of arsenic species in plasma and their role of arsenic species as predictors for clinical efficacy in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide.

Background: Arsenic trioxide (ATO) is successfully applied to treat acute promyelocytic leukemia (APL). Arsenic species levels in blood are critical to reveal metabolic mechanism and relationship between arsenic species and clinical response. Characteristics and influence factors of arsenic species in APL patients have not been studied.Methods: 305 plasma samples from APL patients treated with ATO were analyzed using HPLC-HG-AFS. Trough concentration (Ctrough), distribution, methylation levels of arsenic species were evaluated. The influence factors on arsenic species levels of plasma and association between arsenic concentrations and clinical efficacy were explored.Results: Ctrough of arsenic in effective treatment groups provide basis for defining the target range of arsenic plasma concentrations in APL patients treated with ATO. Distribution trends: DMAV > AsIII, MMAV> AsV (p < 0.0001) for continuous slow-rate (CS) infusion and DMAV > MMAV > AsIII > AsV (p < 0.0001) for conventional infusion. Infusion methods and combined medication may affect arsenic metabolism. There was a weak correlation between ATO dose and plasma Ctrough of arsenic species. Ctrough of plasma arsenic species had predictive value for treatment efficacy.Conclusion: Arsenic concentration monitoring in APL patients treated with ATO is required. These findings are critical to optimize treatment outcomes of ATO therapy.

Characteristics of arsenic species in cerebrospinal fluid (CSF) of acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide plus mannitol.

Arsenic speciation in cerebrospinal fluid (CSF) is critical for treatment/prevention of central nervous system (CNS) relapse in acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide (ATO). Previous study showed low total arsenic level in CSF of APL patients. Mannitol infusion was applied to improve blood-brain barrier (BBB) permeability for arsenic. Arsenite (AsIII ), monomethylarsonic acid (MMAV ), dimethylarsinic acid (DMAV ), and arsenate (AsV ) in CSF and plasma were analysed by high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS). The profile and concentration of arsenic species in CSF from APL patients administered ATO alone and in combination with mannitol were compared. The overall distribution trend of arsenic species in CSF was AsIII , DMAV > MMAV > AsV . Arsenicals accumulated in CSF with administration frequency. The permeability of BBB for AsIII was higher than that for MMAV and DMAV . Arsenic concentration in CSF was much lower than that in plasma. There were significantly higher arsenic species concentrations in CSF of APL patients treated with mannitol than that without mannitol. Mannitol infusion significantly increased AsIII penetration into CSF, which was beneficial to optimize efficacy in APL patients with CNS relapse.

TRPV1 genetic polymorphisms and risk of COPD or COPD combined with PH in the Han Chinese population.

COPD is a common chronic disease with genetic predisposition. TRPV1 is mainly expressed in peripheral neuron which widely exists in entire respiratory tract. In present study, we aimed to study the relationship between single nucleotide polymorphisms (SNPs) of transient receptor potential vanilloid-1 (TRPV1) and the risk of chronic obstructive pulmonary disease (COPD) or COPD combined with pulmonary hypertension (PH) in Chinese Han population. A total of 1019 individuals, including 506 healthy volunteers and 513 COPD patients (150 patients combined with PH among them) were recruited in this study. Genomic DNA were extracted and sequenced. Genotype and allele frequencies of the TRPV1 SNPs among COPD, COPD combined with PH and control groups were compared. Then, the association of TRPV1 SNPs and smoking status were analyzed. Genotype frequencies of SNP rs3744683 had a significant difference in COPD patients with PH patients compared with control (p = 0.006) or COPD patients without PH patients (p = 0.016). Likewise, SNP rs3744683 was remarkedly associated with the risk of COPD (p = 0.004) in current-smoker groups which phenomenon was not observed in nonsmoker or former-smoker groups. Compared with the control group, there was a significant difference for the distribution of SNP rs4790521 alleles in the COPD group (p = 0.041). For further, logical regression analysis showed that SNP rs3744683 genotype of "TC" was a protective factor for PH in COPD patients compared with the genotype of "TT" (OR = 0.364, 95%CI = 0.159-0.829, p = 0.016). Our findings firstly revealed the relevance between TRPV1 SNPs and the risk for COPD/COPD combined with PH.

The biocompatibility and mechanical properties of plasma sprayed zirconia coated abutment.

PURPOSE: The aim of this study was to evaluate the clinical performance and reliability of plasma sprayed nanostructured zirconia (NSZ) coating. MATERIALS AND METHODS: This study consisted of three areas of analysis: (1) Mechanical property: surface roughness of NSZ coating and bond strength between NSZ coating and titanium specimens were measured, and the microstructure of bonding interface was also observed by scanning election microscope (SEM). (2) Biocompatibility: hemolysis tests, cell proliferation tests, and rat subcutaneous implant test were conducted to evaluate the biocompatibility of NSZ coating. (3) Mechanical compatibility: fracture and artificial aging tests were performed to measure the mechanical compatibility of NSZ-coated titanium abutments. RESULTS: In the mechanical study, 400 µm thick NSZ coatings had the highest bond strength (71.22 ± 1.02 MPa), and a compact transition layer could be observed. In addition, NSZ coating showed excellent biocompatibility in both hemolysis tests and cell proliferation tests. In subcutaneous implant test, NSZ-coated plates showed similar inflammation elimination and fibrous tissue formation processes with that of titanium specimens. Regarding fatigue tests, all NSZ-coated abutments survived in the five-year fatigue test and showed sufficient fracture strength (407.65-663.7 N) for incisor teeth. CONCLUSION: In this study, the plasma-sprayed NSZ-coated titanium abutments presented sufficient fracture strength and biocompatibility, and it was demonstrated that plasma spray was a reliable method to prepare high-quality zirconia coating.

Loss of Adipose Growth Hormone Receptor in Mice Enhances Local Fatty Acid Trapping and Impairs Brown Adipose Tissue Thermogenesis.

Growth hormone (GH) binds to its receptor (growth hormone receptor [GHR]) to exert its pleiotropic effects on growth and metabolism. Disrupted GH/GHR actions not only fail growth but also are involved in many metabolic disorders, as shown in murine models with global or tissue-specific Ghr deficiency and clinical observations. Here we constructed an adipose-specific Ghr knockout mouse model Ad-GHRKO and studied the metabolic adaptability of the mice when stressed by high-fat diet (HFD) or cold. We found that disruption of adipose Ghr accelerated dietary obesity but protected the liver from ectopic adiposity through free fatty acid trapping. The heat-producing brown adipose tissue burning and white adipose tissue browning induced by cold were slowed in the absence of adipose Ghr but were recovered after prolonged cold acclimation. We conclude that at the expense of excessive subcutaneous fat accumulation and lower emergent cold tolerance, down-tuning adipose GHR signaling emulates a healthy obesity situation which has metabolic advantages against HFD.

APS could potentially activate hepatic insulin signaling in HFD-induced IR mice.

Astragalus polysaccharide (APS) is the main component of Astragalus membranaceus, an anti-diabetic herb being used for thousands of years in Traditional Chinese medicine (TCM). In this study, we aimed to evaluate the impact of APS on hepatic insulin signaling, autophagy and ER stress response in high-fat-diet (HFD)-induced insulin resistance (IR) mice. APS was intra-gastrically administrated and metformin was used as a control medicine. Apart from monitoring the changes in the important parameters of IR progression, the gene and protein expression of the key factors marking the state of hepatic ER stress and autophagic flux were examined. We found that, largely comparable to the metformin regime, APS treatment resulted in an overall improvement of IR, as indicated by better control of body weight and blood glucose/lipid levels, recovery of liver functions and regained insulin sensitivity. In particular, the excessive and pro-apoptotic ER stress response and inhibition of autophagy, as a result of prolonged HFD exposure, were significantly corrected by APS administration, indicating a switch of the cellular fate in favor of cell survival. Using the HepG2/IR cell model, we demonstrated that APS modulated the insulin-initiated phosphorylation cascades in a similar manner to metformin. This study provides a rationale for exploiting the insulin-sensitizing potential of APS, which has a therapeutic performance almost equivalent to metformin, to enrich our options in the treatment of IR.

Speciation analysis of arsenic in urine samples from APL patients treated with single agent As2O3 by HPLC-HG-AFS.

Arsenic trioxide [As2O3, arsenite (AsIII) in solution] has been applied successfully for the treatment of acute promyelocytic leukemia (APL). The arsenic speciation analysis of urine is critical to reveal the metabolic mechanism and the relationship between arsenic species and the clinical response. To characterize the arsenic species in urine, a simple and robust HPLC-HG-AFS method was developed and validated to quantify the levels of arsenic species [AsIII and its metabolites, monomethylarsonic acid (MMAV), dimethylarsinic acid (DMAV), and arsenate (AsV)] in urine samples from 66 patients with APL. Patients received As2O3 (0.16 mg/kg/day) via continuous slow-rate infusion or conventional infusion. Urine samples were collected at steady state before the start of the next daily administration. The relative proportions (median) of arsenic species in urine were: AsIII, 33.00% (IQR: 24.34%-46.82%); DMAV, 36.42% (IQR: 25.82%-51.98%); MMAV, 23.89% (IQR: 19.52%-27.19%); and AsV, 2.22% (IQR: 1.293%-3.665%). The levels and proportions of arsenic species vary widely among individual patients. DMAV and un-metabolized AsIII were the dominant arsenic compounds excreted from the urine of patients with APL treated with As2O3. AsV was the least abundant arsenic species in all urine samples. Good positive correlations were found between the levels and proportions of arsenic species in urine and those in plasma; thus, urinary arsenic can reflect the levels of arsenic in plasma. Urinary arsenic is a critical biomarker to evaluate the metabolism and toxicity of arsenic in the clinical application of As2O3.

Time course of arsenic species in red blood cells of acute promyelocytic leukemia (APL) patients treated with single agent arsenic trioxide.

BACKGROUND: Arsenic trioxide (ATO) is widely applied to treat acute promyelocytic leukemia (APL). To elucidate metabolism and toxicity of arsenic, we analyzed time course of arsenic species in red blood cells (RBCs) of APL patients. METHODS: Nine APL patients received ATO (0.16 mg/kg/day) through 18-h infusion. Blood was collected before daily administration (days 2 to 9), and at different time points on day 8. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were detected by HPLC-ICP-MS. RESULTS: Arsenic species reached Cmax at 18 h on day 8. Arsenicals gradually accumulated during days 2 to 9, whereas their percentages remained almost constant. The general trend in red blood cells (RBCs) was iAs > MMA > DMA. MMA was consistently the predominant methylated arsenic metabolite in RBCs. iAs, MMA, and tAs (tAs = iAs + DMA + MMA) concentrations (P < 0.0001), MMA/DMA ratios (P = 0.0016) and iAs% (P = 0.0013) were higher in RBCs than in plasma. CONCLUSIONS: Time course of arsenic species reveal kinetic characteristic of ATO metabolites in RBCs. Arsenic species accumulated with administration frequency. Arsenic species in RBCs were remarkably different from those in plasma. Time course of arsenic species in RBCs is important in ATO clinical application.

Effect of continuous venovenous haemodialysis on outcome and pharmacokinetics of arsenic species in a patient with acute promyelocytic leukaemia and acute kidney injury.

This study presents outcome and pharmacokinetics of arsenic trioxide (ATO) metabolites in patients on continuous venovenous haemodialysis (CVVHD). Of 3 acute promyelocytic leukaemia patients receiving CVVHD in management of acute kidney injury, only 1 patient was included. The patient presented disseminated intravascular coagulation and acute kidney injury before induction therapy was conducted. CVVHD was performed and ATO was initiated. Species of ATO metabolites in plasma and effluent were analysed using high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry. Plasma concentrations of AsIII , monomethylarsonic acid and dimethylarsinic acid with CVVHD were lower than those without CVVHD. Area under the concentration-time curve from 0 to the last sample with quantifiable concentration of AsIII without CVVHD was significantly higher than that with CVVHD (292.10 ng h/mL vs 195.86 ng h/mL, P = .037), which were not observed for monomethylarsonic acid and dimethylarsinic acid. Dialysate saturation of arsenic species was remarkable, especially for AsIII . Complete remission was achieved and renal function recovered. In this study, ATO can be used safely and effectively to treat acute promyelocytic leukaemia patients undergoing CVVHD without dose adjustment.

Trimethylamine N-oxide as a risk marker for ischemic stroke in patients with atrial fibrillation.

Trimethylamine N-oxide (TMAO) is an independent risk factor of cardiovascular disease. Our objective was to explore the relation between TMAO and ischemic stroke (IS) in patients with atrial fibrillation (AF). A total of 68 patients with AF with IS and 111 ones without IS were enrolled. The plasma levels of TMAO remarkably increased in IS-AF patients (8.25 ± 1.58 µM) compared with patients with AF (2.22 ± 0.09 µM, P < 0.01). The receiver operating characteristic analysis revealed that the best cutoff value of TMAO to predict IS in patients with AF was 3.53 µM with 75.0% sensitivity and 92.8% specificity (area under the curve: 0.917, 95% confidence intervals: 0.877-0.957). Univariate and multivariate logistic regression analysis showed that TMAO was an independent predictor in IS. The level of TMAO was correlated with the CHA2DS2-VASc score. In conclusion, TMAO was an independent predictor of IS, which could potentially refine stroke stratification in patients with AF.