Chronic vascular pathogenesis results in the reduced serum Metrnl levels in ischemic stroke patients.

Metrnl is a secreted protein involved in neurite outgrowth, insulin sensitivity, immunoinflammatory responses, blood lipids and endothelial protection. In this study, we investigated the role of Metrnl in ischemic stroke. Fifty-eight ischemic stroke patients (28 inpatient patients within 2 weeks of onset and 30 emergency patients within 24 h of onset) and 20 healthy controls were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. We showed that serum Metrnl levels were significantly reduced in both inpatient and emergency patient groups compared with the controls. Different pathological causes for ischemic stroke such as large artery atherosclerosis and small artery occlusion exhibited similar reduced serum Metrnl levels. Transient ischemic attack caused by large artery atherosclerosis without brain infarction also had lower serum Metrnl levels. Metrnl was correlated with some metabolic, inflammatory and clotting parameters. Reduced serum Metrnl was associated with the severity of intracranial arterial stenosis and the presence of ischemic stroke. In order to elucidate the mechanisms underlying the reduced serum Metrnl levels, we established animal models of ischemic stroke in normal mice, atherosclerotic apolipoprotein E-knockout mice and Metrnl-knockout mice by middle cerebral artery occlusion (MCAO) using intraluminal filament or electrocoagulation. We demonstrated that serum Metrnl levels were significantly lower in atherosclerosis mice than normal mice, whereas acute ischemic stroke injury in normal mice and atherosclerosis mice did not alter serum Metrnl levels. Metrnl knockout did not affect acute ischemic stroke injury and death. We conclude that reduced serum Metrnl levels are attributed to the chronic vascular pathogenesis before the onset of ischemic stroke. Metrnl is a potential target for prevention of ischemic stroke.

Milk yield variation partially attributed to blood oxygen-mediated neutrophil activation in lactating dairy goats.

Blood oxygen is an essential component for numerous biological processes of mammalian animals. Milk production of ruminants largely relies on the supply of nutrients, such as glucose, amino acids and fatty acids. To define the regulatory role of blood oxygen availability in regard to milk production, seventy-five healthy Guanzhong dairy goats with similar body weight, days in milk and parities were selected. For each animal, milk yield was recorded and milk sample was collected to determine compositions. Milk vein blood was collected to determine parameters including blood gas, physio-biochemistry and haematology. Another blood sample was prepared for transcriptome and RT-qPCR. Results showed that both pressure of oxygen (pO2) in the milk vein (positively) and numbers of neutrophils in mammary vein (negatively) were associated with milk yield of the animals. To learn the role of pO2 in blood cell functionality, twelve animals (six with higher yield (H-group) and six with lower yield (L-group)) from seventy-five goats were selected. Compared with animals in L-group, goats in H-group were higher in pO2 but lower in pCO2, lactate, lactate dehydrogenase activity and neutrophil abundance in milk vein, compared with L-group. The blood transcriptome analysis suggested that compared with L-group, animals in H-group were depressed in functionality including neutrophil activation and metabolic pathways including glycolysis, NF-κB and HIF-1. Our result revealed that lower milk production could be associated with neutrophil activation responding to low pO2 in the mammary vein. In the meantime, we highlighted the potential importance of blood oxygen as a milk yield regulator.

Angiogenesis after ischemic stroke.

Owing to its high disability and mortality rates, stroke has been the second leading cause of death worldwide. Since the pathological mechanisms of stroke are not fully understood, there are few clinical treatment strategies available with an exception of tissue plasminogen activator (tPA), the only FDA-approved drug for the treatment of ischemic stroke. Angiogenesis is an important protective mechanism that promotes neural regeneration and functional recovery during the pathophysiological process of stroke. Thus, inducing angiogenesis in the peri-infarct area could effectively improve hemodynamics, and promote vascular remodeling and recovery of neurovascular function after ischemic stroke. In this review, we summarize the cellular and molecular mechanisms affecting angiogenesis after cerebral ischemia registered in PubMed, and provide pro-angiogenic strategies for exploring the treatment of ischemic stroke, including endothelial progenitor cells, mesenchymal stem cells, growth factors, cytokines, non-coding RNAs, etc.

Humanized cerebral organoids-based ischemic stroke model for discovering of potential anti-stroke agents.

Establishing a stoke experimental model, which is better in line with the physiology and function of human brain, is the bottleneck for the development of effective anti-stroke drugs. A three-dimensional cerebral organoids (COs) from human pluripotent stem cells can mimic cell composition, cortical structure, brain neural connectivity and epigenetic genomics of in-vivo human brain, which provides a promising application in establishing humanized ischemic stroke model. COs have been used for modeling low oxygen condition-induced hypoxic injury, but there is no report on the changes of COs in response to in vitro oxygen-glucose deprivation (OGD)-induced damage of ischemic stroke as well as its application in testing anti-stroke drugs. In this study we compared the cell composition of COs at different culture time and explored the cell types, cell ratios and volume size of COs at 85 days (85 d-CO). The 85 d-CO with diameter more than 2 mm was chosen for establishing humanized ischemic stroke model of OGD. By determining the time-injury relationship of the model, we observed aggravated ischemic injury of COs with OGD exposure time, obtaining first-hand evidence for the damage degree of COs under different OGD condition. The sensitivity of the model to ischemic injury and related treatment was validated by the proven pan-Caspase inhibitor Z-VAD-FMK (20 µM) and Bcl-2 inhibitor navitoclax (0.5 µM). Neuroprotective agents edaravone, butylphthalide, P7C3-A20 and ZL006 (10 µM for each) exerted similar beneficial effects in this model. Taken together, this study establishes a humanized ischemic stroke model based on COs, and provides evidence as a new research platform for anti-stroke drug development.

Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice.

Aging is one of the main risk factors for cognitive dysfunction. During aging process, the decrease of brain-derived neurotrophic factor (BDNF) and the impairment of astrocyte function contribute to the cognitive impairment. Metrnl, a neurotrophic factor, promotes neural growth, migration and survival, and supports neural function. In this study, we investigated the role of Metrnl in cognitive functions. D-galactose (D-gal)-induced aging model was used to simulate the process of aging. Cognitive impairment was assessed by the Morris water maze test. We showed that Metrnl expression levels were significantly increased in the hippocampus of D-gal-induced aging mice. Metrnl knockout did not affect the cognitive functions in the baseline state, but aggravated the cognitive impairment in the D-gal-induced aging mice. Furthermore, Metrnl knockout significantly reduced hippocampal BDNF, TrkB, and glial fibrillary acidic protein (GFAP) levels in the D-gal-induced aging mice. In the D-gal-induced aging cell model in vitro, Metrnl levels in the hippocampal astrocytes were significantly increased, and Metrnl knockdown and overexpression regulated the BDNF levels in primary hippocampal astrocytes rather than in neurons. We conclude that Metrnl regulates cognitive functions and hippocampal BDNF levels during aging process. As a neurotrophic factor and an endogenous protein, Metrnl is expected to become a new candidate for the treatment or alleviation of aging-related cognitive dysfunction.

Metrnl deficiency retards skin wound healing in mice by inhibiting AKT/eNOS signaling and angiogenesis.

Meteorin-like (Metrnl) is a novel secreted protein with various biological activities. In this study, we investigated whether and how Metrnl regulated skin wound healing in mice. Global Metrnl gene knockout mice (Metrnl-/-) and endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl-/-) were generated. Eight-mm-diameter full-thickness excisional wound was made on the dorsum of each mouse. The skin wounds were photographed and analyzed. In C57BL/6 mice, we observed that Metrnl expression levels were markedly increased in skin wound tissues. We found that both global and endothelial cell-specific Metrnl gene knockout significantly retarded mouse skin wound healing, and endothelial Metrnl was the key factor affecting wound healing and angiogenesis. The proliferation, migration and tube formation ability of primary human umbilical vein endothelial cells (HUVECs) were inhibited by Metrnl knockdown, but significantly promoted by addition of recombinant Metrnl (10 ng/mL). Metrnl knockdown abolished the proliferation of endothelial cells stimulated by recombinant VEGFA (10 ng/mL) but not by recombinant bFGF (10 ng/mL). We further revealed that Metrnl deficiency impaired VEGFA downstream AKT/eNOS activation in vitro and in vivo. The damaged angiogenetic activity in Metrnl knockdown HUVECs was partly rescued by addition of AKT activator SC79 (10 µM). In conclusion, Metrnl deficiency retards skin wound healing in mice, which is related to impaired endothelial Metrnl-mediated angiogenesis. Metrnl deficiency impairs angiogenesis by inhibiting AKT/eNOS signaling pathway.

Design and Investigation of a Dynamic Auto-Adjusting Ejector for the MED-TVC Desalination System Driven by Solar Energy.

Ejectors have been widely used in multi-effect distillation, thermal vapor compression (MED-TVC) desalination systems due to their simple structures and low energy consumption. However, traditional fixed geometry ejectors fail to operate under unstable working conditions driven by solar energy. Herein, a dynamic auto-adjusting ejector, equipped with a needle at the nozzle throat, is proposed to improve the ejector's performance under changeable operating conditions. A two-dimensional computational fluid dynamics (CFD) model is built to analyze the performance and flow field of the ejector. It is found that the achievable entrainment ratio gradually increases as the needle approaches the nozzle, and the entrainment ratio of the ejector is relatively stable, varying slightly between 1.1-1.2 when the primary pressure changes from 2.5 to 4 bar. Besides, the performance comparison between the proposed ejector and the traditional ejector is studied under the same primary pressure range. The entrainment ratio of the designed ejector was 1.6 times higher than that of the conventional ejector at a primary pressure of 2.5 bar. Furthermore, the average entrainment ratio of the designed ejector is 1.14, as compared to 0.84 for the traditional ejector. Overall, the proposed auto-adjusting ejector could be potentially used in MED-TVC desalination systems under variable conditions.

Allisartan isoproxil reduces mortality of stroke-prone rats and protects against cerebrovascular, cardiac, and aortic damage.

Stroke is a common cause of death and disability. Allisartan isoproxil (ALL) is a new angiotensin II receptor blocker and a new antihypertensive drug discovered and developed in China. In the present study we investigated the therapeutic effects of ALL in stroke-prone renovascular hypertensive rats (RHR-SP) and the underlying mechanisms. The model rats were generated via two-kidney two-clip (2K2C) surgery, which led to 100% of hypertension, 100% of cerebrovascular damage as well as 100% of mortality 1 year after the surgery. Administration of ALL (30 mg · kg-1 · d-1 in diet, for 55 weeks) significantly decreased stroke-related death and prolonged lifespan in RHR-SP, but the survival ALL-treated RHR-SP remained of hypertension and cardiovascular hypertrophy compared with sham-operated normal controls. In addition to cardiac, and aortic protection, ALL treatment for 10 or 12 weeks significantly reduced cerebrovascular damage incidence and scoring, along with a steady reduction of blood pressure (BP) in RHR-SP. Meanwhile, it significantly decreased serum aldosterone and malondialdehyde levels and cerebral NAD(P)H oxidase expressions in RHR-SP. We conducted 24 h continuous BP recording in conscious freely moving RHR-SP, and found that a single intragastric administration of ALL produced a long hypotensive effect lasting for at least 12 h on systolic BP. Taken together, our results in RHR-SP demonstrate that ALL can be used for stroke prevention via BP reduction and organ protection, with the molecular mechanisms related to inhibition of angiotensin-aldosterone system and oxidative stress. This study also provides a valuable scoring for evaluation of cerebrovascular damage and drug efficacy.

Pharmacological characterization of MT-1207, a novel multitarget antihypertensive agent.

Hypertension is a serious public health problem worldwide. MT-1207, chemically named 3-(4-(4-(1H-benzotriazole-1-yl)butyl)piperazine-1-yl) benzisothiazole hydrochloride, is a new chemical entity that has entered into clinical trial as antihypertensive agent in China. In this paper we report the pharmacological profile of MT-1207 regarding its acute, subacute, and long-term effects on hypertensive animal models, and its actions on isolated organs in vitro as well as its molecular targets. Blood pressure (BP) was measured in conscious animals; amlodipine was taken as a positive control drug. We showed that both single dose of MT-1207 (1.25-20 mg/kg, ig) in spontaneously hypertensive rats (SHR) and MT-1207 (0.25-6 mg/kg, ig) in two-kidney one-clip (2K1C) dogs dose-dependently decreased BP. MT-1207 quickly decreased BP within 5 min after administration; the hypotensive effect lasted for 8 and 12 h, respectively, in SHR and 2K1C dogs without reflex increase in heart rate. Multiple doses of MT-1207 (5 mg · kg-1 · d-1 in SHR; 2 mg · kg-1 · d-1 in 2K1C dogs, for 7 days) significantly decreased BP, slightly reduced heart rate, and both of them recovered after withdrawal. Long-term administration of MT-1207 (10 mg · kg-1 · d-1 for 4 months or more time) produced a stable BP reduction, improved baroreflex sensitivity, reduced renal and cardiovascular damage in SHR, and delayed stroke occurrence and death in stroke-prone SHR. In isolated rat aortic rings precontracted by adrenaline, KCl, noradrenaline or 5-hydroxytryptamine (5-HT), MT-1207 (10-9-10-4 M) caused concentration-dependent relaxation. In a panel of enzyme activity or radioligand binding assays of 87 molecular targets, MT-1207 potently inhibited adrenergic α1A, α1B, α1D, and 5-HT2A receptors with Ki < 1 nM. The antagonism of MT-1207 against these receptors was confirmed in isolated rabbit arteries. We conclude that MT-1207 is a novel and promising single-molecule multitarget agent for hypertension treatment to reduce hypertensive organ damage and stroke mortality.

iTRAQ- and LC-MS/MS-based quantitative proteomics reveals Pqlc2 as a potential regulator of hepatic glucose metabolism and insulin signalling pathway during fasting.

Glucose homeostasis is tightly controlled by balance between glucose production and uptake in liver tissue upon energy shortage condition. Altered glucose homeostasis contributes to the pathophysiology of metabolic disorders including diabetes and obesity. Here, we aimed to analyse the change of proteomic profile upon prolonged fasting in mice with isobaric tag for relative and absolute quantification (iTRAQ) labelling followed by liquid chromatography-mass spectrometry (LC/MS) technology. Adult male mice were fed or fasted for 16 hours and liver tissues were collected for iTRAQ labelling followed by LC/MS analysis. A total of 322 differentially expressed proteins were identified, including 189 upregulated and 133 downregulated proteins. Bioinformatics analyses, including Gene Ontology analysis (GO), Kyoto encyclopaedia of genes and genomes analysis (KEGG) and protein-protein interaction analysis (PPI) were conducted to understand biological process, cell component, and molecular function of the 322 differentially expressed proteins. Among 322 hepatic proteins differentially expressed between fasting and fed mice, we validated three upregulated proteins (Pqlc2, Ehhadh and Apoa4) and two downregulated proteins (Uba52 and Rpl37) by western-blotting analysis. In cultured HepG2 hepatocellular cells, we found that depletion of Pqlc2 by siRNA-mediated knockdown impaired the insulin-induced glucose uptake, inhibited GLUT2 mRNA level and suppressed the insulin-induced Akt phosphorylation. By contrast, knockdown of Pqlc2 did not affect the cAMP/dexamethasone-induced gluconeogenesis. In conclusion, our study provides important information on protein profile change during prolonged fasting with iTRAQ- and LC-MS/MS-based quantitative proteomics, and identifies Pqlc2 as a potential regulator of hepatic glucose metabolism and insulin signalling pathway in this process.

Alcohol consumption in relation to cardiovascular and non-cardiovascular mortality in an elderly male Chinese population.

BACKGROUND: We investigated the association of alcohol consumption with cardiovascular and non-cardiovascular mortality in elderly Chinese men. METHODS: Our participants were recruited from residents living in a suburban town of Shanghai (≥60 years of age, n = 1702). Alcohol intake was classified as non-drinkers, past drinkers (stopped drinking for ≥12 months), and current light-to-moderate (1 to 299 g/week) and heavy drinkers (≥300 g/week). Alcoholic beverages were classified as beer/wine, rice aperitif and liquor/mix drinking. RESULTS: During 5.9 years (median) of follow-up, all-cause, cardiovascular and non-cardiovascular deaths occurred in 211, 98 and 113 participants, respectively. The corresponding incidence rates were 23.6/1000, 10.9/1000 and 12.6/1000 person-years, respectively. Both before and after adjustment for confounding factors, compared with non-drinkers (n = 843), past drinkers (n = 241), but not the current light-to-moderate (n = 241) or heavy drinkers (n = 377), had a higher risk of all-cause (adjusted hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.35-2.68, P = 0.0003) and non-cardiovascular mortality (HR 2.46, 95% CI 1.55-3.91, P = 0.0001). Similar trends were observed for cardiovascular mortality (HR 1.44, 95% CI 0.85-2.44, P = 0.18). In similar unadjusted and adjusted analyses, compared with the current beer/wine drinkers (n = 203), liquor/mix drinkers (n = 142), but not aperitif drinkers (n = 273), had a significantly higher risk of all-cause (HR 3.07, 95% CI 1.39-6.79, P = 0.006), and cardiovascular mortality (HR 10.49, 95% CI 2.00-55.22, P = 0.006). Similar trends were observed for non-cardiovascular mortality (HR 1.94, 95% CI 0.73-5.16, P = 0.18). CONCLUSIONS: Our study showed risks of mortality associated with past drinking and liquor drinking in the elderly Chinese men.

Involvement of the secreted protein Metrnl in human diseases.

Metrnl, a secreted protein expressed in white adipose tissue, has been identified as a novel adipokine. It is also highly expressed in barrier tissues, including the skin, intestinal and respiratory tract epithelium in both mice and humans. Research shows that its expression is upregulated by inflammation, chronic high-fat diets, exercise, cold exposure, etc., and it plays important roles in promoting neurite extension, enhancing white fat browning, improving insulin sensitivity, modulating lipid metabolism and regulating inflammatory response, the latter implying Metrnl is a new cytokine. These studies suggest that Metrnl could be a promising biomarker and a potential therapeutic target for the related diseases. For proving this, clinical studies need to be performed to bridge the gap between bench and bedside. In this paper, we summarize the progress in recent clinical research on Metrnl. Most of these clinical studies are designed to confirm the relationship between circulating Metrnl and metabolic or cardiovascular disease (type 2 diabetes and coronary heart disease), or immune inflammation-related diseases, such as colitis, psoriasis and arthritis. Although blood Metrnl seems to fluctuate and are affected by many factors, such as drugs, physical exercise, and cold exposure, these clinical studies provide reliable clues that Metrnl is associated with coronary heart disease, inflammation-related diseases, etc. Nevertheless, the roles of Metrnl in some diseases such as nervous system diseases remain unclear, and its putative involvement should be further clarified. These studies could promote the application of Metrnl in clinic as a new therapeutic target.

Metrnl deficiency decreases blood HDL cholesterol and increases blood triglyceride.

Dyslipidemia is a risk factor for cardiovascular diseases and type 2 diabetes. Several adipokines play important roles in modulation of blood lipids. Metrnl is a recently identified adipokine, and adipose Metrnl participates in regulation of blood triglyceride (TG). In this study, we generated Metrnl global, intestine-specific and liver-specific knockout mice, and explored the effects of Metrnl on serum lipid parameters. Global knockout of Metrnl had no effects on serum lipid parameters under normal chow diet, but increased blood TG by 14%, and decreased total cholesterol (TC) by 16% and high density lipoprotein cholesterol (HDL-C) by 24% under high fat diet. Nevertheless, intestine-specific knockout of Metrnl did not alter the serum lipids parameters under normal chow diet or high fat diet. Notably, liver-specific knockout of Metrnl decreased HDL-C by 24%, TC by 20% and low density lipoprotein cholesterol (LDL-C) by 16% without alterations of blood TG and nonesterified fatty acids (NEFA) under high fat diet. But deficiency of Metrnl in liver did not change VLDL secretion and expression of lipid synthetic and metabolic genes. We conclude that tissue-specific Metrnl controls different components of blood lipids. In addition to modulation of blood TG by adipose Metrnl, blood HDL-C is regulated by liver Metrnl.

Aggravated ulcerative colitis caused by intestinal Metrnl deficiency is associated with reduced autophagy in epithelial cells.

Metrnl is a newly identified secreted protein highly expressed in the intestinal epithelium. This study aimed to explore the role and mechanism of intestinal epithelial Metrnl in ulcerative colitis. Metrnl-/- (intestinal epithelial cell-specific Metrnl knockout) mice did not display any phenotypes of colitis under basal conditions. However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl-/- mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. DSS-induced colitis activated autophagy in the colon. This activation was partially inhibited by intestinal epithelial Metrnl deficiency, as indicated by a decrease in Beclin-1 and LC3-II/I and an increase in p62 in DSS-treated Metrnl-/- mice compared with WT mice. These phenomena were further confirmed by observation of autophagosomes and immunofluorescence staining for LC3 in epithelial cells. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl-/- mice compared with WT mice. Therefore, Metrnl deficiency deteriorated ulcerative colitis at least partially through inhibition of autophagy via the AMPK-mTOR-p70S6K pathway, suggesting that Metrnl is a therapeutic target for ulcerative colitis.

Nicotinamide phosphoribosyltransferase aggravates inflammation and promotes atherosclerosis in ApoE knockout mice.

Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme of nicotinamide adenine dinucleotide (NAD) salvage biosynthesis in mammals, and is involved in fundamental physiological processes and pathophysiology of many diseases. Thus far, however, the role of Nampt in atherosclerosis development is still in debate. In this study, we crossed global Nampt transgenic mice (Nampt-Tg) with a well-established atherosclerosis animal model (ApoE knockout mice, ApoE-/-) to generate ApoE-/-;Nampt-Tg mice and investigated the effects of Nampt overexpression on atherosclerosis development in ApoE-/- mice. Both ApoE-/- and ApoE-/-;Nampt-Tg mice were fed with a pro-atherosclerotic high-fat diet (HFD) for 16 weeks. Their serum lipid contents and atherosclerotic lesion were assessed. The results showed that there was no significant difference in body weight or serum levels of glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol between the two strains of mice, but ApoE-/-;Nampt-Tg mice had a significantly higher level of serum non-esterified fatty acid. Compared with ApoE-/- mice, ApoE-/-;Nampt-Tg mice displayed significantly increased atherosclerotic lesion area and thickness, lower collagen content, decreased collagen I/III ratio (collagen immaturation), increased number of apoptotic cells, and enhanced activities of caspase-3, caspase-8, and caspase-9. Moreover, macrophage infiltration (F4/80 staining), tumor necrosis factor signaling, and chemokines expression (ICAM-1 and CXCR-4) were all activated in aortic atherosclerotic plaque of ApoE-/-;Nampt-Tg mice compared with ApoE-/- mice. Our results provide in vivo evidence that Nampt transgene aggravates atherosclerotic inflammation and promotes atherosclerosis development in ApoE-/- mice.

Hand-spinning chrysotile exposure and risk of malignant mesothelioma: A case-control study in Southeastern China.

While chrysotile has been commonly used by Chinese textile industry for many years, investigations on the association of chrysotile exposure with risk of mesothelioma in China are scarce. We conducted a case-control study in a county located at Southeastern China, including 46 cases and 230 individually matched controls. A semi-quantitative method based on experts' assessment was used for evaluating hand-spinning chrysotile exposure. Conditional logistic regression models were used to assess the association of asbestos exposure with risk of mesothelioma. We found that hand-spinning chrysotile exposure was associated with significantly elevated risk of mesothelioma, reaching OR =10 (95% CIs: 1.4-65) for possible exposure and 64 (12-328) for definite exposure. Our data suggested a dose-response relationship of chrysotile exposure duration with risk of mesothelioma, reaching 28 (6-134) for <6 years, 51 (11-247) for 7-17 years and 56 (9-351) for ≥18 years. A dose-response relationship of cumulative exposure index (CEI) with risk of mesothelioma was found, reaching 28 (6-137) for CEI at 0-0.5 fibers per milliliter years (f/mL-year), 36 (7-184) for CEI at 0.5-28.6 f/mL-years and 79 (14-451) for CEI > 28.6 f/mL-years. We found a dose-response relationship of chrysotile exposure duration and CEI with risk of mesothelioma in Southeastern China, adding valuable information on health hazards of chrysotile exposure in China where chrysotile is still used nationwide.

Crystal structure-based comparison of two NAMPT inhibitors.

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a novel strategy for cancer therapy, but only two inhibitors of NAMPT (FK866 and CHS828) have progressed into clinical trials. This study seeks to compare a novel potent NAMPT inhibitor, MS0, with a classical inhibitor FK866 in their biological activity and molecular binding mode, thereby contributing to future chemical optimization and a further understanding of the action mode of NAMPT inhibitors. The IC50 values of MS0 and FK866 in inhibition of recombinant human NAMPT activity were 9.08±0.90 and 1.60±0.32 nmol/L, respectively. Consistently, FK866 exerted better antiproliferation in 6 human cancer cell lines (HepG2, A2780, 95-D, A549, U2OS and U266) than MS0 with IC50 values nearly 12-fold to 225-fold lower than those of MS0. Co-crystal structures of wild-type human NAMPT complexed with MS0 or FK866 were elucidated, which revealed that MS0 did not interact with Ser241. The hydrogen bond mediated by crystallographic water between MS0 and His191 or Val350 of NAMPT did not exist in FK866. Instead, FK866 exhibited hydrophobic interactions with Arg349. Based on the activity assays and crystal structure analyses, we elaborate the reason why the antiproliferation activity of MS0 was not as good as that of FK866, which would contributes to the current understanding of the mode of action of NAMPT inhibitors and will also contribute to further development of anticancer drugs in the future.

Evaluation of Two Commercial Enzyme-Linked Immunosorbent Assay Kits for the Detection of Human Circulating Metrnl.

Metrnl is a newly discovered secreted protein with neurotrophic activity and metabolic effect, while in earlier studies its circulating level in human was not explored. We evaluated two commercial enzyme-linked immunosorbent assay kits (DY7867-05, R&D Systems and SK00478-02, Aviscera Bioscience) for the detection of human circulating Metrnl. The DY7867-05 kit showed superiority over the SK00478-02 kit since it generated better curve fitting degree, smaller variation among tests, higher inter-assay reproducibility and better specificity, and could effectively detect human Metrnl in six types of blood samples. Subsequent analysis was performed using the DY7867-05 kit. Sample storage conditions were investigated. No gender difference in circulating Metrnl levels was found, while people with newly diagnosed type 2 diabetes mellitus (T2DM) had significantly lower Metrnl levels compared to the healthy controls.

Pituitary gland and bone involvement of Langerhans cell histiocytosis in a boy and brief review of the literature.

A 3 years old boy was hospitalized with a month's history of polydipsia, polyuria and low fever. There was no relevant family history. This is a rare case of Langerhans cell histiocytosis (LCH) with both bone and pituitary infiltration shown on the technetium-99m methylene diphosphonate (99mTc-MDP) scan and brain magnetic resonance imaging (MRI). Sagittal and coronal T1-weighted images on MRI showed the typical lack of high signal intensity of the posterior pituitary which corresponded to the central signs of diabetes insipidus (DI). The diagnosis of LCH was suspected by 99mTc-MDP whole-body bone scan showing multiple bone lesions. The disease was further confirmed by pathology of the biopsy specimen from the right tibia. Brain MRI and bone scan are indicated for pediatric patients with DI. The high signal intensity of the posterior pituitary on MRI and the bone lytic lesions on scintigraphy suggested the diagnosis of LCH. This paper is original because it is the first full description of bone and pituitary involvement detected by bone scan and brain MRI in a pediatric LCH.

Polymorphisms at microRNA binding sites of Ara-C and anthracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients.

BACKGROUND: Gene polymorphisms at microRNA-binding sites (poly-miRTS) may affect gene transcription and expression through miRNA regulation, which is associated with cancer susceptibility, sensitivity to chemotherapy and prognosis. This study investigated the association between poly-miRTS of Ara-C/anthracycline metabolic pathways genes and the outcome of acute myeloid leukemia (AML) in Chinese patients after Ara-C-based chemotherapy. METHODS: A total of 17 poly-miRTS were selected from the SNPinfo Web Server and genotyped in 206 Chinese Han non-FAB-M3 AML patients using the SEQUENOM Mass-ARRAY system. RESULTS: Among these 17 poly-miRTS, five Ara-C metabolic gene single nucleotide polymorphisms (SNPs, NT5C2 rs10786736 and rs8139, SLC29A1 rs3734703, DCTD rs7278, and RRM1 rs1042919) were identified to significantly associate with complete AML remission and/or overall and relapse-free survival (OS and RFS, respectively), and four anthracycline-metabolic gene SNPs (ABCC1 rs3743527, rs212091, and rs212090 and CBR1 rs9024) were significantly associated with chemotherapy-related toxicities. Moreover, SLC29A1 rs3734703 was shown to associate with both chemotherapy response and survival (adjusted OR 2.561 in the overdominant model; adjusted HR 2.876 for OS and 2.357 for RFS in the dominant model). CONCLUSIONS: The data from the current study demonstrated that the poly-miRTS of Ara-C/anthracyclines metabolic genes predicted the sensitivity and side effects of AML to Ara-C-based chemotherapy and patient survival. Further study will confirm them as biomarkers for AML patients after Ara-C-based chemotherapy.