Highlights • CP−/− mice and mice that received FAC had high levels of brain iron. • Brain iron accumulation exacerbated TH-positive neurons apoptosis in MPTP-treated mice. • DFO reduced the neuronal ...damage in MPTP-treated CP−/− mice. • Increased oxidative stress was involved in cell apoptosis exacerbated by the increased brain iron.
Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is ...unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A
TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1
) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10
macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10
M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1
myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1
myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1
myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic niche formation and metastasis, and may serve as a potential therapeutic target in human cancer.
Summary
Background
Patients with nonalcoholic steatohepatitis (NASH) have gut dysbiosis and intestinal bacterial overgrowth.
Aim
To test the hypothesis that endotoxemia is associated with the ...histological severity of nonalcoholic fatty liver disease (NAFLD) and determine factors associated with endotoxemia.
Methods
The endotoxemia markers lipopolysaccharide‐binding protein (LBP) and endotoxin levels were measured in 237 NAFLD patients 1 day before liver biopsy. Biomarkers of liver injury and transient elastography were performed as additional markers of disease severity.
Results
A total of 114/237 (48%) patients had NASH and 80/237 (34%) had F2‐4 fibrosis. LBP was correlated with lobular inflammation (P=.001), while both LBP (P=.0004) and endotoxin levels (P=0.008) were correlated with fibrosis. LBP was also correlated with cytokeratin‐18 fragments (P=.002) and aspartate aminotransferase‐to‐alanine aminotransferase ratio (P=.006), and both LBP (P=.019) and endotoxin (P=.006) were correlated with liver stiffness measurement by transient elastography. LBP was increased in patients with NASH (15.3±4.6 vs 13.8±3.3 μg/mL; P=.005) and F2‐4 fibrosis (15.4±4.4 vs 14.0±3.7 μg/mL; P=.008). Interestingly, patients harbouring the TM6SF2 rs58542926 T allele that predispose to NAFLD/NASH had higher LBP level. By multivariate analysis, gender, higher body mass index and glycated haemoglobin, and TM6SF2 variants were independent factors associated with increased LBP level.
Conclusions
Endotoxemia is positively associated with NASH and significant fibrosis. The association between TM6SF2 and endotoxemia warrants further investigations. The findings may shed light on the pathogenesis of NASH and inform a novel treatment target.
Linked ContentThis article is linked to Valenti and Romeo paper. To view this article visit https://doi.org/10.1111/apt.14154.
MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid ...leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
Summary
Background
Metabolic syndrome is a known risk factor of cirrhosis in chronic hepatitis B (CHB).
Aim
To investigate the effects of coincidental metabolic syndrome on liver fibrosis progression ...in treatment‐naïve CHB patients.
Methods
A total of 1466 CHB patients underwent liver stiffness measurement (LSM) by transient elastography in 2006–2008; 663 patients remained treatment‐naïve and had second LSM in 2010–2012. Liver fibrosis progression was defined as an increase in LSM ≥30% at the second assessment. The impact of coincidental metabolic syndrome and its factors on liver fibrosis progression were evaluated after adjustment for viral load and hepatitis activity.
Results
At baseline, the mean age was 43 ± 12 years, 55% were males, serum alanine aminotransferase (ALT) was 44 ± 40 IU/L, HBV DNA was 4.0 ± 2.0 log IU/mL and LSM was 6.3 ± 3.6 kPa. Metabolic syndrome was diagnosed in 80 (12%) and 142 (21%) patients at baseline and follow‐up visit, respectively; 84 (13%) and 22 (3%) patients had coincidental and resolved metabolic syndrome respectively. After an interval of 44 ± 7 months, 107 (16%) patients developed liver fibrosis progression. Coincidental metabolic syndrome adjusted odds ratio (aOR) 2.0, 95% confidence interval (CI) 1.1–3.5, P = 0.015, central obesity (aOR 2.0, 95% CI 1.0–4.1, P = 0.05) and low level of high‐density lipoprotein cholesterol (aOR 1.9, 95% CI 1.0–3.7, P = 0.04) were associated with liver fibrosis progression independent of change in viral load and ALT level. The effects of coincidental metabolic syndrome were most apparent in the immune‐tolerant phase.
Conclusion
Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B infection, independent of viral load and hepatitis activity.
Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% ...of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome.
We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls.
Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans.
HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).
We report the first experimental demonstration of quantum entanglement among ten spatially separated single photons. A near-optimal entangled photon-pair source was developed with simultaneously a ...source brightness of ∼12 MHz/W, a collection efficiency of ∼70%, and an indistinguishability of ∼91% between independent photons, which was used for a step-by-step engineering of multiphoton entanglement. Under a pump power of 0.57 W, the ten-photon count rate was increased by about 2 orders of magnitude compared to previous experiments, while maintaining a state fidelity sufficiently high for proving the genuine ten-particle entanglement. Our work created a state-of-the-art platform for multiphoton experiments, and enabled technologies for challenging optical quantum information tasks, such as the realization of Shor's error correction code and high-efficiency scattershot boson sampling.
With the aim of gathering temporal trends on bacterial epidemiology and resistance from multiple laboratories in China, the CHINET surveillance system was organized in 2005. Antimicrobial ...susceptibility testing was carried out according to a unified protocol using the Kirby-Bauer method or automated systems. Results were analyzed according to Clinical and Laboratory Standards Institute (CLSI) 2014 definitions. Between 2005 and 2014, the number of bacterial isolates ranged between 22 774 and 84 572 annually. Rates of extended-spectrum β-lactamase production among Escherichia coli isolates were stable, between 51.7 and 55.8%. Resistance of E. coli and Klebsiella pneumoniae to amikacin, ciprofloxacin, piperacillin/tazobactam and cefoperazone/sulbactam decreased with time. Carbapenem resistance among K. pneumoniae isolates increased from 2.4 to 13.4%. Resistance of Pseudomonas aeruginosa strains against all of antimicrobial agents tested including imipenem and meropenem decreased with time. On the contrary, resistance of Acinetobacter baumannii strains to carbapenems increased from 31 to 66.7%. A marked decrease of methicillin resistance from 69% in 2005 to 44.6% in 2014 was observed for Staphylococcus aureus. Carbapenem resistance rates in K. pneumoniae and A. baumannii in China are high. Our results indicate the importance of bacterial surveillance studies.
We report a measurement of electron antineutrino oscillation from the Daya Bay Reactor Neutrino Experiment with nearly 4 million reactor νover ¯_{e} inverse β decay candidates observed over 1958 days ...of data collection. The installation of a flash analog-to-digital converter readout system and a special calibration campaign using different source enclosures reduce uncertainties in the absolute energy calibration to less than 0.5% for visible energies larger than 2 MeV. The uncertainty in the cosmogenic ^{9}Li and ^{8}He background is reduced from 45% to 30% in the near detectors. A detailed investigation of the spent nuclear fuel history improves its uncertainty from 100% to 30%. Analysis of the relative νover ¯_{e} rates and energy spectra among detectors yields sin^{2}2θ_{13}=0.0856±0.0029 and Δm_{32}^{2}=(2.471_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the normal hierarchy, and Δm_{32}^{2}=-(2.575_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the inverted hierarchy.
The present study was conducted to compare the differences in gut microbiota composition and gut-phenotypes among pig breeds, and determine whether these differences would transmit to mice colonized ...with fecal microbiota of different pig breeds. A total of 24 1-day-old germ-free BALB/C mice were divided into 3 groups (TFM, YFM and RFM), which were transplanted with intact fecal microbiota of Tibetan pig (TP), Yorkshire pig (YP) and Rongchang pig (RP), respectively.
Results showed that different pig breeds exhibited distinct gut microbiota profile based on high-throughput pyrosequencing. YP exhibited a lower Firmicutes/Bacteroidetes ratio and apparent genera differences compared with RP and TP, and higher levels of bacteria from Spirochaetes were observed in TP compared with RP and YP (P < 0.05). Transplanted porcine microbiota into GF mice replicated the phenotypes of pig donors. Moreover, the three groups of donor pigs and their mice recipients exhibited different intestinal index and morphology. TP and RP had higher intestinal weight and relative CDX2 mRNA expression in ileum than YP, and longer intestine, higher villus height of duodenum and jejunum were observed in TP compared with YP and RP (P < 0.05). TP exhibited higher GLP-2 mRNA expression in duodenum and jejunum than RP (P < 0.05). Similarly, YFM had lower intestine weight and CDX2 mRNA expression in ileum than TFM and RFM (P < 0.05). The intestine length in TFM was longer than that in RFM, and TFM had higher villus height in duodenum and jejunum and GLP-2 mRNA expression in ileum than the other two groups (P < 0.05). Besides, the digestive and absorptive ability was different among the three groups in donor pigs and mice recipients. YP had higher jejunal lactase and maltase activities than TP and RP, while TP had higher activities of jejunal ATPase, γ-GT, and relative SGLT1 mRNA expression in duodenum and jejunum than YP and RP (P < 0.05). Likewise, YFM had higher jejunal sucrase and maltase activities than TFM and RFM, whereas higher jejunal γ-GT activity and relative SGLT1 mRNA expression in duodenum and ileum were observed in TFM compared with YFM and RFM (P < 0.05). In addition, Tibetan pigs-derived microbiota improved gut barrier in mice recipients. The concentration of MDA in YP was higher than that in TP and RP (P = 0.078), and the relative ZO-1 mRNA expression in ileum in TP was higher than that in YP (P < 0.05). Likely, compared with TFM and RFM, YFM exhibited increasing MDA concentration in jejunum (P = 0.098), and the relative ZO-1 mRNA expression in duodenum and ileum in TFM were higher than that in YFM (P < 0.05).
There were huge differences in gut microbiota composition and gut characteristics among pig breeds, and gut microbiota could partially convey host gut characteristics from pigs to mice.
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