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1.
ACS Nano ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33818058

RESUMO

The highest quality hexagonal boron nitride (hBN) crystals are grown from molten solutions. For hBN crystal growth at atmospheric pressure, typically the solvent is a combination of two metals, one with a high boron solubility and the other to promote nitrogen solubility. In this study, we demonstrate that high-quality hBN crystals can be grown at atmospheric pressure using pure iron as a flux. The ability to produce excellent-quality hBN crystals using pure iron as a solvent is unexpected, given its low solubility for nitrogen. The properties of crystals produced with this flux matched the best values ever reported for hBN: a narrow Raman E2g vibration peak (7.6 cm-1) and strong phonon-assisted peaks in the photoluminescence spectra. To further test their quality, the hBN crytals were used as a substrate for WSe2 epitaxy. WSe2 was deposited with a low nucleation density, indicating the low defect density of the hBN. Lastly, the carrier tunneling through our hBN thin layers (3.5 nm) follows the Fowler-Nordheim model, with a barrier height of 3.7 eV, demonstrating hBN's superior electrical insulating properties. This ability to produce high-quality hBN crystals in such a simple, environmentally friendly and economical process will advance two-dimensional material research by enabling integrated devices.

2.
Nanomaterials (Basel) ; 11(3)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809781

RESUMO

Perovskite solar cells have exhibited astonishing photoelectric conversion efficiency and have shown a promising future owing to the tunable content and outstanding optoelectrical property of hybrid perovskite. However, the devices with planar architecture still suffer from huge Voc loss and severe hysteresis effect. In this research, Guanidine hydrobromide (GABr) post-treatment is carried out to enhance the performance of MAPbI3 n-i-p planar perovskite solar cells. The detailed characterization of perovskite suggests that GABr post-treatment results in a smoother absorber layer, an obvious reduction of trap states and optimized energy level alignment. By utilizing GABr post-treatment, the Voc loss is reduced, and the hysteresis effect is alleviated effectively in MAPbI3 solar cells. As a result, solar cells based on glass substrate with efficiency exceeding 20%, Voc of 1.13 V and significantly mitigated hysteresis are fabricated successfully. Significantly, we also demonstrate the effectiveness of GABr post-treatment in flexible device, whose efficiency is enhanced from 15.77% to 17.57% mainly due to the elimination of Voc loss.

3.
Cancer Res ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795251

RESUMO

New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival, but no persistent tumor control was observed. Despite lower response rates, MSLN-4-1BB (MBBz) CAR T cells induced long-term remission in some SKOV-3-bearing mice. Tumor-infiltrating M28z and MBBz CAR T cells upregulated PD-1 and LAG-3 in an antigen-dependent manner while MSLN+ tumor cells expressed the corresponding ligands (PD-L1 and HLA-DR), demonstrating the co-inhibitory pathways impede CAR T cell persistence in the ovarian tumor microenvironment. Furthermore, profiling plasma soluble factors identified a cluster of M28z and MBBz-treated mice characterized by elevated T cell secreted factors that had increased survival, higher CD8+ T cell tumor infiltration, less exhausted CAR T cell phenotypes, and increased HLA-DR expression by tumor cells. Altogether, our study demonstrates the therapeutic potential of MSLN-CAR T cells to treat ovarian cancer.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33876551

RESUMO

The first all-amidinate-protected gold nanocluster [Au28(Ph-form)12](OTf)2 (Ph-form = N,N'-Diphenylformamidine) ( Au28 ) has been synthesized and structurally resolved. Single crystal X-ray diffraction reveals that Au28 has a compact Au4@Au24 tetrahedral core-shell structure of T symmetry, which is fully protected by 12 bridging formamidinate ligands. This cluster is quite robust as indicated by the fact that it can stay intact in solution at 80 °C for 6 d. It exhibits excellent catalytic performance for the electroreduction of CO2 with 96.5% Faradaic efficiency (FE) at -0.57 V and a maximum TOF of 48492 h-1 at -0.87 V. Its superior stability is also manifested in the fact that the supported catalyst Au28/CNTs maintains stable potentials at ca. -0.69 V for 40 h with FE(CO)s >91%. A superatomic electron configuration of 1S21P62S21D4 has been clarified by DFT computations, and the strong gold-ligand binding and geometric shell closure account for the superior stability of Au28 .

5.
Zhongguo Yi Liao Qi Xie Za Zhi ; 45(2): 153-158, 2021 Apr 08.
Artigo em Chinês | MEDLINE | ID: mdl-33825373

RESUMO

Electronic endoscope is one of the crucial tools for minimally invasive diagnosis and treatment. Along with the continuous development of clinical applications, conventional electronic endoscope has not been able to meet all the clinical requirements. In recent years, with the rapid development of the material, sensor and electronic technologies, electronic endoscope has attracted many researchers and companies' attention. Nowadays, because of being suitable for some special mobile medical scenes like field operations, natural calamities and hospital first aids, various portable electronic endoscopes have been developed and applied in clinic. The present study aims to give a review on portable electronic endoscopes development and clinical applications.


Assuntos
Eletrônica , Endoscópios
6.
Artigo em Inglês | MEDLINE | ID: mdl-33803594

RESUMO

This study explored the relationships between media exposure, cancer beliefs, and cancer information-seeking or information-avoidance behaviors. Based on the planned risk information-seeking model and its extended framework, two predictive models were constructed: one for cancer information seeking and the other for cancer information avoidance. A structural equation modeling strategy was applied to survey data from China HINTS 2017 (n = 3090) to compare the impact of traditional mass media and social media exposure to cancer-related information on cancer information-seeking and information-avoidance behaviors. The study findings suggest that health-related information exposure through different media channels may generate distinctive information-seeking or information-avoidance behaviors based on various cancer beliefs. Additionally, the findings indicate that social media exposure to health-related and cancer curability beliefs does not lead to cancer information avoidance; both mass media and social media exposure encourage people to seek cancer-related information. Cancer fatalism is positively associated with cancer information-seeking and avoiding intentions, suggesting that negative cancer beliefs predict seemingly contradictory yet psychologically coherent information intentions and behaviors.

7.
Proc Natl Acad Sci U S A ; 118(16)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33846258

RESUMO

Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor originally cloned from LPS-activated macrophages, has recently been shown to regulate immune responses under several inflammatory conditions. However, whether CCRL2 influences macrophage function and regulates tumor immunity remains unknown. Here, we found that tumoral CCRL2 expression is a predictive indicator of robust antitumor T-cell responses in human cancers. CCRL2 is selectively expressed in tumor-associated macrophages (TAM) with immunostimulatory phenotype in humans and mice. Conditioned media from tumor cells could induce CCRL2 expression in macrophages primarily via TLR4, which is negated by immunosuppressive factors. Ccrl2 -/- mice exhibit accelerated melanoma growth and impaired antitumor immunity characterized by significant reductions in immunostimulatory macrophages and T-cell responses in tumor. Depletion of CD8+ T cells or macrophages eliminates the difference in tumor growth between WT and Ccrl2 -/- mice. Moreover, CCRL2 deficiency impairs immunogenic activation of macrophages, resulting in attenuated antitumor T-cell responses and aggravated tumor growth in a coinjection tumor model. Mechanically, CCRL2 interacts with TLR4 on the cell surface to retain membrane TLR4 expression and further enhance its downstream Myd88-NF-κB inflammatory signaling in macrophages. Similarly, Tlr4 -/- mice exhibit reduced CCRL2 expression in TAM and accelerated melanoma growth. Collectively, our study reveals a functional role of CCRL2 in activating immunostimulatory macrophages, thereby potentiating antitumor T-cell response and tumor rejection, and suggests CCLR2 as a potential biomarker candidate and therapeutic target for cancer immunotherapy.

8.
Vascul Pharmacol ; : 106860, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33794383

RESUMO

5-Hydroxytryptamine (5-HT)-dependent signaling mediated through its transporters and receptors plays important roles in chronic hypoxic pulmonary hypertension (CHPH), which is associated with aberrant reactive oxygen species (ROS) production. NADPH oxidase 4 (NOX4) is one of the major sources of ROS in pulmonary vasculature, and has been implicated in the development of PH. NOX4 generates H2O2, which can activate the transient receptor potential melastatin 2 (TRPM2) channels, providing Ca2+ signals for cell proliferation and migration. However, the connection between 5-HT, NOX4, ROS and TRPM2 in the context of PH has not been established. Here we examined the level of 5-HT and expression of NOX4 and TRPM2, and their roles in pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration. NOX4 and TRPM2 were upregulated in pulmonary arteries of CHPH rats, which were associated with elevated levels of 5-HT and ROS, and enhanced proliferation and migration in PASMCs. The increase in ROS, and the enhanced proliferation and migration of PASMCs from CHPH rats were mimicked by treating normoxic PASMCs with 5-HT. 5-HT; and CH-induced ROS production were reversed by catalase, the NOX1/NOX4 inhibitor GKT137831, and Nox4 siRNA. 5-HT and H2O2 elicited Ca2+ responses were significantly augmented in CHPH PASMCs; and the augmented Ca2+ responses were obliterated by the 2-Aminoethoxydiphenyl borate (2-APB) and Trpm2-specific siRNA. Moreover, 5-HT and CH-induced proliferation and migration were suppressed by Nox4 or Trpm2 siRNA; and simultaneous transfection of both siRNA did not cause further inhibition. These results suggest that the 5-HT and CH-induced PASMC proliferation and migration were mediated, at least in part, by TRPM2 via activation of NOX4-dependent ROS production; and revealed a novel NOX4-ROS-TRPM2 signaling pathway for the pathogenesis of CHPH.

9.
J Biomater Sci Polym Ed ; : 1-14, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33685369

RESUMO

Pullulan hydrogels are widely used in tissue engineering and drug delivery. However, these hydrogels do not meet the requirements of articular cartilage repair because of their fast degradation rate and poor mechanical strength. Herein, we fabricated a hybrid hydrogel system by combining pullulan with synthetic polymers polyethylene (glycol) diacrylate (PEGDA). In this study, pullulan was modified with methacrylic anhydride (MA) to obtain photo-crosslinkable methacrylated pullulan (PulMA). Moreover, the lithium phenyl(2,4,6-trimethylbenzoyl)phosphinate (LAP) was used as a water-soluble UV photoinitiator to form the PulMA/PEGDA hydrogel by photopolymerization strategy. Compared with the pure PulMA hydrogel, the increase of PEGDA concentration led to a slower degradation rate and an increase of residual mass from 63.9% to 86.8%. There was about 8-fold increase in storage modulus (G') (reach to 16.0 × 103 Pa) and 13-fold increase in compressive modulus (reach to 1.17 ± 0.17 MPa) with increasing the concentration of PEGDA to 15% (w/v) in the hydrogel. In cell culture in vitro, the rabbit's mesenchymal stem cells (MSCs) encapsulated in the PulMA/PEGDA hydrogel could adhere and proliferate, indicating that the PulMA/PEGDA hydrogel had a good biocompatibility. Furthermore, the hydrogels supported glycosaminoglycan (GAG) synthesis, and chondrogenic phenotype of MSCs with TGF-ß3-containing chondrogenic medium. This study demonstrated that the photo-crosslinking PulMA/PEGDA hydrogels, with good mechanical properties and slow degradation rate are promising scaffolds for cartilage repair and regeneration.

10.
Cancer Control ; 28: 1073274821997426, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33626920

RESUMO

PURPOSE: Although breast conservation surgery(BCS) followed by adjuvant radiotherapy is now the mainstream treatment method for breast ductal carcinoma in situ(DCIS), mastectomy is still performed in some patients who refuse to undergo radiation. However, the most effective treatment method for these patients is still unknown. In the current study, we aimed to compare the survival rates between mastectomy and BCS plus adjuvant radiotherapy in patients with DCIS. MATERIALS AND METHODS: We performed a retrospective study of 333 patients with DCIS from May 2004 to December 2016. There were 209 patents who were treated with BCS and adjuvant radiotherapy, while the remaining of 124 patients underwent mastectomy. The disease-free survival (DFS) and local recurrence-free survival(LRFS) rates were compared between the 2 treatment groups. Cox proportional hazards regression was performed to explore factors associated with DFS and LRFS. RESULTS: The 10-year local recurrence(LR) rates in the mastectomy and BCS plus adjuvant radiotherapy groups were 2.6% and 7.5%, respectively. There was no difference in the LR rate between the 2 groups. Furthermore the DFS rate was also similar between the mastectomy and BCS plus adjuvant radiotherapy groups. Based on the multivariable analysis, age and tumor grade were significantly correlated with the LRFS and DFS rates. In the subgroup analysis based on the factors of age and tumor grade, patients with a tumor grade of III who underwent mastectomy had better LRFS and DFS rates compared to those who received BCS plus radiotherapy. CONCLUSION: In patients with DCIS, the long-term efficacy was similar between mastectomy and BCS followed by adjuvant radiotherapy. However, in the subgroup of patients with grade III tumors, mastectomy seems to offer a better LRFS and DFS than BCS plus radiotherapy.

11.
Invest Ophthalmol Vis Sci ; 62(2): 35, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33620373

RESUMO

Purpose: To investigate environmental factors associated with corneal morphologic changes. Methods: A cross-sectional study was conducted, which enrolled adults of the Han ethnicity aged 18 to 44 years from 20 cities. The cornea-related morphology was measured using an ocular anterior segment analysis system. The geographic indexes of each city and meteorological indexes of daily city-level data from the past 40 years (1980-2019) were obtained. Correlation analyses at the city level and multilevel model analyses at the eye level were performed. Results: In total, 114,067 eyes were used for analysis. In the correlation analyses at the city level, the corneal thickness was positively correlated with the mean values of precipitation (highest r [correlation coefficient]: >0.700), temperature, and relative humidity (RH), as well as the amount of annual variation in precipitation (r: 0.548 to 0.721), and negatively correlated with the mean daily difference in the temperature (DIF T), duration of sunshine, and variance in RH (r: -0.694 to 0.495). In contrast, the anterior chamber (AC) volume was negatively correlated with the mean values of precipitation, temperature, RH, and the amount of annual variation in precipitation (r: -0.672 to -0.448), and positively associated with the mean DIF T (r = 0.570) and variance in temperature (r = 0.507). In total 19,988 eyes were analyzed at the eye level. After adjusting for age, precipitation was the major explanatory factor among the environmental factors for the variability in corneal thickness and AC volume. Conclusions: Individuals who were raised in warm and wet environments had thicker corneas and smaller AC volumes than those from cold and dry ambient environments. Our findings demonstrate the role of local environmental factors in corneal-related morphology.

12.
J Clin Apher ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33587767

RESUMO

BACKGROUND: Since early 2020, convalescent plasma has been widely used for treating coronavirus disease 2019 (COVID-19). There is limited information regarding donor tolerability of convalescent plasma donation. In this study, we evaluated the short-term donor tolerability of convalescent plasma donation. METHODS: A prospective study of 309 convalescent plasma donation related adverse events were conducted at Wuhan Blood Center of China, from February 12 to April 1, 2020. Additionally, up to 28-day post-donation follow-ups were performed on the donors. RESULTS: Sixteen (5.2%) adverse events were reported in 309 donations. All of these were mild vasovagal without loss of consciousness. The frequency of adverse reactions was higher in donors with a per donation volume of >8 mL/kg body weight or ≥ 600 mL, <100 mm Hg in pre-donation systolic blood pressure, or less than 28 days from the onset of COVID-19 symptoms. There was no correlation to donation history, weight, sex, ABO blood type, pre-donation diastolic blood pressure, pulse, or hemoglobin. CONCLUSION: The donation of convalescent plasma is generally safe. Mitigation of risk factors associated with adverse events can further enhance donor tolerability of convalescent plasma donation.

13.
Org Biomol Chem ; 19(9): 1955-1959, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33599240

RESUMO

We report a stereodivergent Pd/Cu catalyst system that was successfully applied to the asymmetric allylic alkylation of symmetrical 1,3-disubstituted allyl acetates with prochiral imino esters, providing efficient access to enantiopure products bearing vicinal stereocenters in a fully stereodivergent manner. The protocol proceeds smoothly under mild reaction conditions and can accommodate a range of imino esters, delivering the substituted products in high yields and with excellent diastereoselectivities (up to >20 : 1 dr) and enantioselectivities (up to >99% ee).

14.
Sci Total Environ ; 773: 145581, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33582346

RESUMO

The upper elevational range limit of tree species (including treeline and non-treeline species) is generally considered to result from either carbon limitation or sink limitation. Some evidence also suggests that tree line might reflect preferential carbon allocation to NSC storage at the expense of growth. How might the importance of these potential mechanisms be determined? We used an elevational gradient to examine light-saturated photosynthesis (Asat) and NSC concentrations in plant tissues of three different functional types of tree species. We also examined the effects of consecutive 4 years of in situ defoliation on growth and NSCs at the upper elevational range limit. Declining temperature with increasing elevation did not reduce Asat in any of the species. We found NSC increased with elevation in major storage tissues (e.g., roots and twigs) but not in leaves. The defoliation showed that C storage took priority over growth. Such preferential carbon allocation, directly caused by growth decline, always existed in the deciduous tree species. In the evergreen tree species, however, growth decline resulted from preferential carbon allocation to storage was only detected in 2017 and then disappeared as the intensity of defoliation increased. Our results showed that trees prioritized sustaining stores of C more highly than allocation of growth, regardless of the trees' C or sink limitations. At the cold range limits, the prioritized carbon allocation to storage in deciduous tree species was in response to low temperature stress, while in evergreen tree species, the prioritization of carbon allocation was only a transient physiological response to defoliation disturbances.


Assuntos
Carbono , Árvores , Fotossíntese , Folhas de Planta , Temperatura
15.
Nat Commun ; 12(1): 98, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397935

RESUMO

Glucose metabolism and innate immunity evolved side-by-side. It is unclear if and how the two systems interact with each other during hepatitis B virus (HBV) infections and, if so, which mechanisms are involved. Here, we report that HBV activates glycolysis to impede retinoic acid-inducible gene I (RIG-I)-induced interferon production. We demonstrate that HBV sequesters MAVS from RIG-I by forming a ternary complex including hexokinase (HK). Using a series of pharmacological and genetic approaches, we provide in vitro and in vivo evidence indicating that HBV suppresses RLR signaling via lactate dehydrogenase-A-dependent lactate production. Lactate directly binds MAVS preventing its aggregation and mitochondrial localization during HBV infection. Therefore, we show that HK2 and glycolysis-derived lactate have important functions in the immune escape of HBV and that energy metabolism regulates innate immunity during HBV infection.


Assuntos
Vírus da Hepatite B/fisiologia , Imunidade Inata , Metaboloma , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Anaerobiose , Animais , Células Cultivadas , Proteína DEAD-box 58/metabolismo , Glucose/metabolismo , Glicólise , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Evasão da Resposta Imune , Interferons/metabolismo , Ácido Láctico/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Transdução de Sinais , Vírion/metabolismo
16.
BMC Infect Dis ; 21(1): 104, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482756

RESUMO

BACKGROUND: Dengue virus (DENV) infection is increasingly common in southern China and can be transmitted through blood transfusion but is not currently part of donor screening throughout the region. We assessed DENV prevalence among donors at the Xishuangbanna Blood Center, Yunnan, to support development of DENV screening strategies. METHODS: Blood samples were collected randomly between June 2019 and August 2019. These were screened for anti-DENV IgG and IgM using enzyme-linked immunosorbent assay (ELISA). Then, all reactive samples and some randomly-chosen non-reactive samples were used to detect DENV RNAs using real-time polymerase-chain-reaction (RT-PCR) assays. After RT-PCR, samples were further tested for soluble nonstructural protein 1 (NS1) using the colloidal gold method. Donors demographics were also collected and assessed. RESULTS: Over the study period, 2254 donor samples were collected and tested for anti-DENV IgG and IgM by ELISA. This revealed 598 anti-DENV IgG and/or IgM reactive samples, a serological prevalence of 26.53%. Of these, 26 were RT-PCR positive and/or NS1 positive. Significant differences in DENV prevalence were noted by occupation (P = 0.001), education (P < 0.001), and ethnicity (P = 0.026). CONCLUSION: The prevalence of DENV in Xishuangbanna Blood Center was higher than most other blood centers that have implemented DENV donor screening. Our study provides first-hand data about the prevalence of DENV and allows the development of a screening strategy for clinical use.


Assuntos
Doadores de Sangue , Vírus da Dengue/isolamento & purificação , Dengue/diagnóstico , Dengue/epidemiologia , Programas de Rastreamento/métodos , Adulto , Anticorpos Antivirais/sangue , China/epidemiologia , Dengue/sangue , Vírus da Dengue/genética , Vírus da Dengue/imunologia , Feminino , Humanos , Masculino , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Prevalência , RNA Viral/genética , Proteínas não Estruturais Virais/genética , Adulto Jovem
17.
Appl Environ Microbiol ; 87(6)2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33419738

RESUMO

Escherichia coli cells swim in aqueous environment in a random walk of alternating runs and tumbles. The diffusion characteristics of this random walk remains unclear. In this study, by tracking the swimming of wild-type cells in a three-dimensional (3D) homogeneous environment, we found that their trajectories are superdiffusive, consistent with Lévy walk behavior. For comparison, we tracked the swimming of mutant cells that lack the chemotaxis signaling noise (the steady-state fluctuation of the concentration of the chemotaxis response regulator CheY-P) and found that their trajectories are normal diffusive. Therefore, wild-type E. coli cells explore the environment by Lévy walk, which originates from the chemotaxis signaling noise. This Lévy walk pattern enhances their efficiency in environmental exploration.IMPORTANCE E. coli cells explore the environment in a random walk of alternating runs and tumbles. By tracking the 3D trajectories of E. coli cells in an aqueous environment, we found that their trajectories are superdiffusive, with a power-law shape for the distribution of run lengths, which is characteristics of Lévy walk. We further show that this Lévy walk behavior is due to the random fluctuation of the output level of the bacterial chemotaxis pathway, and it enhances the efficiency of the bacteria in exploring the environment.


Assuntos
Quimiotaxia , Escherichia coli/fisiologia , Fenômenos Fisiológicos Bacterianos , Simulação por Computador
18.
Toxicol Sci ; 180(2): 369-382, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33483752

RESUMO

Lead (Pb) is a highly toxic heavy metal that broadly exists in our living environment. Although Pb has been shown to influence the development of immune cells, to date, the impact of Pb on hematopoietic stem cells (HSCs) in the bone marrow (BM) remains unknown. As people are ubiquitously exposed to Pb and HSC are essential for human health, understanding the impact of Pb on HSC is significant for public health. In this study, we found that wild-type B6 mice treated with 1250 ppm Pb, but not 125 ppm Pb via drinking water for 8 weeks had increased quiescence of HSC in the BM. Functional analyses demonstrated that wild-type mice treated with 1250 ppm Pb had increased potential for HSC to repopulate the immune system and engraft to the niche in the BM under a competitive chimeric microenvironment of lethally irradiated recipients. Moreover, we found that Pb-increased quiescence of HSC critically relied on a synergetic action of Pb and interferon γ (IFNγ) on BM-resident macrophages (BM-MΦ), but not a direct action of Pb on HSC. Specifically, in steady state, BM-MΦ promoted HSC proliferation; and upon Pb treatment, IFNγ was induced in the BM, and thereafter Pb in synergism with IFNγ acted on BM-MΦ to cause BM-MΦ to become suppressive for HSC proliferation, thus leading to increased quiescence of HSC. Our study suggests that Pb increased the quiescence of HSC via a synergetic action of Pb and IFNγ on BM-MΦ, which was previously unrecognized toxicity of Pb.

19.
Obesity (Silver Spring) ; 29(2): 327-336, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33342076

RESUMO

OBJECTIVE: Adipose tissue macrophages (ATMs) play critical roles in obesity-associated inflammation that contributes to metabolic dysfunction. Talabostat (TB) exerts some therapeutic effects on tumors and obesity. However, it remains unknown whether the metabolic benefits of TB on obesity is dependent on ATM-mediated adipose inflammation. METHODS: Male C57BL/6J mice were fed a normal chow diet (NCD) or a high-fat diet for 12 weeks, and mice were orally administered TB daily at a low dose (0.5 mg/kg). RESULTS: Administration of TB to mice fed a high-fat diet significantly improved adiposity and obesity-associated metabolic dysfunction, including glucose intolerance and insulin resistance, hyperlipidemia and hepatic steatosis, which were accompanied by increased whole-body energy expenditure. RNA sequencing analysis revealed extensive alterations in the transcriptome profiles associated with lipid metabolism and immune responses in adipose tissue of obese mice. Notably, TB treatment led to a significant reduction in ATM accumulation and a shift of the activation state of ATMs from the proinflammatory M1-like to the anti-inflammatory M2-like phenotype. Moreover, depletion of ATMs significantly abolished the TB-induced metabolic benefits. CONCLUSIONS: Our study demonstrates that TB at a low dose could increase energy expenditure and control ATM-mediated adipose inflammation in obese mice, thereby alleviating obesity and its associated metabolic dysfunction.

20.
Clin Immunol ; 223: 108659, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33352294

RESUMO

Endoplasmic reticulum (ER) stress results in the activation of the unfolded protein response (UPR), a process that is involved in the pathogenesis of many inflammatory diseases. However, the role of ER stress in chronic rhinosinusitis with nasal polyps (CRSwNP) has yet to be elucidated. In this study, we found that the protein expression levels of a range of ER stress regulators, including p-PERK, ATF4, ATF6 and XBP1s, were significantly increased in CRSwNP compared to controls. Importantly, the expression of ATF4 and XBP1s was positively correlated with heightened inflammation in CRSwNP. In human nasal epithelial cells, the ER stress inducer tunicamycin (TM) could potentiate Toll-like receptors (TLRs) induced proinflammatory cytokines production. Furthermore, we found that the silencing of XBP1, but not ATF4 or ATF6, abrogated the proinflammatory effect of TM. Mechanistically, ER stress did not affect the NF-κB, MAPK or IRF3 signaling pathways. However, the ER stress regulator XBP1s was able to bind directly to the promoter region of inflammatory genes to modulate gene transcription. Besides, the commensal bacteria Staphylococcus aureus and several inflammatory factors, such as IL4, IL13, IL17 and IFNγ, could induce ER stress in epithelial cells. Collectively, ER stress plays a crucial role in facilitating TLR-induced inflammation. Targeting XBP1 can inhibit the inflammatory response, thus offering a potential approach to treat CRSwNP.

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