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1.
Nat Cell Biol ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32367048

RESUMO

How transplanted haematopoietic stem cells (HSCs) behave soon after they reside in a preconditioned host has not been studied due to technical limitations. Here, using single-cell RNA sequencing, we first obtained the transcriptome-based classifications of 28 haematopoietic cell types. We then applied them in conjunction with functional assays to track the dynamic changes of immunophenotypically purified HSCs in irradiated recipients within the first week after transplantation. Based on our transcriptional classifications, most homed HSCs in bone marrow and spleen became multipotent progenitors and, occasionally, some HSCs gave rise to megakaryocytic-erythroid or myeloid precursors. Parallel in vitro and in vivo functional experiments supported the paradigm of robust differentiation without substantial HSC expansion during the first week. Therefore, this study uncovers the previously inaccessible kinetics and fate choices of transplanted HSCs in myeloablated recipients at early stage, with implications for clinical applications of HSCs and other stem cells.

2.
Nat Microbiol ; 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393858

RESUMO

Plant pathogenic bacteria cause high crop and economic losses to human societies1-3. Infections by such pathogens are challenging to control as they often arise through complex interactions between plants, pathogens and the plant microbiome4,5. Experimental studies of this natural ecosystem at the microbiome-wide scale are rare, and consequently we have a poor understanding of how the taxonomic and functional microbiome composition and the resulting ecological interactions affect pathogen growth and disease outbreak. Here, we combine DNA-based soil microbiome analysis with in vitro and in planta bioassays to show that competition for iron via secreted siderophore molecules is a good predictor of microbe-pathogen interactions and plant protection. We examined the ability of 2,150 individual bacterial members of 80 rhizosphere microbiomes, covering all major phylogenetic lineages, to suppress the bacterium Ralstonia solanacearum, a global phytopathogen capable of infecting various crops6,7. We found that secreted siderophores altered microbiome-pathogen interactions from complete pathogen suppression to strong facilitation. Rhizosphere microbiome members with growth-inhibitory siderophores could often suppress the pathogen in vitro as well as in natural and greenhouse soils, and protect tomato plants from infection. Conversely, rhizosphere microbiome members with growth-promotive siderophores were often inferior in competition and facilitated plant infection by the pathogen. Because siderophores are a chemically diverse group of molecules, with each siderophore type relying on a compatible receptor for iron uptake8-12, our results suggest that pathogen-suppressive microbiome members produce siderophores that the pathogen cannot use. Our study establishes a causal mechanistic link between microbiome-level competition for iron and plant protection and opens promising avenues to use siderophore-mediated interactions as a tool for microbiome engineering and pathogen control.

3.
BMC Cancer ; 20(1): 378, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370744

RESUMO

BACKGROUND: Skin cutaneous melanoma (SKCM) is one of most aggressive type of cancers worldwide. Serglycin (SRGN) is an intracellular proteoglycan that playing an important role in various tumors. However, its effect on immune infiltrates and whether it associates with survival of SKCM and SKCM-metastasis patients has not been explored. METHODS: We evaluated SRGN expression via the databases of Oncomine, Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). The influence of SRGN expression on survival of SKCM and SKCM-metastasis patients was analyzed using TIMER database. Furthermore, the correlations between SRGN expression and immune infiltrates or gene marker sets of immune infiltrates were also analyzed via TIMER database. RESULTS: We found that the expression of SRGN in SKCM and SKCM-metastasis tissues was significantly increased compared to the normal skin tissues (P < 0.001). Interestingly, it was showed that lower level of SRGN expression and lower immune infiltrates of B cell, CD8+ T cell, Neutrophil, and Dendritic cell were correlated with poor survival rate of SKCM and SKCM-metastasis patients (P < 0.001) but not SKCM primary patients. We also demonstrated that SRGN expression was positively associated with the immune infiltrates and diverse immune marker sets in SKCM and SKCM-metastasis. CONCLUSIONS: Our findings indicated that SRGN was associated with the survival of SKCM and SKCM-metastasis patients. SRGN may be a new immune therapy target for treating SKCM and SKCM-metastasis.

4.
Nanotechnology ; 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32320964

RESUMO

Liver cancer remains a major cause of cancer-related death across the globe. Nano medicines have emerged as promising candidates to improve liver cancer chemotherapy. In this study, a glycyrrhetinic acid (GA) modified metal-organic framework-based drug delivery system (GA-MOFs) was developed to enhance the liver targeting ability of 5-FU. The physicochemical properties of GA-MOFs regarding particle size, size distribution and morphology were evaluated. The results showed that the obtained 5-FU@GA-MOFs had an octahedral structure, a uniform particle size distribution, and a diameter of ~200 nm. In vitro release experiments demonstrated that 5-FU@GA-MOFs exhibited a pH-dependent release pattern. MTT assays indicated that 5-FU-loaded GA-MOFs showed greater cytotoxicity towards HepG2 cells when compared to 5-FU alone at the same dose. In vivo tissue distribution demonstrated that the 5-FU@GA-MOFs significantly increased the accumulation of 5-FU in the liver. In vivo imaging analysis further manifested the liver targeting ability of GA-MOFs. Taken together, these results suggested that GA-modified MOFs showed promising potential as liver-targeting nanocarriers for the delivery of anti-tumor drugs.

5.
Bioorg Chem ; 99: 103833, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32305694

RESUMO

Two novel water-soluble pyrazolo[1,5-a]pyrimidine derivatives, 5-chloro-7-(4-methyl-piperazin -1-yl)-pyrazolo[1,5-a]pyrimidine (CMPS) and N'-(5-chloro-pyrazolo[1,5-a]pyrimidin-7-yl)-N,N-dimethyl -propane-1,3-diamine (NCPS), were synthesized and characterized with antibacterial activity. Then, the interactions of these compounds with bovine serum albumin (BSA) were studied by fluorescence, time-resolved fluorescence, circular dichroism (CD) spectroscopy and molecular docking. The results indicate that both CMPS and NCPS could effectively quench the intrinsic fluorescence of BSA via a static quenching process. The energy transfer from BSA to CMPS and NCPS may occur with high probability. Both CMPS and NCPS bind in the site I of BSA. The hydrophobic force and hydrogen bonds play major roles in the complex formation. Binding constants for both systems show that the affinity of CMPS binding to BSA is stronger than that of NCPS. The results of three-dimensional fluorescence and CD spectra reveal that the binding of CMPS and NCPS to BSA can induce conformational changes of BSA, and the influence of CMPS is slightly stronger than that of NCPS.

6.
J Immunol ; 204(11): 2984-2994, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32284332

RESUMO

Vitamin A deficiency (VAD) is a major public health problem and is associated with increased host susceptibility to infection; however, how VAD influences viral infection remains unclear. Using a persistent lymphocytic choriomeningitis virus infection model, we showed in this study that although VAD did not alter innate type I IFN production, infected VAD mice had hyperactive, virus-specific T cell responses at both the acute and contraction stages, showing significantly decreased PD-1 but increased cytokine (IFN-γ, TNF-α, and IL-2) expression by T cells. Compared with control mice, VAD mice displayed excessive inflammation and more severe liver pathology, with increased death during persistent infection. Of note, supplements of all-trans retinoic acid (RA), one of the important metabolites of vitamin A, downregulated hyperactive T cell responses and rescued the persistently infected VAD mice. By using adoptive transfer of splenocytes, we found that the environmental vitamin A or its metabolites acted as rheostats modulating antiviral T cells. The analyses of T cell transcriptional factors and signaling pathways revealed the possible mechanisms of RA, as its supplements inhibited the abundance of NFATc1 (NFAT 1), a key regulator for T cell activation. Also, following CD3/CD28 cross-linking stimulation, RA negatively regulated the TCR-proximal signaling in T cells, via decreased phosphorylation of Zap70 and its downstream signals, including phosphorylated AKT, p38, ERK, and S6, respectively. Together, our data reveal VAD-mediated alterations in antiviral T cell responses and highlight the potential utility of RA for modulating excessive immune responses and tissue injury in infectious diseases.

8.
Plant Biol (Stuttg) ; 2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32270571

RESUMO

Flowers, the reproductive organs of angiosperms, show a high degree of diversity in morphological structure and flowering habits to ensure pollination and fertilization of plants. Effect of flower movement on pollination and fertilization was investigated in Ipomoea purpurea (Convolvulaceae) in this study. Fluorescence microscope was used to observe the germination of pollen grains at different temperatures. From 4:00 am to 6:00 am, the stigma was taller than the filaments so that self-pollination had no chance to be completed and cross-pollination was carried out by insects. Pollen grains germinated rapidly after falling on the stigma, the pollen tube reached the ovule to complete the fertilization after 2-3 h. From 7:00 am to 9:00 am, filaments of two stamens grew rapidly and reached the same height as the stigma to allow self-crossing. But at this time, the natural temperature was already high and not conducive to the germination of pollen grains. The corolla formed a closed inverted bell-shaped corolla, where the inner microenvironment ensured the completion of pollen germination and fertilization. Preferential cross-pollination and delayed self-crossing of I. purpurea provided a doubly guaranteed mechanism for pollination and fertilization, allowing its adaptation to high temperature climate.

9.
Cell Signal ; 72: 109649, 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32335259

RESUMO

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disorder associated with polycystic liver disease (PLD) and other extrarenal manifestations, the most common monogenic cause of end-stage kidney disease, and a major burden for public health. Many studies have shown that alterations in G-protein and cAMP signaling play a central role in its pathogenesis. As for many other diseases (35% of all approved drugs target G-protein coupled receptors (GPCRs) or proteins functioning upstream or downstream from GPCRs), treatments targeting GPCR have shown effectiveness in slowing the rate of progression of ADPKD. Tolvaptan, a vasopressin V2 receptor antagonist is the first drug approved by regulatory agencies to treat rapidly progressive ADPKD. Long-acting somatostatin analogs have also been effective in slowing the rates of growth of polycystic kidneys and liver. Although no treatment has so far been able to prevent the development or stop the progression of the disease, these encouraging advances point to G-protein and cAMP signaling as a promising avenue of investigation that may lead to more effective and safe treatments. This will require a better understanding of the relevant GPCRs, G-proteins, cAMP effectors, and of the enzymes and A-kinase anchoring proteins controlling the compartmentalization of cAMP signaling. The purpose of this review is to provide an overview of general GPCR signaling; the function of polycystin-1 (PC1) as a putative atypical adhesion GPCR (aGPCR); the roles of PC1, polycystin-2 (PC2) and the PC1-PC2 complex in the regulation of calcium and cAMP signaling; the cross-talk of calcium and cAMP signaling in PKD; and GPCRs, adenylyl cyclases, cyclic nucleotide phosphodiesterases, and protein kinase A as therapeutic targets in ADPKD.

10.
J Med Chem ; 63(7): 3723-3736, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32134263

RESUMO

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.

11.
J Phys Chem B ; 124(17): 3540-3547, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32212659

RESUMO

In aqueous solution, fluorescence Stokes shift experiments monitor the relaxation of the solute-solvent interactions upon photon excitation of the solute chromophore. Linear response (LR) theory expects the identical dynamics between the Stokes shift and the system's spontaneous fluctuations. Whether this identity guarantees similar dynamics between the nonequilibrated and equilibrium processes for the decomposition energy of the Stokes shift is the main focus of this study. In our previous work [Li, T. J. Chem. Theory Comput. 2017, 13, 1867-1873], Stokes shift is properly correlated with various order time-correlation functions. As a continuation, its decomposition energy from the subsystem is further represented as the full summation of all of the cross-time correlation functions between the decomposition energy and the total solute-solvent interactions. Gaussian statistics of the total solute-solvent interactions ensure the same decay rates among the odd orders not only for the time-correlation functions but also for the cross-time correlation functions, validating the LR of the Stokes shift and the decompositions, respectively. The above mechanism is verified by molecular dynamics simulations in the protein Staphylococcus nuclease and is robust even as the decomposed energy associated with an individual residue exhibits typical non-Gaussian properties. Further examinations reveal the consistent molecular motions for a specific residue over the nonequilibrium and equilibrium processes, which are responsible for the nonequilibrium dynamics of the associated decomposed energy. Our results show the appropriateness of LR on finer molecular scales.

12.
Gene Expr Patterns ; 36: 119109, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32220631

RESUMO

The hierarchical interactions between the dental epithelium and dental mesenchyme represent a common paradigm for organogenesis. During tooth development, various morphogens interact with extracellular components in the extracellular matrix and on the cell surfaces to transmit regulatory signaling into cells. We recently found pivotal roles of FAM20B-catalyzed proteoglycans in the control of murine tooth number at embryonic stages. However, the expression pattern of proteoglycans in embryonic teeth has not been well understood. We extracted total RNA from E14.5 murine tooth germs for semi-quantitative RT-PCR analysis of 29 proteoglycans, and identified 23 of them in the embryonic teeth. As a major subfamily of FAM20B-catalyzed proteoglycans, Syndecans are important candidates being potentially involved in the tooth development of mice. We examined the expression pattern of Syndecans in embryonic teeth using in situ hybridization (ISH) and immunohistochemistry (IHC) approaches. Syndecan-1 is mainly present in the dental mesenchyme at early embryonic stages. Subsequently, its expression expands to both dental epithelium and dental mesenchyme. Syndecan-2 is strongly expressed in the dental mesenchyme at early embryonic stages, then shifts to the stratum intermedium and inner dental epithelium at cap stages. Syndecan-3 shows a gradually increased expression that initially in the dental epithelium of both incisors and molars and then in the inner dental epithelium and stratum intermedium in molars alone. Syndecan-4 is localized in the dental epithelium in incisors and the dental follicle mesenchyme in molars at early cap stage. The spatiotemporal expression pattern of Syndecans in murine embryonic teeth suggest potential roles of these proteoglycans in murine tooth morphogenesis.

13.
Bioorg Med Chem ; 28(7): 115395, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113844

RESUMO

Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities. From these, we identified that compounds 2, 5, 6 and 13 inhibited the cell viability in a dose-dependent manner and that the IC50s of 2 and 6 are<10 µM concentration in the HCT116 colon cancer cell line. Lead compound 13 (NSC295720) was a GLUT1 inhibitor. Docking studies show that GLUT1 residues Phe291, Phe379, Glu380, Trp388, and Trp412 were important for inhibitor binding.

14.
Environ Sci Pollut Res Int ; 27(12): 13409-13416, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32026370

RESUMO

Triclosan (TCS), a broad-spectrum antibacterial agent, exhibits a high exposure in the environment. However, the residual TCS in the environment poses a potential risk to human health. In this study, spectroscopic methods, molecular docking and animal experiment were conducted to completely understand the interaction between trypsin and TCS. The formation of the TCS-trypsin complex was spontaneously achieved through hydrogen bonds and Van der Waals forces with a binding constant (Ka) between 103 and 104 L mol-1. In addition, the trypsin activity in fish intestine was inhibited by TCS exposure, revealing the potentially negative effects of TCS on metabolism. The results might be explained by changes in the conformation of the trypsin, inducing the content of unordered coil increasing significantly (from 36.2% to over 80%). This work provides useful information for assessing the toxicity of TCS at the molecular level.

15.
Arch Virol ; 165(4): 977-983, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32095877

RESUMO

A novel rotavirus A (RVA) strain (JZ) was detected in RVA-positive stool specimens from three pediatric patients in Jinzhou, Liaoning Province, in 2018-2019. The electrophoresis pattern of the JZ strain showed a long electropherotype. The genomic constellation G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E2-H1 was detected, suggesting that a new inter-genogroup reassortment had occurred. Whole-genome sequencing showed that the JZ isolates were identical to each other. Phylogenetic analysis revealed that VP7 and VP4 clustered in lineages G9-VI and P[8]-3, respectively. JZ strain-specific amino acid substitutions were detected in VP7, VP4 and NSP4. This study provides information on the epidemiology and characteristics of G9 strains circulating in China.


Assuntos
Vírus Reordenados/isolamento & purificação , Infecções por Rotavirus/virologia , Rotavirus/genética , Rotavirus/isolamento & purificação , China , Genoma Viral , Humanos , Filogenia , Vírus Reordenados/classificação , Vírus Reordenados/genética , Rotavirus/classificação , Proteínas Virais/genética
16.
Cancer Med ; 9(7): 2427-2434, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32048817

RESUMO

AIM: To investigate the impact of biological subtypes in locoregional recurrence in Chinese breast cancer patients receiving postmastectomy radiotherapy (PMRT). METHODS AND MATERIALS: About 583 patients who received postmastectomy radiation between 2010 and 2012 were retrospectively analyzed. According to immunohistochemical staining profile, patients were classified into: Luminal A-like, Luminal B-like, HER2-positive, and triple-negative breast cancer (TNBC). Local and regional recurrence (LRR) cumulative incidences were calculated by competing risks methodology and the power of prognostic factors was examined by Gray's test and the test of Fine and Gray. RESULTS: The median follow-up was 70.9 months. About 34 LRR events occurred. For Luminal A, Luminal B, HER2-positive, and TNBC patients, the 5-year LRR cumulative incidence rates were 1.57%, 4.09%, 10.74%, and 10.28%. Compared with Luminal A, HER2-positive subtype and TNBC had a significant increased risk of LRR (HR was 5.034 and 5.188, respectively). In univariate analysis, predictive factors for higher LRR were HER2-positive subtype (HR = 4.43, P < .05), TNBC (HR = 4.70, P < .05), and pN3 (HR = 5.83, P < .05). In the multivariate model, HER2-positive subtype (HR = 5.034, P < .05), TNBC (HR = 5.188, P < .05), and pN3 (HR = 9.607, P < .01) were independent predictors of LRR. LRR without trastuzumab was similar to that of TNBC (without vs TNBC, 17.88% vs 10.28%, P > .05) in HER2-positive subtype patients, while LRR with trastuzumab was approximate to Luminal A (with vs Luminal A, P > .05). Additionally, endocrine therapy also significantly reduced LRR incidence in the luminal subtype cohort (without vs with therapy, 6.25% vs 2.89%, HR = 0.365, P < .1). CONCLUSIONS: Biological subtype was a prognostic factor of LRR in the PMRT setting among Chinese breast cancer patients.

17.
Bioorg Chem ; 97: 103674, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32097796

RESUMO

Natural products have shown promise for epigenetic modulations and thus are therapeutically potential for cancer prevention and treatment. In this work, we report the identification of natural product Biochanin A as a new LSD1 inhibitor and further biological evaluation in gastric MGC-803 cells. Biochanin A effectively and reversibly inhibited LSD1 (IC50 = 2.95 µM) and showed selective inhibition to LSD1 over MAO-A/B. In gastric MGC-803 cells, Biochanin A induced accumulation of H3K4me1/2, inhibited cell growth moderately (IC50 = 6.77 µM), but was less toxic to normal GES-1 (IC50 > 32 µM). Mechanistic studies showed that Biochanin A suppressed colony formation, cell apoptosis, and migration of MGC-803 cells. This study may help to elucidate the anticancer mechanisms of Biochanin A.

18.
Cell Death Dis ; 11(2): 96, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029708

RESUMO

Cathelicidin-related antimicrobial peptide (CRAMP), an antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. However, the effect of CRAMP on pressure overload-induced cardiac hypertrophy was unknown. This study explored the role of CRAMP on cardiac hypertrophy. A cardiac hypertrophy mouse model was induced by aortic banding surgery. Seven days after surgery, mice were given mCRAMP by intraperitoneal injection (8 mg/kg/d) for 7 weeks. Cardiac hypertrophy was evaluated by the hypertrophic response and fibrosis level as well as cardiac function. Mice were also injected with AAV9-shCRAMP to knockdown CRAMP in the mouse heart. CRAMP levels first increased and then reduced in the remodeling heart, as well as in angiotensin II-stimulated endothelial cells but not in cardiomyocytes and fibroblasts. mCRAMP protected against the pressure overload-induced cardiac remodeling process, while CRAMP knockdown accelerated this process. mCRAMP reduced the inflammatory response and oxidative stress in the hypertrophic heart, while mCRAMP deficiency deteriorated the pressure overload-induced inflammatory response and oxidative stress. mCRAMP inhibited the angiotensin II-stimulated hypertrophic response and oxidative stress in neonatal rat cardiomyocytes, but mCRAMP did not help the angiotensin II-induced inflammatory response and oxidative stress in endothelial cells. Mechanistically, we found that mCRAMP suppressed the cardiac hypertrophic response by activating the IGFR1/PI3K/AKT pathway via directly binding to IGFR1. AKT knockout mice completely reversed the anti-hypertrophic effect of mCRAMP but not its anti-oxidative effect. We also found that mCRAMP ameliorated cardiac oxidative stress by activating the TLR9/AMPKa pathway. This was confirmed by a TLR9 knockout mouse experiment, in which a TLR9 knockout partly reversed the anti-hypertrophic effect of mCRAMP and completely counteracted the anti-oxidative effect of mCRAMP. In summary, mCRAMP protected against pressure overload-induced cardiac hypertrophy by activating both the IGFR1/PI3K/AKT and TLR9/AMPKa pathways in cardiomyocytes.

19.
Death Stud ; : 1-9, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32027226

RESUMO

The current research used questionnaire data to examine the direct and indirect paths between physical health and fear of death. For 386 rural residents, physical health, meaning in life, and mental health were negatively related to fear of death. Physical health affected fear of death through three paths: one was the independent mediation of meaning in life, the other was the independent mediation of mental health, and the third was the serial mediation of meaning in life and mental health. To reduce the fear of death and improve the quality of life among rural residents, educational interventions of meaning in life and mental health are imperative.

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