Exosomes derived from bladder epithelial cells infected with uropathogenic Escherichia coli increase the severity of urinary tract infections (UTIs) by impairing macrophage function.

Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections (UTIs) in humans. Moreover, as one of the most common bacterial pathogens, UPEC imposes a substantial burden on healthcare systems worldwide. Epithelial cells and macrophages are two major components of the innate immune system, which play critical roles in defending the bladder against UPEC invasion. Yet, the routes of communication between these cells during UTI pathogenesis are still not fully understood. In the present study, we investigated the role of membrane-bound nanovesicles (exosomes) in the communication between bladder epithelial cells and macrophages during UPEC infection, using an array of techniques such as flow cytometry, miRNA profiling, RNA sequencing, and western blotting. Moreover, our in vitro findings were validated in a mouse model of UPEC-induced cystitis. We found that UPEC infection induced the bladder epithelial MB49 cell line to secrete large numbers of exosomes (MB49-U-Exo), which were efficiently absorbed by macrophages both in vivo and in vitro. Assimilation of MB49-U-Exo induced macrophages to produce proinflammatory cytokines, including tumor necrosis factor (TNF)α. Exposure of macrophages to MB49-U-Exo reduced their phagocytic activity (by downregulating the expression of phagocytosis-related genes) and increased their rate of apoptosis. Mechanistically, we showed that MB49-U-Exo were enriched in miR-18a-5p, which induced TNFα expression in macrophages by targeting PTEN and activating the MAPK/JNK signaling pathway. Moreover, administration of the exosome secretion inhibitor GW4869 or a TNFα-neutralizing antibody alleviated UPEC-mediated tissue damage in mice with UPEC-induced cystitis by reducing the bacterial burden of the bladder and dampening the associated inflammatory response. Collectively, these findings suggest that MB49-U-Exo regulate macrophage function in a way that exacerbates UPEC-mediated tissue impairment. Thus, targeting exosomal -release or TNFα signaling during UPEC infection may represent promising non-antibiotic strategies for treating UTIs.

Histone Deacetylase SIRT1 Negatively Regulates the Differentiation of Interleukin-9-Producing CD4(+) T Cells.

Distinct metabolic programs support the differentiation of CD4(+) T cells into separate functional subsets. In this study, we investigated metabolic mechanisms underlying the differentiation of IL-9-producing CD4(+) T cells (Th9) in allergic airway inflammation and cancerous tumors. We found that histone deacetylase SIRT1 negatively regulated Th9 cell differentiation. A deficiency of SIRT1 induced by either conditional deletion in mouse CD4(+) T cells or the use of small interfering RNA (siRNA) in mouse or human T cells increased IL-9 production, whereas ectopic SIRT1 expression inhibited it. Notably, SIRT1 inhibited Th9 cell differentiation that regulated anti-tumor immunity and allergic pulmonary inflammation. Glycolytic activation through the mTOR-hypoxia-inducible factor-1α (HIF1α) was required for the differentiation of Th9 cells that conferred protection against tumors and is involved in allergic airway inflammation. Our results define the essential features of SIRT1-mTOR-HIF1α signaling-coupled glycolytic pathway in inducing Th9 cell differentiation, with implications for metabolic reprogramming as an immunotherapeutic approach.

A Functionally Asymmetric Janus Hygro-Photothermal Hybrid for Atmospheric Water Harvesting in Arid Regions.

Metal-organic frameworks (MOFs) are high-performance adsorbents for atmospheric water harvesting but have poor water-desorption ability, requiring excess energy input to release the trapped water. Addressing this issue, a Janus-structured adsorbent with functional asymmetry is presented. The material exhibits contrasting functionalities on either face - a hygroscopic face interfaced with a photothermal face. Hygroscopic aluminum fumarate MOF and photothermal CuxS layers are in-situ grown on opposite sides of a Cu/Al bimetallic substrate, resulting in a CuxS-Cu/Al-MOF Janus hygro-photothermal hybrid. The two faces serve as independent "factories" for photothermal conversion and water adsorption-desorption respectively, while the interfacing bimetallic layer serves as a "heat conveyor belt" between them. Due to the high porosity and hydrophilicity of the MOF, the hybrid exhibits a water-adsorption capacity of 0.161 g g-1 and a fast adsorption rate (saturation within 52 min) at 30% relative humidity. Thanks to the photothermal CuxS, the hybrid can reach 71.5 °C under 1 Sun in 20 min and desorb 97% adsorbed water in 40 min, exhibiting a high photothermal conversion efficiency of over 90%. CuxS-Cu/Al-MOF exhibits minimal fluctuations after 200 cycles, and its water-generation capacity is 3.21 times that of powdery MOF in 3 h in a self-designed prototype in one cycle.

Bimetallic MOF-Derived Solar-Triggered Monolithic Adsorbent for Enhanced Atmospheric Water Harvesting.

The development of economical, energy-saving, and efficient metal-organic framework (MOF)-based adsorbents for atmospheric water collection is highly imperative for the rapid advancement of renewable freshwater resource exploitation. Herein, a feasible one-step solvothermal formation strategy of bimetallic MOF (BMOF) is proposed and applied to construct a solar-triggered monolithic adsorbent for enhanced atmospheric water collection. Benefiting from the reorganization and adjustment of topology structure by Al atoms and Fe atoms, the resultant BMOF(3) consisting of Al-fumarate and MIL-88A has a higher specific surface area (1202.99 m2  g-1 ) and pore volume (0.51 cm3  g-1 ), thereby outperforming the parental MOFs and other potential MOFs in absorbing water. Expanding upon this finding, the solar-triggered monolithic adsorbent is further developed through a bottom-up assembly of polyaniline/chitosan layers and hybridized BMOF(3) skeletons on a glass fiber support. The resultant monolithic adsorbent exhibits superior sorption-desorption kinetics, leading to directional water transport and rapid solar-assisted vapor diffusion. As a proof-of-concept demonstration, an exquisite water harvester is constructed to emphasize a high water yield of 1.19 g g-1 per day of the designed monolithic adsorbent. Therefore, the design and validation of bimetallic MOF-derived solar-triggered adsorbent in this work are expected to provide a reference for the large-scale applications of MOF-based atmospheric water harvesting.

Nanoscale-to-Mesoscale Heterogeneity and Percolating Favored Clusters Govern Ultrastability of Metallic Glasses.

Comprehending and controlling the stability of glasses is one of the most challenging issues in glass science. Here we explore the microscopic origin of the ultrastability of a Cu-Zr-Al metallic glass (MG). It is revealed that the ultrastable window (0.7-0.8 Tg) of MGs correlates with the enhanced degree of nanoscale-to-mesoscale structural/mechanical heterogeneity and the connection of stability-favored clusters. On one side, the increased fraction of stability-favored clusters promotes the formation of a stable percolating network through a critical percolation transition, which is essential to form ultrastable MG. On the other side, the enhanced heterogeneity arising from an increased distribution in local clusters may promote synergistically a more efficient and frustrated packing of amorphous structure, contributing to the ultrastability. The present work sheds new light on the stability of MGs and provides a step toward next-generation MGs with superior stability and performances.

[Dumai moxibustion combined with low-dose tadalafil for erectile dysfunction: Evaluation of therapeutic effect].

OBJECTIVE: To investigate the clinical effect of dumai (governor meridian) moxibustion combined with low-dose tadalafil in the treatment of ED with decline of vital gate fire. METHODS: We enrolled in this study 130 ED patients with decline of vital gate fire who met the inclusion criteria and equally randomized them into a control and an experimental group, the former treated with low-dose tadalafil tablets at 5 mg once a day while the latter by dumai moxibustion once a week in addition, all for 4 weeks. Of the total number of subjects, 62 in the control group and 63 in the experimental group completed the experiment. We recorded the scores on IIEF-5, Erection Quality Scale (EQS), Erection Hardness Scale (EHS), TCM symptoms and Treatment Satisfaction Scale (TSS) as well as the penile hemodynamic parameters peak systolic velocity (PSV), end diastolic velocity (EDV) and resistance index (RI) before and after treatment and compared them between the two groups. RESULTS: The total response rate was significantly higher in the experimental group than in the control (87.30% vs 66.13%, P < 0.05). IIEF-5, EQS, EHS and TSS scores, PSV and RI were markedly increased while TCM symptoms and EDV remarkably decreased in both groups after treatment (P < 0.05), even more significantly in the experimental than in the control group (P < 0.05). CONCLUSION: Dumai moxibustion combined with low-dose tadalafil can improve erectile function, increase penile blood flow velocity and alleviate clinical symptoms in ED patients with decline of vital gate fire, with definite clinical effect and safety.

Cellular nanomechanics derived from pattern-dependent focal adhesion and cytoskeleton to balance gene transfection of malignant osteosarcoma.

Gene transfection was supposed to be the most promising technology to overcome the vast majority of diseases and it has been popularly reported in clinical applications of gene therapy. In spite of the rapid development of novel transfection materials and methods, the influence of morphology-dependent nanomechanics of malignant osteosarcoma on gene transfection is still unsettled. In this study, cell spreading and adhesion area was adjusted by the prepared micropatterns to regulate focal adhesion (FA) formation and cytoskeletal organization in osteosarcoma cells. The micropattern-dependent FA and cytoskeleton could induce different cellular nanomechanics to affect cell functions. Our results indicated that transfection efficiency was improved with enlarging FA area and cell nanomechanics in micropatterned osteosarcoma. The difference of gene transfection in micropatterned cells was vigorously supported by cellular internalization capacity, Ki67 proliferation ability and YAP mechanotranduction through the regulation of focal adhesion and cytoskeletal mechanics. This study is an attempt to disclose the relationship of cell nanomechanics and gene transfection for efficient gene delivery and develop multifunctional nanomedicine biomaterials for accurate gene therapy in osteosarcoma cells.

Uropathogenic Escherichia coli Virulence Factor α-Hemolysin Reduces Histone Acetylation to Inhibit Expression of Proinflammatory Cytokine Genes.

Urinary tract infections are common and costly diseases affecting millions of people. Uropathogenic Escherichia coli (UPEC) is a primary cause of these infections and has developed multiple strategies to avoid the host immune response. Here, we dissected the molecular mechanisms underpinning UPEC inhibition of inflammatory cytokine in vitro and in vivo. We found that UPEC infection simulates nuclear factor-κB activation but does not result in transcription of cytokine genes. Instead, UPEC-mediated suppression of the metabolic enzyme ATP citrate lyase results in decreased acetyl-CoA levels, leading to reduced H3K9 histone acetylation in the promotor region of CXCL8. These effects were dependent on the UPEC virulence factor α-hemolysin and were reversed by exogenous acetate. In a murine cystitis model, prior acetate supplementation rapidly resolved UPEC-elicited immune responses and improved tissue recovery. Thus, upon infection, UPEC rearranges host cell metabolism to induce chromatin remodeling processes that subvert expression of host innate immune response genes.

Cancer derived exosomes induce macrophages immunosuppressive polarization to promote bladder cancer progression.

BACKGROUND: Exosomes mediated crosstalk between tumor cells and other stromal cells including tumor associated macrophages plays an essential role in reprogramming tumor microenvironment (TME) to facilitate tumor progression. However, the mechanism of tumor derived exosomes promotes bladder cancer progression have not been defined. METHODS: Exosomes were extracted from bladder cancer cells MB49 conditioned medium by ultracentrifugation. The effects of MB49-derived exosomes on macrophages polarization were analyzed by qPCR, flow cytometry, and Western blot. The immunosuppressive phenotype and function of MB49-derived exosomes stimulated macrophages were verified by tumor xenograft assays and T cell co-culture experiments. Exosomal miRNAs were analyzed by microarray to identify potential targets regulating macrophage polarization. RESULTS: MB49-derived exosomes could be ingested by macrophages, consequently promoting macrophages immunosuppressive polarization. Mechanically, the MB49-derived exosomes induced macrophage M2 polarization was mediated by down-regulation of PTEN and activation of AKT/STAT3/6 signaling. Moreover, hindrance of the generation or secretion of exosomes by GW4869 inhibited macrophages differentiation into immunosuppressive phenotype and function, thereby suppressed tumor growth in a mouse subcutaneous tumor model. CONCLUSION: Our study confirmed the contribution of bladder cancer derived exosomes on the establishment of immunosuppressive TME and provided a potential therapeutic target for bladder cancer treatment. Video Abstract.

Nanochannel {InZn}-Organic Framework with a High Catalytic Performance on CO2 Chemical Fixation and Deacetalization-Knoevenagel Condensation.

The rare combination of InIII 5p and ZnII 3d in the presence of a structure-oriented TDP6- ligand led to a robust hybrid material of {(Me2NH2)[InZn(TDP)(OH2)]·4DMF·4H2O}n (NUC-42) with the interlaced hierarchical nanochannels (hexagonal and cylindrical) shaped by six rows of undocumented [InZn(CO2)6(OH2)] clusters, which represented the first 5p-3d nanochannel-based heterometallic metal-organic framework. With respect to the multifarious symbiotic Lewis acid-base and Brønsted acid sites in the high porous framework, the catalytic performance of activated NUC-42a upon CO2 cycloaddition with styrene oxide was evaluated under solvent-free conditions with 1 atm of CO2 pressure, which exhibited that the reaction could be well completed at ambient temperature within 48 h or at 60 °C within 4 h with high yield and selectivity. Moreover, because of the acidic function of metal sites and a central free pyridine in the TDP6- ligand, deacetalization-Knoevenagel condensation of acetals and malononitrile could be efficiently facilitated by an activated sample of NUC-42a under lukewarm conditions.

Uropathogenic Escherichia coli virulence factor hemolysin A causes programmed cell necrosis by altering mitochondrial dynamics.

Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infections. In this study, UPEC strains harboring hemolysin A (HlyA) did not induce programmed cell death pathways by the activation of caspases. Instead, the UPEC pore-forming toxin HlyA triggered an increase in mitochondrial Ca2+ levels and manipulated mitochondrial dynamics by causing fragmentation of the mitochondrial network. Alterations in mitochondrial dynamics resulted in severe impairment of mitochondrial functions by loss of membrane potential, increase in reactive oxygen species production, and ATP depletion. Moreover, HlyA caused disruption of plasma membrane integrity that was accompanied by extracellular release of the danger-associated molecules high-mobility group box 1 (HMGB1) and histone 3 (H3). Our results indicate that UPEC induced programmed cell necrosis by irreversibly impairing mitochondrial function. This finding suggests a strategy devised by UPEC at the onset of infection to escape early innate immune response and silently propagate inside host cells.-Lu, Y., Rafiq, A., Zhang, Z., Aslani, F., Fijak, M., Lei, T., Wang, M., Kumar, S., Klug, J., Bergmann, M., Chakraborty, T., Meinhardt, A., Bhushan, S. Uropathogenic Escherichia coli virulence factor hemolysin A causes programmed cell necrosis by altering mitochondrial dynamics.

Compounding MgCl2·6H2O with NH4Al(SO4)2·12H2O or KAl(SO4)2·12H2O to Obtain Binary Hydrated Salts as High-Performance Phase Change Materials.

Developing phase change materials (PCMs) with suitable phase change temperatures and high latent heat is of great significance for accelerating the development of latent heat storage technology to be applied in solar water heating (SWH) systems. The phase change performances of two mixtures, NH4Al(SO4)2·12H2O-MgCl2·6H2O (mixture-A) and KAl(SO4)2·12H2O-MgCl2·6H2O (mixture-B), were investigated in this paper. Based on the DSC results, the optimum contents of MgCl2·6H2O in mixture-A and mixture-B were determined to be 30 wt%. It is found that the melting points of mixture-A (30 wt% MgCl2·6H2O) and mixture-B (30 wt% MgCl2·6H2O) are 64.15 °C and 60.15 °C, respectively, which are suitable for SWH systems. Moreover, two mixtures have high latent heat of up to 192.1 kJ/kg and 198.1 kJ/kg as well as exhibit little supercooling. After 200 cycles heating-cooling experiments, the deviations in melting point and melting enthalpy of mixture-A are only 1.51% and 1.20%, respectively. Furthermore, the XRD patterns before and after the cycling experiments show that mixture-A possesses good structure stability. These excellent thermal characteristics make mixture-A show great potential for SWH systems.

Dendritic cell SIRT1-HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-ß1.

The differentiation of naive CD4(+) T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (TH1) cells and antiinflammatory Foxp3(+) regulatory T cells (T(reg) cells). Genetic deletion of SIRT1 in DCs restrained the generation of T(reg) cells while driving TH1 development, resulting in an enhanced T-cell-mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal TH1 and T(reg) lineage commitment through DC-derived IL-12 and TGF-ß1. Our studies implicates a DC-based SIRT1-HIF1α metabolic checkpoint in controlling T-cell lineage specification.

A Modification of the Stapled TransAnal Rectal Resection (STARR) Procedure for Rectal Prolapse.

PURPOSE: This study was designed to assess the safety, efficacy, and postoperative outcomes of the modified Stapled TransAnal Rectal Resection (modified STARR) in patients presenting with cases of limited external rectal prolapse. METHODS: A prospective cohort of patients with mild rectal prolapse undergoing rectal resection with the Tissue-Selecting Technique Stapled TransAnal Rectal Resection Plus (TSTStarr Plus) stapler between February 2014 and September 2016 was reviewed retrospectively. RESULTS: Twenty-five eligible patients underwent rectal resection with the TSTStarr Plus stapler. The median vertical height of the resected specimen was 5.0 cm (range = 3.1-10 cm) with all cases being confirmed histologically as full-thickness resections. Over a follow-up of 33.6 ± 9.4 months, only 1 case (4%) was encountered with recurrence. The mean postoperative Wexner score was significantly improved when compared with the preoperative scores (preoperative: median = 3, range = 0-20, vs postoperative: median = 2, range = 0-20, respectively; P = .010). The median preoperative Symptom Severity Score and Obstructed Defecation Score were both decreased compared with the postoperative scores ( P = .001). CONCLUSIONS: Modified STARR in management of mild rectal prolapse appear to be a safe and effective technique. The initial results would encourage a more formal prospective assessment of this technique as part of a randomized trial for the management of mild rectal prolapse.

A multi-controlled drug delivery system based on magnetic mesoporous Fe3O4 nanopaticles and a phase change material for cancer thermo-chemotherapy.

Herein a novel multi-controlled drug release system for doxorubicin (DOX) was developed, in which monodisperse mesoporous Fe3O4 nanoparticles were combined with a phase change material (PCM) and polyethylene glycol 2000 (PEG2000). It is found that the PCM/PEG/DOX mixture containing 20% PEG could be dissolved into water at 42 °C. The mesoporous Fe3O4 nanoparticles prepared by the solvothermal method had sizes of around 25 nm and exhibited a mesoporous microstructure. A simple solvent evaporation process was employed to load the PCM/PEG/DOX mixture on the mesoporous Fe3O4 nanoparticles completely. In the Fe3O4@PCM/PEG/DOX system, the pores of the Fe3O4 nanoparticles were observed to be filled with the mixture of PCM/PEG/DOX. The Fe3O4@PCM/PEG/DOX system showed a saturation magnetization value of 50.0 emu g-1, lower than 71.1 emu g-1 of the mesoporous Fe3O4 nanoparticles, but it was still high enough for magnetic targeting and hyperthermia application. The evaluation on drug release performance indicated that the Fe3O4@PCM/PEG/DOX system achieved nearly zero release of DOX in vitro in body temperature, while around 80% of DOX could be released within 1.5 h at the therapeutic threshold of 42 °C or under the NIR laser irradiation for about 4 h. And a very rapid release of DOX was achieved by this system when applying an alternating magnetic field. By comparing the systems with and without PEG2000, it is revealed that the presence of PEG2000 makes DOX easy to be released from 1-tetradecanol to water, owing to its functions of increasing the solubility of DOX in 1-tetradecanol as well as decreasing the surface tension between water and 1-tetradecanol. The novel drug release system shows great potential for the development of thermo-chemotherapy of cancer treatment.

Uropathogenic Escherichia coli Epigenetically Manipulate Host Cell Death Pathways.

Urinary tract infections caused by uropathogenic Escherichia coli (UPEC) pathovars belong to the most frequent infections in human. It is well established that UPEC can subvert innate immune responses, but the role of UPEC in interfering with host cell death pathways is not known. Here, we show that UPEC abrogates activation of the host cell prosurvival protein kinase B signaling pathway, which results in the activation of mammalian forkhead box O (FOXO) transcription factors. Although FOXOs were localized in the nucleus and showed increased DNA-binding activity, no change in the expression levels of FOXO target genes were observed. UPEC can suppress BIM expression induced by LY249002, which results in attenuation of caspase 3 activation and blockage of apoptosis. Mechanistically, BIM expression appears to be epigenetically silenced by a decrease in histone 4 acetylation at the BIM promoter site. Taken together, these results suggest that UPEC can epigenetically silence BIM expression, a molecular switch that prevents apoptosis.

Targeting S1P1 receptor protects against murine immunological hepatic injury through myeloid-derived suppressor cells.

Although FTY720 may alter migration and homing of lymphocytes via sphingosine-1-phosphate (S1P) receptors, our recent studies indicated that FTY720 directly controls the differentiation of Th1 cells to regulatory T cells (Tregs) by targeting S1P1. However, the pharmacological function of FTY720 in immunological hepatic injury remains unknown. In this study, the role and regulatory signaling pathway of S1P receptor were investigated using a pharmacological approach in immune-mediated hepatic injury (IMH). In the context of IMH, FTY720 significantly ameliorated mortality and hepatic pathology. In FTY720-treated mice, recruited CD11b(+)Gr1(+) myeloid-derived suppressor cells (MDSCs) mediate protection against IMH and are functional suppressive immune modulators that result in fewer IFN-γ-producing Th1 cells and more Foxp3(+) Tregs. In agreement, FTY720-treated MDSCs promote the reciprocal differentiation between Th1 cells and Tregs in vitro and in vivo. Mechanistically, FTY720 treatment induced inducible NO synthase expression and NO production in MDSCs. Pharmacologic inhibition of inducible NO synthase completely eliminates MDSC suppressive function and eradicates their inducible effects on T cell differentiation. Finally, the mTOR inhibitor, rapamycin, photocopies the effects of FTY720 on MDSCs, implicating mTOR as a downstream effector of S1P1 signaling. This study identifies MDSCs as an essential component that provides protection against IMH following FTY720 or rapamycin treatment, validating the S1P1-mTOR signaling axis as a potential therapeutic target in hepatic injury.

Intercellular interplay between Sirt1 signalling and cell metabolism in immune cell biology.

Sirtuins are evolutionarily conserved class III histone deacetylases that have been the focus of intense scrutiny and interest since the discovery of Sir2 as a yeast longevity factor. Early reports demonstrated an important role of Sirt1 in aging and metabolism, but its critical regulatory role in the immune system has only been unveiled in recent years. In this review we discuss the latest advances in understanding the regulatory role of Sirt1 in immune responses as well as how Sirt1 translates metabolic cues to immune signals, which would bring new insights into both pathogenesis and potential therapeutic strategies of a variety of immune-related diseases, such as cancer, microbial infection, autoimmune diseases and transplantation.

Cellular metabolism modulation in T lymphocyte immunity.

T lymphocytes are a central component, and play an important role in controlling immunity and immunological diseases. Recent studies have shown that T cell metabolism is highly dynamic and has a tremendous impact on the modulation of T lymphocyte immunity. Specific metabolic pathways meet energy and biosynthetic requirements that can support specific T cell functional activities in immunity and immunological diseases. This review summarizes the recent progresses about the modulatory role of cell metabolism in T cell development, differentiation, activation and function in immunity. These might provide new opportunities to modulate the immune responses and treat clinical immunological diseases. This article is protected by copyright. All rights reserved.