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Solute carrier transporters (SLCs) mediate nutrient and metabolite cellular homeostasis. Immune cells depend on SLCs to induce rapid and robust metabolic reprogramming, thereby controlling diverse immunological responses. Recent studies hint toward an important role of SLCs in immunity. Here, we review the emerging roles of SLCs in immunotherapy via modifying the metabolism and effector functions of immune cells. We focus on the roles of three major nutrient (glucose, amino acid, and lipid)-related transporters in immunity of representative cells [T cells, dendritic cells (DCs), natural killer (NK) cells, and macrophages) in innate and adaptive immunity. Other SLCs, such as ion transporters are also briefly discussed. Finally, we propose some potential strategies for targeting SLCs to augment tumour immunotherapy.

Background Adults with atherosclerotic cardiovascular disease (ASCVD) at very high-risk for recurrent events who have low-density lipoprotein cholesterol ≥ 70 mg/dL despite maximally-tolerated statin therapy are recommended to initiate ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Objective Compare the initiation of ezetimibe and a PCSK9 inhibitor after a myocardial infarction (MI) among very high-risk ASCVD patients by race/ethnicity and sex. Methods We analyzed data from 374,786 adults ≥ 66 years of age with Medicare fee-for-service coverage who had an MI between July 1, 2015 and December 31, 2018, were not taking ezetimibe or a PCSK9 inhibitor, and had very high-risk ASCVD defined by the 2018 American Heart Association/American College of Cardiology multi-society cholesterol guideline. Pharmacy claims through December 31, 2018 were used to determine ezetimibe and PCSK9 inhibitor initiation. Results Overall, 6980 (1.9%) beneficiaries initiated ezetimibe, and 1433 (0.4%) initiated a PCSK9 inhibitor. Adjusted hazard ratios (aHR) for ezetimibe initiation among non-Hispanic Black, Hispanic, and Asian versus non-Hispanic White beneficiaries were 0.77 (95% confidence interval [95%CI]: 0.70–0.86), 0.92 (95%CI: 0.76–1.11) and 0.73 (95%CI: 0.59–0.89), respectively. Compared to non-Hispanic White beneficiaries, the aHRs for PCSK9 inhibitor initiation were 0.63 (95%CI: 0.48–0.81) among non-Hispanic Black, 0.70 (95%CI: 0.43–1.13) among Hispanic, and 0.93 (95%CI: 0.62–1.39) among Asian beneficiaries. The aHRs for ezetimibe and PCSK9 inhibitor initiation comparing women to men were 1.11 (95%CI: 1.06–1.17) and 1.13 (95%CI: 1.01–1.25), respectively. Conclusion There are race/ethnic and sex disparities in the initiation of ezetimibe and a PCSK9 inhibitor following MI among very high-risk ASCVD patients.

This study focused on the volatile organic compounds (VOCs) abatement by catalytic combustion/adsorption over Rh-based/ZSM-5. A series of Rh-based catalysts were prepared by wet co-impregnation method and evaluated by toluene combustion. Rh1Cu3/ZSM-5 presented superb toluene catalytic activity, great long-run stability, and excellent catalytic adaptability to various VOCs. Besides, Rh1Cu3/ZSM-5 performed good toluene adsorption capability in the column breakthrough experiments. Characterization results indicated that the interaction between Rh species and Cu oxides increased the content of chemisorbed oxygen in lattice layer (Oads-chem), which improved the catalytic performance efficiently. Moreover, Rh1Cu3/ZSM-5 showed excellent adsorption ability for toluene due to its large specific surface area, and the strong interaction between metal nanoparticles and VOCs molecules. Overall, this kind of bifunctional materials with dual-metal modification were significant for the development of VOCs abatement.

Ceria-promoted Co@NC (NC, N doped carbon) catalysts are prepared by pyrolysis of biomass materials. Characterization results indicate that ceria and Co species facilitate the distribution of each other due to the formation of a Ce–O–Co solid solution. The specific surface area of the catalyst increased from 378.77 to 537.7 m2 g−1via the introduction of ceria. The electron transfer from Co to Ce further enhanced their interaction, and Co species facilitate the formation of more defective oxygen vacancies on ceria, which are beneficial to the activities of catalytic hydrogenation and catalytic transfer hydrogenation (CTH), respectively. Thus, Co/Ce@NC (0.99% Co loading) pyrolyzed at 850 °C exhibits excellent performance in the hydrodeoxygenation (HDO) of vanillin with high metal utilization. Catalytic hydrogenation and CTH coexisted in the presence of H2 and ethanol, and >99% yield of creosol can be obtained in each of them. The reaction processes are monitored. No intermediate is found in aqueous media, while ethoxymethyl-4-methoxy-2-phenol is detected in ethanol. Moreover, Co/Ce@NC presents outstanding stability and general applicability. This work provides new insights into the construction of M@NC (M, metal) catalysts and the HDO process of biofuel upgrade.

A novel dual-site fluorescent probe (CTPA) was rationally designed and synthesized for the detection of hypochlorite (ClO−) and polarity. CTPA displayed an excellent sensitivity (LOD = 11.9 nM) and selectivity as well as a rapid response within 30 s to ClO−. Besides, it is worth noting that the introduction of triphenylamine into the D–π–A structure is beneficial to monitor the fluctuation of polarity. It was found that CTPA could respond to polarity fluctuation via the two channels of fluorescence intensity and maximum emission wavelength. In addition, CTPA exhibited low toxicity and was successfully applied to detect the endogenous and exogenous ClO− in HeLa cells and HIN-3T3 cells and distinguish the two kinds of cells by ClO− and polarity. Furthermore, this work provides a promising strategy for the development of dual-site fluorescent probes aiming at the detection of biologically relevant analytes by the collocation of recognizing groups.

Photocatalytic technology is a potential technology to meet energy and environmental requirements. Herein, the solvothermal method was used for the first time to synthesize a Bi2O2CO3/TiO2 hybrid with 0D/1D nanostructure, and the obtained materials were characterized systematically. In the architecture of the composite, Bi2O2CO3 quantum dots (QDs) (1.40–1.50 nm) uniformly grew on the surface of TiO2 nanobelts (NBs). The degradation efficiency of Rhodamine B under visible light irradiation was applied to evaluate the photocatalytic performance of the obtained materials. Of them, TB-3 exhibited the best photocatalytic performance, and more than 95.43% RhB was degraded under visible light. The reaction rate constant is 18.51 × 10−3 min−1, which is nine times larger than that of TiO2 NBs. Moreover, it exhibited remarkable stability and recyclability in a recycling experiment. According to the photoelectric characterization, the excellent performance may be attributed to the construction of a heterojunction and hybrid structure with 0D Bi2O2CO3 QDs and 1D TiO2 NBs, which endows the catalyst with faster migration of photo-generated carriers and less recombination of electron/hole pairs. Our work provides a promising method to build novel visible light-driven photocatalysts with a 0D/1D hybrid structure.

Covalent organic frameworks have attracted great attention due to their extensive applications in energy storage, gas separation, catalysis, and photoelectric devices over the past decades. However, the design and synthesis of COFs with fluorescent units have been considered as a big challenge. Herein, we report a porphyrin-based covalent organic framework (TPE-Por-4) by the condensation of the C4-symmetric and D2h-symmetric monomers. Through a series of characterizations, its structure was confirmed. It was found that TPE-Por-4 shows unique fluorescent properties originated from both of porphyrin and tetraphenylethylene building blocks, its suspensions emit strong fluorescence and display an apparent response to pH fluctuation ranging from 2 to 4, and thus, a promising method was provided for spectroscopic monitoring of medium pH value.

Hypochlorite (ClO−) and hydrogen peroxide (H2O2) commonly coexist in organism and are involved in the same physiological and pathological processes. So it is of great importance to develop fluorescent probes to detect both simultaneously. Herein, we reported the first dual-site fluorescent probe (Geisha-1) for the quantitative detection of ClO− and H2O2. This probe is constructed by chemically grafting N,N-dimethylthiocarbamate and borate to a fluorescence resonance energy transfer (FRET) platform. As a result, Geisha-1 not only presents three different responses to ClO−, H2O2, and ClO− + H2O2 (the coexistence of ClO− and H2O2) with high sensitivity and selectivity, but also exhibits low toxicity and cell membrane and tissue permeability, and it was further successfully applied to image ClO− and H2O2 in living cells and tissues. Thus, Geisha-1 provides a promising application prospect in biological systems and an alternative strategy for the construction of dual-site fluorescent probes aiming at the multi-response detection of other biologically relevant analytes.

A series of alkaline-earth-metal-modified Pd/Al2O3 nanocatalysts were prepared by an impregnation and kneading method. It was found that all of the catalysts doped by alkaline metals exhibit better...

A series of Fe-NC catalysts were synthesized by pyrolyzing an Fe complex and wheat flour at 500 °C. All of them were characterized and applied in the catalytic transfer hydrogenation of nitroarenes with formic acid. It was found that the catalytic activity was significantly affected by the size and distribution of Fe-based nanoparticles (NPs), which could be easily regulated by altering the Fe source. Meanwhile, more basic nitrogen sites were preserved on the catalyst so that the reaction ran smoothly without base additives. Among all catalysts, Fe-NC-FeCl2 exhibited the best catalytic performance due to smaller Fe3O4 NPs and greater N doping. Moreover, it showed excellent applicability for diverse nitroarenes. Obviously, this work demonstrates the importance of the metallic NPs' size and distribution, providing a new insight into the design of M-NC catalysts. The catalyst is economical and eco-friendly, and shows potential application value in industry.

The activation and utilization of hydrogen energy is an effective method to solve the global energy crisis and environmental pollution. Herein, biomass-derived Fe–N–C catalysts for H2 activation were synthesized via the imitation of sponge cake baking. The sample pyrolyzed at 500 °C (Fe–N–C-500) presented the well-defined cake-like architecture with uniform distribution of Fe3O4 nanoparticles (NPs). Doping N species dispersed around metallic NPs in high density. Fe–N–C-500 exhibited excellent performance in the catalytic hydrogenation of nitrobenzene. The activity of Fe–N–C-500 depended on Fe3O4 NPs and pyridinic N, rather than Fe–N. The typical core-shell structure deemed vital for H2 activation in previous reports was not necessary. Notably, water could significantly promote the H2 activation, which might establish the communication between hydrogen molecules adsorbed on Fe3O4 NPs and doping N species through hydrogen bonds. Moreover, low temperature pyrolytic Fe–N–C-500 exhibited excellent stability and provided a promising potential for selective hydrogenation of nitroarenes or alkyne by regulating the reaction condition. This work provides an innovative approach to construct heterogeneous catalysts for H2 activation.

Synthesis of an easily separable and efficient catalyst is of great significance for selective hydrogenation of unsaturated functional groups. In this work, novel magnetic flower-like carbonaceous Pd catalysts are constructed for the selective reduction of the CC bond. According to the characterization results, a flower-like architecture is observed in the catalysts containing both Fe3O4 and Pd NPs, which is constructed by the secondary self-assembly in the preparation process due to the interaction between Pd and magnetic nitrogen-doped graphene (Fe3O4-NG). More flower-like structures are formed by increasing the Pd loading amount, further enhancing the specific surface area of the catalyst. The specific surface area of Pd-FONG-3 is the highest (521.17 m2 g−1). Combining the results of characterization and experiments, it is found that the catalytic activity is positively related to the flower-like architecture and the interaction between Pd NPs (6.0 nm) and Fe3O4 NPs (6.7 nm). Fe3O4 is not only beneficial to the magnetic recovery of the catalyst, but also acts as a cocatalyst, which can significantly improve the reactant conversion. Moreover, N species play an important role in protecting the CO bond, resulting in the selective hydrogenation of the CC group. Herein, Pd-FONG-3 exhibits excellent activity in the selective hydrogenation of cinnamaldehyde (CAL) with 99.5% conversion and 96.5% hydrocinnamaldehyde (HCAL) selectivity, and its catalytic performance is much better than that of the commercial 5% Pd/C catalyst (100% conversion and 69.1% HCAL selectivity). This work provides a new strategy to construct highly active catalysts with magnetic recovery properties for selective hydrogenation of CC bonds, and Pd-FONG-3 shows tremendous application foreground.

Significance Zinc plays important roles in numerous cellular processes. Deficiency or excess of Zn 2+ leads to many diseases. Zn 2+ concentration at various cellular compartments is regulated. Imbalance of Zn 2+ in mitochondria has been linked to neurodegeneration. However, little is known about how mitochondrial Zn 2+ is regulated. We find that SLC-30A9 is required for Zn 2+ export from mitochondria in both Caenorhabditis elegans and human cells. Loss of slc-30a9 leads to excessive Zn 2+ accumulation in mitochondria, severe mitochondrial swelling, compromised mitochondrial metabolic function, reductive stress, and induction of the mitochondrial stress response. SLC-30A9 is also essential for organismal fertility and sperm activation. In neurons, slc-30a9 mutations cause dramatically reduced mitochondria in neurites, providing a potential mechanism for the Birk–Landau–Perez cerebrorenal syndrome.

Glucose and fatty acids are the major sources of energy for human body. Cholesterol, the most abundant sterol in mammals, is a key component of cell membranes although it does not generate ATP. The metabolisms of glucose, fatty acids and cholesterol are often intertwined and regulated. For example, glucose can be converted to fatty acids and cholesterol through de novo lipid biosynthesis pathways. Excessive lipids are secreted in lipoproteins or stored in lipid droplets. The metabolites of glucose and lipids are dynamically transported intercellularly and intracellularly, and then converted to other molecules in specific compartments. The disorders of glucose and lipid metabolism result in severe diseases including cardiovascular disease, diabetes and fatty liver. This review summarizes the major metabolic aspects of glucose and lipid, and their regulations in the context of physiology and diseases.

Photocatalytic composites with high activity have great potential in the purification of dye wastewater. Herein, reduced graphene oxide (rGO) modified TiO2 nanobelts (TG) hybrids with desirable nanostructures were successfully prepared by regulating the addition amount of Li+ via a facile solvothermal process. The results of characterizations indicate that the introduction of two-dimensional (2D) graphene sheet restricts the agglomeration of 1D nanostructures and drives the freestanding growth of TiO2 nanobelts. Meanwhile, the addition of Li+ not only promotes the formation of TiO2 nanobelts but also affects the distribution of TiO2 nanobelts on the surface of rGO. The TG-2 synthesized by adding an appropriate amount of Li+ exhibits the best photodegradation activity of these samples, even better than commercial P25. The excellent photocatalytic performance of TG-2 is mainly attributed to the effective separation of charge carriers promoted by the synergistic effect between uniform TiO2 nanobelts and rGO. The trapping experiments of reactive species show that ∙OH may be the dominant species in the photodegradation process. Moreover, the activity of the catalyst does not decrease after five cycles.

A series of Co-based N, S dual-doped carbon catalysts were prepared successfully via the pyrolysis of porous organic polymers (POPs) impregnated with cobalt salt and characterized by TEM, XRD, XPS, etc. The successful construction of cobalt-nitrogen (Co-Nx) sites is confirmed by XPS spectra. It was found that the content of Co-Nx sites is markedly affected by the type of cobalt salt, and the catalyst derived by the pyrolysis of the complex of POPs with Co(NO3)2·6H2O displays the best activity and outstanding selectivity for catalytic hydrogenation of various aromatic nitro compounds, it also demonstrates good recyclability. According to the results of control experiments, the activity for catalytic hydrogenation is mainly attributed to the Co-Nx sites. In addition, the doped S species in carbon shells can promote the formation of the active sites, which can effectively improve the performance of catalysts. Thus, this work can provide an effective and green approach for design highly effective transition metal-based multi-doped carbon catalysts with abundant metal-Nx sites.

Functionalization of covalent organic frameworks (COFs) with specific groups will endow them special characteristics, and further complexation with transition metals may improve their catalytic performance and widen their applications. Herein, we constructed an amino-functionalized covalent organic framework TpPa–NH2 by the facile reduction in TpPa–NO2 and took it as a carrier for transition metal ion Cu(II) to yield a hybrid Cu–COF. All characterizations verified that the crystallinity and porosity of original COF were retained after functionalization. Subsequent evaluation of their catalytic performance indicated that the framework TpPa–NH2 has potential application in alkali-catalyzed reactions, while the hybrid Cu–COF displayed satisfactory catalytic performance both in selective oxidation of styrene and the reduction in 4-nitrophenol to 4-aminophenol. The above results demonstrated that TpPa–NH2 is a promising platform with diverse applications, and the introduction of Cu(II) will endow the material with more potential applications in oxidation and reduction reactions.

Aerobic epoxidation of alkene is a green and economical route to produce epoxides. For such reaction, transition metal complexes exhibit favorable catalytic activity. In this work, NH2-MIL-101, a stable metal–organic framework (MOF) material with large surface area and high pore volume, was functionalized with pyridine-2,6-dicarbaldehyde and Co(NO3)2, to realize the immobilization of Co(II) via imine–pyridine–carbonyl (N,N,O) tridentate ligands bonding to MOF skeleton. The modified materials were applied as heterogeneous catalysts for the aerobic epoxidation of cyclohexene at ambient temperature, and multiple factors were studied to explore their influences on catalytic effects. Under the optimal reaction conditions, satisfactory substrate conversion and epoxide selectivity were reached. In addition, this catalytic system is suitable for a variety of alkene substrates. Furthermore, recycle experiments and infrared spectroscopy characterization illustrated that the coordination surroundings of Co are altering smoothly during the reaction process, thus having an impact on the performance of catalyst.

Herein, N,S-codoped carbon materials embedded with ultrafine and well-distributed Co nanoparticles (1.14 wt % Co) were prepared through pyrolysis of the hybrids of SNW-1 and Co(Ac)2 coated with glu...

ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC).DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specificFasnknockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type andFasnknockout mice. Human HCC cell lines were used for in vitro studies.ResultsAblation ofFasnsignificantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged inFasnknockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss ofFasnpromoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis inFasnknockout mice. Similarly, silencing ofFASNresulted in increasedSREBP2activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR)expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture.ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.

Heteroatom-doped porous carbon materials have exhibited promising applications in various fields. In this work, sulfur, nitrogen co-doped carbon materials (SNCs) with abundant pore structure were prepared by pyrolysis of sulfur, nitrogen-containing porous organic polymers (POPs) mixed with nano-CaCO3 at high temperature. Among the resultant materials, SNC-Ca-850 possesses a relatively high level of doped heteroatoms and exhibits an excellent catalytic performance for the selective oxidation of benzylic C-H bonds. It is noteworthy that nano-CaCO3 increases the doped sulfur content in the synthesized carbon materials to a large extent and impacts the existence modes of sulfur. In addition, it enhances the porous structure and specific surface area of the resultant SNCs significantly. This work provides a viable strategy to promote the doping of sulfur into carbon materials during the pyrolysis process.

A series of 3D nitrogen-doped graphene gels (NG) were synthesized by the hydrothermal process and further modified by pyrolysis. Characterization results indicated that the distribution of nitrogen- and oxygen-containing groups on the pyrolytic NG surface was significantly affected by the pyrolysis temperature. In the adsorption test, the NG adsorbent treated at 1000 °C showed the best performance for methylene blue. As the temperature increases from 200 to 1000 °C, the adsorptive capacity of pyrolytic NG hybrids was enhanced gradually, accompanied by the improvement of the adsorptive rate. Moreover, all NG adsorbents were fit for Langmuir isotherm. However, the adsorption dynamic behavior of pyrolytic NG hybrids followed pseudo-second-order model rather than pseudo-first-order model when the pyrolysis temperature exceeds 1000 °C. The above results are possibly attributed to the synergistic effect between specific surface area and the functional groups on the surface of adsorbents.

MOF-derived catalysts with nickel nanoparticles (NPs) uniformly embedded in nitrogen doped carbon shells were developed by pyrolysis of nickel-based metal–organic frameworks (MOFs), in which amino groups were introduced to act as the nitrogen source and possible anchoring sites for Ni NPs. The resulting materials were characterized systematically. In the architecture of the catalysts, a core–shell structure was discovered, in which Ni NPs with a diameter of 6–7 nm were surrounded by N doped graphitic layers, indicating that the introduction of amino groups into precursors is beneficial to the dispersion of NPs. One-step hydrogenation and reductive amination (OHRA) is a promising route to produce secondary amines, which avoids tedious separation of intermediates. Accordingly, we applied the prepared composites as catalysts to OHRA of benzaldehyde with nitrobenzene. Among them, the catalyst pyrolyzed at 600 °C for 1.5 h exhibited the best catalytic performance (conversion: >99%, selectivity for N-benzylaniline: 97.96%) and excellent recyclability. N-doping remarkably promotes the dispersion and stability of Ni NPs, thus improving their catalytic activity and selectivity. Furthermore, the Ni–N species as well as synergism of Ni NPs and adjacent pyridinic N may also facilitate the activation of H2. And its excellent stability and recyclability can be attributed to the core–shell structure. The achieved success in MOF-derived nanocomposites may pave the way for further industrial applications.

Rationale: Heat shock protein 9 (HSP90) are a family of the most highly expressed cellular proteins and attractive drug targets against cancer, neurodegeneration diseases, etc. HSP90 proteins have also been suggested to be linked to lipid metabolism. However, the specific function of HSP90 paralogs, as well as the underlying molecular cascades remains largely unknown. This study aims to unravel the paralog-specific role of HSP90 in lipid metabolism and try to discover paralog-specific HSP90 inhibitors. Methods: In non-alcohol fatty liver disease (NAFLD) patients, as well as in diet induced obese (DIO) mice, expression of HSP90 paralogs were analyzed by immunohistochemistry and western blot. In hepatocytes and in DIO mice, HSP90 proteins were knockdown by siRNAs/shRNAs, metabolic parameters, as well as downstream signaling were then investigated. By virtue screening, corylin was found to bind specifically to HSP90β. Using photo-affinity labeling and mass spectrum, corylin binding proteins were identified. After oral administration of corylin, its lipid lowering effects in different metabolic disease mice models were evaluated. Results: We showed that hepatic HSP90β, rather than HSP90α, was overexpressed in NAFLD patients and obese mice. Hepatic HSP90β was also clinical relevant to serum lipid level. Depletion of HSP90β promoted mature sterol regulatory element-binding proteins (mSREBPs) degradation through Akt-GSK3β-FBW7 pathway, thereby dramatically decreased the content of neutral lipids and cholesterol. We discovered an HSP90β-selective inhibitor (corylin) that only bound to its middle domain. We found that corylin treatment partially suppressed Akt activity only at Thr308 site and specifically promoted mSREBPs ubiquitination and proteasomal degradation. Corylin treatment significantly reduced lipid content in both liver cell lines and human primary hepatocytes. In animal studies, we showed that corylin ameliorated obesity-induced fatty liver disease, type 2 diabetes and atherosclerosis. Principle conclusions: HSP90β plays a parolog-specific role in regulating lipid homeostasis. Compound that selectively inhibits HSP90β could be useful in the clinic for the treatment for metabolic diseases.

Covalent organic frameworks (COFs) have attracted considerable interest over the past few years, but the available type of monomers is still limited. Herein, two novel imine-linked COFs (TaDAP and TaDA) were constructed by the condensation of 1,3,5-tris-(4-aminophenyl) triazine with 2,6-diformylpyridine (forming TaDAP) and 1,3-benzenedialdehyde (forming TaDA) under solvothermal conditions. The structures of the COFs were confirmed and characterized by solid state 13C NMR, FT-IR, PXRD, TGA, SEM, TEM and nitrogen sorption isotherms. They appear as regular spherical particles and possess excellent thermal stability. It was also found that their dispersions emit strong fluorescence, and display quick response to certain metal ions. In particular, TaDAP can detect Fe3+ with sensitivity and selectivity. Moreover, both the COFs present excellent catalytic activity towards the Knoevenagel reaction. Accordingly, this study not only provides a new way to enrich the family of COFs, but also develops their potential applications in metal ion detection.

According to numerous epidemiological studies, aspirin is a non-steroidal anti-inflammatory drug (NSAID) that reduces the occurrence and mortality of colorectal cancer (CRC). However, the underlying mechanisms are not well identified. In an effort to fill these gaps, we administered aspirin on mice one day before induction in an azoxymethane (AOM)/dextran sulfate sodium (DSS) induced CRC model. In this study, we assessed the effects of aspirin on tumorigenesis and tumor cell proliferation. Multi-layer analyses were carried out to identify changes in cytokines, metabolites, level of gene expressions, and proteins associated with tumorigenesis and aspirin treatment. The results showed that aspirin-treated mice developed fewer colon tumors in response to AOM/DSS, and aspirin can actively block cyclooxygenase (COX) metabolism and reduce levels of pro-inflammatory cytokines. In addition, the transcriptomic and proteomic analyses both indicated that aspirin has an inhibitory effect on the Wnt pathway. The in vitro results further indicated that aspirin inhibits WNT6 production, possibly by suppressing its transcription factor NR4A2, which in turn is regulated by prostaglandin E2, thereby ultimately inhibiting the Wnt pathway. These findings improve our understanding of the mechanisms behind aspirin's chemoprevention effect on CRC.

Metal-free afterglow materials have brought about widespread attention due to application advantages. Nevertheless, it is an attractive but formidable challenge to achieve long-persistent afterglow materials with high quantum yield (QY) at ambient conditions. Particularly, those with tunable afterglow are very rare. Herein, an economical strategy is proposed to construct a series of multi-color (cyan, green and orange) afterglow materials via one-step melting (within 5–10 min) of boric acid (BA) with unconventional precursors. The highly rigid framework, B − C bond and hydrogen bond interactions can efficiently inhibit non-radiative deactivation by locking the triplet excitons in carbon dots (CDs) clusters. 66.13% high QY and 1.74 s long lifetime have been achieved simultaneously, as well as the afterglow can be observed by naked eyes for ∼ 26 s. According to the adjustment of the precursor structure, dynamic afterglow color-changing (from orange, yellow, white to cyan) material was successfully realized. These excellent features allow them to be more applicable in time-resolved information security. In brief, this work provides a simple, flexible and effective strategy to construct highly efficient afterglow materials, and further facilitates their optical regulation and various potential applications.

ObjectiveTo evaluate exposure–response between 1,3-butadiene, styrene and lymphohaematopoietic cancers in an updated cohort of workers at six North American plants that made synthetic rubber polymers.MethodsEmployees were followed from 1943 through 2009 to determine mortality outcomes. Cox regression analyses estimated rate ratios (RRs) and 95% CIs by quartile of cumulative exposure to butadiene or styrene, measured in parts per million-years (ppm-years), and exposure–response trends for all leukaemia, lymphoid leukaemia, myeloid leukaemia, acute myeloid leukaemia, non-Hodgkin’s lymphoma (NHL), multiple myeloma and all B-cell malignancies.ResultsAmong 21 087 workers, adjusted RRs for butadiene and all leukaemia (132 deaths) rose with increasing exposure, with an RR of 2.53 (95% CI 1.37 to 4.67) in the highest exposure quartile (≥363.64 ppm-years), and the exposure–response trend was statistically significant for all leukaemia (p=0.014) and for lymphoid leukaemia (52 deaths, p=0.007). Styrene exposure–response trends for all leukaemia and lymphoid leukaemia were less consistent than those for butadiene. Cumulative exposures to butadiene and styrene were not associated consistently with myeloid leukaemias or the B-cell malignancies, NHL and multiple myeloma.ConclusionsWe confirmed a positive exposure–response relationship between butadiene and all leukaemia among workers, most of whom had coexposure to styrene. Results supported an association between butadiene and lymphoid leukaemia, but not myeloid leukaemia, and provided little evidence of any association of butadiene or styrene exposures with major subtypes of B-cell malignancies other than lymphoid leukaemia, including NHL and multiple myeloma.

A major obstacle for using human pluripotent stem cells (hPSCs) derived vascular cells for cell therapy is the lack of simple, cost-saving, and scalable methods for cell production. Here we described a simplified and chemically defined medium (AATS) for endothelial cells (ECs) and smooth muscle cells (SMCs) differentiation. AATS medium does not contain insulin, enabling the rapid and highly efficient vascular mesoderm formation through accelerating metabolic and autophagy-enhanced mesoderm induction. Transcriptome profiling confirmed that hPSC-derived ECs and SMCs in the AATS medium closely resembled primary ECs and SMCs formed in vivo. ECs appeared to adhere and grow better in the AATS medium over other cell types, which allowed the purification of CD31+CD144+ double-positive cells. Furthermore, the AATS medium was compatible with 3D microscaffold (MS) culture, which may facilitate large-scale bioproduction of ECs. HPSC-derived ECs and SMCs in the AATS medium exhibited strong revascularization potential in treating murine ischemic models. Our study provided a cost-effective and efficient medium system to manufacture GMP compatible, off-the-shelf ECs, and SMCs to model human diseases and vascular repair.

Ablation of Slc22a14 causes male infertility in mice, but the underlying mechanisms remain unknown. Here, we discovered that SLC22A14 is a riboflavin transporter localized at the mitochondrial inner membranes of spermatozoa midpiece, and showed via genetic, biochemical, multi-omic and nutritional evidence that riboflavin transport deficiency suppresses the oxidative phosphorylation and reprograms spermatozoa energy metabolism by disrupting flavoenzyme functions. Specifically, we found that fatty acid β-oxidation (FAO) is defective with significantly reduced levels of acyl-carnitines and metabolites from TCA cycle, but accumulated triglycerides and free fatty acids in Slc22a14 knockout spermatozoa. We demonstrated that Slc22a14-mediated FAO is essential for spermatozoa energy generation and motility. Furthermore, sperm from wildtype mice treated with riboflavin deficient diet mimics those in Slc22a14 knockout mice, confirming that altered riboflavin level causes spermatozoa morphological and bioenergetic defects. Beyond substantially advancing our understanding of spermatozoa energy metabolism, our study provides an attractive target for development of male contraceptives.

Three fluorinated phenothiazine compounds (P-1, P-2, P-3) were synthesized and characterized. It was found that all of them displayed significant solvatochromism and aggregation-induced emission behaviors. It was worth noting that P-1 and P-2 exhibited obvious mechanochromic properties compared to P-3. Specifically, P-1 displayed two different colors upon grinding and smashing, and emission bands showed different shift direction. P-2 exhibited polymorphic emission, its powder emitted yellow fluorescence, whereas crystal emitted orange fluorescence. After grinding, these two states had red shifts of 76 nm and 35 nm, respectively. But P-3 only presented a red shift of 10 nm. In addition, P-1 and P-2 also had thermochromic properties. After heating, their maximum emission wavelengths all would red-shift, and the maximum red shift can be up to 71 nm. These results can be explained by wide-angle X-ray diffraction, the differential scanning calorimetry and single crystal diffraction analysis. This work provided a new idea for the preparation of materials with both mechanochromic and thermochromic characteristics.

Derivatives of oxazine dyes were synthesized on mulitigram scales via efficient synthetic strategies. One practical route was selected to prepare compounds 6, 9 and 10, especially water-soluble compound 6 was obtained in better yield than reported, and compound 10 was insoluble in aqueous media in absence of phenolic-OH. Compounds 3 and 9 were found to be clear pH-dependent between pH = 4.0 and 10.0, and could be used as acid-base indicators to measure intracellular pH. Compounds 6, 9, 10 all have carboxylic acid functionalities, which could be activated and used to conjugate the dyes to biomolecules. In addition, compounds 6 and 9 with good solubility in aqueous media were used to develop a simple, quick, safe, highly sensitive staining method to detect PHAs-producing bacteria on heat-fixed smears, which was confirmed by fluorescence images of PHAs granules of bacteria.

Monometallic Pd@ZIF-8, Ni@ZIF-8 and bimetallic PdxNiy@ZIF-8 catalysts have been successfully synthesized by a simple liquid impregnation-reduction method. The structure of catalysts and the electronic states of introduced metals were characterized and their catalytic performances were evaluated in Cu free and ligands free Sonogashira coupling reaction under atmosphere. Compared with monometallic catalyst, the as-synthesized bimetallic Pd5Ni95@ZIF-8 catalyst exhibited excellent catalytic performance with 94.50% yield. Therefore, the above experimental results suggested a synergistic effect derived from palladium and nickel, which enhanced Sonogashira coupling reaction obviously. Moreover, modification of Ni@ZIF-8 with trace of palladium can effectively promote its catalytic activity, indicating an economical way to develop efficient catalysts.

A series of 2,6-diarylethene-4H-pyran-4-one organic functional materials (pp-s) were designed and successfully synthesized, characterized by PL spectra. It was found that all of them displayed the aggregation induced emission enhancement (AIEE) phenomenon, and three of them presented different emission spectra in different solvents i.e. solvatochromism, which was confirmed by density functional theory (DFT) calculation on the ICT process. Remarkably, an inverted U-shaped mechanochromic behavior (MFC) and red-shifted phenomenon of their emission spectra (bathochromism) was observed along with the increasing of conjugation degree. In which, the compound containing triphenylamine units (pp-3) showcasing the best MFC nature. PXRD profiles indicated the transformation between two different crystalline states upon grinding. Thus, we offer a way to manipulate the chromism performance via conjugation-regulating strategy.

Two Wang resin-supported (1R,2R)-(+)-1,2-DPEN(DPEN=diphenylthylenediamine) catalysts were synthesized from cyanuric chloride and trimesoyl chloride, respectively. These two catalysts were characterized by FTIR, TGA and elemental analysis. The results demonstrated that (1R,2R)-(+)-1,2-DPEN was successfully bonded to the surface of Wang resin through the amido linkage. Subsequently, the asymmetric Michael addition of acetone to β-nitrostyrene was employed to evaluate their catalytic performance. It was found that the catalyst generated from trimesoyl chloride exhibited much better catalytic behavior than our previously reported catalyst, likely attributed to the multiple hydrogen-bond interaction between β-nitrostyrene and amide group, which made the catalytic transition intermediates more stable. Under the optimal conditions, 76.1% β-nitrostyrene conversion and 93.8% enantioselectivity were obtained. Finally, the generality of this catalyst was examined with Michael additions of acetone to β-nitroolefins and excellent enantioselectivities(91.9% to 99.9%) were achieved.

It's of great importance to detect SO2 and its derivatives (bisulfite/sulfite) because of their harmful effects on the environment and human health. In this work, three probes based on hemicyanine were designed and synthesized to detect SO2 derivatives in aqueous solution (containing 10% DMSO) through a 1,4-addition reaction. All probes displayed rapid and selective responses toward SO2 derivatives, and could quantitatively detect HSO3− with detection limits of 8.7 μM, 6.5 μM and 4.0 μM, respectively. Meanwhile, the color of the probe solution changed immediately (within 10 s), which provides a simple way to recognize bisulfite with the naked eye. Finally, visual detection of SO2 gas has been successfully realized.

Small cell lung cancer (SCLC) is of a highly invasive and metastatic lung cancer subtype and there had not been effective targeted therapies. CD56, a cell surface marker highly expressed on most SCLC, is a promising therapeutic target for treatment of this aggressive cancer. In this study, we generated a novel anti-CD56 antibody named promiximab, characterized by high affinity, internalization and tumor specificity. Then, the promiximab was conjugated with a potent DNA alkylating agent duocarmycin via reduced interchain disulfides to yield the promiximab-Duocarmycin (promiximab-DUBA) conjugates. Mass spectrometry analysis showed promiximab-DUBA had an average DAR (Drug-to-Antibody Ratio) of about 2.04. In vitro, promiximab-DUBA exerted strong inhibitory effects on SCLC cell lines NCI-H526, NCI-H524 and NCI-H69, with IC50 values of 0.07 nmol/L, 0.18 nmol/L and 0.29 nmol/L, respectively. In vivo antitumor activity, promiximab-DUBA at the dose of 5 mg/kg and 10 mg/kg every three days with a total of three times were sufficient to induce sustained regression of NCI-H526 tumors over control treatment with promiximab. Mostly, no recurrence was observed until 65 days post treatment with promiximab-DUBA. In the NCI-H69 subcutaneous xenograft model, significant inhibition of tumor growth was also observed following administration of promiximab-DUBA at the dose of 5 mg/kg or 10 mg/kg. Moreover, body weight and histopathology of major organs (liver, spleen, heart, lung and kidney) showed no significant changes after treatment of promiximab-DUBA. In conclusion, promiximab-DUBA is highly efficacious in small cell lung cancer xenograft models, and provides a new immunotherapy approach for SCLC.

An efficient [3+3] tandem reaction between 1-phenyl-3-methyl-5-pyrazolones and 2-(1-alkynyl)-2-alken-1-ones over a tertiary amine–squaramide catalyst is described. The pyran fused pyrazolone derivatives were successfully obtained in 53–88% yields and with 62–84% ee by this synthetic methodology. This methodology involves easily accessible starting material, mild condition, satisfied yields and ee values. Additionally, when enynes were used as the substrates for the [3+3] cascade reaction, isomerized target products could be obtained directly.

A novel multiple stimuli-responsive fluorophore TPI was rationally designed and synthesized. Based on its excellent response behavior to polarity, it has been successfully applied in the quantitative determination of trace water in organic solvents, active pharmaceutical ingredient and vacuum pump oil. More impressively, it can be utilized for a promising candidate for efficient “turn on” type luminescence thermometers with broad-temperature detection range (covering physiological temperature), good linearity and reversibility, more striking and accurate. Furthermore, the introduction of an aliphatic primary amine group endowed TPI the ability to capture and recognize acid vapors. Remarkably, the prepared test scrip was sensitively and quantitatively respond to acid vapors (TFA, HCl and formic acid), especially to the polluting gas SO2. Their limits of detection are 118 ppb, 54.6 ppb, 86.8 ppb and 421 ppb, respectively. Obviously, this study realized rapid, simple and visual quantitative sensing of polarity, temperature, acid vapors, especially SO2 by virtue of single component fluorescent molecule.

Objective – To evaluate exposure-response relationships between 1,3-butadiene and styrene and selected diseases among synthetic rubber polymer workers. Methods – 21,087 workers (16,579 men; 4508 women) were followed from 1943 through 2009 to determine mortality outcomes. Cox regression models estimated rate ratios (RRs) and 95% confidence intervals (CIs) by quartile of cumulative exposure to butadiene or styrene and exposure-response trends for cancers of the bladder, lung, kidney, esophagus and pancreas, and for all nonmalignant respiratory disease (NMRD), chronic obstructive pulmonary disease (COPD) and pneumonia. Results – Bladder cancer RRs were 2.13 (95% CI = 1.03 to 4.41) and 1.64 (95% CI = 0.76 to 3.54) in the highest quartiles of cumulative exposure to butadiene and styrene, respectively, and exposure-response trends were positive for both monomers (butadiene, trend p = 0.001; styrene, trend p = 0.004). Further analyses indicated that the exposure-response effect of each monomer on bladder cancer was demonstrated clearly only in the subgroup with high cumulative exposure (at or above the median) to the other monomer. Lung cancer was not associated with either monomer among men. Among women, lung cancer RRs were above 1.0 in each quartile of cumulative exposure to each monomer, but exposure-response was not seen for either monomer. Male workers had COPD RRs slightly above 1.0 in each quartile of cumulative exposure to each monomer, but there was no evidence of exposure-response among the exposed. Monomer exposure was not consistently associated with COPD in women or with the other cancer outcomes. Conclusions – This study found a positive exposure-response relationship between monomer exposures and bladder cancer. The independent effects of butadiene and styrene on this cancer could not be delineated. In some analyses, monomer exposure was associated with lung cancer in women and with COPD in men, but inconsistent exposure-response trends and divergent results by sex do not support a causal interpretation of the isolated positive associations.

Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFβ pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 μM) as compared with those in controls. Zoledronate treatments in cells (50 μM) and mice (3 mg/kg) increased TGFβ/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid β-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy. Electronic supplementary material The online version of this article (doi:10.1007/s00204-017-2048-0) contains supplementary material, which is available to authorized users.

Two near-infrared (NIR) pH-activated heptamethine indocyanine probes with quaternary ammonium unit were designed and synthesized. The absorption and emission titrations indicate that cationic structure improves the cyanine dye’s aqueous solubility and these two probes exhibit highly sensitive response to pH in acid condition. Their fluorescence intensities both gradually increase about 25-fold from pH 7.60 to 3.00 with pKa values of 4.72 and 4.45 respectively, which are suitable for studying acidic organelles in living cells. Moreover, their fluorescence intensities are linearly proportional to pH values in the range of 5.50–4.00. These results are probably attributed to the protonation of the indole nitrogen atoms, which are verified by 1H NMR spectra. Furthermore, these two probes can achieve real-time imaging of cellular pH and detection of pH in situ in living HeLa cells due to their excellent properties, including good reversibility, desirable photostability, high selectivity, low cytotoxicity and remarkable membrane permeability.

Four derivatives of 9,10-bis[2-(2-alkoxynaphthalen-1-yl)vinyl]anthracene (BNAs) were designed, successfully synthesized and characterized by spectrofluorometer, powder wide-angle X-ray diffraction (PXRD) and differential scanning calorimetry experiments (DSC), etc. It was found that these compounds exhibited aggregation-induced emission phenomenon. Moreover, these target compounds displayed reversible color change from yellow to orange upon pressing and annealing process. Interestingly, all of BNAs obviously presented red-shifted piezofluorochromic (PFC) properties and behaved mainly length dependence of alkoxy group, in which, BNA displayed the largest PFC spectral shift (ΔlPFC = 26 nm). The PXRD profiles demonstrated the transformation from crystalline to amorphous state upon grinding, and the mechanism of PFC behaviors was proposed. Thus, changing the length of alkoxyl chain could be an alternative way to tune their PFC behaviors.

Two-dimensional imine-linked covalent organic frameworks with hydroxyl groups, TAPT-DHTA-COFHX and TAPT-DHTA-COFDMF, were respectively constructed by the condensation of 1,3,5-tris-(4-aminophenyl)triazine and 2,5-dihydroxyl-terephthalaldehyde under solvothermal and reflux conditions. Both COFs possess excellent thermal stability and a similar eclipsed stacking structure verified by XRD patterns. However, TAPT-DHTA-COFHX presented a larger surface area (2238 m2/g) and higher crystallinity than TAPT-DHTA-COFDMF. Significantly, copper ions are efficiently incorporated into the pores of these two COFs via the coordination interaction with hydroxyl groups and imine linkers. The obtained copper-containing COFs (Cu-COFHX and Cu-COFDMF) were employed in the selective oxidation of styrene to benzaldehyde. Cu-COFHX with superior surface area (1886 m2/g) and pore volume (1.11 cm3/g) exhibited excellent catalytic performance and recyclability. This strategy not only provides a convenient approach to design imine-link...

Magnetic 3D nitrogen doped graphene gels (MNG) were easily obtained via one-pot hydrothermal synthesis process. It was found that N doping process, reduction of graphene oxide and Fe3O4 nanoparticles (NPs) generation in situ proceeded simultaneously, accompanied by the three-dimensional self-assembly. The MNG hybrids were confirmed to be interconnected poriferous frameworks of graphene sheets with uniform dispersion of Fe3O4 NPs embedded or encapsulated in N-doped graphene layers. The catalytic performance of MNG nanocatalysts was evaluated by the reduction of 4-nitrophenol to 4-aminophenol. It was worth noting that the catalytic activity of MNG hybrids was remarkably enhanced by Fe3O4 NPs loading due to the change of N doping mode induced by the in situ synthesis of these magnetic NPs, which did not alter the C/N mass ratio in fact. Meanwhile, the reaction no longer simply followed the pseudo-zero-order kinetics in late stage, this might be attributed to the enhancement of catalytic activity. Furthermore, MNG nanocatalysts were easily recycled by virtue of their superparamagnetism and exhibited excellent stability.