Carbon monoxide(CO)is a crucial gaseous signaling molecule that regulates various physiological and pathological processes,and may exert an anti-inflammatory and protective role in drug-induced liver injury(DILI).Desp...Carbon monoxide(CO)is a crucial gaseous signaling molecule that regulates various physiological and pathological processes,and may exert an anti-inflammatory and protective role in drug-induced liver injury(DILI).Despite this,understanding the exact relationship between CO and the occurrence and development of DILI remains challenging.Hence,there is an urgent need to develop a reliable and robust tool for the rapid visual detection and assessment of CO in this context.Herein,we presented a novel near-infrared(NIR)fluorescent nanoprobe with aggregation-induced emission(AIE)properties and excited-state intramolecular proton transfer(ESIPT)characteristics for the detection and imaging of CO both in vitro and in vivo.Simultaneously,the nanoprobe enables self-assembly form nanoaggregates in aqueous media with high biocompatible,which can sense CO in situ through the conversion of yellowto-red fluorescence facilitated aggregation-induced dual-color fluorescence.What is more,this nanoprobe shows ratiometric respond to CO,which demonstrates excellent stability,high sensitivity(with a detection limit of 12.5 nmol/L),and superior selectivity.Crucially,this nanoprobe enables the visual detection of exogenous and endogenous CO in living cells and tissues affected by DILI,offering a user-friendly tool for real-time visualization of CO in living system.Hence,it holds great promise in advancing our understanding of CO’s role.展开更多
To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithromb...To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithrombin （TAT） complex. Thirty normal pregnant women served as controls. ELISA was employed for the detection. The results showed that the TAFI antigen levels in normal pregnancy group, gestational hypertension group and PE group were （85.35±24.69）%, （99.65±18.27）%, （110.12±23.36）%; （97.06±21.40）%, （114.08±27.76）%, （125.49±24.70）%; （106.6±19.21）%, （129.2±25.07）%, （139.1±30.12）%, in the 1st, 2nd and 3rd trimester respectively. No significant differences were found between the normal pregnancy group and gestational hypertension group but significant difference existed between normal pregnancy group and PE group in each trimester （P〈0.05）. TAT complexes were significantly higher in patients with PE than that in controls （P〈0.05）, but no correlation was found between TAT and TAFI. It is concluded that TAFI may contributed to the impairment of fibrinolysis in the patients with PE and may serves as a sensitive indicator for PE, but it may not help in the diagnosis of the gestational hypertension.展开更多
AIM: To evaluate the effects of butein on inflammatory cytokines, matrix metalloproteinase-9(MMP-9), andcolitis in interleukin(IL)-10-/- mice.METHODS: To synchronize colitis, 8- to 10-wk-old IL-10-/- mice were fed pel...AIM: To evaluate the effects of butein on inflammatory cytokines, matrix metalloproteinase-9(MMP-9), andcolitis in interleukin(IL)-10-/- mice.METHODS: To synchronize colitis, 8- to 10-wk-old IL-10-/- mice were fed pellet-chow containing piroxicam for 2 wk. Subsequently, phosphate-buffered saline or butein(1 mg/kg per day, ip) was injected for 4 wk. Histologic scores, inflammatory cytokines, MMP-9 and phosphorylated signal transducer and activator of transcription 3(p STAT3) expressions were analyzed in IL-10-/- mice and in Colo 205 cells.RESULTS: Butein reduced the colonic inflammatory score by > 50%. Expression levels of IL-6, IL-1β, interferon(IFN)-γ and MMP-9 were decreased in the colons of mice exposed to butein, whereas other inflammatory cytokines(IL-17 A, IL-21 and IL-22) were unchanged. Immunohistochemical staining for p STAT3 and MMP-9 was significantly decreased in the buteintreated groups compared with the controls. Butein inhibited IL-6-induced activation of STAT3 in Colo 205 cells.CONCLUSION: Butein ameliorated colitis in IL-10-/-mice by regulating IL-6/STAT3 and MMP-9 activation.展开更多
CO2sequestration by mineral carbonation can permanently store CO2and mitigate climate change. However, the cost and reaction rate of mineral carbonation must be balanced to be viable for industrial applications. In th...CO2sequestration by mineral carbonation can permanently store CO2and mitigate climate change. However, the cost and reaction rate of mineral carbonation must be balanced to be viable for industrial applications. In this study, it was attempted to reduce the carbonation costs by using mine waste rock as a feed stock and to enhance the reaction rate using wet mechanical activation as a pre-treatment method. Slurry rheological properties, particle size distribution, specific surface area, crystallinity, and CO2 sequestration reaction efficiency of the initial and mechanically activated mine waste rock and olivine were characterized. The results show that serpentine acts as a catalyst, increasing the slurry yield stress, assisting new surface formation, and hindering the size reduction and structure amorphization. Mechanically activated mine waste rock exhibits a higher carbonation conversion than olivine with equal specific milling energy input. The use of a high-speed stirred mill may render the mineral carbonation suitable for mining industrial practice.展开更多
AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T<sub>3</sub>)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit meta...AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T<sub>3</sub>)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver.展开更多
Caspases are a family of proteases that play critical roles in controlling inflammation and cell death.Apoptosis is a caspase-3 mainly controlled behavior to avoid inflammation and damage to surrounding cells,whereas ...Caspases are a family of proteases that play critical roles in controlling inflammation and cell death.Apoptosis is a caspase-3 mainly controlled behavior to avoid inflammation and damage to surrounding cells,whereas anomalistic cell apoptosis may be associated with many diseases.The detection and imaging of caspase-3 will be of great significance in evaluating the early therapeutic effect of tumors.Developing smart fluorescent probes may be helpful for the visualization of the rapeutic effect compared with "always on" probes.Thus,more and more works toward activatable fluorescent probes for caspase-3 imaging have been reported.In addition,multifunctional probes have also been designed to further improve the imaging of caspase-3.Herein,this review systematically summarized the representative wo rk of caspase-3 from the perspective of molecular design that it will play a guiding role in the design of probes that respond to caspase-3.Also,challenges and perspectives toward the field for imaging of cell apoptosis(caspase-3) are also discussed.展开更多
Recent years have seen the design and implementation of many optical activatable smart probes.These probes are activatable because they change their optical properties and are smart because they can identify specific ...Recent years have seen the design and implementation of many optical activatable smart probes.These probes are activatable because they change their optical properties and are smart because they can identify specific targets.This broad class of detection agents has allowed previously unperformed visualizations,facilitating the study of diverse biomolecules including enzymes,nucleic acids,ions and reactive oxygen species.Designed to be robust in an in vivo environment,these probes have been used in tissue culture cells and in live small animals.An emerging class of smart probes has been designed to harness the potency of singlet oxygen generating photosensitizers.Combining the discrimination of activatable agents with the toxicity of photosensitizers represents a new and powerful approach to disease treatment.This review highlights some applications of activatable smart probes with a focus on developments of the past decade.展开更多
Rich oxygen-biological activated carbon(RO-BAC)method developed from traditional BAC method is a sys-tem in which high pressure is applied to improve the oxy-gen concentration of the influent.Experiment withwastewater...Rich oxygen-biological activated carbon(RO-BAC)method developed from traditional BAC method is a sys-tem in which high pressure is applied to improve the oxy-gen concentration of the influent.Experiment withwastewater and the slightly deteriorated raw water showsthe system is an effective option for advanced treatmentof industry wastewater and pretreatment of slightly dete-riorated raw water.The experiment results and the in-fluential factors are discussed in this paper.展开更多
Antibacterial agent of activatable photosensitizer not only has the advantages of traditional photosensitizers,such as good curative effect and low resistance,but also has better selectivity for bacteria and lower tox...Antibacterial agent of activatable photosensitizer not only has the advantages of traditional photosensitizers,such as good curative effect and low resistance,but also has better selectivity for bacteria and lower toxicity to normal tissues.Limited reports of activatable photosensitizer can be used to treat drugresistant bacteria.In order to meet this challenge,we designed and synthesized an activatable photosensitizer(Ce-OHOA),which can not only selectively identify methicillin-resistant Staphylococcus aureus(MRSA)with high expression ofβ-lactamase by fluorescence imaging,but also kill MRSA with less than10 times the concentration and 10 times the irradiation dose of CySG-2 reported.Ce-OHOA not only combines the dual functions of fluorescence diagnosis and photodynamic therapy,but also selectively acts on bacteria with high expression ofβ-lactamase and has little toxicity to normal cells.We expect that the study of this activating photosensitizer will provide a new solution for antibacterial photodynamic therapy(aPDT)of drug-resistant bacteria.展开更多
Early cancer diagnosis in molecular level shows great promise in relevant prevention and clinical treatment. Herein, we developed a novel method to detect and evaluate biomarkers on cancer cell surface. Based on the e...Early cancer diagnosis in molecular level shows great promise in relevant prevention and clinical treatment. Herein, we developed a novel method to detect and evaluate biomarkers on cancer cell surface. Based on the excellent selectivity of AS1411 aptamer to targeted nucleolin-overexpressed cells, we used a fluorescent probe with a pH-sensitive function to label the AS1411 aptamer modified with azide by click-reaction. The spectral characteristics of fluorophore naphthalimide has a good pH dependence. By this way, nucleolin-overexpressed cell could be discriminated from normal cell. Further, this strategy could also discriminate the breast cancer tissue from the adjacent benign tissue in formalin-fixed and parrffin-embedded（FFPE） tissue specimens. It is considered that our method has the potential to be applied in medical detection.展开更多
The biggest challenge in using CRISPR technologies,which limits their widespread application in medicine,is off-target effects.These effects could,in principle,be minimized by ensuring that CRISPR is activated primari...The biggest challenge in using CRISPR technologies,which limits their widespread application in medicine,is off-target effects.These effects could,in principle,be minimized by ensuring that CRISPR is activated primarily in the targeted cells,thereby reducing the likelihood of unintended genetic modifications in non-target tissues.Therefore,the development of a light activatable CRISPR approach to dynamically control gene activation in both space and time would be highly beneficial.A drawback is that the overwhelming majority of recently introduced light activatable CRISPR systems require UV or blue light exposure,severely limiting the penetration depth of light in tissue at which CRISPR can be activated,and,in the case of UV light,raising safety concerns.A small number of systems that activate CRISPR using longer wavelengths are hindered by either slow light activation or issues related to toxicity and biocompatibility of the proposed techniques in humans.To address this,we developed a split-Cas9/dCas9 system in which activation is achieved through a near-infrared photocleavable dimerization complex.This photoactivation method can be safely used in humans in vivo,easily adapted to different split-Cas9/dCas9 systems,and enables rapid,spatially precise light activation across various cell types.展开更多
Dysregulated energy metabolism has recently been recognized as an emerging hallmark of cancer.Tumor cells,which are characterized by abnormal glycolysis,exhibit a lower extracellular pH(6.5–7.0)than nor-mal tissues(...Dysregulated energy metabolism has recently been recognized as an emerging hallmark of cancer.Tumor cells,which are characterized by abnormal glycolysis,exhibit a lower extracellular pH(6.5–7.0)than nor-mal tissues(7.2–7.4),providing a promising target for tumor-specific imaging and therapy.However,most pH-sensitive materials are unable to distinguish such a subtle pH difference owing to their wide and continuous pH-responsive range.In this study,we developed an efficient strategy for the fabrication of a tumor metabolic acidity-activatable calcium phosphate(CaP)fluorescent probe(termed MACaP9).Unlike traditional CaP-based biomedical nanomaterials,which only work within more acidic organelles,such as endosomes and lysosomes(pH 4.0–6.0),MACaP9 could not only specifically respond to the tumor extra-cellular pH but also rapidly convert pH variations into a distinct fluorescence signal to visually dis-tinguish tumor from normal tissues.The superior sensitivity and specificity of MACaP9 enabled high-contrast visualization of a broad range of tumors,as well as small tumor lesions.展开更多
An activatable photosensitizer that could induce phototoxicity only in target sites is highly demanded to overcome the potential off-target toxicity in photodynamic therapy.It is of great significance to design tailor...An activatable photosensitizer that could induce phototoxicity only in target sites is highly demanded to overcome the potential off-target toxicity in photodynamic therapy.It is of great significance to design tailored photosensitizers with a new caging mechanism that can be activated by molecular signatures of pathogenic tissues.Herein,we report a novel supramolecularly activatable photosensitizer that employs cucurbit[7]uril(CB[7])to regulate the J-aggregate and monomer state of a thio-pentamethine cyanine dye withα-naphthyl group on side arms(Naph-α-TCy5),switching its photosensitizing property between off-on states.The host–vip complex Naph-α-TCy5-CB[7]is a caged photosensitizer with a superior luminescence property in an aqueous solution.It could be effectively activated by polyamines in cancer cells through competitive host–vip complexation;then the restored J-aggregates of Naph-α-TCy5 could efficiently generate singlet oxygen.Eventually,the supramolecularly activatable Naph-α-TCy5-CB[7]demonstrated appreciable antitumor bioactivity in vivo with excellent biosafety.It is anticipated that this design strategy of supramolecularly activatable photosensitizers opens new horizons for efficient photodynamic therapy with specificity and safety.展开更多
Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin...Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin(SN38),the active metabolite of irinotecan,has been limited in clinical development due to poor water solubility and stability.Here,the thioether bond and disulfide bond were employed as response modules to construct tumor-selective SN38 prodrug nanoassemblies(SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs).11-Henicosanol was chosen as a self-assembly module to enhance stability.Both SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs presented ultra-high in vivo stability with a 12146-fold and 23151-fold elevation in the area under the curve(AUC)compared to SN38.Moreover,SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs showed a significant reduction of SN38exposure in blood compared to irinotecan.Importantly,the prodrug nanoassemblies enabled selective activation within tumor cells,and the conversion rates of SN38-SS-C_(21) NPs and SN38-S-C_(21) NPs to SN38 were 10-and 7-fold higher than irinotecan.Compared with SN38-S-C_(21) NPs,the superior in vivo stability,SN38 conversion efficiency and tumor selectivity of SN38-SSC_(21) NPs resulted in potent antitumor effects and safety.Our findings proved that the disulfide bond was more suitable for constructing high-performance SN38 prodrug nanoassemblies,which showed significant promise for the rational design of SN38 nanomedicines.展开更多
Real-time intraoperative guidance is indispensable for ensuring complete and safe tumor resection during oncological surgery.Activatable fluorescence probes have demonstrated promise in guiding surgery during intricat...Real-time intraoperative guidance is indispensable for ensuring complete and safe tumor resection during oncological surgery.Activatable fluorescence probes have demonstrated promise in guiding surgery during intricate procedures,offering high-contrast images with the“turn-on”fluorescence signal upon reaction with tumor markers.However,single-factor activatable probes still encounter the limitation of potentially generating“false positive”results in the complex in vivo environment.Herein,we have developed a dualfactor recognition activatable probe,NBD-BDP-E,to further enhance specificity to tumors via a cascade process.The incorporation of an epidermal growth factor receptor(EGFR)inhibitor,erlotinib,in the probe ensures tumor recognition and accelerated cellular uptake firstly.Following the probe response to the high concentration of Glutathione in cells,molecular fluorescence emission is restored for fluorescence image guidance.Ultimately,the d-PeT-based activatable probe,NBD-BDP-E,exhibited the ability to light up an EGFR-overexpressed tumor tissue accurately with a superior tumor-to-normal tissue ratio for image-guided surgery via in situ spraying.Moreover,it shows the ability to image tumor tissue about 1 mm in diameter,highlighting the potential for this probe to be used as a tool in surgical resection.展开更多
Comprehensive Summary,Stimuli-controlled disassembly process has shown promise to direct delivery of probes and/or spatial-temporally control imaging signals for molecular imaging in vivo.Via the disassembly process,w...Comprehensive Summary,Stimuli-controlled disassembly process has shown promise to direct delivery of probes and/or spatial-temporally control imaging signals for molecular imaging in vivo.Via the disassembly process,well defined nanoprobes with a stimulus-responsive moiety can be controllably converted into small-molecular imaging agents in response to a stimulus,leading to a switch in imaging signals.Moreover,the on-site released small-molecule probes could enhance penetration into the deep tissue for improved imaging of deep-seated molecular targets.Therefore,such a stimuli-controllable disassembly approach has been widely utilized to build activatable molecular imaging probes for the noninvasive detection of various molecular targets in living subjects.In this review article,we first briefly introduce the general principle of stimuli-controlled disassembly.We then summarize the activatable probes based on different internal or external stimulus that has been utilized to control disassembly process.Activatable probes by using multiple stimuli to control cascaded in situ self-assembly and disassembly processes are also discussed.Finally,we close with a conclusion of current challenges and perspective in this field.展开更多
Precise measurement of enzyme activity in living systems with molecular imaging probes is becoming an important technique to unravel the functional roles of different enzymes in biological processes. Recent progress h...Precise measurement of enzyme activity in living systems with molecular imaging probes is becoming an important technique to unravel the functional roles of different enzymes in biological processes. Recent progress has been made in the development of a myriad of molecular imaging probes featuring different imaging modalities, including optical imaging, magnetic resonance imaging, nuclear imaging, and photoacoustic imaging, allowing for non-invasive detection of various enzyme activities in vivo with high sensitivity and high spatial resolution. Among these imaging probes, activatable or ＂smart＂ probes, whose imaging signal can be specifically switched from the ＂off＂ to ＂on＂ state upon interaction with a target enzyme, are particularly attractive due to their improved sensitivity and specificity. Here, recent advances in the development of activatable probes capable of imaging different enzyme activities in vivo are summarized based on different imaging modalities, and current challenges and future perspectives are discussed.展开更多
Chemotherapy is one of the commonly used methods to treat various types of cancers in clinic by virtue of its high efficiency and universality. However, strong side effects and low concentration of conventional drugs ...Chemotherapy is one of the commonly used methods to treat various types of cancers in clinic by virtue of its high efficiency and universality. However, strong side effects and low concentration of conventional drugs at the tumor site have always been important factors that plague the chemotherapy effects of patients, further precluding their practical applications. Thereof, to solve the above dilemma, by integration of anticancer drug(nitrogen mustard, NM) into an NIR fluorophore(a dicyanoisophorone derivative), an intelligent prodrug NIR-NM was developed via molecular engineering strategy. Prodrug NIR-NM stimulated in hypoxia condition exhibits significantly higher toxicity to cancer cells than normal cells, essentially reducing the collateral damage to healthy cells and tissues of nitrogen mustard. More importantly, the nanoparticle prodrug FA-lip@NIR-NM showed the advantages of the high accumulation of drug at tumor site and long-circulation capacity in vivo, which endowed it the ability to track the release of the active chemotherapeutic drug and further treat solid tumors.展开更多
We present here a pH-responsive activatable aptamer probe for targeted cancer imaging based on i-motif-driven conformation alteration. This pH-responsive activatable aptamer probe is composed of two single-stranded DN...We present here a pH-responsive activatable aptamer probe for targeted cancer imaging based on i-motif-driven conformation alteration. This pH-responsive activatable aptamer probe is composed of two single-stranded DNA. One was used for target recognition, containing a central, target specific aptamer sequence at the 3＇-end and an extension sequence at the 5＇-end with 5-carboxytetramethylrhodamine （TAMRA） label （denoted as strand A）. The other （strand ｜）, being competent to work on the formation of i-motif structure, contained four stretches of the cytosine （C） rich domain and was labeled with a Black Hole Quencher 2 （BHQ2） at the 3＇-end. At neutral or slightly alkaline pH, strand ｜ was hybridized to the extension sequence of strand A to form a double-stranded DNA probe, termed i-motif-based activatable aptamer probe （I-AAP）. Because of proximity- induced energy transfer, the I-AAP was in a ＂signal off＇ state. The slightly acidic pH enforced the strand I to form an intramo- lecular i-motif and then initiated the dehybridization of I-AAP, leading to fluorescence readout in the target recognition. As a demonstration, AS1411 aptamer was used for MCF-7 cells imaging. It was displayed that the I-AAP could be carried out for target cancer cells imaging after being activated in slightly acidic environment. The applicability of I-AAP for tumor tissues imaging has been also investigated by using the isolated MCF-7 tumor tissues. These results implied the I-AAP strategy is promising as a novel approach for cancer imaging.展开更多
Achieving activatable antibiotics represents one promising solution to tackle the occurrence of side effects,one major issue now plaguing antibiotic usage in collagen-based biomaterials.Despite considerable effort,how...Achieving activatable antibiotics represents one promising solution to tackle the occurrence of side effects,one major issue now plaguing antibiotic usage in collagen-based biomaterials.Despite considerable effort,however,rationale design of activatable antibiotics that display high activation efficiency and uncompromised bactericidal potency in the activated state remains difficult.Here,we demonstrate a design principle that helps to address this challenge.This strategy differs from previous attempts by underscoring photolytic removal of a functionality directly conjugated to the pharmacophore of an antibiotic,enabling not only an activation efficiency significantly improved beyond previous light-activatable antibiotics,but also bactericidal activity in the activated state as potent as the parent drug.展开更多
基金the National Natural Science Foundation of China(Nos.82272067,81974386,22107123 and M-0696)the Natural Science Foundation of Hunan Province(Nos.2021JJ41008,2022JJ80052,2022JJ40656,2023JJ20077)+2 种基金the Key Project of Changsha Science and Technology Plan(No.kh2201059)the Scientific Research Project of Health Commission of Hunan Province(No.B202313057213)the Youth Science Foundation of Xiangya Hospital(No.2022Q16).
文摘Carbon monoxide(CO)is a crucial gaseous signaling molecule that regulates various physiological and pathological processes,and may exert an anti-inflammatory and protective role in drug-induced liver injury(DILI).Despite this,understanding the exact relationship between CO and the occurrence and development of DILI remains challenging.Hence,there is an urgent need to develop a reliable and robust tool for the rapid visual detection and assessment of CO in this context.Herein,we presented a novel near-infrared(NIR)fluorescent nanoprobe with aggregation-induced emission(AIE)properties and excited-state intramolecular proton transfer(ESIPT)characteristics for the detection and imaging of CO both in vitro and in vivo.Simultaneously,the nanoprobe enables self-assembly form nanoaggregates in aqueous media with high biocompatible,which can sense CO in situ through the conversion of yellowto-red fluorescence facilitated aggregation-induced dual-color fluorescence.What is more,this nanoprobe shows ratiometric respond to CO,which demonstrates excellent stability,high sensitivity(with a detection limit of 12.5 nmol/L),and superior selectivity.Crucially,this nanoprobe enables the visual detection of exogenous and endogenous CO in living cells and tissues affected by DILI,offering a user-friendly tool for real-time visualization of CO in living system.Hence,it holds great promise in advancing our understanding of CO’s role.
基金a grant from the Key Program of Clinical Sciences of Ministry of Health of China (No. WGCF468)
文摘To clarify the role of TAFI in hypertensive disorders in pregnancy, 22 subjects, including 10 with pre-eclampsia （PE） and 12 with gestational hypertension were examined for the levels of TAFI and thrombin-antithrombin （TAT） complex. Thirty normal pregnant women served as controls. ELISA was employed for the detection. The results showed that the TAFI antigen levels in normal pregnancy group, gestational hypertension group and PE group were （85.35±24.69）%, （99.65±18.27）%, （110.12±23.36）%; （97.06±21.40）%, （114.08±27.76）%, （125.49±24.70）%; （106.6±19.21）%, （129.2±25.07）%, （139.1±30.12）%, in the 1st, 2nd and 3rd trimester respectively. No significant differences were found between the normal pregnancy group and gestational hypertension group but significant difference existed between normal pregnancy group and PE group in each trimester （P〈0.05）. TAT complexes were significantly higher in patients with PE than that in controls （P〈0.05）, but no correlation was found between TAT and TAFI. It is concluded that TAFI may contributed to the impairment of fibrinolysis in the patients with PE and may serves as a sensitive indicator for PE, but it may not help in the diagnosis of the gestational hypertension.
基金Supported by Grants from the National Research Foundation of Korea,No.R1102452Korea University,No.K1220161by experimental techniques from the Core Laboratory for Convergent Translational Research of College of Medicine
文摘AIM: To evaluate the effects of butein on inflammatory cytokines, matrix metalloproteinase-9(MMP-9), andcolitis in interleukin(IL)-10-/- mice.METHODS: To synchronize colitis, 8- to 10-wk-old IL-10-/- mice were fed pellet-chow containing piroxicam for 2 wk. Subsequently, phosphate-buffered saline or butein(1 mg/kg per day, ip) was injected for 4 wk. Histologic scores, inflammatory cytokines, MMP-9 and phosphorylated signal transducer and activator of transcription 3(p STAT3) expressions were analyzed in IL-10-/- mice and in Colo 205 cells.RESULTS: Butein reduced the colonic inflammatory score by > 50%. Expression levels of IL-6, IL-1β, interferon(IFN)-γ and MMP-9 were decreased in the colons of mice exposed to butein, whereas other inflammatory cytokines(IL-17 A, IL-21 and IL-22) were unchanged. Immunohistochemical staining for p STAT3 and MMP-9 was significantly decreased in the buteintreated groups compared with the controls. Butein inhibited IL-6-induced activation of STAT3 in Colo 205 cells.CONCLUSION: Butein ameliorated colitis in IL-10-/-mice by regulating IL-6/STAT3 and MMP-9 activation.
基金financially supported by the State Scholarship Fund from the China Scholarship Council(No.2008110820) and Carbon Management Canada
文摘CO2sequestration by mineral carbonation can permanently store CO2and mitigate climate change. However, the cost and reaction rate of mineral carbonation must be balanced to be viable for industrial applications. In this study, it was attempted to reduce the carbonation costs by using mine waste rock as a feed stock and to enhance the reaction rate using wet mechanical activation as a pre-treatment method. Slurry rheological properties, particle size distribution, specific surface area, crystallinity, and CO2 sequestration reaction efficiency of the initial and mechanically activated mine waste rock and olivine were characterized. The results show that serpentine acts as a catalyst, increasing the slurry yield stress, assisting new surface formation, and hindering the size reduction and structure amorphization. Mechanically activated mine waste rock exhibits a higher carbonation conversion than olivine with equal specific milling energy input. The use of a high-speed stirred mill may render the mineral carbonation suitable for mining industrial practice.
基金Supported by National Commission for Scientific and Technological Research Grant No.1120034
文摘AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T<sub>3</sub>)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver.
基金financially supported by the National Natural Science Foundation of China(Nos.22074050,22022404,21804033)Wuhan Scientific and Technological Projects(No.2019020701011441)+2 种基金Open Research Fund supported by the Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(No.SKL-HIDCA-2019-11)State Key Laboratory of Elemento-Organic Chemistry,Nankai University(No.201901)the ministry of education Key laboratory for the Synthesis and Application of Organic Functional Molecules,Hubei University(No.KLSAOFM2011).
文摘Caspases are a family of proteases that play critical roles in controlling inflammation and cell death.Apoptosis is a caspase-3 mainly controlled behavior to avoid inflammation and damage to surrounding cells,whereas anomalistic cell apoptosis may be associated with many diseases.The detection and imaging of caspase-3 will be of great significance in evaluating the early therapeutic effect of tumors.Developing smart fluorescent probes may be helpful for the visualization of the rapeutic effect compared with "always on" probes.Thus,more and more works toward activatable fluorescent probes for caspase-3 imaging have been reported.In addition,multifunctional probes have also been designed to further improve the imaging of caspase-3.Herein,this review systematically summarized the representative wo rk of caspase-3 from the perspective of molecular design that it will play a guiding role in the design of probes that respond to caspase-3.Also,challenges and perspectives toward the field for imaging of cell apoptosis(caspase-3) are also discussed.
基金supported by Canadian Cancer Society Grant#018510 through the National Cancer Institute of Canada.
文摘Recent years have seen the design and implementation of many optical activatable smart probes.These probes are activatable because they change their optical properties and are smart because they can identify specific targets.This broad class of detection agents has allowed previously unperformed visualizations,facilitating the study of diverse biomolecules including enzymes,nucleic acids,ions and reactive oxygen species.Designed to be robust in an in vivo environment,these probes have been used in tissue culture cells and in live small animals.An emerging class of smart probes has been designed to harness the potency of singlet oxygen generating photosensitizers.Combining the discrimination of activatable agents with the toxicity of photosensitizers represents a new and powerful approach to disease treatment.This review highlights some applications of activatable smart probes with a focus on developments of the past decade.
文摘Rich oxygen-biological activated carbon(RO-BAC)method developed from traditional BAC method is a sys-tem in which high pressure is applied to improve the oxy-gen concentration of the influent.Experiment withwastewater and the slightly deteriorated raw water showsthe system is an effective option for advanced treatmentof industry wastewater and pretreatment of slightly dete-riorated raw water.The experiment results and the in-fluential factors are discussed in this paper.
基金financially supported by the National Natural Science Foundation of China (No.21977081)Zhejiang Provincial Natural Science of Foundation of China (No.LQ21H190006)。
文摘Antibacterial agent of activatable photosensitizer not only has the advantages of traditional photosensitizers,such as good curative effect and low resistance,but also has better selectivity for bacteria and lower toxicity to normal tissues.Limited reports of activatable photosensitizer can be used to treat drugresistant bacteria.In order to meet this challenge,we designed and synthesized an activatable photosensitizer(Ce-OHOA),which can not only selectively identify methicillin-resistant Staphylococcus aureus(MRSA)with high expression ofβ-lactamase by fluorescence imaging,but also kill MRSA with less than10 times the concentration and 10 times the irradiation dose of CySG-2 reported.Ce-OHOA not only combines the dual functions of fluorescence diagnosis and photodynamic therapy,but also selectively acts on bacteria with high expression ofβ-lactamase and has little toxicity to normal cells.We expect that the study of this activating photosensitizer will provide a new solution for antibacterial photodynamic therapy(aPDT)of drug-resistant bacteria.
基金Supported by the National Program on Key Basic Research Project(973 Program)(2012CB720600,2012CB720603,2012CB720605)the National Natural Science Foundation of China(21432008,91413109,81373256,91213302)
文摘Early cancer diagnosis in molecular level shows great promise in relevant prevention and clinical treatment. Herein, we developed a novel method to detect and evaluate biomarkers on cancer cell surface. Based on the excellent selectivity of AS1411 aptamer to targeted nucleolin-overexpressed cells, we used a fluorescent probe with a pH-sensitive function to label the AS1411 aptamer modified with azide by click-reaction. The spectral characteristics of fluorophore naphthalimide has a good pH dependence. By this way, nucleolin-overexpressed cell could be discriminated from normal cell. Further, this strategy could also discriminate the breast cancer tissue from the adjacent benign tissue in formalin-fixed and parrffin-embedded（FFPE） tissue specimens. It is considered that our method has the potential to be applied in medical detection.
基金supported by US National Science Foundation grants EFRI 1830878,CBET 1948722,CBET 2220273,and CBET 2325317US National Institutes of Health grants R01 EB025173,R01 CA228029,R01 CA293050,R01 GM143749,and R21 AG085089.
文摘The biggest challenge in using CRISPR technologies,which limits their widespread application in medicine,is off-target effects.These effects could,in principle,be minimized by ensuring that CRISPR is activated primarily in the targeted cells,thereby reducing the likelihood of unintended genetic modifications in non-target tissues.Therefore,the development of a light activatable CRISPR approach to dynamically control gene activation in both space and time would be highly beneficial.A drawback is that the overwhelming majority of recently introduced light activatable CRISPR systems require UV or blue light exposure,severely limiting the penetration depth of light in tissue at which CRISPR can be activated,and,in the case of UV light,raising safety concerns.A small number of systems that activate CRISPR using longer wavelengths are hindered by either slow light activation or issues related to toxicity and biocompatibility of the proposed techniques in humans.To address this,we developed a split-Cas9/dCas9 system in which activation is achieved through a near-infrared photocleavable dimerization complex.This photoactivation method can be safely used in humans in vivo,easily adapted to different split-Cas9/dCas9 systems,and enables rapid,spatially precise light activation across various cell types.
基金the National Key Research and Development Program of China(2017YFC1309100,2017YFA0205200,and 2020YFA0211100)National Natural Science Foundation of China(81671753,91959124,21804104,32071406,51922077,and 51872205)+6 种基金China Postdoctoral Science Foundation(2019M650259)the Youth Innovation Team of Shaanxi UniversitiesNatural Science Foundation of Shaanxi Province of China(2020PT-020)the Fundamental Research Funds for the Central Universities(JB211202,and JC2112)the Open Project Program of the State Key Laboratory of Cancer Biology(Fourth Military Medical University)(CBSKL2019ZDKF06)the Foundation of National Facility for Translational Medicine(Shanghai)(TMSK2020-012)Young Talents Program,and Shanghai Municipal Commission of Health and Family Planning Foundation(2017YQ050)。
文摘Dysregulated energy metabolism has recently been recognized as an emerging hallmark of cancer.Tumor cells,which are characterized by abnormal glycolysis,exhibit a lower extracellular pH(6.5–7.0)than nor-mal tissues(7.2–7.4),providing a promising target for tumor-specific imaging and therapy.However,most pH-sensitive materials are unable to distinguish such a subtle pH difference owing to their wide and continuous pH-responsive range.In this study,we developed an efficient strategy for the fabrication of a tumor metabolic acidity-activatable calcium phosphate(CaP)fluorescent probe(termed MACaP9).Unlike traditional CaP-based biomedical nanomaterials,which only work within more acidic organelles,such as endosomes and lysosomes(pH 4.0–6.0),MACaP9 could not only specifically respond to the tumor extra-cellular pH but also rapidly convert pH variations into a distinct fluorescence signal to visually dis-tinguish tumor from normal tissues.The superior sensitivity and specificity of MACaP9 enabled high-contrast visualization of a broad range of tumors,as well as small tumor lesions.
基金supported by the National Natural Science Foundation of China(grant nos.22193020,22193021,and 21821001)the Strategic Priority Research Program of the Chinese Academy of Sciences(grant no.XDB36000000).
文摘An activatable photosensitizer that could induce phototoxicity only in target sites is highly demanded to overcome the potential off-target toxicity in photodynamic therapy.It is of great significance to design tailored photosensitizers with a new caging mechanism that can be activated by molecular signatures of pathogenic tissues.Herein,we report a novel supramolecularly activatable photosensitizer that employs cucurbit[7]uril(CB[7])to regulate the J-aggregate and monomer state of a thio-pentamethine cyanine dye withα-naphthyl group on side arms(Naph-α-TCy5),switching its photosensitizing property between off-on states.The host–vip complex Naph-α-TCy5-CB[7]is a caged photosensitizer with a superior luminescence property in an aqueous solution.It could be effectively activated by polyamines in cancer cells through competitive host–vip complexation;then the restored J-aggregates of Naph-α-TCy5 could efficiently generate singlet oxygen.Eventually,the supramolecularly activatable Naph-α-TCy5-CB[7]demonstrated appreciable antitumor bioactivity in vivo with excellent biosafety.It is anticipated that this design strategy of supramolecularly activatable photosensitizers opens new horizons for efficient photodynamic therapy with specificity and safety.
基金supported by the National Key R&D Program of China(2022YFE0111600)the Key Research and Development Program of Liaoning Province(2024JH2/102500061)+7 种基金the Youth Innovation Team of Liaoning Provincial Department of Education(LJ222410163049)the Liaoning Revitalization Talents Program(XLYC2203083)the Open Fund of High-level Key Discipline of Chemistry of Chinese Medicine of the State Administration of Traditional Chinese Medicinethe Anhui University of Chinese Medicine(HKDCCM2024007)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(CPSF)(GZC20231-732)the China Postdoctoral Science Foundation(2023TQ0222,2023MD744229)the General Program of Department of Education of Liaoning Province(JYTMS20231372)the Doctoral Scientific Research Staring Foundation of Liaoning Province(2024-BS-073)。
文摘Irinotecan,one of the most effective chemotherapeutic agents for the treatment of advanced colorectal cancer,suffers from extremely low activatability and non-selective tumor activation.7-Ethyl-10-hydroxy-camptothecin(SN38),the active metabolite of irinotecan,has been limited in clinical development due to poor water solubility and stability.Here,the thioether bond and disulfide bond were employed as response modules to construct tumor-selective SN38 prodrug nanoassemblies(SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs).11-Henicosanol was chosen as a self-assembly module to enhance stability.Both SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs presented ultra-high in vivo stability with a 12146-fold and 23151-fold elevation in the area under the curve(AUC)compared to SN38.Moreover,SN38-S-C_(21) NPs and SN38-SS-C_(21) NPs showed a significant reduction of SN38exposure in blood compared to irinotecan.Importantly,the prodrug nanoassemblies enabled selective activation within tumor cells,and the conversion rates of SN38-SS-C_(21) NPs and SN38-S-C_(21) NPs to SN38 were 10-and 7-fold higher than irinotecan.Compared with SN38-S-C_(21) NPs,the superior in vivo stability,SN38 conversion efficiency and tumor selectivity of SN38-SSC_(21) NPs resulted in potent antitumor effects and safety.Our findings proved that the disulfide bond was more suitable for constructing high-performance SN38 prodrug nanoassemblies,which showed significant promise for the rational design of SN38 nanomedicines.
基金supported by National Natural Science Foundation of China(grant nos.21925802 and 22338005)Liaoning Binhai Laboratory(grant no.LBLB-2023-03)the Fundamental Research Funds for the Central Universities(grant no.DUT22LAB601).
文摘Real-time intraoperative guidance is indispensable for ensuring complete and safe tumor resection during oncological surgery.Activatable fluorescence probes have demonstrated promise in guiding surgery during intricate procedures,offering high-contrast images with the“turn-on”fluorescence signal upon reaction with tumor markers.However,single-factor activatable probes still encounter the limitation of potentially generating“false positive”results in the complex in vivo environment.Herein,we have developed a dualfactor recognition activatable probe,NBD-BDP-E,to further enhance specificity to tumors via a cascade process.The incorporation of an epidermal growth factor receptor(EGFR)inhibitor,erlotinib,in the probe ensures tumor recognition and accelerated cellular uptake firstly.Following the probe response to the high concentration of Glutathione in cells,molecular fluorescence emission is restored for fluorescence image guidance.Ultimately,the d-PeT-based activatable probe,NBD-BDP-E,exhibited the ability to light up an EGFR-overexpressed tumor tissue accurately with a superior tumor-to-normal tissue ratio for image-guided surgery via in situ spraying.Moreover,it shows the ability to image tumor tissue about 1 mm in diameter,highlighting the potential for this probe to be used as a tool in surgical resection.
基金the National Natural Science Foundation of China(22137003 and 21922406)Natural Science Foundation of Jiangsu Province(BK20200301 and BK20190055)the Fundamental Research Funds for the Central Universities(020514380251)are acknowledged.
文摘Comprehensive Summary,Stimuli-controlled disassembly process has shown promise to direct delivery of probes and/or spatial-temporally control imaging signals for molecular imaging in vivo.Via the disassembly process,well defined nanoprobes with a stimulus-responsive moiety can be controllably converted into small-molecular imaging agents in response to a stimulus,leading to a switch in imaging signals.Moreover,the on-site released small-molecule probes could enhance penetration into the deep tissue for improved imaging of deep-seated molecular targets.Therefore,such a stimuli-controllable disassembly approach has been widely utilized to build activatable molecular imaging probes for the noninvasive detection of various molecular targets in living subjects.In this review article,we first briefly introduce the general principle of stimuli-controlled disassembly.We then summarize the activatable probes based on different internal or external stimulus that has been utilized to control disassembly process.Activatable probes by using multiple stimuli to control cascaded in situ self-assembly and disassembly processes are also discussed.Finally,we close with a conclusion of current challenges and perspective in this field.
基金Acknowledgments This work was supported by the National Natural Science Foundation of China （21505070, 21632008） and Natural Foundation of Jiangsu Province （BK20150567）.
文摘Precise measurement of enzyme activity in living systems with molecular imaging probes is becoming an important technique to unravel the functional roles of different enzymes in biological processes. Recent progress has been made in the development of a myriad of molecular imaging probes featuring different imaging modalities, including optical imaging, magnetic resonance imaging, nuclear imaging, and photoacoustic imaging, allowing for non-invasive detection of various enzyme activities in vivo with high sensitivity and high spatial resolution. Among these imaging probes, activatable or ＂smart＂ probes, whose imaging signal can be specifically switched from the ＂off＂ to ＂on＂ state upon interaction with a target enzyme, are particularly attractive due to their improved sensitivity and specificity. Here, recent advances in the development of activatable probes capable of imaging different enzyme activities in vivo are summarized based on different imaging modalities, and current challenges and future perspectives are discussed.
基金supported by the National Creative Research Initiative programs of the National Research Foundation of Korea(NRF),the Korean Government(MSIP)(2012R1A3A2048814)the National Natural Science Foundation of China(21421005,21808028)the Natural Science Foundation of Liaoning United Fund(U1608222,U1908202)。
文摘Chemotherapy is one of the commonly used methods to treat various types of cancers in clinic by virtue of its high efficiency and universality. However, strong side effects and low concentration of conventional drugs at the tumor site have always been important factors that plague the chemotherapy effects of patients, further precluding their practical applications. Thereof, to solve the above dilemma, by integration of anticancer drug(nitrogen mustard, NM) into an NIR fluorophore(a dicyanoisophorone derivative), an intelligent prodrug NIR-NM was developed via molecular engineering strategy. Prodrug NIR-NM stimulated in hypoxia condition exhibits significantly higher toxicity to cancer cells than normal cells, essentially reducing the collateral damage to healthy cells and tissues of nitrogen mustard. More importantly, the nanoparticle prodrug FA-lip@NIR-NM showed the advantages of the high accumulation of drug at tumor site and long-circulation capacity in vivo, which endowed it the ability to track the release of the active chemotherapeutic drug and further treat solid tumors.
基金supported by the Key Project of National Natural Science Foundation of China (21175039, 21322509, 21305035, 21190044, 21221003, 21305038, 2015JJ3044)
文摘We present here a pH-responsive activatable aptamer probe for targeted cancer imaging based on i-motif-driven conformation alteration. This pH-responsive activatable aptamer probe is composed of two single-stranded DNA. One was used for target recognition, containing a central, target specific aptamer sequence at the 3＇-end and an extension sequence at the 5＇-end with 5-carboxytetramethylrhodamine （TAMRA） label （denoted as strand A）. The other （strand ｜）, being competent to work on the formation of i-motif structure, contained four stretches of the cytosine （C） rich domain and was labeled with a Black Hole Quencher 2 （BHQ2） at the 3＇-end. At neutral or slightly alkaline pH, strand ｜ was hybridized to the extension sequence of strand A to form a double-stranded DNA probe, termed i-motif-based activatable aptamer probe （I-AAP）. Because of proximity- induced energy transfer, the I-AAP was in a ＂signal off＇ state. The slightly acidic pH enforced the strand I to form an intramo- lecular i-motif and then initiated the dehybridization of I-AAP, leading to fluorescence readout in the target recognition. As a demonstration, AS1411 aptamer was used for MCF-7 cells imaging. It was displayed that the I-AAP could be carried out for target cancer cells imaging after being activated in slightly acidic environment. The applicability of I-AAP for tumor tissues imaging has been also investigated by using the isolated MCF-7 tumor tissues. These results implied the I-AAP strategy is promising as a novel approach for cancer imaging.
基金We gratefully acknowledge financial support of this work by National Natural Science Foundation of China(21878196)Sichuan Science and Technology Program(2020YJ0315)Science and Technology Program of State Administration for Market Regulation(2020YJ024).
文摘Achieving activatable antibiotics represents one promising solution to tackle the occurrence of side effects,one major issue now plaguing antibiotic usage in collagen-based biomaterials.Despite considerable effort,however,rationale design of activatable antibiotics that display high activation efficiency and uncompromised bactericidal potency in the activated state remains difficult.Here,we demonstrate a design principle that helps to address this challenge.This strategy differs from previous attempts by underscoring photolytic removal of a functionality directly conjugated to the pharmacophore of an antibiotic,enabling not only an activation efficiency significantly improved beyond previous light-activatable antibiotics,but also bactericidal activity in the activated state as potent as the parent drug.
