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Overexposure of sewage workers to bioaerosol released from wastewater treatment plants (WWTPs) can cause serious infections, but practical method for controlling their health risk is lacking. In this study, reverse quantitative microbial risk assessment was used to estimate the daily critical exposure time (CET) of sewage workers exposing to Staphylococcus aureus bioaerosol emitted by three emission sources facilities in a WWTP based on either U.S. EPA or WHO benchmark, and sensitivity analysis was conducted to analyze the influence of various parameters on the outcomes of CET. The results showed that the CET of females was always 1.12-1.29 times that of males. In addition, the CET after wearing face masks was 28.28-52.37 times as long as before. The working time can be determined based on the CET results of male workers wearing face masks exposed to the inverted-umbrella aeration tank (14.73-550.98 min for U.S. EPA benchmark and 55.07-1972.24 min for WHO benchmark). In each scenario, the variable parameter exposure concentration (ec) always showed the most influence on the CET results. After wearing the face masks, the removal fraction by employing face masks also had a significant effect on the results, only second to ec. Therefore, the wearing of face mask is the most convenient and effective measure to prolong the CET. Furthermore, practical methods to reducing bioaerosol concentration in WWTPs exposure are also necessary to extend CET and safeguard worker health. This study enriches the application range of reverse quantitative microbial risk assessment framework and provides theoretical support for stakeholders to establish reasonable working time threshold guidelines, and practical method and novel perspective to protect the on-site health risks of sewage workers exposing to various facilities.
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Directly targeted KRAS inhibitors are now facing resistance problems, which might be partially solved by the combination of SOS1 inhibitors with KRAS inhibitors. However, this combination may still have some resistance mitigation potential. Comparatively, SOS1 PROTAC may have promising applications in addressing the drug resistance problem by degrading the SOS1 protein. Herein, we report the discovery of novel SOS1 PROTACs and their antitumor activity both in vitro and in vivo. In vitro studies demonstrated that degrader 4 had strong inhibitory effects on the proliferation of NCI-H358 cells with IC50 of 5 nM, together with significant degradation of SOS1 protein with DC50 of 13 nM. In the NCI-H358 xenograft model, degrader 4 exhibited significant antitumor activities with TGITV values of 58.8% at 30 mg/kg bid. The PK and safety profiles also supported degrader 4 for further studies as an effective tool compound.
Assuntos
Proteínas Proto-Oncogênicas p21(ras) , Proteína SOS1 , Humanos , Animais , Modelos Animais de Doenças , Projetos de Pesquisa , ProteóliseRESUMO
Luminogens characteristic of aggregation-induced emission (AIEgens) have been extensively exploited for the development of imaging-guided photodynamic therapeutic (PDT) agents. However, intramolecular rotation of donor-acceptor (D-A) type AIEgens favors non-radiative decay of photonic energy which results in unsatisfactory fluorescence quantum and singlet oxygen yields. To address this issue, we developed several molecularly engineered AIEgens with partially "locked" molecular structures enhancing both fluorescence emission and the production of triplet excitons. A triphenylphosphine group was introduced to form a D-A conjugate, improving water solubility and the capacity for mitochondrial localization of the resulting probes. Experimental and theoretical analyses suggest that the much higher quantum and singlet oxygen yield of a structurally "significantly-locked" probe (LOCK-2) than its "partially locked" (LOCK-1) and "unlocked" equivalent (LOCK-0) is a result of suppressed AIE and twisted intramolecular charge transfer. LOCK-2 was also used for the mitochondrial-targeting, fluorescence image-guided PDT of liver cancer cells.
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Several aggregation-induced emission luminogens (AIEgens) with excellent water-solubility and near-infrared emission were designed and synthesized for wash-free "off-on" mitochondrial imaging and photodynamic therapy of HeLa cells. The AIEgen TEPP exhibits both bright near-infrared emission (φF = 17.8%) and high hybrid ROS productivity (including OHË and 1O2).
Assuntos
Fotoquimioterapia , Diagnóstico por Imagem , Células HeLa , Humanos , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio , ÁguaRESUMO
Biothiols including cysteine (Cys) and glutathione (GSH) are biological signaling molecules responsible for cell detoxification, cell metabolism and neutralization of reactive oxygen species. Here, we synthesized a long-wavelength fluorescent probe, DCIMA, for lysosome-targeted imaging of Cys and GSH in living cells. DCIMA is consisted of a dicyanoisophorone core modified with an acrylate group for biothiol detection through the Michael addition reaction and a morpholine group as the lysosome-targeting agent. The presence of the electron-donating morpholine group also enhances the intramolecular charge transfer mechanism of the probe, thereby enabling its long-wavelength fluorescence emission (670 nm) and large Stokes shift (180 nm). In concentration range of 0-30 µM, the probe was determined to react quickly with both Cys and GSH with low detection limits (<5 min, 35.2 nM for GSH and 34.8 nM for Cys) and achieve the sensitive fluorescence imaging of the biothiols located in the lysosomes of living cells.
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Cisteína , Corantes Fluorescentes , Glutationa , Células HeLa , Homocisteína , Humanos , Lisossomos , Imagem Óptica , Espectrometria de FluorescênciaRESUMO
Depression is closely related to overactivation of N-methyl-d-aspartic acid (NMDA) receptors, and Zn2+ is a vital NMDA receptor modulator involved in the pathophysiological and physiological processes of depression. Therefore, quantitative and real-time detection of Zn2+ is very important for understanding the pathogenesis of depression. In this work, a near-infrared (NIR) fluorescent probe ISO-DPA was designed and synthesized for Zn2+ detection with a large Stokes shift (185 nm), high quantum yield (up to 44%), high sensitivity (LOD = 0.106 µM) and good pH stability. The probe showed rapid response within 10 s, accompanied by a distinct fluorescence change from faint to bright pink with the fluorescence intensity increasing 4.5-fold. Moreover, the sensing mechanism of ISO-DPA towards Zn2+ was supported by MALDI-TOF-MS and Job's plot. The probe ISO-DPA could detect instantaneous variation of exogenous and endogenous Zn2+ in PC12 cells. The bioimaging results reveal the increase of the endogenous Zn2+ concentration in PC12 cells under the oxidative stress induced by glutamate and confirm that overactivation of NMDA receptors results in an increase of the Zn2+ level. All the results proved that ISO-DPA is an excellent probe for detecting Zn2+ in solution and living cells and could help us better understand Zn2+ associated pathogenesis of depression.
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Depressão , Corantes Fluorescentes , Animais , Diagnóstico por Imagem , Células PC12 , Ratos , Zinco/toxicidadeRESUMO
Sulfur dioxide (SO2) plays significant roles in regulating cell apotosis and inflammation. However, there are complex interactions between small biomolecules in cells, and the identification of these coexisting biomarkers remains a challenge. Herein, we report an AND logic gate based fluorescent probe (NY-Lyso), operating by responding to pH differences between organelles in cell and selectively reacting with bisulfite (HSO3-). This approach allows the fluorescence of the probe to remain silent under neutral or alkaline conditions, notably, is activated by costimulation of lower pH and bisulfite. Furthermore, it was confirmed to be biocompatible and could be employed to monitor HSO3- in lysosomes of living cells. The proposed method demonstrated more practical and outstanding capabilities in targeted and real-time monitoring, providing an effective optical tool for biomarker sensing.
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Corantes Fluorescentes/química , Naftalimidas/química , Sulfitos/análise , Sobrevivência Celular , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/química , Estrutura Molecular , Naftalimidas/síntese químicaRESUMO
Developing fluorescent probes for selective determination of the toxic and carcinogenic hydrazine are pretty significant. Herein, a rhodamine dye coupled to naphthalene was selected as a near-infrared fluorophore and acetyl group as a trigger unit for hydrazine sensing with a Stokes shifts of 62â¯nm. The probe showed about 77-fold NIR fluorescence enhancement in the presence of hydrazine. In addition, the detection limit was as low as 3.4â¯ppb, and the fluorescence intensity at 654â¯nm showed a satisfactory linearity with the concentration range of hydrazine from 0 to 120⯵M. More importantly, the practical utility of probe has been successfully proved through the fluorescence bioimaging of hydrazine in living cells with low cytotoxicity and quantitative N2H4 detection in environmental water samples.
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Corantes Fluorescentes/química , Hidrazinas/análise , Espectroscopia de Luz Próxima ao Infravermelho , Xantenos/química , Sobrevivência Celular , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Espectrometria de Fluorescência , Água/químicaRESUMO
Developing fluorescent probes for specific detection of extremely toxic thiophenols is pretty significant in the field of environment, chemistry and biology. We report herein a turn-on red fluorescent xanthene-based probe (RD-Probe) for detecting thiophenol with high selectivity over other analytes including aliphatic thiols. The probe could play the part of a "naked-eye"colorimetric indicator toward thiophenol. Moreover, the relative fluorescence intensity at 653â¯nm displayed good linearity with the concentration of thiophenol ranging from 0 to 6⯵M, and the limit of detection for thiophenol could be as low as 15â¯nM. Furthermore, the practicability of RD-Probe has been successfully proved through the quantitative thiophenol detection in real water samples and fluorescence bioimaging of thiophenol in HeLa cells.
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Colorimetria , Corantes Fluorescentes/química , Imagem Óptica , Fenóis/análise , Compostos de Sulfidrila/análise , Poluentes Químicos da Água/análise , Xantenos/química , Corantes Fluorescentes/síntese química , Raios Infravermelhos , Estrutura Molecular , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Xantenos/síntese químicaRESUMO
In this work, a new reversible colorimetric and fluorescent probe for sequential recognition of copper ions and biothiols is synthesized easily. Based on the chelation-enhanced fluorescence quenching (CHEQ) effect, this probe shows high sensitivity and selectivity towards Cu2+, which can be detected by the naked eye. And this experimental phenomenon can also be realised upon addition of biothiols, restoring their initial fluorescence intensity. This probe also features a very high response speed (less than 5 seconds) and a large stokes shift (178 nm) toward Cu2+ and biothiols. Moreover, the detection limit for Cu2+ and biothiols is as low as 7.34 nM and 10.3 nM, respectively. Additionally, this ON-OFF-ON-type fluorescence recognition cycle can be repeated more than 5 times by addition of Cu2+ and biothiols in turn. Particularly, this 1-Cu2+ ensemble is further successfully applied for GSH detection in living cells.
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Fístula Anastomótica/etiologia , Tratamento Conservador/métodos , Perfuração Esofágica/etiologia , Perfuração Esofágica/terapia , Fundoplicatura/efeitos adversos , Adulto , Fístula Anastomótica/fisiopatologia , Fístula Anastomótica/terapia , Doença Crônica , Perfuração Esofágica/fisiopatologia , Seguimentos , Fundoplicatura/métodos , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/cirurgia , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Masculino , Medição de Risco , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate the expression characteristics of miR-155 and miR-146a in mice with schistosomiasis and praziquantel (PZQ) treatment. METHODS: Totally 40 BABL/c mice were divided into 4 groups: a normal group, a 6W infected group that were infected cutaneously with 10 Schistosoma japonicum cercariae for 6 weeks, a 12W infected group that were infected cutaneously with 10 Schistosoma japonicum cercariae for 12 weeks, and a praziquantel treated group that were infected cutaneously with 10 Schistosomajaponicum cercariae and intragastrically administered with PZQ (300 mg/kg/day) for 1 day in 6 weeks post-infection and continuing surviving 6 weeks. The animals were sacrificed in 6 weeks and 12 weeks post-infection respectively. The left front lobe of each liver was stained with hematoxylin-eosin (HE) to detect pathological lesions. The levels of mRNA expressions of miR-155, miR-146a and pro-inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) in the liver tissue were determined by using quantitative real-time PCR. RESULTS: The levels of mRNA expressions of miR-155, miR-146a and pro-inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) in the 6W infected mice were significantly higher than those of the normal mice and of the 12W infected mice. Compared with the 12W infected mice, the inflammation response of liver egg granuloma in the PZQ-treated mice was ameliorated. Furthermore, there was a marked increase in the levels of mRNA expressions of miR-155, miR-146a and three pro-inflammatory cytokines in the PZQ-treated mice compared to the 12W infected mice. CONCLUSION: miR-155 and miR-146a may play a role in schistosomiasis liver inflammation response and the inflammation regulation of praziquantel treatment.
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Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Praziquantel/farmacologia , Esquistossomose/tratamento farmacológico , Esquistossomose/genética , Animais , Feminino , Interleucina-1beta/genética , Interleucina-6/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Praziquantel/uso terapêutico , Esquistossomose/patologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
The aim of this research is to develop a novel branched polyethylenimine (PEI)-like polycation as a potential gene carrier with high gene transfection efficiency and low toxicity. In particular, alpha,beta-poly(l-aspartate-graft-PEI) (Asp-g-PEI), a pseudo-branched PEI, was synthesized by the ring-opening reaction of poly(l-succinimide) (PSI) with low molecular weight branched PEI (LMW PEI, MW=600 and 1200). Good plasmid condensation and protection ability of Asp-g-PEI were confirmed by agarose gel electrophoresis assay. Asp-g-PEI/DNA complexes showed high positive zeta potential, narrow size distribution, good dispersity and a compact spherical shape with size below 250nm when the N/P ratio was above 5, suggesting that they can be endocytosed. Cytotoxicity of Asp-g-PEI/DNA complexes was rather lower than that of PEI25K/DNA complexes, especially at high N/P ratio. The most efficient gene transfection of Asp-g-PEI/DNA complexes was similar or a little higher than that of PEI25K in 293T, HeLa and HepG2 cell lines, while almost 4 and 6 times higher than that of parent PEI1200 and PEI600, respectively, in HeLa cell line; as the molecular weight of parent PEI in Asp-g-PEI was increased from 600 to 1200, the transfection efficiency showed a tendency to decrease. The mechanism of Asp-g-PEI-mediated gene transfection was attributed to the "proton sponge effect" due to PEI in the copolymer.
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Sobrevivência Celular/efeitos dos fármacos , DNA/química , DNA/genética , Portadores de Fármacos/síntese química , Iminas/química , Iminas/farmacologia , Polietilenos/química , Polietilenos/farmacologia , Transfecção/métodos , Ácido Aspártico/química , Ácido Aspártico/farmacologia , Materiais Biocompatíveis/síntese química , DNA/administração & dosagem , Células HeLa , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Teste de MateriaisRESUMO
In the title mol-ecule, C(18)H(21)NO(3), the dihedral angle between the two benzene rings is 42.2â (2)° and it adopts a trans configuration with respect to the central C=N bond.
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The asymmetric unit of the title compound, C(17)H(19)NO(4), contains two independent mol-ecules in which the dihedral angles between the two benzene rings are 83.1â (2) and 88.5â (2)°. Each mol-ecule adopts a trans configuration with respect to the C=N bond. In the crystal structure, mol-ecules are linked by inter-molecular O-Hâ¯N hydrogen bonds, forming two independent one-dimensional chains running along the b-axis direction.
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In the title compound, C(21)H(21)NO(3), the dihedral angle between the naphthalene ring system and the substituted benzene ring is 55.7â (2)°. The mol-ecules are linked into a zigzag chain running along the b axis by C-Hâ¯O hydrogen bonds.
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The aqueous phase oxidation of gaseous elemental mercury (Hg(0)) by potassium persulfate (KPS) catalyzed by Ag(+) was investigated using a glass bubble column reactor. Concentration of gaseous mercury and potassium persulfate were measured by cold vapor atom absorption (CVAA) and ion chromatograph (IC), respectively. The effects of pH value, concentration of potassium persulfate and silver nitrate (SN), temperature, Hg(0) concentration in the reactor inlet and tertiary butanol (TBA), free radical scavenger, on the removal efficiency of Hg(0) were studied. The results showed that the removal efficiency of Hg(0) increased with increasing concentration of potassium persulfate and silver nitrate, while temperature and TBA were negatively effective. Furthermore, the removal efficiency of Hg(0) was much better in neutral solution than in both acidic and alkaline solution. But the influence of pH was almost eliminated by adding AgNO(3). High Hg(0) concentration has positive effect. The possible reaction mechanism of gaseous mercury was also discussed.
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A new method for the determination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in cosmetics by gas chromatography-mass spectrometry selected ion storage (SIS) method was developed. The BHA and BHT in samples were extracted by methanol. The m/z 165 and m/z 205 were the monitoring ion for BHA and BHT respectively. The detection limits of BHA and BHT in samples were 2.5 micrograms/g and 0.5 microgram/g, respectively. The method is simple, rapid and accurate.