Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors.

Inhibition of methionine adenosyltransferase 2A (MAT2A) has received significant interest because of its implication as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers. Here, we report the discovery of a series of 3H-pyrido[1,2-c]pyrimidin-3-one derivatives as novel MAT2A inhibitors. The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270.

Retinoid X receptor gamma dictates the activation threshold of group 2 innate lymphoid cells and limits type 2 inflammation in the small intestine.

Group 2 innate lymphoid cells (ILC2s) are crucial in promoting type 2 inflammation that contributes to both anti-parasite immunity and allergic diseases. However, the molecular checkpoints in ILC2s that determine whether to immediately launch a proinflammatory response are unknown. Here, we found that retinoid X receptor gamma (Rxrg) was highly expressed in small intestinal ILC2s and rapidly suppressed by alarmin cytokines. Genetic deletion of Rxrg did not impact ILC2 development but facilitated ILC2 responses and the tissue inflammation induced by alarmins. Mechanistically, RXRγ maintained the expression of its target genes that support intracellular cholesterol efflux, which in turn reduce ILC2 proliferation. Furthermore, RXRγ expression prevented ILC2 response to mild stimulations, including low doses of alarmin cytokine and mechanical skin injury. Together, we propose that RXRγ expression and its mediated lipid metabolic states function as a cell-intrinsic checkpoint that confers the threshold of ILC2 activation in the small intestine.

Certification of visinin-like protein-1 (VILIP-1) certified reference material by amino acid-based and sulfur-based liquid chromatography isotope dilution mass spectrometry.

As an emerging neurodegenerative disease, Alzheimer's disease (AD) has become a leading cause of dementia in older adults. Visinin-like protein-1 (VILIP-1) is an increasingly used biomarker for AD besides the widely accepted Aß1-40, Aß1-42, and tau. However, significant variations exist in the commercial immuno-based assays for VILIP-1 quantification, underlining the necessity to establish a traceability chain. Certified reference materials (CRMs) located at the top of the traceability chain are traceability sources for relevant matrix standard materials. In this work, VILIP-1 solution CRM with a certified value and uncertainty of 39.82±1.52 µg·g-1 was developed and certified using amino acid-based isotope dilution mass spectrometry (AA-ID-MS) and sulfur-based isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS). Certified values from both strategies showed great consistency, with traceability to SI units. Moreover, the candidate VILIP-1 CRM shows excellent homogeneity and can be stable for at least 7 days at -20°C and 12 months at -70°C. The VILIP-1 CRM developed can be used in value assignment to secondary calibrators and clinical matrix CRMs, showing prospects in early diagnosis and disease monitoring for AD.

Fabrication of multifunctional metal-organic frameworks nanoparticles via layer-by-layer self-assembly to efficiently discover PSD95-nNOS uncouplers for stroke treatment.

BACKGROUND: Disruption of the postsynaptic density protein-95 (PSD95)-neuronal nitric oxide synthase (nNOS) coupling is an effective way to treat ischemic stroke, however, it still faces some challenges, especially lack of satisfactory PSD95-nNOS uncouplers and the efficient high throughput screening model to discover them. RESULTS: Herein, the multifunctional metal-organic framework (MMOF) nanoparticles as a new screening system were innovatively fabricated via layer-by-layer self-assembly in which His-tagged nNOS was selectively immobilized on the surface of magnetic MOF, and then PSD95 with green fluorescent protein (GFP-PSD95) was specifically bound on it. It was found that MMOF nanoparticles not only exhibited the superior performances including the high loading efficiency, reusability, and anti-interference ability, but also possessed the good fluorescent sensitivity to detect the coupled GFP-PSD95. After MMOF nanoparticles interacted with the uncouplers, they would be rapidly separated from uncoupled GFP-PSD95 by magnet, and the fluorescent intensities could be determined to assay the uncoupling efficiency at high throughput level. CONCLUSIONS: In conclusion, MMOF nanoparticles were successfully fabricated and applied to screen the natural actives as potential PSD95-nNOS uncouplers. Taken together, our newly developed method provided a new material as a platform for efficiently discovering PSD95-nNOS uncouplers for stoke treatment.

Bifunctional monomer oligomers-based composite molecularly imprinted membranes for the electrochemical monitoring of Sudan I.

Herein, we developed a highly sensitive electrochemical sensor for the trace detection of Sudan I (SDI) dye based on composite molecularly imprinted membranes (MIMs). The pentenyl (lipoic acyl)-isoleucyl-chitosan oligosaccharide (P(L)ICO) and pentenyl-asparaginyl-chitosan oligosaccharide (PASCO) served as bifunctional monomer oligomers. After deposition of gold nanoparticles on a glassy carbon electrode (GCE) surface, a P(L)ICO layer successfully self-assembled on the surface. Subsequently, the primary MIM was polymerised on the electrode surface by using SDI as a template, PASCO as a functional monomer oligomer, and ethylene glycol dimethacrylate as a cross-linking agent. Electrochemical polymerisation was then conducted in an N,N'-methylenebisacrylamide solution. After eluting the SDI molecules from the composite MIMs, the fabricated SDI-MIM(PM)/Fn-Au/GCE demonstrated specific adsorption of SDI. Under optimal conditions, the constructed sensor exhibited a linear relationship between decreasing peak current and SDI concentration from 0.02 to 3.5 µM with a low detection limit of 4 nM (S/N = 3). As a proof of concept, SDI-MIM(PM)/Fn-Au/GCE was also applied to detect SDI in chili powder samples, with recoveries ranging from 96.8 to 106.6%.

Photodynamic Therapy of Up-Conversion Nanomaterial Doped with Gold Nanoparticles.

Two key concerns exist in contemporary cancer chemotherapy: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating the revolutionary cancer treatment techniques of photodynamic therapy (PDT) and photothermal therapy (PTT) proposed by many scholars. A photothermal treatment of cancer was synthesized using the hydrothermal method which has high photothermal conversion efficiency and can generate reactive oxygen species (ROS) in cells. Photothermal treatment of tumors has a good short-term effect and photodynamic therapy lasts longer. However, both PTT and PDT have their inevitable shortcomings and it is difficult to completely eradicate a tumor using a single mode of treatment. PTT and PDT synergistic treatment not only inherits the advantages of low toxicity and side effects of phototherapy but also enables the two treatment methods to complement each other. It is an effective strategy to improve curative effects and reduce toxic and side effects. Furthermore, gold doped UCNPs have an exceptionally high target recognition for tumor cells. The gold doped UCNPs, in particular, are non-toxic to normal tissues, endowing the as-prepared medications with outstanding therapeutic efficacy and exceptionally low side effects. These findings may encourage the creation of fresh, effective imaging-guided approaches to meet the goal of photothermal cancer therapy.

Synthesis of Rare-Earth Nanomaterials Ag-Doped NaYF4:Yb3+/Er3+@NaYF4:Nd3+@NaGdF4 for In Vivo Imaging.

In this study. a novel near-infrared fluorescent-driven contrast agent (Ag-doped NaYF4:Yb3+/Er3+@NaYF4:Nd3+@NaGdF4) was synthesized using a coprecipitation-hydrothermal-solvothermal-solvothermal (CHSS) method. The results shows that hexagonal NaYF4:Yb3+/Er3+ with a diameter of 300 nm was successfully synthesized by the CHSS method. The new contrast agent was characterized using scanning electron microscopy, fluorescence spectrometry, transmission electron microscopy, energy-dispersive spectrometry and ultraviolet-visible light diffuse reflectance absorption spectroscopy. Even at low concentrations (0.2 M), this proposed contrast agent can be excited by near-infrared light with a wavelength of 980 nm and emits a dazzling green light with a wavelength of 540 nm, and the comparison of the luminescence intensity proves that doping with silver increases the luminescence intensity of the upconverted nanomaterial by nearly 13 times based on the calculated quantum yield. TEM images show the successful preparation of silver nanoparticles with a diameter of 30 nm, and the energy spectrum shows the successful doping of silver nanoparticles and the successful preparation of the core-shell structure of NaYF4:Yb3+/Er3+@NaYF4:Nd3+@NaGdF4. Furthermore, the mechanism of the increased luminous intensity has been studied using simulation calculations. Finally, cytotoxicity tests were used to test material which was modified by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2K), and the biocompatibility was significantly improved, meeting the standard for biological applications.

Photodynamic Therapy and Multi-Modality Imaging of Up-Conversion Nanomaterial Doped with AuNPs.

Two key concerns exist in contemporary cancer chemotherapy in clinic: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating a revolutionary cancer treatment technique, and photodynamic therapy (PDT) has been proposed by many scholars. A drug for photodynamic cancer treatment was synthesized using the hydrothermal method, which has a high efficiency to release reactive oxygen species (ROS). It may also be utilized as a clear multi-modality bioimaging platform for photoacoustic imaging (PAI) due to its photothermal effect, computed tomography (CT), and magnetic resonance imaging (MRI). When compared to single-modality imaging, multi-modality imaging delivers far more thorough and precise details for cancer diagnosis. Furthermore, Au-doped up-conversion nanoparticles (UCNPs) have an exceptionally high luminous intensity. The Au-doped UCNPs, in particular, are non-toxic to tissues without laser at an 808 nm wavelength, endowing the as-prepared medications with outstanding therapeutic efficacy but exceptionally low side effects. These findings may encourage fresh effective imaging-guided approaches to meet the goal of photodynamic cancer therapy to be created.

Photothermal Effect and Multi-Modality Imaging of Up-Conversion Nanomaterial Doped with Gold Nanoparticles.

Two key concerns exist in contemporary cancer chemotherapy in clinics: limited therapeutic efficiency and substantial side effects in patients. In recent years, researchers have been investigating revolutionary cancer treatment techniques and photo-thermal therapy (PTT) has been proposed by many scholars. A drug for photothermal cancer treatment was synthesized using the hydrothermal method, which has a high light-to-heat conversion efficiency. It may also be utilized as a clear multi-modality bioimaging platform for photoacoustic imaging (PAI), computed tomography (CT), and magnetic resonance imaging (MRI). When compared to single-modality imaging, multi-modality imaging delivers far more thorough and precise details for cancer diagnosis. Furthermore, gold-doped upconverting nanoparticles (UCNPs) have an exceptionally high target recognition for tumor cells. The gold-doped UCNPs, in particular, are non-toxic to normal tissues, endowing the as-prepared medications with outstanding therapeutic efficacy but exceptionally low side effects. These findings may encourage the creation of fresh effective imaging-guided approaches to meet the goal of photothermal cancer therapy.

SiO2 Coated Up-Conversion Nanomaterial Doped with Ag Nanoparticles for Micro-CT Imaging.

In this study, a new method for synthesizing Ag-NaYF4:Yb3+/Er3+ @ SiO2 nanocomposites was introduced. Using a hydrothermal method, the synthesized Yb3+- and Er3+-codoped NaYF4 up-conversion luminescent materials and Ag nanoparticles were doped into up-conversion nanomaterials and coated with SiO2 up-conversion nanomaterials. This material is known as Ag-UCNPs@SiO2, it improves both the luminous intensity because of the doped Ag nanoparticles and has low cytotoxicity because of the SiO2 coating. The morphology of UCNPs was observed using scanning electron microscopy (SEM), and the mapping confirmed the successful doping of Ag nanoparticles. Successful coating of SiO2 was confirmed using transmission electron microscopy (TEM). Fluorescence spectra were used to compare changes in luminescence intensity before and after doping Ag nanoparticles. The reason for the increase in luminescence intensity after doping with Ag nanoparticles was simulated using first-principles calculations. The cytotoxicity of Ag-UCNPs@SiO2 was tested via the cell counting kit-8 (CCK-8) method, and its imaging ability was characterized using the micro-CT method.

Electrochemistry/Photoelectrochemistry-Based Immunosensing and Aptasensing of Carcinoembryonic Antigen.

Recently, electrochemistry- and photoelectrochemistry-based biosensors have been regarded as powerful tools for trace monitoring of carcinoembryonic antigen (CEA) due to the fact of their intrinsic advantages (e.g., high sensitivity, excellent selectivity, small background, and low cost), which play an important role in early cancer screening and diagnosis and benefit people's increasing demands for medical and health services. Thus, this mini-review will introduce the current trends in electrochemical and photoelectrochemical biosensors for CEA assay and classify them into two main categories according to the interactions between target and biorecognition elements: immunosensors and aptasensors. Some recent illustrative examples are summarized for interested readers, accompanied by simple descriptions of the related signaling strategies, advanced materials, and detection modes. Finally, the development prospects and challenges of future electrochemical and photoelectrochemical biosensors are considered.

Thermal Decomposition of Brominated Butyl Rubber.

The thermal decomposition of brominated butyl rubber under air atmosphere was investigated by thermogravimetry (TG) and derivative thermogravimetry (DTG) at various heating rates. The kinetic parameters were evaluated by TG and the isoconversional method developed by Ozawa. One prominent decomposition stage was observed in the DTG curves at high heating rates, while an additional small peak was observed at low heating rates. The apparent activation energy determined using the TG method ranged from 219.31 to 228.13 kJ·mol-1 at various heating rates. The non-isothermal degradation was found to be a first-order reaction, and the activation energy, as determined by the isoconversional method, increased with an increase in mass loss. The kinetic data suggest that brominated butyl rubber has excellent thermal stability. This study can indirectly aid in improving rubber pyrolysis methods and in enhancing the heat resistance of materials.

Immune response of C57BL/6J mice to herpes zoster subunit vaccines formulated with nanoemulsion-based and liposome-based adjuvants.

Herpes zoster (HZ) is a recurrent nerve tissue infection caused by the reactivation of varicella-zoster virus (VZV). At present, two vaccines, the live attenuated vaccine Zostavax™ and AS01B-adjuvanted recombinant subunit vaccine Shingrix™, are commercially available for HZ. The latter is superior to the former in terms of efficacy and duration of immunity in the elderly. In this study, we used glycoprotein E (gE) as an antigen, and investigated the effects of various adjuvants (MF59, MF59/CpG 2006, and MF59/QS-21) on the immune response of C57BL/6J mice to find an alternative adjuvant to AS01B-like adjuvant of liposome/QS-21/MPL. In addition to safety, the gE-specific antibody, IgG antibody subtype, and cytokine secretion by splenocytes, and cell-mediated immune responses were determined using ELISA and ELISPOT assays, respectively. Our results showed no significant effects on the body weight, temperature, or behavior of mice vaccinated with PBS or all adjuvanted vaccines. All adjuvanted vaccine groups showed significantly higher gE-specific IgG antibody levels than the gE-alone group on day 28 after the first vaccine dose. In addition, all adjuvants induced a remarkable increase in both IgG1 and IgG2b levels. However, MF59/QS-21 and MF59/CpG 2006 showed comparable capacities to those of liposome/QS-21/MPL in increasing the IgG2c levels, being superior to MF59. Further investigation revealed that MF59 only induced a limited increase in the levels of Th1 and Th2 cytokines, while MF59/QS-21, MF59/CpG 2006, and liposome/QS-21/MPL led to a significant increase in the secretion of interferon gamma (IFN-γ), IL-2, IL-4, and IL-10 and showed a Th1-biased immune response. Moreover, MF59/QS-21, MF59/CpG 2006, and liposome/QS-21/MPL adjuvanted vaccines resulted in comparable gE-specific IFN-γ + immune cell responses. These results suggest that the combination of MF59 with QS-21 or CpG 2006 may be a promising adjuvant candidate for subunit HZ vaccines. Further investigations are needed to illustrate their durability and efficacy in aged mice.

Concentrations and Related Health Risk Assessment of Pesticides, Phthalates, and Heavy Metals in Strawberries from Shanghai, China.

ABSTRACT: In the present study, a risk assessment of pesticides, phthalates, and heavy metals in strawberries (n = 335) in recent years was conducted by determining the estimated daily intake, target hazard quotient, and hazard index. The study used 128 pesticides, 18 phthalates, and three heavy metals in this determination. It detected 51 pesticide residues in the strawberry samples, and 97.91% samples had levels of at least 1 of the 51 pesticides above the limit of detection. In addition, 2.39% of samples had pesticides higher than the Chinese maximum residue limit. Multiple pesticide residues were detected in most samples. Bis-2-ethylhexyl phthalate, diisobutyl phthalate, and dibutyl phthalate were detected in the strawberry samples, with a high frequency of detection. Their detectable rates were 100, 100, and 89.9%, respectively. In most samples, lead, cadmium, and nickel were detected, with detectable rates 75.76, 92.93, and 92.93%, respectively. The estimated daily intake of analyzed pesticide, phthalate, and heavy metal residues appears to be relatively low compared with the acceptable daily intake. The average target hazard quotients and hazard indices were less than 1. That means that customers who are exposed to the average contaminant levels may not pose a significant health risk. Our results show that the strawberries may be polluted by many kinds of contaminants. Therefore, monitoring of pesticide, phthalate, and heavy metal residues in strawberries should be increasingly developed to fully protect the health of the consumer.

TiO2-sensitized double-shell ZnCdS hollow nanospheres for photoelectrochemical immunoassay of carcinoembryonic antigen coupled with hybridization chain reaction-dependent Cu2+ quenching.

A novel photoelectrochemical immunosensor was constructed to monitor carcinoembryonic antigen (CEA) based on hybridization chain reaction (HCR)-mediated in situ generation of copper nanoparticles (Cu NPs) and subsequent Cu2+-dependent quenching reaction, in which titanium dioxide nanoparticles-sensitized double-shell zinc cadmium sulfide hollow nanospheres (TiO2/DS-ZnCdS)-modified ITO electrode and anti-CEA antibody-modified 96-well plate served as biological recognition and signal detection platforms, respectively. The synergistic effect of TiO2 NPs and DS-ZnCdS hollow nanospheres contributed to the improvement of photoelectric conversion efficiency, and HCR-mediated signal cascade benefited the enhancement of detection sensitivity. In the presence of CEA, biotin-labelled anti-CEA antibodies were immobilized onto anti-CEA antibody-modified 96-well plate, and triggered HCR process to form long double stranded DNA, which could adsorb a large number of Cu2+ ions and then in situ form Cu NPs on double stranded DNA template by a facile reduction reaction. After acid treatment, the dissolved Cu2+ ions could significantly reduce the photocurrent response due to the generation of CuxS. Under optimal conditions, the immunosensor exhibited a desirable liner range of 1 pg mL-1 - 50 ng mL-1 and a low detection limit of 0.1 pg mL-1, as well as excellent selectivity and stability. Meanwhile, the recoveries of human serum sample analysis ranged from 96.8% to 103.6%, and the relative standard deviation was less than 7.40%, showing a good feasibility in early clinical diagnosis.

4-Pentenoyl-isoleucyl-chitosan oligosaccharide and acrylamide functional monomer-dependent hybrid bilayer molecularly imprinted membrane for sensitive electrochemical sensing of bisphenol A.

In this work, an electrochemical sensor was designed for trace monitoring of bisphenol A (BPA) by decorating a hybrid bilayer molecularly imprinted membrane (MIM) on a multi-walled carbon nanotube-modified glassy carbon electrode. When BPA in the MIM was eluted, a composite molecularly imprinted electrochemical sensor was constructed. Under optimal conditions, the developed sensor showed two linear relationships between ΔI p and BPA concentration in the range of 0.04 µM to 8 µM, as well as good selectivity and stability, and was also applied to detect BPA in water samples with desirable recoveries ranging from 92.0% to 107.0%.

Hypocalcemia in sepsis: analysis of the subcellular distribution of Ca2+ in septic rats and LPS/TNF-α-treated HUVECs.

INTRODUCTION: Hypocalcemia has been widely recognized in sepsis patients. However, the cause of hypocalcemia in sepsis is still not clear, and little is known about the subcellular distribution of Ca2+ in tissues during sepsis. METHODOLOGY: We measured the dynamic change in Ca2+ levels in body fluid and subcellular compartments, including the cytosol, endoplasmic reticulum and mitochondria, in major organs of cecal ligation and puncture (CLP)-operated rats, as well as the subcellular Ca2+ flux in HUVECs which treated by endotoxin and cytokines. RESULTS: In the model of CLP-induced sepsis, the blood and urinary Ca2+ concentrations decreased rapidly, while the Ca2+ concentration in ascites fluid increased. The Ca2+ concentrations in the cytosol, ER, and mitochondria were elevated nearly synchronously in major organs in our sepsis model. Moreover, the calcium overload in CLP-operated rats treated with calcium supplementation was more severe than that in the non-calcium-supplemented rats but was alleviated by treatment with the calcium channel blocker verapamil. Similar subcellular Ca2+ flux was found in vitro in HUVECs and was triggered by lipopolysaccharide (LPS)/TNF-α. CONCLUSIONS: Ca2+ influx from the blood into the intercellular space and Ca2+ release into ascites fluid may cause hypocalcemia in sepsis and that this process may be due to the synergistic effect of endotoxin and cytokines.

Beta-cyclodextrin-functionalized CdS nanorods as building modules for ultrasensitive photoelectrochemical bioassay of HIV DNA.

Nowadays, acquired immunodeficiency syndrome has become a formidable danger to human health, and its early diagnosis is urgent need with the increasing quantity of patients around the world. Herein, we first synthesized beta-cyclodextrin-functionalized CdS nanorods (ß-CD@CdS NRs) with high stability and desirable photo-electricity activity, and served as easy-to-assemble building modules to design a novel photoelectrochemical biosensor for human immune deficiency virus (HIV) DNA detection by coupling with catalytic hairpin assembly (CHA)-mediated biocatalytic precipitation and the host-guest interaction between adamantine (ADA) and ß-CD. In the presence of HIV DNA, CHA process was triggered with the aid of hairpin DNA1 and ADA-labelled hairpin DNA2, and then generated large amounts of G-quadruplex, which could be formed hemin/G-quadruplex DNAzyme to catalyze 4-chloro-1-naphthol to generate insoluble precipitation on photoelectrode surface, followed by the decreased photocurrent response due to the corresponding stereo-hindrance effect. Under optimized conditions, this biosensor exhibited wide linear dynamic range (10 fM - 1 nM) and low detection limit of 1.16 fM, as well as high sensitivity, excellent stability, and satisfactory feasibility in human-serum samples. Moreover, the prepared ß-CD@CdS NRs could be applied to the construction of other advanced sensing platform, showing great prospect in clinical diagnostics.

Cu2+-Modulated in situ growth of quantum dots for split-type photoelectrochemical immunoassay of prostate-specific antigen.

A split-type photoelectrochemical immunosensor was designed for the ultrasensitive monitoring of prostate-specific antigen (PSA) based on a Cu2+-mediated catalytic reaction for inhibiting the in situ generation of CdS quantum dots (QDs) coupled with the enhancement of the CdS/MoS2 heterojunction; it was constructed by the stepwise modification of MoS2 QDs and CdS QDs onto an ITO electrode surface. In the presence of PSA, CuO NP-labeled anti-PSA antibodies were immobilized onto an anti-PSA antibody-modified 96-well plate via a sandwich immunoreaction and dissolution by hydrochloric acid to obtain a large number of Cu2+ ions. As the Cu2+-triggered catalytic oxidization of glutathione occurred, the in situ growth of CdS QDs as a signal indicator was significantly suppressed, resulting in reduction in the photocurrent response. Under optimal conditions, the biosensor exhibited desirable linearity in the range from 0.5 pg mL-1 to 10 ng mL-1, low detection limit of 0.29 pg mL-1, satisfactory selectivity, and good stability. It was applied to PSA detection in human serum, suggesting a great potential for early diagnostics of some cancers.