Search

Osteosarcoma has a relatively high incidence rate among primary malignant tumors, and the survival rate is low. Clinically, surgical resection and chemotherapy are mainly used, which are difficult to utilize to treat metastatic or recurrent osteosarcoma. The combination of chemotherapy and immunotherapy can achieve a better tumor treatment effect. M1 macrophages (M1 Mø) can kill tumor cells and have tumor-targeting and phagocytosis ability, which are an ideal tool for tumor-targeted drug delivery. However, as carriers, living cells have the disadvantages of uncontrollable size, poor tissue permeability, and poor stability. In this study, the M1 macrophage membrane (M1M) was used as the carrier and loaded with MMP-2 (matrix metalloproteinase-2)-sensitive drug-loaded liposomes (GL) to prepare a complex nanovesicle drug delivery system M1M (GL/DOX/TPI-1), with a tumor active targeting function, for combined chemical and immune therapy from doxorubicin (DOX) and tyrosine phosphatase inhibitor 1 (TPI-1). The complex nanovesicles not only retain the tumor-targeting ability from the M1 macrophage membrane but also have the advantages of controllable size, responsive drug release, and high stability. The results of in vivo efficacy test show that the drug delivery system realizes active targeted enrichment in osteosarcoma tissue. Under the response of MMP-2, the internally encapsulated antitumor drugs DOX and TPI-1 from the system are released. This drug delivery system combined with chemical and immune treatment can effectively achieve the aim of the treatment of osteosarcoma. [ABSTRACT FROM AUTHOR]

The photocatalytic enhancement of sliver-based metals compounded with semiconductor materials has been demonstrated. However, there are relatively few studies on the effect of particle size in the system on photocatalytic performance. In this paper, silver nanoparticles of two different sizes, 25 and 50 nm, were prepared by a wet chemical method and subsequently sintered to obtain a photocatalyst with a core-shell structure. The photocatalyst Ag@TiO 2 -50/150 prepared in this study has a hydrogen evolution rate as high as 4538.90 μmol·g -1 ·h -1 . It is interesting to find that when the ratio of silver core size to composite size is 1:3, the hydrogen yield is almost not affected by the silver core diameter, and the hydrogen production rate is basically the same. In addition, the rate of hydrogen precipitation in air for 9 months was still more than 9 times those of previous studies. This provides a new idea for the study of the oxidation resistance and stability of photocatalysts.

Tumor-specific targeting and tumor visualization are major obstacles for clinical diagnosis and treatment. Herein, a dual-targeted "all-in-one" nanoplatform (FAA@CM) for trimodal imaging-guided photothermal/chemodynamic synergistic therapy was successfully synthesized by encapsulating Fe 3 O 4 , Ag 2 S, and ascorbic acid with the 4T1 cell membrane. The dual-targeting capability derived from 4T1 cell membrane cloaking and magnetic targeting enables the highly precise tumor-specific delivery of FAA@CM. Fe 2+ released from FAA@CM in a weakly acidic tumor microenvironment can trigger the Fenton reaction to achieve chemodynamic therapy (CDT). The photothermal performance of FAA@CM not only enables photothermal therapy but also promotes the CDT effect. In order to relieve H 2 O 2 deficiency, a biosafe H 2 O 2 prodrug, ascorbic acid, was introduced to greatly increase the H 2 O 2 concentration in tumors, promoting the Fenton reaction to produce more • OH to enhance the oxidative damage to tumors. Interestingly, FAA@CM exhibits trimodal imaging capabilities, including second near-infrared (NIR-II, 1000-1700 nm) fluorescence imaging, photoacoustic imaging, and magnetic resonance imaging, which can guide the laser irradiation, achieving complete elimination of 4T1 tumors in BALB/c mice. This work provided a novel dual-targeted, multifunctional theranostic nanoplatform for highly effective tumor therapy.

Chemodynamic therapy (CDT) is an innovative and effective treatment that relies on the Fenton or Fenton-like reaction, in which endogenous H 2 O 2 overproduction is converted into cytotoxic hydroxyl radicals ( • OH) to suppress tumor growth. Nevertheless, the therapeutic efficiency of CDT is severely restricted by undesirable properties, such as reaction conditions and catalyst performance. Herein, a 2D Ti 3 C 2 MXene/Cu 2 O nanosheet (MCP NS)-based multifunctional nanoplatform (3-BP@MCG NSs) has been constructed, in which glucose oxidase (GOx) and respiration inhibitor 3-bromopyruvate (3-BP) are sequentially embedded. In this structure, the copper-based catalyst Cu 2 O releases Cu + in an acid-triggered manner in the tumor microenvironment (TME), which activates the Fenton-like reaction to catalyze the generation of • OH for CDT. The composite has excellent photothermal properties and a high-resolution photoacoustic imaging (PAI) capability in the near-infrared (NIR) region, and especially under NIR irradiation, the photothermal effect generated by the nanosheets accelerates catalysis. GOx is a natural enzyme catalyst for depleting glucose and oxygen content in cells, upregulating H 2 O 2 levels in situ , and thereby improving the therapeutic effect of CDT. What is more, the supported 3-BP not only reduces oxygen consumption to alleviate hypoxia levels but also inhibits the glycolysis process and lowers ATP levels by suppressing hexokinase activity. As a result, 3-BP@MCG NSs optimize the unique properties of MCP NSs, GOx, and 3-BP via mutual promotion, realizing self-enhanced PTT/CDT synergistic therapy. This work establishes an emerging strategy for highly efficient PAI-guided integrated treatment and provides a proof of concept for the cooperation of hypoxia relief and in situ H 2 O 2 and NIR synergistic enhancement to improve therapeutic efficiency.

The hybrid coupling of biocatalysts and chemical catalysts plays a vital role in the fields of catalysis, sensing, and medical treatment due to the integrated advantages in the high activity of natural enzymes and the excellent stability of nanozymes. Herein, a new nanozyme/natural enzyme hybrid biosensor was established for ultrasensitive glutamate detection. The MIL-88B(Fe)-NH 2 material with remarkable peroxidase mimic activity and stability was used as a nanozyme and carrier for immobilizing glutamate oxidase (GLOX) through Schiff base reaction to construct a chem-enzyme cascade detector (MIL-88B(Fe)-NH 2 @GLOX). The resultant MIL-88B(Fe)-NH 2 @GLOX exhibited a wide linear range (1-100 μM), with a low detection limit of 2.5 μM for glutamate detection. Furthermore, the MIL-88B(Fe)-NH 2 @GLOX displayed excellent reusability and storage stability. After repeated seven cycles, MIL-88B(Fe)-NH 2 -GLOX (GLOX was adsorbed on MIL-88B(Fe)-NH 2 ) lost most of its activity, whereas MIL-88B(Fe)-NH 2 @GLOX still retained 69% of its initial activity. Meanwhile, MIL-88B(Fe)-NH 2 @GLOX maintained 60% of its initial activity after storage for 90 days, while free GLOX only retained 30% of its initial activity. This strategy of integrating MOF mimics and natural enzymes for cascade catalysis makes it possible to design an efficient and stable chemo-enzyme composite catalysts, which are promising for applications in biosensing and biomimetic catalysis.

In this study, we aimed to identify potential metabolic biomarkers that can improve the diagnostic accuracy of sepsis. Sixty-six patients including 30 septic and 36 nonsepsis patients from an intensive care unit were recruited. The global plasma and urine metabolomic profiles were determined by ultraperformance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometry-based methodology. The risk factors, including both traditional physiological indicators and metabolic biomarkers, were investigated by binary logistic regression analysis and used to build a least absolute shrinkage and selection operator (Lasso) regression model to evaluate the ability of diagnosis. Fifty-five metabolites in plasma and 11 metabolites in urine were identified through orthogonal projections to latent structures discriminant analysis (OPLS-DA). Among them, ten (PE (20:4(5Z, 8Z, 11Z, 14Z)/P-18:0), harderoporphyrinogen, chloropanaxydiol, ( Z )-2-octenal, N 1 , N 8 -diacetylspermidine, 1-nitroheptane, venoterpine, α-CEHC, LysoPE (20:0/0:0), corticrocin) metabolites were identified as risk factors. The Lasso regression model incorporating these ten metabolic biomarkers and five traditional physiological indicators displayed better differentiation than the traditional model, represented by the elevated area under receiver operating characteristic curve (AUROC) from 96.80 to 100.0%. Furthermore, patients with septic shock presented a significantly lower level of PE-Cer (d16:1(4E)/19:0). This study suggests that metabolomic profiling could be an effective tool for sepsis diagnosis.

We report herein a pincer Ru-catalyzed dual intramolecular dehydrogenative silylation of primary C(sp 3 )-H bonds. The reaction features high efficiency, scalability, and good functional group tolerance, allowing a facile and atom-economical access to structurally diverse silicon-centered spirocycles, including unprecedented oxa-spirosilabiindanes and aza-spirosilabiindanes.

A novel adsorbent lignin-calcium was fabricated by a simple flocculation-sedimentation approach to remove methylene blue. The structure and morphology of the well-prepared sample were analyzed by multiple characterization methods. Lignin-calcium microspheres demonstrated a mesoporous and inserted layer structure with a coarse surface. Methylene blue (MB) adsorption by lignin-calcium complied with the Langmuir model, showing a maximum adsorption amount of 803.9 mg/g, exceeding that reported in the literature by 3-22-fold. The adsorption kinetics matched the pseudo-second-order model well. The pore volume diffusion model was technically applied to evaluate the mass transfer mechanisms. The effective pore volume diffusion coefficient was 6.28 × 10 -12 m 2 /s. Furthermore, lignin-calcium exhibited excellent adsorbability for methylene blue across a pH range from 3 to 11 and could be regenerated by hydrochloric acid with an elution efficiency of 62.44%. Multiple mechanisms may support the adsorption. Altogether, the tailor-made lignin-calcium is promising as an efficient and sustainable adsorbent for scavenging cationic dyes from dyestuff effluent., Competing Interests: The authors declare no competing financial interest., (© 2020 The Authors. Published by American Chemical Society.)

Cytochrome c , an essential protein of the electron transport chain, is known to be capable of amplifying the toxicity of carbon nanomaterials via free-radical generation. To understand their interaction, as well as the more general protein-nanoparticle interaction at molecular levels, we investigate the adsorptions between cytochrome c and carbon nanotubes (CNTs) in dynamic and thermodynamic ways using molecular dynamics simulations. The results reveal a well-defined three-phase process separated by two transition points: the diffusion phase where the protein diffuses in the water box, the lockdown phase I where the protein inserts into the surface-bound water layers and rearranges its conformation to fit to the surface of the CNT, and the lockdown phase II where cytochrome c repels the water molecules standing in its way to the surface of CNT and reaches stable adsorption states. The structured water layers affect the movement of atoms by electrostatic forces. In lockdown phase I, the conformation adjustment of the protein dominates the adsorption process. The most thermally favorable adsorption conformation is determined. It shows that except for the deformation of short β sheets and some portions of α helixes, most of the secondary structures of cytochrome c remain unchanged, implying that most of the functions of cytochrome c are preserved. During these processes, the energy contributions of the hydrophilic residues of cytochrome c are much larger than those of hydrophobic residues. Interestingly, the structured water layers at the CNT surface allow more hydrophilic residues such as Lys to get into close contact with the CNT, which plays a significant role during the anchoring process of adsorption. Our results demonstrate that the heme group is in close contact with the CNT in some of the adsorbed states, which hence provides a way for electron transfer from cytochrome c to the CNT surface.

In the receptor tyrosine kinase family, conformational change induced by ligand binding is transmitted across the membrane via a single transmembrane helix and a flexible juxtamembrane domain (JMD). Membrane dynamics makes it challenging to study the structural mechanism of receptor activation experimentally. In this study, we employ all-atom molecular dynamics with highly mobile membrane mimetic (HMMM) to capture the native conformation of the JMD in tropomyosin receptor kinase A (TrkA). We find that phosphatidylinositol 4,5-bisphosphate (PIP 2 ) lipids engage in stable binding with multiple basic residues. Anionic lipids can compete with salt bridges within the peptide and alter TrkA-JMD conformation. We discover three-residue insertion into the membrane and are able to either enhance or reduce the level of insertion through computationally-designed point mutations. The vesicle-binding experiment supports computational results and indicates that hydrophobic insertion is comparable to electrostatic binding for membrane anchoring. Biochemical assays on cell lines with mutated TrkA show that enhanced TrkA-JMD insertion promotes receptor degradation but does not affect the short-term signaling capacity. Our joint work points to a scenario where lipid headgroups and tails interact with basic and hydrophobic residues on disordered domain, respectively, to restrain flexibility and potentially modulate protein function.

Direct inhibition of the protein-protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6 W could potently inhibit cellular ERα's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein-protein interactions involved in a range of disorders.