RESUMEN

The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.

Asunto(s)

Cobre , Hidrogeles , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Activación de Linfocitos , Triterpenos Pentacíclicos , Especies Reactivas de Oxígeno , Linfocitos T , Microambiente Tumoral , Triterpenos Pentacíclicos/farmacología , Hidrogeles/química , Animales , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ratones , Activación de Linfocitos/efectos de los fármacos , Cobre/química , Microambiente Tumoral/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Humanos , Ratones Endogámicos C57BL , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/química , Femenino , Triterpenos/farmacología , Triterpenos/química

RESUMEN

Studies have confirmed that the spatial arrangement of chiral molecules has a decisive influence on supramolecular assembly. However, the effect of epimerization caused by the change of a single chiral center on the self-assembly of chiral molecules has not been reported. Herein, we explored a pair of epimers 18 α-glycyrrhetinic acid and 18 ß-glycyrrhetinic acid from Glycyrrhiza uralensis Fisch, which had completely different medicinal activities. In this study, we found that these epimers of glycyrrhetinic acid showed distinct self-assembly properties under the condition of the deionized water and a small amount of DMSO solution. Interestingly, the cis-configured 18 ß-GA could form a 'head-to-tail' interlaced structure and further self-assembled to form nanoparticles, while trans-configured 18 α-GA was connected in a "head-to-head" manner, and due to the excessive steric hindrance that made it difficult to assemble. This work not only clearly demonstrates the impact of epimerization due to changes in a single chiral center on the self-assembly of chiral molecules as well as biological activity, but also provides new insights into the self-assembly of natural organic molecules in the development of nanomedicines and biofunctional materials.

Asunto(s)

Antibacterianos , Ácido Glicirretínico , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacología , Ácido Glicirretínico/análogos & derivados , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Estereoisomerismo , Pruebas de Sensibilidad Microbiana , Nanopartículas/química , Glycyrrhiza uralensis/química , Escherichia coli/efectos de los fármacos , Tamaño de la Partícula , Staphylococcus aureus/efectos de los fármacos

RESUMEN

BACKGROUND: Mahuang Fuzi decoction (MGF) is composed of three herb medicines that has been clinically used to treat inflammatory diseases for a long history. At present, more and more active phytochemicals' aggregations have been found during the thermodynamic process of herb medicine decoction, and revealing the clinical efficacy of herb medicine through supramolecular strategies is the focus of current research. However, it is not clear whether decoction induced supermolecules' morphological changes to modify activity. METHODS: Dynamic light scattering (DLS) and field emission scanning electron microscopy (FESEM) were used to analyze the micromorphology of MGF, MGF SA (MGF supermolecules), and MIX (physical mixture of MGF single decoction). The interaction and thermodynamic parameters of single herbs in a decoction were investigated by Isothermal titration calorimetry (ITC). The phytochemicals were systematically analyzed by ultra high performance liquid chromatography-Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS). Under the safe dose on RAW264.7 cells, NO, IL-6 and TNF-α were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA) method. NF-κB p65 translocation from the cytoplasm into the nucleus was examined using the immunofluorescence assay and the western blot, respectively. Furthermore, Metabolomics was used to discover potential biomarkers and the associated metabolic pathways of MGF SA treatment. RESULTS: There were nanoscale aggregations in MGF, and the micromorphology of the extracted MGF SA consisted of uniform particles; while the MIX micromorphology had no uniformity. ITC showed that the interaction MH-GC and FZ-GC were a spontaneous exothermic reaction, indicating that their phytochemicals had the property of self-assembly. Though the micromorphology between MGF, MGF SA, and MIX was obviously different, UHPLC-Q-Orbitrap HRMS results displayed that the main phytochemicals of MGF and MIX had nearly the same components. Interestingly, MGF and MGF SA could significantly inhibit the production of NO, and had better inhibition effect on the expression of nuclear protein NF-κB p65 than MIX, among which MGF SA had the best effect. Further investigation indicated that the perturbance of metabolic profiling in RAW264.7 inflammatory cells was obviously reversed by MGF SA. CONCLUSIONS: The decoction enriched the key active phytochemicals and regulated the formation of homogeneous nanoparticles in MGF SA. The supermolecules in MGF SA significantly enhanced its anti-inflammatory activity, primarily affecting the NF-κB signaling pathway and the biosynthesis and metabolism of arginine in RAW264.7 inflammatory cells. Current study displayed that co-decocting herbal medicine were beneficial to the treatment of diseases than the mixture of the single herbs' extraction.

RESUMEN

We investigate and experimentally demonstrate a fast and robust chromatic dispersion (CD) estimation method based on temporal auto-correlation after digital spectrum superposition. The estimation process is fast, because neither tentative CD scanning based on CD compensation nor specific cost function calculations are used. Meanwhile, the proposed CD estimation method is robust against polarization mode dispersion (PMD), amplified spontaneous emission (ASE) noise and fiber nonlinearity. Furthermore, the proposed CD estimation method can be used for various modulation formats and digital pulse shaping technique. Only 4096 samples are necessary for CD estimation of single carrier either 112 Gbps DP-QPSK or 224 Gbps DP-16QAM signal with various pulse shapes. 8192 samples are sufficient for the root-raised-cosine pulse with roll-off factor of 0.1. As low as 50 ps/nm standard deviation together with a worst estimation error of about 160 ps/nm is experimentally obtained for 7×112 Gbps DP-QPSK WDM signal after the transmission through 480 km to 9120 km single mode fiber (SMF) loop using different launch powers.

RESUMEN

We propose and demonstrate a novel multi-input multi-output (MIMO) equalization based inter-carrier-interference (ICI) cancellation approach employing constant modulus algorithm (CMA) for supperchanels with sub-Nyquist channel spacing, where optical combs are used as optical sources. Compared with the least mean square (LMS) algorithm based ICI canceller, the proposed approach has comparable capability to accomplish the ICI mitigation for 56 Gbaud dual-polarization quadrature phase shift keying (DP-QPSK) signals with tight channel spacing till 50 GHz. In particular, compared with the LMS-MIMO based ICI canceller, the optical linewidth tolerance of 6 MHz is relaxed to 20 MHz given a 1dB required optical signal-to-noise ratio (OSNR) penalty for the CMA-MIMO based ICI canceller. Meanwhile, the CMA-MIMO based ICI canceller is ideal for real-time processing, since the number of parallel processing pipelines can be greater than 240 even in the presence of large linewidth.