Thioredoxin facilitates hepatocellular carcinoma stemness and metastasis by increasing BACH1 stability to activate the AKT/mTOR pathway.

Thioredoxin (TXN) is essential for preserving balance and controlling the intracellular redox state. Most studies have focused on the function of TXN in redox reactions, which is critical for tumor progression. Here, we showed that TXN promotes hepatocellular carcinoma (HCC) stemness properties in a non-redox-dependent manner, which has rarely been reported in previous studies. TXN exhibited upregulated expression in human HCC specimens, which was associated with a poor prognosis. Functional studies showed that TXN promoted HCC stemness properties and facilitated HCC metastasis both in vitro and in vivo. Mechanistically, TXN promoted the stemness of HCC cells by interacting with BTB and CNC homology 1 (BACH1) and stabilized BACH1 expression by inhibiting its ubiquitination. BACH1 was positively correlated with TXN expression and was significantly upregulated in HCC. In addition, BACH1 promotes HCC stemness by activating the AKT/mammalian target of rapamycin (mTOR) pathway. Furthermore, we found that the specific inhibition of TXN in combination with lenvatinib in mice significantly improved the treatment of metastatic HCC. In summary, our data demonstrate that TXN plays a crucial role in HCC stemness and BACH1 plays an integral part in regulating this process by activating the AKT/mTOR pathway. Thus, TXN is a promising target for metastatic HCC therapy.

High-Resolution Magnetoelectric Sensor and Low-Frequency Measurement Using Frequency Up-Conversion Technique.

The magnetoelectric (ME) sensor is a new type of magnetic sensor with ultrahigh sensitivity that suitable for the measurement of low-frequency weak magnetic fields. In this study, a metglas/PZT-5B ME sensor with mechanical resonance frequency fres of 60.041 kHz was prepared. It is interesting to note that its magnetic field resolution reached 0.20 nT at fres and 0.34 nT under a DC field, respectively. In order to measure ultralow-frequency AC magnetic fields, a frequency up-conversion technique was employed. Using this technique, a limit of detection (LOD) under an AC magnetic field lower than 1 nT at 8 Hz was obtained, and the minimum LOD of 0.51 nT was achieved at 20 Hz. The high-resolution ME sensor at the sub-nT level is promising in the field of low-frequency weak magnetic field measurement technology.

LDP alleviates TKI-induced proteinuria through reversing the expression of RelA in renal tissues.

Tyrosine kinase inhibitors (TKIs), as an important tumor therapy, can induce severe proteinuria that significantly affects anti-tumor therapy. Existing therapies against proteinuria induced by other etiologies are currently ineffective for TKI-induced proteinuria. It has been shown that various types of proteinuria are related to podocyte damage caused by changes in the RelA signaling pathway. Our experiments confirmed that TKIs activate the renal RelA signaling pathway, and induce death of podocytes and destruction of the glomerular filtration barrier. Here we found that Liuwei Dihuang Pill (LDP) attenuated the inflammatory injury of podocytes through inhibiting activation of RelA, and subsequently relieved TKI-related proteinuria and prevented the progression of TMA and FSGS. Our finding indicated that LDP may be effective for the treatment of TKI-induced proteinuria, which is clinically significant.

Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma.

Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD). However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance. Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD. Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents. Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms. Here, in vitro and in vivo, we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD. Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells. In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ. Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.

The Combination of R848 with Sorafenib Enhances Antitumor Effects by Reprogramming the Tumor Immune Microenvironment and Facilitating Vascular Normalization in Hepatocellular Carcinoma.

Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage-to-FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell-mediated antitumor immunity. Additionally, low-dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low-dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment.

Enhanced Microwave Absorption and Electromagnetic Properties of Si-Modified rGO@Fe3O4/PVDF-co-HFP Composites.

Graphene has been regarded as one of the most promising two-dimensional nanomaterials. Even so, graphene was still faced with several key issues such as impedance mismatching and narrow bandwidth, which have hindered the practical applications of graphene-based nanocomposites in the field of microwave absorption materials. Herein, a series of Si-modified rGO@Fe3O4 composites were investigated and fabricated by a simple method. On one hand, the degree of defects in graphene carbon could be tuned by different silane coupling reagents, which were beneficial to enhancing the dielectric loss. On the other hand, the spherical Fe3O4 nanoparticles provided the magnetic loss resonance, which contributed to controlling the impedance matching. Subsequently, the electromagnetic absorption (EMA) properties of Si-modified rGO@Fe3O4 composites with poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-co-HFP) were investigated in this work. As a result, the Si(2)-rGO@Fe3O4/PVDF-co-HFP composite exhibited the excellent EMA performance in the range of 2-18 GHz. The maximum reflection loss (RLmax) reached -32.1 dB at 3.68 GHz at the thickness of 7 mm and the effective absorption frequency bandwidth for reflection loss (RL) below -10 dB was 4.8 GHz at the thickness of 2 mm. Furthermore, the enhanced absorption mechanism revealed that the high-efficiency absorption performance of Si(2)-rGO@Fe3O4/PVDF-co-HFP composite was attributed to the interference absorption (quarter-wave matching model) and the synergistic effects between Si(2)-rGO@Fe3O4 and PVDF-co-HFP. This work provides a potential strategy for the fabrication of the high-performance EMA materials.