Biodegradable Silk Fibroin Nanocarriers to Modulate Hypoxia Tumor Microenvironment Favoring Enhanced Chemotherapy

Biopolymer silk fibroin (SF) is a great candidate for drug carriers characterized by its tunable biodegradability, and excellent biocompatibility properties. Recently, we have constructed SF-based nano-enabled drug delivery carriers, in which doxorubicin (Dox) and atovaquone (Ato) were encapsulated with Arg-Gly-Asp-SF-Polylactic Acid (RSA) to form micellar-like nanoparticles (RSA-Dox-Ato NPs). The RGD peptide was decorated on micellar-like nanoparticles, promoting tumor accumulation of the drug. Meanwhile, Ato, as a mitochondrial complex III inhibitor inhibiting mitochondrial respiration, would reverse the hypoxia microenvironment and enhance chemotherapy in the tumor. In vitro, the biopolymer alone showed extremely low cytotoxicity to 4T1 cell lines, while the RSA-Dox-Ato demonstrated a higher inhibition rate than other groups. Most significantly, the ROS levels in cells were obviously improved after being treated with RSA-Dox-Ato, indicating that the hypoxic microenvironment was alleviated. Eventually, SF-based targeted drug carrier provides biocompatibility to reverse hypoxia microenvironment in vivo for enhancing chemotherapy, strikingly suppressing tumor development, and thereby suggesting a promising candidate for drug delivery system

Integrative analysis of disulfidptosis and immune microenvironment in hepatocellular carcinoma: a putative model and immunotherapeutic strategies

BackgroundHepatocellular carcinoma (HCC) is a malignant tumor with a high rate of recurrence and m metastasis that does not respond well to current therapies and has a very poor prognosis. Disulfidptosis is a novel mode of cell death that has been analyzed as a novel therapeutic target for HCC cells.MethodsThis study integrated bulk ribonucleic acid (RNA) sequencing datasets, spatial transcriptomics (ST), and single-cell RNA sequencing to explore the landscape of disulfidptosis and the immune microenvironment of HCC cells.ResultsWe developed a novel model to predict the prognosis of patients with HCC based on disulfidptosis. The model has good stability, applicability, and prognostic and immune response prediction abilities. N-myc downregulated gene1 (NDRG1) may contribute to poor prognosis by affecting macrophage differentiation, thus allowing HCC cells to evade the immune system.ConclusionOur study explores the disulfidptosis of HCC cells through multi-omics and establishes a new putative model that explores possible targets for HCC treatment

Development and Adsorption Characterization of Metal Affinity-Immobilized Magnetic Liposome

A metal affinity-immobilized magnetic liposome (MA-IML) was prepared in this research, which was with lipid and Ni2+ content of 143.25 μg/mg and 32 μmol/mg, respectively. The antihypertensive peptides Ile-Pro-Pro (IPP) and Val-Pro-Pro (VPP) could be adsorbed onto MA-IML under specific conditions, and the adsorption kinetics was explored. The pseudo-second-order kinetics (R2 value>0.98) was more suitable to describe the adsorption process of IPP and VPP than the intraparticle diffusion model and pseudo-first-order kinetic model. The results indicated that MA-IML could be used as an adsorbent for screening antihypertensive peptides from natural products

Collaborative Intelligence Orchestration: Inconsistency-Based Fusion of Semi-Supervised Learning and Active Learning

While annotating decent amounts of data to satisfy sophisticated learning models can be cost-prohibitive for many real-world applications. Active learning (AL) and semi-supervised learning (SSL) are two effective, but often isolated, means to alleviate the data-hungry problem. Some recent studies explored the potential of combining AL and SSL to better probe the unlabeled data. However, almost all these contemporary SSL-AL works use a simple combination strategy, ignoring SSL and AL's inherent relation. Further, other methods suffer from high computational costs when dealing with large-scale, high-dimensional datasets. Motivated by the industry practice of labeling data, we propose an innovative Inconsistency-based virtual aDvErsarial Active Learning (IDEAL) algorithm to further investigate SSL-AL's potential superiority and achieve mutual enhancement of AL and SSL, i.e., SSL propagates label information to unlabeled samples and provides smoothed embeddings for AL, while AL excludes samples with inconsistent predictions and considerable uncertainty for SSL. We estimate unlabeled samples' inconsistency by augmentation strategies of different granularities, including fine-grained continuous perturbation exploration and coarse-grained data transformations. Extensive experiments, in both text and image domains, validate the effectiveness of the proposed algorithm, comparing it against state-of-the-art baselines. Two real-world case studies visualize the practical industrial value of applying and deploying the proposed data sampling algorithm.Comment: Accepted to KDD 202

Inhibitory Effect on the Hepatitis B Cells through the Regulation of miR-122-MAP3K2 signal pathway

Abstract: The aim of this study was to investigate the inhibitory effect of regulation of miR-122-MAP3K2 signal pathway on the hepatitis B cells. We detected the content of MAP3K2 from patients with HBV blood serum samples and analyzed the correlation between content of MAP3K2 and copies of HBV-DNA. Wound healing and Transwell assays were used to detect the function of cells from control group (wild type) and observer group (overexpresses miR-122). Secretion levels of HBsAg and MAP3K2 in the supernatant and level of MAP3K2 in cells were detected by ELISA and western blot, respectively. The results showed that there was a positive correlation between the copies of HBV-DNA and MAP3K2 in serum. In the assays involving detection of the number of HBV-DNA copies, the supernatant levels of HBsAg and MAP3K2, and the level of MAP3K2 in the cells, the rate of increase of these indicators significantly slowed as culture time. In conclusion, overexpression of miR-122 could inhibit the migration of hepatoblastoma cells; however, following transfection with miR-122, DNA synthesis and the secretion of HBsAg were inhibited. Overexpression of miR-122 can also downregulate MAP3K2. Consequently, we concluded that regulating the miR-122-MAP3K2 signaling pathway exerts an inhibitory effect in hepatitis B cells

Zinc Finger and X-Linked Factor (ZFX) Binds to Human SET Transcript 2 Promoter and Transactivates SET Expression

SET (SE Translocation) protein carries out multiple functions including those for protein phosphatase 2A (PP2A) inhibition, histone modification, DNA repair, and gene regulation. SET overexpression has been detected in brain neurons of patients suffering Alzheimer’s disease, follicle theca cells of Polycystic Ovary Syndrome (PCOS) patients, and ovarian cancer cells, indicating that SET may play a pathological role for these disorders. SET transcript 2, produced by a specific promoter, represents a major transcript variant in different cell types. In this study, we characterized the transcriptional activation of human SET transcript 2 promoter in HeLa cells. Promoter deletion experiments and co-transfection assays indicated that ZFX, the Zinc finger and X-linked transcription factor, was able to transactivate the SET promoter. A proximal promoter region containing four ZFX-binding sites was found to be critical for the ZFX-mediated transactivation. Mutagenesis study indicated that the ZFX-binding site located the closest to the transcription start site accounted for most of the ZFX-mediated transactivity. Manipulation of ZFX levels by overexpression or siRNA knockdown confirmed the significance and specificity of the ZFX-mediated SET promoter activation. Chromatin immunoprecipitation results verified the binding of ZFX to its cognate sites in the SET promoter. These findings have led to identification of ZFX as an upstream factor regulating SET gene expression. More studies are required to define the in vivo significance of this mechanism, and specifically, its implication for several benign and malignant diseases related to SET dysregulation

Generation of dual functional nanobody-nanoluciferase fusion and its potential in bioluminescence enzyme immunoassay for trace glypican-3 in serum

Glypican-3 (GPC3) is a serological biomarker for the diagnosis of Hepatocellular carcinoma (HCC), but it is a challenging task to develop a bioassay for determination of the trace GPC3 in serum. In this study, Bioluminescense immunoassay based on bifunctional nanobody-nanoluciferase fusion was developed with the ultra-sensitive feature to achieve this goal. First, nanobodies special against GPC-3 binder as biological recognition element were generated by immunization and phage display technology. Second, The best clone GPN2 was fused with nanoluciferase as a dual-functional immunoreagent to establish an ultra-sensitive bioluminescence enzyme immunoassay (BLEIA), which is 30 and 5 times more sensitive than the traditional colorimetric assay and fluorescent assay, respectively. The cross-reactivity analysis of BLEIA showed that there was no cross-reactivity with HCC related tumor markers AFP, CEA, CA19-9 and GPC1/GPC2. The limit of detection (LOD) of developed BLEIA was 1.5 ng/mL, which assured its application in the diagnosis of GPC3 in 94 serum samples. This study indicates that BLEIA based on nanobody-nanoluciferase fusion could be used as a useful tool for the diagnosis of HCC patients