Peroxisome proliferator-activated receptors as therapeutic target for cancer.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor family. There are three subtypes of PPARs, including PPAR-α, PPAR-ß/δ and PPAR-γ. They are expressed in different tissues and act by regulating the expression of target genes in the form of binding to ligands. Various subtypes of PPAR have been shown to have significant roles in a wide range of biological processes including lipid metabolism, body energy homeostasis, cell proliferation and differentiation, bone formation, tissue repair and remodelling. Recent studies have found that PPARs are closely related to tumours. They are involved in cancer cell growth, angiogenesis and tumour immune response, and are essential components in tumour progression and metastasis. As such, they have become a target for cancer therapy research. In this review, we discussed the current state of knowledge on the involvement of PPARs in cancer, including their role in tumourigenesis, the impact of PPARs in tumour microenvironment and the potential of using PPARs combinational therapy to treat cancer by targeting essential signal pathways, or as adjuvants to boost the effects of current chemo and immunotherapies. Our review highlights the complexity of PPARs in cancer and the need for a better understanding of the mechanism in order to design effective cancer therapies.

The development of CD8 T-cell exhaustion heterogeneity and the therapeutic potentials in cancer.

CD8+ T cells are essential lymphocytes with cytotoxic properties for antitumor immunotherapy. However, during chronic infection or tumorigenesis, these cells often become dysfunctional with a gradually depleted ability to release cytokines and the exhibition of reduced cytotoxicity, the state referred to as "T-cell exhaustion" (Tex). This unique state was characterized by the increasing expression of inhibitory checkpoint receptors, and interventions targeting immune checkpoint blockades (ICBs) have been considered as a promising strategy to stimulate T-cell killing. Recent investigations have demonstrated that exhausted T cells not only display functional, metabolic, transcriptional, and epigenetic differences but also comprise a heterogeneous group of cells. In this review, we summarize the current findings on dynamic differentiation process during Tex heterogeneity development in cancer and chronic infection. We discuss how the responses to immunotherapy are determined by these distinct subsets and highlight prospective approaches for improving the efficacy of ICB therapy for cancer by leveraging the heterogeneity of T cells.

Immunotherapy of Epstein-Barr virus (EBV) infection and EBV-associated hematological diseases with gp350/CD89-targeted bispecific antibody.

Acute and persistent infection of Epstein-Barr virus (EBV) is associated with several life-threatening hematological disorders, including lymphoproliferative disorders (LPD), hemophagocytic lymphohistiocytosis (HLH), and chronic active Epstein-Barr virus infection (CAEBV). Currently, there are no efficacious virus-targeted therapies for EBV-driven hematological diseases. To explore the potential of phagocytosis-based immunotherapy, we created a bispecific antibody by targeting the viral envelope protein gp350 with a novel EBV-neutralizing antibody (named R1) that was paired with a monoclonal antibody against CD89 for redirecting macrophages and neutrophils. In vitro study showed that the bispecific antibody enabled efficient phagocytosis of EBV and killing of gp350 + lymphoma cells in the presence of PBMC. In vivo studies in NSG mice inoculated with EBV showed that bispecific antibody dramatically reduced the viral load in blood, solid organs and tissues. Treatment of mice implanted with EBV-harboring Raji lymphoma cells efficiently prevented tumor formation and massive metastasis to solid organs. Treatment of mice implanted with whole blood from EBV-HLH patients was effective in reducing viral levels in blood and solid organ. The gp350/CD89 bispecific antibody was highly effective in clearing EBV and immunotherapy of EBV-driven hematological diseases such as LPD and EBV-HLH.

An overview: Management of patients with advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has constituted a significant health burden worldwide, and patients with advanced HCC, which is stage C as defined by the Barcelona Clinic Liver Cancer staging system, have a poor overall survival of 6-8 months. Studies have indicated the significant survival benefit of treatment based on sorafenib, lenvatinib, or atezolizumab-bevacizumab with reliable safety. In addition, the combination of two or more molecularly targeted therapies (first- plus second-line) has become a hot topic recently and is now being extensively investigated in patients with advanced HCC. In addition, a few biomarkers have been investigated and found to predict drug susceptibility and prognosis, which provides an opportunity to evaluate the clinical benefits of current therapies. In addition, many therapies other than tyrosine kinase inhibitors that might have additional survival benefits when combined with other therapeutic modalities, including immunotherapy, transarterial chemoembolization, radiofrequency ablation, hepatectomy, and chemotherapy, have also been examined. This review provides an overview on the current understanding of disease management and summarizes current challenges with and future perspectives on advanced HCC.

Different binding characteristics of ciprofloxacin to iron mineral surfaces: Thermodynamic evidence and site energy distribution analysis.

Iron minerals in soil play an important role in controlling the migration of fluoroquinolones. In this study, batch experiments were carried out to investigate interactions in ciprofloxacin (CIP) adsorption to goethite, hematite, and magnetite at pH 6.0. Thermodynamics and the site energy distribution theory (SEDT) were adopted to clarify the complexation types. Using the adsorption results, pH-dependent interactions were qualitatively elucidated. The thermodynamic data revealed the difference in adsorption mechanisms. With increasing sorbate loading, CIP adsorption to hematite and magnetite was endothermic, and both enthalpy change and entropy change decreased; however, CIP sorption to goethite showed opposite characteristics. The higher adsorption capacity and affinity of CIP to hematite and magnetite than those to goethite were caused by their higher site energy of the highest occurring frequency (E0 * ) and the temperature-dependent average site energy, respectively. The E0 * on the surface of goethite was about 17-19 kJ mol-1 , where E0 * values of hematite and magnetite were 20-26 kJ mol-1 . When temperature increased from 289.15 to 308.15 K, the high- and low-energy site densities for three iron minerals changed by -32 to 167% and by -36 to 223%, respectively. The different thermodynamic and SEDT results indicated that CIP adsorption mechanisms to goethite and hematite/magnetite were mainly outer- and inner-sphere complexation, respectively. The findings of this study reveal the adsorption mechanisms and are helpful in evaluating the transport of antibiotics in soils containing typical iron minerals.

Identification of new potential antigen recognized by γδT cells in hepatocellular carcinoma.

In recent years, the application of chimeric antigen receptor T-cell (CAR-T) therapy based on gamma delta T (γδT) cells in hepatocellular carcinoma (HCC) immunotherapy has attracted more and more attention. However, specific antigens recognized by γδT cells are rarely identified, which has become the main restriction on such therapeutic application of γδT cells. In this report, we identified a new peptide and protein antigen recognized by γδT cells in HCC using our previous established strategy. First, we investigated the diversity of the γ9/δ2 T-cell immunorepertoire by sequence analyses of the expressed complementarity-determining region 3 (CDR3) in HCC patients. Then, we constructed γ9/δ2 T-cell receptor (TCR)-transfected cell lines expressing significant HCC CDR3 sequence and identified a series of peptides capable of binding to γδT cells specifically. Next, we identified, further tested and verified the biological functions of these peptides and their matched protein by bioinformatics analysis. We identified that the new protein hepatocyte growth factor-like protein, also called as macrophage-stimulating protein (MSP), and peptide HP1, not only bound to HCC-predominant γδTCR but also effectively activated γδT cells isolated from HCC patients. Moreover, they could stimulate γδT cells in peripheral blood from HCC patients to produce cytokines, which contributed to inhibiting HCC and played an important role in mediating cytotoxicity to HCC cell lines. In conclusion, we identified MSP and HP1, which showed potential as candidates for antigens recognized by γδT cells in HCC.

Microcystin-LR in peripheral circulation worsens the prognosis partly through oxidative stress in patients with hepatocellular carcinoma.

Prognostic significance of serum microcystin in hepatocellular carcinoma has not been well investigated. The aim of the study was to reveal the relationship between serum microcystin-LR and prognosis in these patients. There were 650 early-stage hepatitis B-induced hepatocellular carcinoma patients, who were not affected by hepatitis C, cirrhosis, heavy drinking or excessive aflatoxin exposure. All of them underwent hepatectomy and were followed up for 5 years. Tumor relapse and overall death were recorded. Blood specimens were collected on admission and at the time of relapse. Serum levels of microcystin-LR and fluorescent oxidation products (FlOP_360, FlOP_320 and FlOP_400) were measured separately using enzyme-linked immunosorbent assay and fluorescence spectrometry. Multifactorial COX regression analysis suggested that serum microcystin-LR ≥ 0.97 ng/ml was associated with the increased risk of the tumor relapse (HR: 1.53, 95% CI: 1.35-1.77) and serum microcystin-LR ≥ 1.09 ng/ml was related to the higher risk of the overall death (HR: 1.58, 95% CI: 1.35-1.84) in the follow-up period. Furthermore, there was a linear relationship between serum level of microcystin-LR and serum levels of FlOP_360, FlOP_320 and FlOP_400 (P = 0.001, P = 0.023, P = 0.047). Serum levels of these fluorescent oxidation products were also higher in the patients with tumor relapse (P < 0.001, P < 0.001, P = 0.001) or overall death (P < 0.001, P = 0.001, P = 0.002) compared with the remaining patients. Serum microcystin-LR independently worsens the prognosis partly through promoting oxidative stress in patients with hepatocellular carcinoma.

Study on the Quality Evaluation of Compound Danshen Preparations Based on the xCELLigence Real-Time Cell-Based Assay and Pharmacodynamic Authentication.

Objective: To perform a preliminary study on the quality evaluation of compound Danshen preparations based on the xCELLigence Real-Time Cell-based Assay (RTCA) system and make a pharmacodynamics verification. Methods: The compound Danshen was discussed as a methodological example, and the bioactivity of the compound Danshen preparations were evaluated by real-time cell electronic analysis technology. Meanwhile, an in vivo experiment on an acute blood stasis rat model was performed in order to verify this novel evaluation through the curative effect of dissipating blood stasis. Results: We determined the cell index (CI) and IC50 of the compound Danshen preparations and produced time/dose-dependent cell response profiles (TCRPs). The quality of the three kinds of compound Danshen preparations was evaluated through the RTCA data. The trend of CI and TCRPs reflected the effect of drugs on the cell (promoting or inhibiting), and it was verified that the results correlated with the biological activity of the drugs using a pharmacodynamics experiment. Conclusion: The RTCA system can be used to evaluate the quality of compound Danshen Preparations, and it can provide a new idea and new method for quantitatively characterizing the biological activity of traditional Chinese medicines (TCMs).

Trillin Reduces Liver Chronic Inflammation and Fibrosis in Carbon Tetrachloride (CCl4) Induced Liver Injury in Mice.

UNLABELLED: Trillin is an active ingredient isolated from Dioscorea nipponica Makino. This study investigated the anti-inflammatory and anti-fibrosis effects of trillin on CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation and fibrosis were induced by intraperitoneal administration of CCl4 0.5 µL/g of body weight twice a week for 6 weeks. Trillin (50 mg/kg, 100 mg/kg) was administered by gavage for 12 days before finishing the CCl4 induction. Aspartate amino-transferase (AST) and glutamic-pyruvic transaminase (ALT) in serum were determined by AST and ALT kits. Superoxidase dismutase (SOD) activity and malondialdehyde (MDA) levels in serum were assayed by SOD and MDA kits. Meanwhile, the levels of inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) in serum were detected by enzyme-linked immunosorbent assay (ELISA) method. Pathological changes were observed by hematoxylin-eosin (HE) staining. The proteins of the NF-κB pathway and the TGF-ß/Smad pathway were measured by western blot. The trillin-treated group exhibited reduced AST, ALT, MDA, IL-6, TNF-α, and IL-1ß, and increased SOD. Histological analyses of the trillin-treated group exhibited reduced inflammatory process and prevented liver fibrosis. Western blot analyses of the trillin-treated group showed reduced NF-κB pathway and TGF-ß/Smad pathway. SIGNIFICANCE: Based on the results of the present study, trillin can be used as a potential anti-inflammatory drug for chronic hepatic inflammation.