Deficiency in IL-33/ST2 Axis Reshapes Mitochondrial Metabolism in Lipopolysaccharide-Stimulated Macrophages

The polarization and function of macrophages play essential roles in controlling immune responses. Interleukin (IL)-33 is a member of the IL-1 family that has been shown to influence macrophage activation and polarization, but the underlying mechanisms are not fully understood. Mitochondrial metabolism has been reported to be a central player in shaping macrophage polarization; previous studies have shown that both aerobic glycolysis and oxidative phosphorylation uniquely regulate the functions of M1 and M2 macrophages. Whether IL-33 polarizes macrophages by reshaping mitochondrial metabolism requires further investigation. In this work, we examined the mitochondrial metabolism of bone marrow-derived macrophages (BMDMs) from either wild type (WT), Il33-overexpressing, or IL-33 receptor knockout (St2−/−) mice challenged with lipopolysaccharide (LPS). We found that after LPS stimulation, compared with WT BMDMs, St2−/− BMDMs had reduced cytokine production and increased numbers and activity of mitochondria via the metabolism regulator peroxisome proliferator-activated receptor-C coactivator-1 α (PGC1α). This was demonstrated by increased mitochondrial DNA copy number, mitochondria counts, mitochondria fission- and fusion-related gene expression, oxygen consumption rates, and ATP production, and decreased glucose uptake, lactate production, and extracellular acidification rates. For Il33-overexpressing BMDMs, the metabolic reprogramming upon LPS stimulation was similar to WT BMDMs, and was accompanied by increased M1 macrophage activity. Our findings suggested that the pleiotropic IL-33/ST2 pathway may influence the polarization and function of macrophages by regulating mitochondrial metabolism

Tumor microenvironment-oriented adaptive nanodrugs based on peptide self-assembly

The aberrant metabolism of tumor cells creates an inimitable microenvironment featuring acidic pH, high glutathione (GSH) levels, and overexpression of certain enzymes, which benefits the overwhelming progress of a tumor. Peptide self-assembly, emerging as a biofriendly and versatile fabrication strategy, harnesses multiple noncovalent interactions to obtain a variety of nanostructures tailored on demand. Orchestrating the reversible nature of noncovalent interactions and abnormal physiological parameters in the tumor microenvironment enables peptide-based nanodrugs to be targetable or switchable, thereby improving the drugs' bioavailability and optimizing the treatment outcome. This review will focus on peptide-modulated self-assembly of photosensitizers, chemotherapeutic drugs, immunoactive agents for tumor microenvironment-oriented adaptive phototherapy, chemotherapy, immunotherapy and combinatorial therapy. We will emphasize the building block design, the intermolecular interaction principle, adaptive structural transformation in the tumor microenvironment and corresponding therapeutic efficacy, and aim to elucidate the critical role of peptide-modulated, tumor microenvironment-oriented adaptive assemblies in improving the therapeutic index. Challenges and opportunities will be covered as well to advance the development and clinical application of tumor therapies based on peptide self-assembly materials and techniques

PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model

Abstract Background Blockade of PD-1 receptor may provide proof of concepts for the activity of an immune-modulation approach for the treatment of breast cancer (BC). Zoledronic acid (ZA) has been proven to inhibit angiogenesis, invasion, and adhesion of tumor cells. The aim of this study was to investigate the potential of monoclonal antibody against T cell checkpoint PD-1 in combination with chemotherapeutic drug ZA in BC mouse model. Methods The 4 T1-fLuc mouse BC model was used in this study. The anti-tumor efficacy of anti-PD-1 antibody alone or in combination with ZA was monitored by measuring bioluminescence imaging (BLI) and tumor volume. At the end of study, the flow cytometry was used to determine the immune cell population in tumors after different treatment. Results The results showed that mice treated with the combination therapy of anti-PD-1 antibody plus ZA exhibited better antitumor response compared to untreated controls or single therapy with no obvious toxicity. Conclusion Our study provides preclinical evidence for the enhanced BC treatment benefit through targeting co-signal molecules by combining anti-PD-1 antibody plus ZA treatment

Supramolecular Nanofibrils Formed by Coassembly of Clinically Approved Drugs for Tumor Photothermal Immunotherapy

Pancreatic cancer, one of the most lethal malignancies, compromises the performance of traditional therapeutic regimens in the clinic because of stromal resistance to systemic drug delivery and poor prognosis caused by tumor metastasis. Therefore, a biocompatible therapeutic paradigm that can effectively inhibit pancreatic tumor growth while simultaneously eliminating tumor metastasis is urgently needed. Herein, supramolecular nanofibrils are fabricated through coassembly of clinically approved immunomodulatory thymopentin and near-infrared indocyanine green for localized photothermal immunotherapy of pancreatic tumors. The resulting long-range ordered fibrous nanodrugs show improved photophysical capabilities for fluorescence imaging and photothermal conversion and significantly promote the proliferation and differentiation of antitumor immune cells. Hence, the integration of rapid photothermal therapy and moderate immunomodulation for inhibiting tumor growth and eliminating tumor metastasis is promising. The utilization of clinically approved molecules to construct nanodrugs administered via localized injection amplifies the complementary photothermal immunotherapeutic effects of the components, creating opportunities for clinical translation as a treatment for pancreatic cancer

Analysis of residual stress around a Berkovich nano-indentation by micro-Raman spectroscopy

Nano-indentation is a destructive measurement that introduces non-uniform residual stress around each nano-indentation. Herein, the residual stress distribution around a Berkovich nano-indentation on (001)- and (111)-plane silicon was studied by micro-Raman mapping. All of the in-plane stress state components around the indentation were obtained specifically for the (001)- and (111)-plane silicon based on the expanding cavity model and the Raman-mechanical relationship. Calculating the distribution regularity of the residual stress, the effect of different crystal planes and crystal orientations was further analyzed. Finally, the stress near the vertex of the indentation was revised owing to the crack