Melatonin is present in mammalian follicular fluid and plays an important role in regulating steroidogenesis in follicular cells. In this study, we report the effect of melatonin on steroidogenesis in the theca interna (TI) in small bovine follicles and theca cells (TCs) cultured in vitro. Treatment with melatonin significantly increased the expression of steroidogenic acute regulatory protein (STAR) and the production of progesterone in both TI and in TCs. Melatonin stimulated the phosphorylation of AKT but not ERK1/2, and the addition of luzindole (a nonspecific MT1 and MT2 inhibitor) or 4P-PDOT (specific MT2 inhibitor) reduced melatonin-induced STAR expression, progesterone secretion, and PI3K/AKT pathway activation. The effect of melatonin on the TI in follicles was more obvious than on the TCs in vitro. Results indicate that melatonin stimulates the steroidogenesis of TCs mainly via the activation of the PI3K/AKT pathway by MT1 and MT2.

The tumor microenvironment (TME) plays a central role in regulating antitumor immune responses. As an important part of the TME, alternatively activated type 2 (M2) macrophages drive the development of primary and secondary tumors by promoting tumor cell proliferation, tumor angiogenesis, extracellular matrix remodeling and overall immunosuppression. Immunotherapy approaches targeting tumor-associated macrophages (TAMs) in order to reduce the immunosuppressive state in the TME have received great attention. Although these methods hold great potential for the treatment of several cancers, they also face some limitations, such as the fast degradation rate of drugs and drug-induced cytotoxicity of organs and tissues. Nanomedicine formulations that prevent TAM signaling and recruitment to the TME or deplete M2 TAMs to reduce tumor growth and metastasis represent encouraging novel strategies in cancer therapy. They allow the specific delivery of antitumor drugs to the tumor area, thereby reducing side effects associated with systemic application. In this review, we give an overview of TAM biology and the current state of nanomedicines that target M2 macrophages in the course of cancer immunotherapy, with a specific focus on nanoparticles (NPs). We summarize how different types of NPs target M2 TAMs, and how the physicochemical properties of NPs (size, shape, charge and targeting ligands) influence NP uptake by TAMs in vitro and in vivo in the TME. Furthermore, we provide a comparative analysis of passive and active NP-based TAM-targeting strategies and discuss their therapeutic potential.

Here, we describe the synthesis of a novel type of rare-earth-doped nanoparticles (NPs) for multimodal imaging, by combining the rare-earth elements Ce, Gd and Nd in a crystalline host lattice consisting of CaF₂ (CaF₂: Ce, Gd, Nd). CaF₂: Ce, Gd, Nd NPs are small (15–20 nm), of uniform shape and size distribution, and show good biocompatibility and low immunogenicity in vitro. In addition, CaF₂: Ce, Gd, Nd NPs possess excellent optical properties. CaF₂: Ce, Gd, Nd NPs produce downconversion emissions in the second near-infrared window (NIR-II, 1000–1700 nm) under 808 nm excitation, with a strong emission peak at 1056 nm. Excitation in the first near- infrared window (NIR-I, 700–900 nm) has the advantage of deeper tissue penetration power and reduced autofluorescence, compared to visible light. Thus, CaF₂: Ce, Gd, Nd NPs are ideally suited for in vivo fluorescence imaging. In addition, the presence of Gd³⁺ makes the NPs intrinsically monitorable by magnetic resonance imaging (MRI). Moreover, next to fluorescence and MR imaging, our results show that CaF₂: Ce, Gd, Nd NPs can be used as imaging probes for photoacoustic imaging (PAI) in vitro. Therefore, due to their biocompatibility and suitability as multimodal imaging probes, CaF₂: Ce, Gd, Nd NPs exhibit great potential as a traceable imaging agent in biomedical applications.

Nowadays, cancer poses a significant hazard to humans. Limitations in early diagnosis techniques not only result in a waste of healthcare resources but can even lead to delays in diagnosis and treatment, consequently reducing cure rates. Therefore, it is crucial to develop an imaging probe that can provide diagnostic information precisely and rapidly. Here, we used a simple hydrothermal method to design a multimodal imaging probe based on the excellent properties of rareearth ions. Calcium fluoride co-doped with yttrium, gadolinium, and neodymium (CaF₂:Y,Gd,Nd) nanoparticles (NPs) is highly crystalline, homogeneous in morphology, and displays a high biosafety profile. In addition, in vitro and ex vivo experiments explored the multimodal imaging capability of CaF₂:Y,Gd,Nd and demonstrated the efficient performance of CaF₂:Y,Gd,Nd during NIR-II fluorescence/ photoacoustic/magnetic resonance imaging. Collectively, our novel diagnosis nanoparticle will generate new ideas for the development of multifunctional nanoplatforms for disease diagnosis and treatment.