Addiction is believed to involve glutamate-dependent forms of synaptic plasticity that promote the formation of new habits focused on drug seeking. We used primary cultures of rat prefrontal cortex (PFC) neurons to explore mechanisms by which dopamine-releasing psychomotor stimulants such as cocaine and amphetamine influence synaptic plasticity, focusing on AMPA receptor trafficking because of its key role in long-term potentiation (

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Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti-cytotoxic T lymphocyte-associated protein 4 or anti-programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, CD8+ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8+ T cell accumulation and IFN-γ production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.

Catalytic deoxyribozyme has great potential for gene regulation, but the poor efficiency of the cleavage of mRNA and the lack of versatile DNAzyme vehicles remain big challenges for potent gene therapy. By the rational designing of a diverse vehicle of polydopamine-Mn 2+ nanoparticles (MnPDA), we demonstrate that MnPDA has integrated functions as an effective DNAzyme delivery vector, a self-generation source of DNAzyme cofactor for catalytic mRNA cleavage, and an inherent therapeutic photothermal agent as well as contrast agent for photoacoustic and magnetic resonance imaging. Specifically, the DNAzyme-MnPDA nanosystem protects catalytic deoxyribozyme from degradation and enhances cellular uptake efficiency. In the presence of intracellular glutathione, the nanoparticles are able to in situ generate free Mn 2+ as a cofactor of DNAzyme to effectively trigger the catalytic cleavage of mRNA for gene silencing. In addition, the nanosystem shows high photothermal conversion efficiency and excellent stability against photothermal processing and degradation in complex environments. Unlike previous DNAzyme delivery vehicles, this vehicle exhibits diverse functionalities for potent gene regulation, allowing multimodal imaging-guided synergetic gene regulation and photothermal therapy both in vitro and in vivo.

Awareness of the clinicopathological hallmarks is important to avoid underdiagnosis of MCAH and the immunohistochemical features may contribute to understanding the pathogenesis of this rare disease.

High mortality and rapid development of metastasis requires the development of more effective antimetastasis strategies. However, conventional therapeutic methods, including surgery, radiation therapy, and chemotherapy, show less effectiveness in curbing the metastatic spread of cancer cells and the formation of metastases. A therapeutic platform, targeting the early stage of metastasis cascade, could effectively prevent metastasis dissemination. Herein, Fe/Mn-based metal–organic frameworks (FMM) were constructed for the delivery of a specific DNAzyme with high catalytic cleavage activity on the metastasis-involved Twist mRNA, thus efficiently inhibiting the invasion of cancer cells through DNAzyme-catalyzed gene silencing. Highly potent combined gene/chemodynamic therapy is achieved from the self-supplied DNAzyme cofactors and efficient glutathione depletion. Importantly, by virtue of the intrinsic photo-to-thermal conversion of the FMM nanocarriers, our combined therapeutic strategy could be further promoted under photothermal stimuli to speed up the Fenton reaction and to accelerate the release of the Twist DNAzyme with efficient gene therapy. Consequently, the effective elimination of tumors and the blockage of metastasis are simultaneously achieved under photothermal/magnetic resonance imaging guidance. This work aims at developing versatile theranostic agents to combat metastatic tumors.

Caspases are an evolutionary conserved family of cysteine-dependent proteases that are involved in many vital cellular processes including apoptosis, proliferation, differentiation and inflammatory response. Dysregulation of caspase-mediated apoptosis and inflammation has been linked to the pathogenesis of various diseases such as inflammatory diseases, neurological disorders, metabolic diseases, and cancer. Multiple caspase inhibitors have been designed and synthesized as a potential therapeutic tool for the treatment of cell death-related pathologies. However, only a few have progressed to clinical trials because of the consistent challenges faced amongst the different types of caspase inhibitors used for the treatment of the various pathologies, namely an inadequate efficacy, poor target specificity, or adverse side effects. Importantly, a large proportion of this failure lies in the lack of understanding various caspase functions. To overcome the current challenges, further studies on understanding caspase function in a disease model is a fundamental requirement to effectively develop their inhibitors as a treatment for the different pathologies. Therefore, the present review focuses on the descriptive properties and characteristics of caspase inhibitors known to date, and their therapeutic application in animal and clinical studies. In addition, a brief discussion on the achievements, and current challenges faced, are presented in support to providing more perspectives for further development of successful therapeutic caspase inhibitors for various diseases.

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