Nanoparticle targeting of neutrophil glycolysis prevents lung ischemia-reperfusion injury.

Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]). Intravenously administered NP-Ly6G(2-DG) to mice exhibited high specificity for circulating neutrophils. NP-Ly6G(2-DG)-treated neutrophils were unable to adapt to hypoglycemic conditions of the lung airspace environment as evident by the loss of demand-induced glycolysis, reductions in glycogen and ATP content, and an increased vulnerability to apoptosis. NP-Ly6G(2-DG) treatment inhibited pulmonary IRI following hilar occlusion and orthotopic lung transplantation. IRI protection was associated with less airspace neutrophil extracellular trap generation, reduced intragraft neutrophilia, and enhanced alveolar macrophage efferocytotic clearance of neutrophils. Collectively, our data show that pharmacologically targeting glycolysis in neutrophils inhibits their activation and survival leading to reduced pulmonary IRI.

IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma.

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

Fatty acid binding proteins in multiple myeloma.

Fatty acid binding proteins (FABPs) transport fatty acids (FA) into cells as an energy source, and their inhibition suppressed tumor proliferation in solid tumors. Multiple myeloma (MM) is a hematologic malignancy, known for disrupted protein metabolism including high proteasome activity, where proteasome inhibitors made a dramatic improvement in its treatment. Recent discovery found FABPs as a novel metabolic pathway in MM, which will have an impact on understanding the biology and on therapeutic application in MM.

Tumor-associated macrophages in multiple myeloma: advances in biology and therapy.

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow (BM) and represents the second most common hematological malignancy in the world. The MM tumor microenvironment (TME) within the BM niche consists of a wide range of elements which play important roles in supporting MM disease progression, survival, proliferation, angiogenesis, as well as drug resistance. Together, the TME fosters an immunosuppressive environment in which immune recognition and response are repressed. Macrophages are a central player in the immune system with diverse functions, and it has been long established that macrophages play a critical role in both inducing direct and indirect immune responses in cancer. Tumor-associated macrophages (TAMs) are a major population of cells in the tumor site. Rather than contributing to the immune response against tumor cells, TAMs in many cancers are found to exhibit protumor properties including supporting chemoresistance, tumor proliferation and survival, angiogenesis, immunosuppression, and metastasis. Targeting TAM represents a novel strategy for cancer immunotherapy, which has potential to indirectly stimulate cytotoxic T cell activation and recruitment, and synergize with checkpoint inhibitors and chemotherapies. In this review, we will provide an updated and comprehensive overview into the current knowledge on the roles of TAMs in MM, as well as the therapeutic targets that are being explored as macrophage-targeted immunotherapy, which may hold key to future therapeutics against MM.

Agomelatine attenuates alcohol craving and withdrawal symptoms by modulating the Notch1 signaling pathway in rats.

AIM: Alcohol abuse is a significant causative factor of death worldwide. The Notch1 signaling pathway is involved in alcohol tolerance, withdrawal and dependence. Agomelatine is a known antidepressant acting as a melatonin receptor (MT1/2) agonist and a 5-hydroxytryptamine receptor-2C antagonist. However, its effects on alcohol cravings and alcohol withdrawal symptoms have not been investigated. In this study, we assessed the possibility of using agomelatine for the treatment of these symptoms in a rat model of alcoholism and the possible role of Notch1 signaling. MAIN METHODS: We induced alcoholism in rats using a free-choice drinking model for 60 days. From day 61, free-choice was continued until day 82 for the craving model, whereas only water was offered in the withdrawal model. Meanwhile, the treated groups for both models received agomelatine (50 mg/kg/day) orally from day 61 to 82, followed by behavioral, histopathological and biochemical assessment. KEY FINDINGS: Agomelatine treatment caused significant decrease in alcohol consumption with a positive effect on anxiety-like behavior in the open field, memory in the Morris water maze and immobility in the forced swim test. Moreover, agomelatine induced the expression of Notch1 pathway markers, including Notch1, NICD, CREB, CCNE-2, Hes-1, both total and phosphorylated ERK1/2, MMP9, Per2and RGS-2 in the hippocampal formation. By contrast, NMDAR expression was reduced. Furthermore, agomelatine normalized the serum levels of BDNF, cortisol, dopamine and glutamate which were disrupted by alcohol consumption. SIGNIFICANCE: Based on these findings, agomelatine reversed alcohol cravings and withdrawal symptoms associated with alcohol dependence by modulating the Notch1 signaling pathway.