Deciphering the Microdroplet Acceleration Factors of Aza-Michael Addition Reactions.

Microdroplet chemistry is emerging as a great tool for accelerating reactions by several orders of magnitude. Several unique properties such as extreme pHs, interfacial electric fields (IEFs), and partial solvation have been reported to be responsible for the acceleration; however, which factor plays the key role remains elusive. Here, we performed quantum chemical calculations to explore the underlying mechanisms of an aza-Michael addition reaction between methylamine and acrylamide. We showed that the acceleration in methanol microdroplets results from the cumulative effects of several factors. The acidic surface of the microdroplet plays a dominating role, leading to a decrease of ∼9 kcal/mol in the activation barrier. We speculated that the dissociation of both methanol and trace water contributes to the surface acidity. An IEF of 0.1 V/Šcan further decrease the barrier by ∼2 kcal/mol. Partial solvation has a negligible effect on lowering the activation barrier in microdroplets but can increase the collision frequency between reactants. With acidity revealed to be the major accelerating factor for methanol droplets, reactions on water microdroplets should have even higher rates because water is more acidic. Both theoretically and experimentally, we confirmed that water microdroplets significantly accelerate the aza-Michael reaction, achieving an acceleration factor that exceeds 107. This work elucidates the multifactorial influences on the microdroplet acceleration mechanism, and with such detailed mechanistic investigations, we anticipate that microdroplet chemistry will be an avenue rich in opportunities in the realm of green synthesis.

Paeoniflorin increases the anti-tumor efficacy of sorafenib in tumor-bearing mice with liver cancer via suppressing the NF-κb/PD-l1 axis.

Background: Sorafenib (Sor) represents a first-line therapy for hepatocellular carcinoma (HCC); however, its efficacy is constrained by secondary failure, which limits its clinical use. Recent studies have indicated that the suppression of Programmed cell death-Ligand 1 (PD-L1) may potentiate Sor's anti-liver cancer effects; furthermore, PD-L1 expression is known to be regulated by NF-κB. Previous research has demonstrated that paeoniflorin (PF) downregulates the NF-κB axis, nevertheless, current research has not yet determined whether PF can synergistically enhance the efficacy of Sor against HCC by modulating the NF-κB/PD-L1 pathway. Methods: The study employed a H22 hepatoma-bearing mouse model, which was treated with PF, Sor, and their combination over a period of 12 days. The impact of PF and Sor on tumor growth, proliferation, apoptosis, T-cell subsets, IL-2 and IFN-γ production, and NF-κB and PD-L1 expression was assessed. Moreover, Splenic lymphocyte from normal mice and tumor cells from model mice were co-cultured in vitro, and the tumor-specific cytotoxic T lymphocyte activity was analyzed. In the final phase of the study, Huh-7 cells were stimulated with PF in combination with an NF-κB activator or inhibitor, and the subsequent production of NF-κB and PD-L1 was investigated. Results: PF and Sor exhibit a synergistic anti-tumor effect, compared to the use of Sor alone, the combined use of PF and Sor significantly increased the number of CD4+ and CD8+ T cells in tumor tissue, markedly enhanced the cytotoxic activity of tumor-specific cytotoxic T lymphocytes, and reversed the depletion of interleukin-2 and the increase in PD-L1 expression following Sor intervention. This combination also further reduced the level of IFN-γ in peripheral blood and the expression of NF-κB and PD-L1 in tumor tissue. Additionally, in vitro experiments confirmed that PF reduces the expression of PD-L1 in Huh-7 liver cancer cells by inhibiting NF-κB. Conclusions: PF plays a synergistic role of Sor inhibiting HCC progression by regulating the NF-κB/PD-L1 pathway.

Salidroside enhances NO bioavailability and modulates arginine metabolism to alleviate pulmonary arterial hypertension.

BACKGROUND: Salidroside (SAL), derived from Rhodiola, shows protective effects in pulmonary arterial hypertension (PAH) models, but its mechanisms are not fully elucidated. OBJECTIVES: Investigate the therapeutic effects and the mechanism of SAL on PAH. METHODS: Monocrotaline was used to establish a PAH rat model. SAL's impact on oxidative stress and inflammatory responses in lung tissues was analyzed using immunohistochemistry, ELISA, and Western blot. Untargeted metabolomics explored SAL's metabolic regulatory mechanisms. RESULTS: SAL significantly reduced mean pulmonary artery pressure, right ventricular hypertrophy, collagen deposition, and fibrosis in the PAH rats. It enhanced antioxidant enzyme levels, reduced inflammatory cytokines, and improved NO bioavailability by upregulating endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC), cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) and decreases the expression of endothelin-1 (ET-1). Metabolomics indicated SAL restored metabolic balance in PAH rats, particularly in arginine metabolism. CONCLUSIONS: SAL alleviates PAH by modulating arginine metabolism, enhancing NO synthesis, and improving pulmonary vascular remodeling.