Emerging evidence indicates that aberrant maternal inflammation is associated with several pregnancy-related disorders such as preeclampsia, preterm birth, and intrauterine growth restriction. Sirtuin1 (SIRT1), a class III histone deacetylase, is involved in the regulation of various physiopathological processes including cellular inflammation and metabolism. However, the effect of SIRT1 on the placental proinflammatory environment remains to be elucidated. In this study, we investigated the effect of SIRT1 on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human first-trimester trophoblasts (Sw.71 and HTR-8/SVneo cells). Treatment with LPS elevated SIRT1 expression and induced NLRP3 inflammasome activation in mouse placental tissues and human trophoblasts. Knockdown of SIRT1 enhanced LPS-induced NLRP3 inflammasome activation, inflammatory signaling, and subsequent interleukin (IL)-1β secretion. Furthermore, knockdown of NLRP3 considerably attenuated the increase of IL-1β secretion in SIRT1-knockdown cells treated with LPS. Moreover, SIRT1 inhibited LPS-induced NLRP3 inflammasome activation by reducing oxidative stress. This study revealed a novel mechanism via which SIRT1 exerts anti-inflammatory effects, suggesting that SIRT1 is a potential therapeutic target for the prevention of inflammation-associated pregnancy-related complications.

Introduction: Metabolic dysfunction-associated steatotic liver disease has limited treatment options, posing a serious global health challenge. Epicatechin (EC), a natural flavonoid, exhibits therapeutic potential; however, its clinical utility is hindered by its low solubility and limited bioavailability. Therefore, in this study, we developed liver-targeted EC-loaded galactosylated poly(lactic-coglycolic acid)-polyethylene glycol nanoparticles (EC@PLGA-PEG-GAL NPs) with high therapeutic efficacy. Methods: EC@PLGA-PEG-GAL NPs were synthesized, and their physicochemical properties, biocompatibility, and hepatocytetargeted cellular uptake were characterized. The therapeutic efficacy of the NPs was assessed in high-fat diet (HFD)-fed mice, evaluating metabolic dysfunction and hepatic steatosis. Mechanistic studies were performed to investigate the effects on autophagic flux and mitochondrial function. Results: The EC@PLGA-PEG-GAL NPs exhibited improved EC solubility, sustained drug release, and low cytotoxicity. In HFD-fed mice, administration of EC@PLGA-PEG-GAL NPs significantly ameliorated hepatic steatosis, reduced insulin resistance, and alleviated metabolic dysfunction, without causing toxicity. Mechanistically, these NPs restored the autophagic flux by activating the AMP-activated protein kinase pathway and inhibiting mechanistic target of rapamycin complex 1 signaling, thereby enhancing ubiquitinated protein clearance. They also alleviated mitochondrial dysfunction by enhancing the membrane potential, reducing the reactive oxygen species levels, and promoting mitochondrial biogenesis. Conclusion: Our findings highlight EC@PLGA-PEG-GAL NPs as promising liver-targeted nanotherapeutics simultaneously modulating autophagy and mitochondrial functions in metabolic dysfunction-associated steatotic liver disease.

Red emitting europium (III) complexes Eu(TFAAN)₃(P(Oct)₃)₃ (TFAAN = 2-(4,4,4-Trifluoroacetoacetyl)naphthalene, P(Oct)₃ = trioctylphosphine) chelated on carboxymethyl dextran coated superparamagnetic iron oxide nanoparticles (CMD-SPIONs) was synthesized and the step wise synthetic process was reported. All the excitation spectra of distinctive photoluminesces were originated from f-f transition of Eu^III with a strong red emission. The emission peaks are due to the hypersensitive transition ⁵D₀→⁷F₂ at 621 nm and ⁵D₀→⁷F₁ at 597 nm, ⁵D₀→⁷F₀ at 584 nm. No significant change in PL properties due to addition of CMD-SPIONs was observed. The cytotoxic effects of different concentrations and incubation times of Eu(TFAAN)₃(P(Oct)₃)₃ chelated CMD-SPIONs were evaluated in HEK293T and HepG2 cells using the WST assay. The results imply that Eu(TFAAN)₃(P(Oct)₃)₃ chelated CMD-SPIONs are not affecting the cell viability without altering the apoptosis and necrosis in the range of 10 to 240 μg/mL concentrations.

The core–shell structure of poly(St-co-MAA) nanoparticles containing β-diketonate Eu³⁺ complexes were synthesized by a step-wise process. The β-diketonate Eu³⁺ complexes of Eu (TFTB)₂(MAA)P(Oct)₃ [europium (III); 4,4,4-Trifluoro-1-(2-thienyl)-1,3-butanedione = TFTB; trioctylphosphine = (P(Oct)₃); methacrylic acid = MAA] were incorporated to poly(St-co-MAA). The poly(St-co-MAA) has highly monodispersed with a size of 300 nm, and surface charges of the poly(St-co-MAA) are near to neutral. The narrow particle size distribution was due to the constant ionic strength of the polymerization medium. The activated carboxylic acid of poly(St-co-MAA) further chelated with europium complex and polymerize between acrylic groups of poly(St-co-MAA) and Eu(TFTB)₂(MAA)P(Oct)₃. The E_m spectra of europium complexes consist of multiple bands of E_m at 585, 597, 612 and 650 nm, which are assigned to ⁵D₀→⁷F_{J (J = 0–3)} transitions of Eu³⁺, respectively. The maximum E_m peak is at 621 nm, which indicates a strong red E_m characteristic associated with the electric dipole ⁵D₀→⁷F₂ transition of Eu³⁺ complexes. The cell-specific fluorescence of Eu(TFTB)₂(MAA)P(Oct)₃@poly(St-co-MAA) indicated endocytosis of Eu(TFTB)₂(MAA)P(Oct)₃@poly(St-co-MAA). There are fewer early apoptotic, late apoptotic and necrotic cells in each sample compared with live cells, regardless of the culture period. Eu(TFTB)₂(MAA)P(Oct)₃@poly(St-co-MAA) synthesized in this work can be excited in the full UV range with a maximum E_m at 619 nm. Moreover, these particles can substitute red luminescent organic dyes for intracellular trafficking and cellular imaging agents.