Atherosclerosis is a complex pathology driven by chronic inflammation, lipid accumulation, and thrombosis, necessitating multi-pathway therapeutic strategies. Herein, we engineered an oral multi-stage platform (RALM) comprising aspirin (Asp) and ginsenoside Rg3 co-loaded phosphatidylserine (PS) liposomes (RA-Lipo) encapsulated within sodium alginate microspheres. Physicochemical and biological evaluations revealed that the incorporation of Rg3 into the lipid bilayer as a cholesterol substitute yielded uniform RA-Lipo, which exhibited colloidal stability, intestinal epithelial transport, and prolonged systemic circulation. The electrosprayed alginate matrix functioned as a pH-responsive barrier, preventing premature degradation in the gastric environment and enabling the sustained release of RA-Lipo within the intestinal tract. Following oral administration in HFD-induced ApoE-/- mice, integrated 16 S rRNA sequencing and untargeted metabolomics revealed that RALM reshaped HFD-induced dysbiosis and modulated the metabolic profile, characterized by an increased Bacteroidetes/Firmicutes (B/F) ratio along with decreased prostaglandin E2 (PGE2) and elevated arginine levels. Fluorescence tracking experiment further demonstrated that the liberated RA-Lipo accumulated within aortic plaques. At the cellular level, RA-Lipo activated the PPARγ pathway, thereby enhancing cholesterol efflux and inhibiting foam cell formation. Ultimately, this synergistic regulation translated into remarkable therapeutic efficacy, effectively reducing plaque burden, suppressing pro-inflammatory cytokines, and demonstrating superior anticoagulant activity. Supported by a favorable safety evaluation, this RALM platform offers a comprehensive approach for alleviating atherosclerosis progression.

Clear cell ovarian carcinoma (CCOC) is a rare, aggressive ovarian cancer subtype, comprising approximately 12% of epithelial ovarian carcinoma (EOC) cases in Western countries yet associated with the worst prognoses due to its chemoresistance. Most CCOCs harbor activating PIK3CA mutations that drive PI3K/AKT/mTOR signaling and HIF1α expression. Despite their clinical success in some cancers, mTOR inhibitors have shown limited efficacy in CCOC, even though this pathway is highly active. Consequently, CCOC continues to be managed like other epithelial ovarian cancers. We recently uncovered cystathionine γ-lyase (CTH), a key enzyme in the transsulfuration pathway, as a metabolic vulnerability in CCOC, supporting HIF1α expression, survival and metastasis. This study aims to address whether simultaneously targeting CTH and mTOR could enhance therapeutic outcomes beyond those achieved by mTOR inhibition alone.CCOC lines were engineered with CTH knockout (KO) or treated with the CTH inhibitor Aviglycine hydrochloride (AVG; ABG-3168); mTOR was blocked with everolimus, a clinical stage mTOR inhibitor. Single and combined treatments were tested in two-dimensional cultures and three-dimensional spheroids under normoxia (21% O2) and hypoxia (1% O2). We measured viability, proliferation, colony formation, apoptosis, and protein signaling. Drug interaction was quantified with a synergy model.Everolimus reduced viability and increased apoptosis across CCOC cell lines, but activity was modest as a single agent. Adding CTH inhibition produced synergistic growth suppression at low doses, with the effect being stronger under hypoxia. The combination reduced colony formation over 14 days and decreased spheroid size while increasing caspase-3/7 activity. Dual treatment decreased HIF1α protein expression more than either monotherapy while maintaining strong inhibition of mTOR/S6 kinase signaling; total mTOR and S6 kinase were unchanged. In CTH-deficient models, the synergy was maintained; however, pharmacological inhibition of CTH with AVG did not produce additional effects, indicating dependence on CTH activity and supporting an on-target mechanism. Similar antiproliferative effects with combined treatment were observed in a CTH-expressing Ewing sarcoma (EwS) model.Together, these findings support biomarker-guided strategies and rational combination therapies that achieve dual targeting of mTOR and CTH, thereby disrupting protein translation and hypoxia adaptation in CCOC and other CTH-expressing cancers.

Exercise provides significant benefits for most women, but adverse effects on reproduction can and do occur. Increased frequency, duration, and intensity of exercise are associated with a higher risk of female infertility. In particular, exercise-induced reproductive dysfunction is linked to alterations in the hypothalamic-pituitary-gonadal (HPG) axis. However, the role of meteorin-like protein (metrnl), as an exercise-induced myokine, in female reproductive function and the HPG axis is not yet fully understood. In this study, we investigated the effects of metrnl, compared with a swimming exercise protocol, on sexual motivation and the HPG axis in female rats. Female rats with regular estrous cycles were randomly allocated into three groups (n = 9 per group), and subjected to deionized water (1 mL/kg), metrnl (1 µg/day) or swimming-based moderate-intensity exercise (30 min/day, 5 days/week) for about 19 consecutive days. The results showed that metrnl administration reduced the time spent near the male rat and the male preference ratio, indicators of sexual motivation. It also decreased hypothalamic GnRH expression (in the median eminence and preoptic area), serum concentrations of reproductive hormones (follicle-stimulating hormone and anti-Müllerian hormone), and the numbers of ovarian follicles (primordial and primary follicles), similar to the effects observed after the swimming exercise protocol. Furthermore, metrnl concentrations in serum remained unchanged in female rats treated with metrnl and exercise. In conclusion, metrnl treatment reduced sexual incentive motivation and altered HPG axis regulation in female rats. These findings suggest that exercise-induced metrnl may be a potential exerkine associated with changes in female sexual motivation and HPG axis regulation due to exercise.

The present study investigates the effectiveness of carbon nanotube (CNT)-reinforced soybean oil as a nano-lubricant under minimum quantity lubrication (MQL) for machining Monel 400 alloy. CNTs were dispersed in soybean oil at varying concentrations (0-0.8 vol%), and their thermo-physical properties were evaluated through wettability (contact angle) and rheological (viscosity) analyses. The results identified 0.5 vol% CNT as the optimal concentration, exhibiting improved wettability and enhanced viscosity, which are favorable for stable lubricating film formation. Machining experiments were conducted under different lubrication environments, namely dry, compressed air, pure soybean oil, and CNT-enriched soybean oil. The results demonstrated that the CNT-based nano-lubricant significantly improved machining performance. Relative to dry machining conditions, substantial improvements were observed across all performance metrics. Surface roughness decreased by 73.7%, while cutting force and cutting temperature were reduced by 56.1% and 59.0%, respectively. In addition, tool wear exhibited a significant decline of 82.1%, indicating enhanced machining efficiency and tool longevity. These improvements are attributed to the superior tribological characteristics of CNTs, including tribo-film formation, enhanced thermal conductivity, reduced interfacial shear resistance, and improved load-bearing capacity. Furthermore, a Taguchi L16 experimental design integrated with a Fuzzy Mamdani inference system was employed to determine the optimal machining conditions. The best-performing combination of machining conditions-cutting speed of 70 m/min, feed rate of 0.05 mm/tooth, and depth of cut of 0.15 mm under CNT-MQL lubrication-resulted in the maximum multi-performance characteristics index (MPCI), achieving a value of 0.78. Overall, CNT-reinforced soybean oil demonstrates strong potential as an effective nano-lubricant for improving machining performance of nickel-based alloys under MQL conditions. The findings of this research demonstrate that nano-lubrication incorporating carbon nanotubes (CNTs) serves as a promising strategy to significantly improve machining performance, prolong tool durability, and achieve superior surface finish when processing hard-to-machine materials.

Idiopathic pulmonary fibrosis (IPF) represents a chronic, non-reversible, and irreversible interstitial lung disease with the lack of curative interventions and a poor prognosis; identifying safe and effective therapeutic agents is of paramount importance. The Ophiopogon-Ginseng herb pair, a classical traditional Chinese medicine (TCM), exerts Qi-replenishing and Yin-nourishing effects. Its active constituents Ophiopogonin D (OP-D), Ginsenoside Rg1 (Rg1), and Ginsenoside Rg3 (Rg3) have individual anti-fibrotic potential, while their synergistic effects in IPF remain to be elucidated. This study aimed to explore how OP-D-Rg1-Rg3 attenuates IPF and to clarify its possible molecular mechanisms. Bleomycin (BLM)-induced cellular senescence and transforming growth factor-β1 (TGF-β1) induce epithelial-mesenchymal transition (EMT) in A549 cells. MTT assay and RSM determined the optimal combination ratio. Cellular senescence and EMT were assessed by SA-β-Gal staining, RT-qPCR, WB, and ELISA. An IPF mouse model was established by intratracheal BLM administration, followed by treatment with the optimized OP-D-Rg1-Rg3 combination, pirfenidone (PFD), or saline for 21 days. Pulmonary structural alterations and molecular changes were then evaluated by micro-CT, HE, Masson, and molecular analyses. The results showed that the synergistic OP-D-Rg1-Rg3 combination markedly attenuated A549 cell senescence, as evidenced by reduced SA-β-Gal activity and decreased expression of p53, p21, p16, and TGF-β1-induced EMT (upregulated E-cadherin, downregulated vimentin, fibronectin, Col-I). In vivo, the combination alleviated AEC2s senescence and pulmonary EMT, improved mouse body weight and lung morphology, reduced histopathological damage, and attenuated IPF. In conclusion, the OP-D-Rg1-Rg3 combination ameliorates IPF by inhibiting AEC2s senescence and EMT, highlighting promising clinical application prospects for IPF treatment.