GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC.

Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy.

Effects of different levels of rapeseed cake containing high glucosinolates in steer ration on rumen fermentation, nutrient digestibility and the rumen microbial community.

This trial was conducted to study the effects of dietary rapeseed cake (RSC) containing high glucosinolates (GLS) on rumen fermentation, nutrient digestion and the rumen microbial community in steers. Eight growing steers and four rations containing RSC (GLS 226·1 µmol/g DM) at 0·00, 2·65, 5·35 and 8·00 % DM were assigned in a replicate 4 × 4 Latin square design. The results indicated that increasing RSC levels increased the ruminal concentration of thiocyanate (SCN) (P < 0·01), decreased the ruminal concentration of ammonia nitrogen (NH3-N) and the molar proportion of isovalerate (P < 0·05), did not affect the ruminal concentration of total volatile fatty acids (P > 0·05), decreased the crude protein (CP) digestibility (P < 0·05) and increased the ether extract (EE) digestibility (P < 0·01). Increasing RSC levels tended to decrease the abundances of ruminal Ruminobacter amylophilus (P = 0·055) and Ruminococcus albus (P = 0·086) but did not affect methanogens, protozoa, fungi and other bacteria (P > 0·05). Increasing RSC levels in the ration did not affect the ruminal bacterial diversity (P > 0·05), but it increased the operational taxonomic units and the bacterial richness (P < 0·05) and affected the relative abundances of some bacteria at the phylum level and genus level (P < 0·05). In conclusion, RSC decreased the ruminal concentration of NH3-N and the CP digestibility, increased the EE digestibility and partly affected the ruminal bacterial community. SCN, as the metabolite of GLS, could be a major factor affecting these indices.

Hypothalamic-Pituitary-Thyroid Axis Crosstalk With the Hypothalamic-Pituitary-Gonadal Axis and Metabolic Regulation in the Eurasian Tree Sparrow During Mating and Non-mating Periods.

Reproduction is an energetically costly phenomenon. Therefore, to optimize reproductive success, male birds invest enough energetic resources for maintaining well-developed testes. The hypothalamic-pituitary-thyroid (HPT) axis in birds can crosstalk with the hypothalamic-pituitary-gonadal (HPG) axis, thus orchestrating both the reproduction and metabolism. However, until now, how the free-living birds timely optimize both the energy metabolism and reproduction via HPT-axis is not understood. To uncover this physiological mechanism, we investigated the relationships among body mass, testis size, plasma hormones including thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), metabolites including glucose (Glu), triglyceride (TG), total cholesterol (TC), uric acid (UA), diencephalon mRNA expressions of type 2 (Dio2) and 3 (Dio3) iodothyronine deiodinase enzymes, thyrotropin-releasing hormone (TRH), thyroid-stimulating hormone (TSH), gonadotropin-releasing hormone I (GnRH-I), and gonadotropin-inhibitory hormone (GnIH) in a male Eurasian tree sparrow (ETS, Passer montanus). We found significantly larger testis size; elevated diencephalon Dio2 and TRH mRNA expressions, plasma T3, and UA levels; and significantly lowered Glu, TG, and TC levels during mating relative to the non-mating stages in male ETSs. However, Dio3, TSH, GnRH-I, and GnIH mRNA expression did not vary with the stage. Furthermore, life-history stage dependent variation in plasma T3 had both direct effects on the available energy substrates and indirect effects on body mass and testis size, indicating a complex regulation of metabolic pathways through the HPT- and HPG-axes. The identified differences and relationships in mRNA expression, plasma T3 and metabolites, and testis size in male ETSs contribute to our understanding how free-living birds adjust their molecular, endocrinal, and biochemical features to orchestrate their reproductive physiology and metabolism for the maintenance of well-developed testes.