Search

Considering that the precise delivery of Celastrol (Cst) into mitochondria to induce mitochondrial dysfunction may be a potential approach to improve the therapeutic outcomes of Cst on TNBC, a novel tumor mitochondria dual-targeted mixed-micelle nano-system was fabricated via self-synthesized triphenylphosphonium-modified cholesterol (TPP-Chol) and hyaluronic acid (HA)-modified cholesterol (HA-Chol). The Cst-loaded mixed micelles (Cst@HA/TPP-M) exhibited the characteristics of a small particle size, negative surface potential, high drug loading of up to 22.8%, and sustained drug release behavior. Compared to Cst-loaded micelles assembled only by TPP-Chol (Cst@TPP-M), Cst@HA/TPP-M decreased the hemolysis rate and upgraded the in vivo stability and safety. In addition, a series of cell experiments using the triple-negative breast cancer cell line MDA-MB-231 as a cell model proved that Cst@HA/TPP-M effectively increased the cellular uptake of the drug through CD44-receptors-mediated endocytosis, and the uptake amount was three times that of the free Cst group. The confocal results demonstrated successful endo-lysosomal escape and effective mitochondrial transport triggered by the charge converse of Cst@HA/TPP-M after HA degradation in endo-lysosomes. Compared to the free Cst group, Cst@HA/TPP-M significantly elevated the ROS levels, reduced the mitochondrial membrane potential, and promoted tumor cell apoptosis, showing a better induction effect on mitochondrial dysfunction. In vivo imaging and antitumor experiments based on MDA-MB-231-tumor-bearing nude mice showed that Cst@HA/TPP-M facilitated drug enrichment at the tumor site, attenuated drug systemic distribution, and polished up the antitumor efficacy of Cst compared with free Cst. In general, as a target drug delivery system, mixed micelles co-constructed by TPP-Chol and HA-Chol might provide a promising strategy to ameliorate the therapeutic outcomes of Cst on TNBC. [ABSTRACT FROM AUTHOR]

To gain insight into the reduction mechanism of water on the dynamic destabilization failure character of coal under mining disturbance conditions, the effect of water on the damage and energy dissipation feature of coal was investigated via cyclic uniaxial compressive loading–unloading test, acoustic emission (AE) monitoring technology, and theoretical analysis. It manifests that the softening effect of water on the mechanical properties of coal is still remarkable, lower uniaxial compressive strength and elastic modulus, while greater axial strain and higher Poisson's ratio are observed under the cyclic loading–unloading condition. Water‐saturated specimens dissipate more energy during the cyclic loading–unloading process, which reduces the proportion of input energy accumulated in the coal mass, thus lowering the burst proneness of coal. A greater amount of damage generates in air‐dried specimens than that in water‐saturated specimens at the first cyclic loading–unloading cycle, while lower damage increments are observed in the following cycles. This may be the reason for the minimal energy dissipation of air‐dried specimens in the following cycles. The elastic modulus behaves logarithmically versus the increasing cyclic loading–unloading cycle counts. The energy dissipated due to the damage evolution and plastic deformation of coal specimens positively correlates with the energy released by AE activities, the AE energy in air‐dried specimens has a greater concentration around the peak axial stress and a stronger correlation with the dissipated energy. The cumulative AE energy and energy dissipation density are linearly correlated during the cyclic loading–unloading process, which indicates a possibility in estimating the damage evolution and the dynamic failure risk of coal via cumulative AE energy, under the cyclic loading–unloading condition. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of high mobility group box 1 (HMGB1) in hepatic endoplasmic reticulum stress (ERS) in rats with trauma., Methods: Sixty SPF Sprague-Dawley (SD) rats were randomly divided into groups (n = 6). The rat model of liver injury following traumatic stress was established by continuous compressing the bilateral hind-limbs of rats for 3 hours and then intermittent compressing and decompressing for 30 minutes respectively three times with standard weight of 15 kg. The experiment 1 was divided into two groups: control group and 6, 18, 30 hours after crush. The experiment 2 was divided into control group, crush model group (18 hours after crush), HMGB1 inhibitor sodium butyrate (SB) or ethyl pyruvate (EP) groups, and SB or EP treatment groups (500 mg/kg SB solution or 40 mg/kg EP solution was injected intraperitoneally after 3 hours crush). The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were measured with automatic biochemistry analyzer. Histopathological severity of liver injury was assessed by hematoxylin and eosin (HE) staining. The expressions of HMGB1 and ERS-related proteins were detected with Western Blot. The expression and translocation of HMGB1 in liver tissue were evaluated by immuno-histochemical technique., Results: (1) Compared with the control group, the pathological changes of liver injury, the levels of AST and ALT in serum and protein expression of HMGB1 as well as ERS-related proteins such as glucose regulated protein 78 (GRP78), caspase-12, and inositol-requiring enzyme 1α (IRE1α) in liver tissue were significantly increased after traumatic stress, and reached the peak at 18 hours. The expression of C/EBP-homologous protein (CHOP) was increased in a time-dependent manner and peaked at 30 hours after crush. Immunohistochemistry showed that HMGB1 expression increased at 6 hours after crush, some HMGB1 shifted from nucleus to cytoplasm, and the expression was more obvious at 18 hours. (2) Compared with crush model group, the expressions of HMGB1 and ERS-related proteins were significantly decreased following the administration of HMGB1 inhibitors SB or EP (HMGB1/β-actin: 0.703±0.213, 0.512±0.075 vs. 1.041±0.186; GRP78/β-actin: 0.614±0.052, 0.450±0.115 vs. 0.847±0.120; caspase-12/β-actin: 0.636±0.066, 0.812±0.142 vs. 1.086±0.130; CHOP/β-actin: 0.314±0.046, 0.621±0.123 vs. 0.996±0.764; IRE1α/β-actin: 0.473±0.033, 0.519±0.094 vs. 0.742±0.054, all P < 0.05), the levels of serum AST and ALT were significantly decreased [AST (U/L): 1 030.50±427.73, 1 414.50±347.86 vs. 2 122.20±322.76; ALT (U/L): 285.75±11.30, 368.50±80.58 vs. 473.80±33.54, all P < 0.01], the degree of acute liver injury was reduced. Only SB or EP could not affect the parameters mentioned above., Conclusions: HMGB1-ERS pathway was involved in mediating traumatic stress-induced acute liver injury in rats.