An Alkaline Nanocage Continuously Activates Inflammasomes by Disrupting Multiorganelle Homeostasis for Efficient Pyroptosis.

Pyroptosis has garnered increasing attention because of its ability to trigger robust antitumor immunity. Pyroptosis is initiated by the activation of inflammasomes, which are regulated by various organelles. The collaboration among organelles offers several protective mechanisms to prevent activation of the inflammasome, thereby limiting the induction of efficient pyroptosis. Herein, a multiorganelle homeostasis disruptor (denoted BLL) is constructed by encapsulating liposomes and bortezomib (BTZ) within a layered double hydroxide (LDH) nanocage to continuously activate inflammasomes for inducing efficient pyroptosis. In lysosomes, the negatively charged liposomes are released to recruit the NLRP3 inflammasomes through electrostatic interactions. ER stress is induced by BTZ to enhance the activation of the NLRP3 inflammasome. Meanwhile, the BLL nanocage exhibited H+-scavenging ability due to the weak alkalinity of LDH, thus disrupting the homeostasis of the lysosome and alleviating the degradation of the NLRP3 inflammasome by lysosomal-associated autophagy. Our results suggest that the BLL nanocage induces homeostatic imbalance in various organelles and efficient pyroptosis. We hope this work can provide new insights into the design of an efficient pyroptosis inducer by disrupting the homeostatic balance of multiple organelles and promote the development of novel antineoplastic platforms.

Targeted inhibition of pyroptosis via a carbonized nanoinhibitor for alleviating drug-induced acute kidney injury.

Pyroptosis is a form of pro-inflammatory programmed cell death and it represents a potential therapeutic target for alleviating drug-induced acute kidney injury (AKI). However, there is a lack of effective and kidney-targeted pyroptosis inhibitors for AKI treatment so far. Herein, we report a pharmacologically active carbonized nanoinhibitor (P-RCDs) derived from 3,4',5-trihydroxystilbene that can preferentially accumulate in the kidneys and ameliorate chemotherapeutic drug-induced AKI by inhibiting pyroptosis. In particular, such a carbonized nanoformulation enables the transfer of desired pyroptosis inhibitory activity as well as the radical eliminating activity to the nanoscale, endowing P-RCDs with a favorable kidney-targeting ability. In cisplatin-induced AKI mice, P-RCDs can not only pharmacologically inhibit GSDME-mediated pyroptosis in renal cells with high efficacy, but also exhibit high antioxidative activity that protects the kidneys from oxidative injury. The present study proposes a feasible but efficacious strategy to construct versatile carbonized nanomedicine for targeted delivery of the desired pharmacological activities.

Effect of statins use on risk and prognosis of breast cancer: a meta-analysis.

The findings regarding the association between statins use and breast cancer are inconsistent. Given the widely and long-term use of statins as first choice drug for dyslipidemia, we conducted this meta-analysis for better understanding the associations between statins use and the risk and prognosis of breast cancer. Articles regarding effect of statins use on risk, prognosis of breast cancer and published before January 2021 were searched in the following databases: Web of Science, PubMed, EMBASE, Medline and Google Scholar. Odds ratios (ORs)/relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs) were computed to generate a pooled effect size and 95% CI. The meta-analysis showed no significant association between statins use and risk of breast cancer (OR/RR = 1.02; 95% CI, 0.97-1.08; I2 = 76.1%; P < 0.001). The meta-analysis showed that statins use was associated with lower breast cancer recurrence, all-cause mortality and disease-specific mortality (breast cancer recurrence: HR = 0.75; 95% CI, 0.67-0.84; I2 = 31.7%; P = 0.154; all-cause mortality: HR = 0.82; 95% CI, 0.77-0.89; I2 = 67.5%; P < 0.001; and disease-specific mortality: HR = 0.82; 95% CI, 0.72-0.93; I2 = 83.6%; P < 0.001). Overall, in this report we demonstrated that the use of statins can improve the prognosis of breast cancer patients including lower risks of breast cancer recurrence, all-cause and cancer-specific mortality, though statins therapy may not have an impact on reducing the risk of breast cancer.

Experimental Investigation on the Freeze-Thaw Resistance of Steel Fibers Reinforced Rubber Concrete.

The reuse of rubber in concrete results in two major opposing effects: an enhancement in durability and a reduction in mechanical strength. In order to strengthen the mechanical properties of rubber concrete, steel fibers were added in this research. The compressive strength, the four-point bending strength, the mass loss rate, and the relative dynamic elastic modulus of steel fiber reinforced rubber concrete, subjected to cyclic freezing and thawing, were tested. The effects of the content of steel fibers on the freeze-thaw resistance are discussed. The microstructure damage was captured and analyzed by Industrial Computed Tomography (ICT) scanning. Results show that the addition of 2.0% steel fibers can increase the compressive strength of rubber concrete by 26.6% if there is no freeze-thaw effect, but the strengthening effect disappears when subjected to cyclic freeze-thaw. The enhancement of steel fibers on the four-point bending strength is effective under cyclic freeze-thaw. The effect of steel fibers is positive on the mass loss rate but negative on the relative dynamic elastic modulus.

Diastereoselective Syntheses of Spiro[indoline-3,4'-pyridin]-2-yl Carbamates via AgOTf/Ph3P-Catalyzed Tandem Cyclizations of Tryptamine-Ynesulfonamides.

Spiro[indoline-3,4'-piperidine] is a significant structural scaffold in numerous polycyclic indole alkaloids with a variety of bioactivities. In this study, a synthetic strategy was developed to access spiro[indoline-3,4'-pyridin]-2-yl carbamate via an AgOTf/PPh3-catalyzed tandem cyclization of tryptamine-ynesulfonamides. The unique feature of this strategy is the efficient intermolecular capturing of the in situ generated spiroindoleninium intermediates with carbamates, leading to the diastereoselective syntheses of spiro[indoline-3,4'-pyridin]-2-yl carbamate derivatives. A broad scope of this cyclization was demonstrated by a variety of tryptamine-ynesulfonamide substrates and several carbamates. A plausible mechanism of this reaction was proposed.

Progressive fatigue damage analysis of composite bolted joint using equivalent stress model.

Composite bolted joints are quite necessary for composite structures connection, which has become the main limit for the use of composites in main load-bearing structures. In this article, a fatigue model of composite bolted joint based on equivalent stress is established by programming in ABAQUS USDFLD subroutine to simulate the progressive failure of composite bolted joints. By introducing three-dimensional Tsai-Hill static failure criterion, equivalent stress is calculated for investigating effects of multiaxial stress on fatigue life. In the subroutine of progressive failure for fatigue model, fatigue life of composite bolted joint and damage state of elements that are meshed in the process of modelling are connected by defining field variable. Different fatigue modes are predicted here by changing stress amplitude and ratio loading, in which simulation results agree well with that obtained in corresponding experiments.

Influence of vacancy defect on surface feature and adsorption of Cs on GaN(0001) surface.

The effects of Ga and N vacancy defect on the change in surface feature, work function, and characteristic of Cs adsorption on a (2 × 2) GaN(0001) surface have been investigated using density functional theory with a plane-wave ultrasoft pseudopotential method based on first-principles calculations. The covalent bonds gain strength for Ga vacancy defect, whereas they grow weak for N vacancy defect. The lower work function is achieved for Ga and N vacancy defect surfaces than intact surface. The most stable position of Cs adatom on Ga vacancy defect surface is at T1 site, whereas it is at B(Ga) site on N vacancy defect surface. The E(ads) of Cs on GaN(0001) vacancy defect surface increases compared with that of intact surface; this illustrates that the adsorption of Cs on intact surface is more stable.