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.

A Self-Adaptive Pyroptosis Inducer: Optimizing the Catalytic Microenvironment of Nanozymes by Membrane-Adhered Microbe Enables Potent Cancer Immunotherapy.

Pyroptosis has garnered increasing attention in cancer immunotherapy. Moreover, increasing plasma membrane damage by reactive oxygen species (ROS) is considered an effective strategy for promoting pyroptosis. However, the current tactics for enhancing membrane rupture in pyroptosis are limited by the inherent drawbacks of ROS and the immunosuppressive tumor microenvironment. Herein, a self-adaptive pyroptosis inducer (LPZ) is designed by integrating Lactobacillus rhamnosus GG (LGG) and an enzyme-like metal-organic framework to achieve potent pyroptosis immunotherapy. LPZ can adhere to cancer cell membranes through the interaction between the pili of LGG and the mucin of cancer cells. In particular, the adaptive formula can gradually enhance the ability of nanozymes to produce ROS by creating an acidic microenvironment through anaerobic respiration. These results verify that LPZ could generate high levels of ROS both on the membrane and within cancer cells, leading to pyroptotic cell death and strong antitumor immunity. Meanwhile, LGG are eventually killed by ROS in this process to halt their respiration and prevent potential biosafety concerns. Overall, this work provides new inspiration for the design of self-adaptive nanocatalytic drugs for cancer immunotherapy.

Study of Intracranial Hematoma Removal and High Intracranial Pressure Reduction Using a Novel Three-Needle Brain Puncture Technique.

Objective: The present study aimed to evaluate the clinical value of minimally invasive surgery for intracranial hematoma removal and high intracranial pressure (ICP) reduction using a novel three-needle brain puncture technique. Methods: A total of 202 cases with supratentorial hematoma were analyzed, 54 of whom received three-needle brain puncture (study group), and the remaining cases received single-needle (control groups 1 and 2) and two-needle brain puncture (control group 3). The amount of intracranial hematoma removed, changes in ICP, retention time of puncture needle, volume of residual blood, the National Institute of Health Stroke Scale (NIHSS) score, and postoperative survival rate were used as indexes to evaluate patient outcomes. Results: We found that three-needle brain puncture (study group) can remove more intracranial hematoma (P < 0.05) and achieve lower ICP (P < 0.05) than single- and two-needle brain puncture (control group). The needle retention time and volume of residual blood significantly decreased in the study group. Additionally, a statistically significant difference was observed in the NIHSS scores and survival rates between the study and control groups (P < 0.05). Conclusion: These data suggest that three-needle minimally invasive stereotactic puncture can effectively remove hematoma, reduce ICP, decrease the degree of brain damage, and improve prognosis.

Activating PPARγ Increases NQO1 and γ-GCS Expression via Nrf2 in Thrombin-activated Microglia.

The present study aimed to explore the molecular mechanisms underlying the increase of nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1 (NQO1) and γ-glutamylcysteine synthetase (γ-GCS) in brain tissues after intracerebral hemorrhage (ICH). The microglial cells obtained from newborn rats were cultured and then randomly divided into the normal control group (NC group), model control group (MC group), rosiglitazone (RSG) intervention group (RSG group), retinoic-acid intervention group (RSG+RA group), and sulforaphane group (RSG+SF group). The expression levels of NQO1, γ-GCS, and nuclear factor E2-related factor 2 (Nrf2) were measured by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. The results showed that the levels of NQO1, γ-GCS and Nrf2 were significantly increased in the MC group and the RSG group as compared with those in the NC group (P<0.01). They were found to be markedly decreased in the RSG+RA group and increased in the RSG+SF group when compared with those in the MC group or the RSG group (P<0.01). The RSG+SF group displayed the highest levels of NQO1, γ-GCS, and Nrf2 among the five groups. In conclusion, a medium dose of RSG increased the anti-oxidative ability of thrombin-activated microglia by increasing the expression of NQO1 and γ-GCS. The molecular mechanisms underlying the increase of NQO1 and γ-GCS in thrombin-activated microglia may be associated with the activation of Nrf2.

Rosiglitazone pretreatment influences thrombin-induced anti-oxidative action via activating NQO1and γ-GCS in rat microglial cells.

Objective To explore the molecular mechanism involved in rosiglitazone against secondary brain damage caused by cerebral hemorrhage, we pretreated thrombin-induced microglial cells by rosiglitazone and then investigated its effect on antioxidant-related genes NQO1and γ-GCS expression change. Methods Primary microglial cells were obtained from the brain tissue of newborn Sprague-Dawley (SD) rats and were randomly divided into three groups: the normal (control), thrombin stimulation (TH), thrombin-treated plus rosiglitazone (TH+RGZ). The expression of NQO1and γ-GCS was measured by immunocytochemistry, real-time PCR, and western blot analysis. Results The immunocytochemistry showed that the number of NQO1and γ-GCS stained cells in TH and TH+RGZ group increased compared to the control group. In addition, the expression of NQO1 and γ-GCS in TH+RGZ group remarkably increased in mRNA and protein level compared to TH only group (p < 0.01). Conclusion Rosiglitazone can increase thrombin-induced microglia anti-oxidative ability by increasing NQO1and γ-GCS expression, which can effectively reduce secondary injury after cerebral hemorrhage.

Mg-Protoporphyrin IX Signals Enhance Plant's Tolerance to Cold Stress.

The relationship between Mg-protoporphyrin IX (Mg-Proto IX) signals and plant's tolerance to cold stress is investigated. Arabidopsis seedlings grown for 3 weeks were pretreated with 2 mM glutamate (Glu) and 2 mM MgCl2 for 48 h at room temperature to induce Mg-Proto IX accumulation. Then cold stress was performed at 4°C for additional 72 h. Glu + MgCl2 pre-treatments alleviated the subsequent cold stress significantly by rising the leaf temperature through inducing Mg-Proto IX signals. The protective role of Glu + MgCl2 treatment was greatly compromised in the mutants of Mg-Proto IX synthesis, Mg-Proto IX signaling, and cyanide-resistant respiration. And the enhancement of cold-responsive gene expression was greatly compromised in the mutants of Mg-Proto IX synthesis, Mg-Proto IX signaling and ABA signaling, but not in the mutant of cyanide-resistant respiration. Cold stress promoted cyanide-resistant respiration and leaf total respiration exponentially, which could be further induced by the Glu + MgCl2 treatment. Mg-Proto IX signals also activate antioxidant enzymes and increase non-enzymatic antioxidants [glutathione but not ascorbic acid (AsA)] to maintain redox equilibrium during the cold stress.