Conformation-Switchable Polypeptides as Molecular Gates for Controllable Drug Release.

The control over secondary structure has been widely studied to regulate the properties of polypeptide materials, which is used to change their functions in situ for various biomedical applications. Herein, we designed and constructed enzyme-responsive polypeptides as gating materials for mesoporous silica nanoparticles (MSNs), which underwent a distorted structure-to-helix transition to promote the release of encapsulated drugs. The polypeptide conjugated on the MSN surface adopted a negatively charged, distorted, flexible conformation, covering the pores of MSN to prevent drug leakage. Upon triggering by alkaline phosphatase (ALP) overproduced by tumor cells, the polypeptide transformed into positively charged, α-helical, rigid conformation with potent membrane-penetrating capabilities, which protruded from the MSN surface to uncover the pores. Such a transition thus enabled cancer-selective drug release and cellular internalization to efficiently kill tumor cells. This study highlights the important role of chain flexibility in modulating the biological function of polypeptides and provides a new application paradigm for synthetic polypeptides with secondary-structure transition.

Prolonged elevated heart rate and 90-Day mortality in acute pancreatitis.

Prolonged elevated heart rate (peHR) is recognized as a risk factor for poor prognosis among critically ill patients. However, there is currently a lack of studies investigating the association between peHR and patients with acute pancreatitis. Multiparameter Intelligent Monitoring in Intensive Care IV (MIMIC-IV) database was used to identify patients with acute pancreatitis. PeHR was defined as a heart rate exceeding 100 beats per minute for at least 11 out of 12 consecutive hours. Cox regression analysis was used to assess the association between peHR and the 90-Day mortality. A total of 364 patients (48.9%) experienced a peHR episode. The 90-day mortality was 25%. PeHR is an independent risk factor for 90-day mortality (HR, 1.98; 95% CI 1.53-2.56; P < 0.001). KM survival curves exhibited a significant decrease in the survival rate at 90 days among patients who experienced a peHR episode (P < 0.001, 84.5% vs. 65.1%). We revealed a significant association of peHR with decreased survival in a large cohort of ICU patients with acute pancreatitis.

Housekeeping U1 snRNA facilitates antiviral innate immunity by promoting TRIM25-mediated RIG-I activation.

U1 small nuclear RNA (snRNA) is an abundant and evolutionarily conserved 164-nucleotide RNA species that functions in pre-mRNA splicing, and it is considered to be a housekeeping non-coding RNA. However, the role of U1 snRNA in regulating host antiviral immunity remains largely unexplored. Here, we find that RNVU1-18, a U1 pseudogene, is significantly upregulated in the host infected with RNA viruses, including influenza and respiratory syncytial virus. Overexpression of U1 snRNA protects cells against RNA viruses, while knockdown of U1 snRNA leads to more viral burden in vitro and in vivo. Knockout of RNVU1-18 is sufficient to impair the type I interferon-dependent antiviral innate immunity. U1 snRNA is required to fully activate the retinoic acid-inducible gene I (RIG-I)-dependent antiviral signaling, since it interacts with tripartite motif 25 (TRIM25) and enhances the RIG-I-TRIM25 interaction to trigger K63-linked ubiquitination of RIG-I. Our study reveals the important role of housekeeping U1 snRNA in regulating host antiviral innate immunity and restricting RNA virus infection.

Inhaled immunoantimicrobials for the treatment of chronic obstructive pulmonary disease.

Effective therapeutic modalities and drug administration strategies for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations are lacking. Here, mucus and biofilm dual-penetrating immunoantimicrobials (IMAMs) are developed for bridging antibacterial therapy and pro-resolving immunotherapy of COPD. IMAMs are constructed from ceftazidime (CAZ)-encapsulated hollow mesoporous silica nanoparticles (HMSNs) gated with a charge/conformation-transformable polypeptide. The polypeptide adopts a negatively charged, random-coiled conformation, masking the pores of HMSNs to prevent antibiotic leakage and allowing the nebulized IMAMs to efficiently penetrate the bronchial mucus and biofilm. Inside the acidic biofilm, the polypeptide transforms into a cationic and rigid α helix, enhancing biofilm retention and unmasking the pores to release CAZ. Meanwhile, the polypeptide is conditionally activated to disrupt bacterial membranes and scavenge bacterial DNA, functioning as an adjuvant of CAZ to eradicate lung-colonizing bacteria and inhibiting Toll-like receptor 9 activation to foster inflammation resolution. This immunoantibacterial strategy may shift the current paradigm of COPD management.

Pulmonary RNA interference against acute lung injury mediated by mucus- and cell-penetrating nanocomplexes.

Trans-mucosal delivery of anti-inflammatory siRNA into alveolar macrophages represents a promising modality for the treatment of acute lung injury (ALI). However, its therapeutic efficacy is often hurdled by the lack of effective carriers that can simultaneously overcome the mucosal barrier and cell membrane barrier. Herein, we developed mucus/cell membrane dual-penetrating, macrophage-targeting polyplexes which enabled efficient intratracheal delivery of TNF-α siRNA (siTNF-α) to attenuate pulmonary inflammation against lipopolysaccharide (LPS)-induced ALI. P-G@Zn, a cationic helical polypeptide bearing both guanidine and zinc dipicolylamine (Zn-DPA) side charged groups, was designed to condense siTNF-α and promote macrophage internalization due to its helicity-dependent membrane activity. Coating of the polyplexes with charge-neutralizing carboxylated mannan (Man-COOH) greatly enhanced the mucus penetration potency due to shielding of the electrostatic adhesive interactions with the mucus, and it cooperatively enabled active targeting to alveolar macrophages to potentiate the intracellular delivery efficiency of siTNF-α. As such, intratracheally administered Man-COOH/P-G@Zn/siTNF-α polyplexes provoked notable TNF-α silencing by ∼75 % in inflamed lung tissues at 500 µg siRNA/kg, and demonstrated potent anti-inflammatory performance to treat ALI. This study provides an effective tool for the synchronized trans-mucosal delivery of siRNA into macrophages, and the unique properties of the polyplexes render remarkable potentials for anti-inflammatory therapy against ALI. STATEMENT OF SIGNIFICANCE: siRNA-mediated anti-inflammatory management of acute lung injury (ALI) is greatly challenged by the insufficient delivery across the mucus layer and cell membrane. To address such critical issue, mucus/cell membrane dual-penetrating, macrophage-targeting polyplexes are herein developed, which are comprised of an outer shell of carboxylated mannan (Man-COOH) and an inner nanocore formed by TNF-α siRNA (siTNF-α) and a cationic helical polypeptide P-G@Zn. Man-COOH coating endowed the polyplexes with high mucus-penetrating capability and macrophage-targeting ability, while P-G@Zn bearing both guanidine and zinc dipicolylamine afforded potent siTNF-α condensation capacity and high intracellular delivery efficiency with reduced cytotoxicity. Intratracheally administered polyplexes solicit pronounced TNF-α silencing and anti-inflammatory efficiencies in ALI mice. This study renders an effective example for overcoming the multiple barriers against trans-mucosal delivery of siRNA into macrophages, and holds profound potentials for gene therapy against ALI.

Trajectory-BERT: Trajectory Estimation Based on BERT Trajectory Pre-Training Model and Particle Filter Algorithm.

In the realm of aviation, trajectory data play a crucial role in determining the target's flight intentions and guaranteeing flight safety. However, the data collection process can be hindered by noise or signal interruptions, thus diminishing the precision of the data. This paper uses the bidirectional encoder representations from transformers (BERT) model to solve the problem by masking the high-precision automatic dependent survey broadcast (ADS-B) trajectory data and estimating the mask position value based on the front and rear trajectory points during BERT model training. Through this process, the model acquires knowledge of intricate motion patterns within the trajectory data and acquires the BERT pre-training Model. Afterwards, a refined particle filter algorithm is utilized to generate alternative trajectory sets for observation trajectory data that is prone to noise. Ultimately, the BERT trajectory pre-training model is supplied with the alternative trajectory set, and the optimal trajectory is determined by computing the maximum posterior probability. The results of the experiment show that the model has good performance and is stronger than traditional algorithms.

Macrophage Membrane-Reversibly Cloaked Nanotherapeutics for the Anti-Inflammatory and Antioxidant Treatment of Rheumatoid Arthritis.

During rheumatoid arthritis (RA) development, over-produced proinflammatory cytokines represented by tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS) represented by H2 O2 form a self-promoted cycle to exacerbate the synovial inflammation and tissue damage. Herein, biomimetic nanocomplexes (NCs) reversibly cloaked with macrophage membrane (RM) are developed for effective RA management via dual scavenging of TNF-α and ROS. To construct the NCs, membrane-penetrating, helical polypeptide first condenses TNF-α siRNA (siTNF-α) and forms the cationic inner core, which further adsorbs catalase (CAT) via electrostatic interaction followed by surface coating with RM. The membrane-coated NCs enable prolonged blood circulation and active joint accumulation after systemic administration in Zymosan A-induced arthritis mice. In the oxidative microenvironment of joints, CAT degrades H2 O2 to produce O2 bubbles, which shed off the outer membrane layer to expose the positively charged inner core, thus facilitating effective intracellular delivery into macrophages. siRNA-mediated TNF-α silencing and CAT-mediated H2 O2 scavenging then cooperate to inhibit inflammation and alleviate oxidative stress, remodeling the osteomicroenvironment and fostering tissue repair. This study provides an enlightened strategy to resolve the blood circulation/cell internalization dilemma of cell membrane-coated nanosystems, and it renders a promising modality for RA treatment.

Chemogenetic activation of the HPC-mPFC pathway improves cognitive dysfunction in lipopolysaccharide -induced brain injury.

Rationale: Although sepsis-associated encephalopathy (SAE) is a common psychiatric complication in septic patients, the underlying mechanisms remain unclear. Here, we explored the role of the hippocampus (HPC) - medial prefrontal cortex (mPFC) pathway in cognitive dysfunction in lipopolysaccharide-induced brain injury. Methods: Lipopolysaccharide (LPS, 5 mg/kg, intraperitoneal) was used to induce an animal model of SAE. We first identified neural projections from the HPC to the mPFC via a retrograde tracer and virus expression. The activation viruses (pAAV-CaMKIIα-hM3Dq-mCherry) were injected to assess the effects of specific activation of mPFC excitatory neurons on cognitive tasks and anxiety-related behaviors in the presence of clozapine-N-oxide (CNO). Activation of the HPC-mPFC pathway was evaluated via immunofluorescence staining of c-Fos-positive neurons in mPFC. Western blotting was performed to determine protein levels of synapse- associated factors. Results: We successfully identified a structural HPC-mPFC connection in C57BL/6 mice. LPS-induced sepsis induces cognitive impairment and anxiety-like behaviors. Chemogenetic activation of the HPC-mPFC pathway improved LPS-induced cognitive dysfunction but not anxiety-like behavior. Inhibition of glutamate receptors abolished the effects of HPC-mPFC activation and blocked activation of the HPC-mPFC pathway. The glutamate receptor-mediated CaMKII/CREB/BDNF/TrKB signaling pathway influenced the role of the HPC-mPFC pathway in sepsis-induced cognitive dysfunction. Conclusions: HPC-mPFC pathway plays an important role in cognitive dysfunction in lipopolysaccharide-induced brain injury. Specifically, the glutamate receptor-mediated downstream signaling appears to be an important molecular mechanism linking the HPC-mPFC pathway with cognitive dysfunction in SAE.

Rational Construction of Protein-Mimetic Nano-Switch Systems Based on Secondary Structure Transitions of Synthetic Polypeptides.

The manipulation of the flexibility/rigidity of polymeric chains to control their function is commonly observed in natural macromolecules but largely unexplored in synthetic systems. Herein, we construct a series of protein-mimetic nano-switches consisting of a gold nanoparticle (GNP) core, a synthetic polypeptide linker, and an optically functional molecule (OFM), whose biological function can be dynamically regulated by the flexibility of the polypeptide linker. At the dormant state, the polypeptide adopts a flexible, random-coiled conformation, bringing GNP and OFM in close proximity that leads to the "turn-off" of the OFM. Once treated with alkaline phosphatase (ALP), the nano-switches are activated due to the increased separation distance between GNP and OFM driven by the coil-to-helix and flexible-to-rigid transition of the polypeptide linker. The nano-switches therefore enable selective fluorescence imaging or photodynamic therapy in response to ALP overproduced by tumor cells. The control over polymer flexibility represents an effective strategy to manipulate the optical activity of nano-switches, which mimics the delicate structure-property relationship of natural proteins.

Effect of ß-blockers on mortality in patients with sepsis: A propensity-score matched analysis.

Objectives: We aimed to evaluate the association between ß-blocker therapy and mortality in patients with sepsis. Methods: Patients with sepsis were selected from the Medical Information Mart for Intensive Care (MIMIC)-III. Propensity score matching (PSM) was used to balance the baseline differences. A multivariate Cox regression model was used to assess the relationship between ß-blocker therapy and mortality. The primary outcome was the 28-day mortality. Results: A total of 12,360 patients were included in the study, involving 3,895 who received ß-blocker therapy and 8,465 who did not. After PSM, 3,891 pairs of patients were matched. The results showed that ß-blockers were associated with improved 28- (hazards ratio (HR) 0.78) and 90-day (HR 0.84) mortality. Long-acting ß-blockers were associated with improved 28-day survival (757/3627 [20.9%] vs. 583/3627 [16.1%], P < 0.001, HR0.76) and 90-day survival (1065/3627 [29.4%] vs.921/3627 [25.4%], P < 0.001, HR 0.77). Short-acting ß-blocker treatment did not reduce the 28-day and 90-day mortality (61/264 [23.1%] vs. 63/264 [23.9%], P = 0.89 and 83/264 [31.4%] vs. 89/264 [31.7%], P = 0.8, respectively). Conclusions: ß-blockers were associated with improved 28- and 90-day mortality in patients with sepsis and septic shock. Long-acting ß-blocker therapy may have a protective role in patients with sepsis, reducing the 28-day and 90-day mortality. However, short-acting ß-blocker (esmolol) treatment did not reduce the mortality in sepsis.

siRNA Delivery against Myocardial Ischemia Reperfusion Injury Mediated by Reversibly Camouflaged Biomimetic Nanocomplexes.

siRNA-mediated management of myocardial ischemia reperfusion (IR) injury is greatly hampered by the inefficient myocardial enrichment and cardiomyocyte transfection. Herein, nanocomplexes (NCs) reversibly camouflaged with a platelet-macrophage hybrid membrane (HM) are developed to efficiently deliver Sav1 siRNA (siSav1) into cardiomyocytes, suppressing the Hippo pathway and inducing cardiomyocyte regeneration. The biomimetic BSPC@HM NCs consist of a cationic nanocore assembled from a membrane-penetrating helical polypeptide (P-Ben) and siSav1, a charge-reversal intermediate layer of poly(l-lysine)-cis-aconitic acid (PC), and an outer shell of HM. Due to HM-mediated inflammation homing and microthrombus targeting, intravenously injected BSPC@HM NCs can efficiently accumulate in the IR-injured myocardium, where the acidic inflammatory microenvironment triggers charge reversal of PC to shed off both HM and PC layers and allow the penetration of the exposed P-Ben/siSav1 NCs into cardiomyocytes. In rats and pigs, BSPC@HM NCs remarkably downregulates Sav1 in IR-injured myocardium, promotes myocardium regeneration, suppresses myocardial apoptosis, and recovers cardiac functions. This study reports a bioinspired strategy to overcome the multiple systemic barriers against myocardial siRNA delivery, and holds profound potential for gene therapy against cardiac injuries.

Oral Delivery of siRNA Using Fluorinated, Small-Sized Nanocapsules toward Anti-Inflammation Treatment.

Oral delivery of small interfering RNA (siRNA) provides a promising paradigm for treating diseases that require regular injections. However, the multiple gastrointestinal (GI) and systemic barriers often lead to inefficient oral absorption and low bioavailability of siRNA. Technologies that can overcome these barriers are still lacking, which hinders the clinical potential of orally delivered siRNA. Herein, small-sized, fluorinated nanocapsules (F-NCs) are developed to mediate efficient oral delivery of tumor necrosis factor α (TNF-α) siRNA for anti-inflammation treatment. The NCs possess a disulfide-cross-linked shell structure, thus featuring robust stability in the GI tract. Because of their small size (≈30 nm) and fluorocarbon-assisted repelling of mucin adsorption, the best-performing F3 -NCs show excellent mucus penetration and intestinal transport capabilities without impairing the intestinal tight junction, conferring the oral bioavailability of 20.4% in relative to intravenous injection. The disulfide cross-linker can be cleaved inside target cells, causing NCs dissociation and siRNA release to potentiate the TNF-α silencing efficiency. In murine models of acute and chronic inflammation, orally delivered F3 -NCs provoke efficient TNF-α silencing and pronounced anti-inflammatory efficacies. This study therefore provides a transformative strategy for oral siRNA delivery, and will render promising utilities for anti-inflammation treatment.

Hippocampus-prefrontal cortex inputs modulate spatial learning and memory in a mouse model of sepsis induced by cecal ligation puncture.

AIMS: Sepsis-associated encephalopathy (SAE) often leads to cognitive impairments. However, the pathophysiology of SAE is complex and unclear. Here, we investigated the role of hippocampus (HPC)-prefrontal cortex (PFC) in cognitive dysfunction in sepsis induced by cecal ligation puncture (CLP) in mice. METHODS: The neural projections from the HPC to PFC were first identified via retrograde tracing and viral expression. Chemogenetic activation of the HPC-PFC pathway was shown via immunofluorescent staining of c-Fos-positive neurons in PFC. Morris Water Maze (MWM) and Barnes maze (BM) were used to evaluate cognitive function. Western blotting analysis was used to determine the expression of glutamate receptors and related molecules in PFC and HPC. RESULTS: Chemogenetic activation of the HPC-PFC pathway enhanced cognitive dysfunction in CLP-induced septic mice. Glutamate receptors mediated the effects of HPC-PFC pathway activation in CLP mice. The activation of the HPC-PFC pathway resulted in significantly increased levels of NMDAR, AMPAR, and downstream signaling molecules including CaMKIIa, pCREB, and BDNF in PFC. However, inhibition of glutamate receptors using 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo (F)quinoxaline (NBQX), which is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR inhibitor), or D-2-amino-5-phosphonopentanoate (D-AP5), which is an NMDA receptor antagonist abolished this increase. CONCLUSION: Our study reveals the important role of the HPC-PFC pathway in improving cognitive dysfunction in a mouse model of CLP sepsis and provides a novel pathogenetic mechanism for SAE.

Association between albumin infusion and septic patients with coronary heart disease: A retrospective study based on medical information mart for intensive care III database.

Coronary heart disease (CHD) is a common comorbidity in intensive care unit (ICU) patients, particularly in the elderly. This particular population may have worse conditions during sepsis, and it presents an overwhelming challenge for clinical practice. Previous studies suggested that patients with CHD have an increased risk of cardiovascular events, and low albumin concentration worsens the prognosis of patients with stable CHD. Hypoalbuminemia in patients with sepsis is common due to nutritional disorders, excessive consumption, and leakage. Albumin is a fluid often used for resuscitation in patients with sepsis. However, albumin infusion in patients with sepsis and CHD has rarely been studied. The effects and safety of albumin infusion in patients with sepsis and CHD remain unclear. Therefore, we collected medical information from Mimic-III (Mimic-III) and compared the all-cause mortality and cardiovascular mortality at 28- or 90-day between the albumin and non-albumin groups in septic patients with CHD. A total of 2,027 patients with sepsis and CHD were included in our study, with 405 in the albumin group and 1,622 in the non-albumin group. After propensity score matching (PSM), 350 pairs were included in our study. Improved survival benefits were found in the albumin group at the 28-day all-cause mortality compared with the non-albumin group (hazard ratio [HR], 0.54; 95% CI: 0.38-0.78; p = 0.0009). However, no difference was detected in the 90-day survival benefits (HR, 0.80, 95% CI: 0.60-1.06, p = 0.1207). Albumin infusion did not reverse cardiovascular mortality neither at 28th day nor at 90th day (cardiovascular mortality: 28 days, HR, 0.52, 95% CI: 0.23-1.19, p = 0.1218; 90 days, HR, 0.66, 95% CI: 0.33-1.33, p = 0.2420).

Machine learning for early prediction of sepsis-associated acute brain injury.

Background: Sepsis-associated encephalopathy (SAE) is defined as diffuse brain dysfunction associated with sepsis and leads to a high mortality rate. We aimed to develop and validate an optimal machine-learning model based on clinical features for early predicting sepsis-associated acute brain injury. Methods: We analyzed adult patients with sepsis from the Medical Information Mart for Intensive Care (MIMIC III) clinical database. Candidate models were trained using random forest, support vector machine (SVM), decision tree classifier, gradients boosting machine (GBM), multiple layer perception (MLP), extreme gradient boosting (XGBoost), light gradients boosting machine (LGBM) and a conventional logistic regression model. These methods were applied to develop and validate the optimal model based on its accuracy and area under curve (AUC). Results: In total, 12,460 patients with sepsis met inclusion criteria, and 6,284 (50.4%) patients suffered from sepsis-associated acute brain injury. Compared other models, the LGBM model achieved the best performance. The AUC for both train set and test set indicated excellent validity (Trainset AUC 0.91, Testset AUC 0.87). Feature importance analysis showed that glucose, age, mean arterial pressure, heart rate, hemoglobin, and length of ICU stay were the top 6 important clinical factors to predict occurrence of sepsis-associated acute brain injury. Conclusion: Almost half of patients admitted to ICU with sepsis had sepsis-associated acute brain injury. The LGBM model better identify patients with sepsis-associated acute brain injury than did other machine-learning models. Glucose, age, and mean arterial pressure were the three most important clinical factors to predict occurrence of sepsis-associated acute brain injury.

Spherical α-helical polypeptide-mediated E2F1 silencing against myocardial ischemia-reperfusion injury (MIRI).

Apoptosis of cardiomyocytes is a critical outcome of myocardial ischemia-reperfusion injury (MIRI), which leads to the permanent impairment of cardiac function. Upregulated E2F1 is implicated in inducing cardiomyocyte apoptosis, and thus intervention of the E2F1 signaling pathway via RNA interference may hold promising potential for rescuing the myocardium from MIRI. To aid efficient E2F1 siRNA (siE2F1) delivery into cardiomyocytes that are normally hard to transfect, a spherical, α-helical polypeptide (SPP) with potent membrane activity was developed via dendrimer-initiated ring-opening polymerization of N-carboxyanhydride followed by side-chain functionalization with guanidines. Due to its multivalent structure, SPP outperformed its linear counterpart (LPP) to feature potent siRNA binding affinity and membrane activity. Thus, SPP effectively delivered siE2F1 into cardiomyocytes and suppressed E2F1 expression both in vitro and in vivo after intramyocardial injection. The E2F1-miR421-Pink1 signaling pathway was disrupted, thereby leading to the reduction of MIRI-induced mitochondrial damage, apoptosis, and inflammation of cardiomyocytes and ultimately recovering the systolic function of the myocardium. This study provides an example of membrane-penetrating nucleic acid delivery materials, and it also provides a promising approach for the genetic manipulation of cardiomyocyte apoptosis for the treatment of MIRI.

ROS-Responsive Selenopolypeptide Micelles: Preparation, Characterization, and Controlled Drug Release.

Sulfur-containing polypeptides, capable of reactive oxygen species (ROS)-responsive structural change, are one of the most important building blocks for the construction of polypeptide-based drug delivery systems. However, the relatively low ROS sensitivity of side-chain thioethers limits the biomedical applications of these polypeptides because they usually require a high concentration of ROS beyond the pathological ROS level in the tumor microenvironment. Herein, we report the design and synthesis of a selenium-containing polypeptide, which undergoes random coil-to-extended helix and hydrophobic-to-hydrophilic transitions in the presence of 0.1% H2O2, a concentration that is much lower than the ROS requirement for thioether. ROS-responsive micelles were thus prepared from the amphiphilic copolymer consisting of the hydrophilic poly(ethylene glycol) (PEG) segment and hydrophobic selenopolypeptide segment and were used to encapsulate doxorubicin (DOX). The micelles could be sensitively dissociated inside tumor cells in consequence of ROS-triggered oxidation of side-chain selenoether and structural change of the micelles, thereby efficiently and selectively releasing the encapsulated DOX to kill cancer cells. This work provides an alternative design of ROS-responsive polypeptides with higher sensitivity than that of the existing sulfur-containing polypeptides, which may expand the biomedical applications of polypeptide materials.

Platelet Pharmacytes for the Hierarchical Amplification of Antitumor Immunity in Response to Self-Generated Immune Signals.

Systemic immunosuppression mediated by tumor-derived exosomes is an important cause for the resistance of immune checkpoint blockade (ICB) therapy. Herein, self-adaptive platelet (PLT) pharmacytes are engineered to mediate cascaded delivery of exosome-inhibiting siRNA and anti-PD-L1 (aPDL1) toward synergized antitumor immunity. In the pharmacytes, polycationic nanocomplexes (NCs) assembled from Rab27 siRNA (siRab) and a membrane-penetrating polypeptide are encapsulated inside the open canalicular system of PLTs, and cytotoxic T lymphocytes (CTLs)-responsive aPDL1 nanogels (NGs) are covalently backpacked on the PLT surface. Upon systemic administration, the pharmacytes enable prolonged blood circulation and active accumulation to tumors, wherein PLTs are activated to liberate siRab NCs, which efficiently transfect tumor cells, silence Rab27a, and inhibit exosome secretion. The immunosuppression is thus relieved, leading to the activation, proliferation, and tumoral infiltration of cytotoxic T cells, which trigger latent aPDL1 release. As such, the competitive aPDL1 exhaustion by PD-L1-expressing exosomes is minimized to sensitize ICB. Synergistically, siRab and aPDL1 induce strong antitumor immunological response and memory against syngeneic murine melanoma. This study reports a bioinspired mechanism to resolve the blood circulation/cell internalization contradiction of polycationic siRNA delivery systems, and renders an enlightened approach for the spatiotemporal enhancement of antitumor immunity.

Association between albumin infusion and outcomes in patients with acute kidney injury and septic shock.

Septic shock with acute kidney injury (AKI) is common in critically ill patients. Our aim was to evaluate the association between albumin infusion and outcomes in patients with septic shock and AKI. Medical Information Mart for Intensive Care (MIMIC)-III was used to identify patients with septic shock and AKI. Propensity score matching (PSM) was employed to balance the baseline differences. Cox proportional hazards model, Wilcoxon rank-sum test, and logistic regression were utilized to determine the associations of albumin infusion with mortality, length of stay, and recovery of kidney function, respectively. A total of 2861 septic shock patients with AKI were studied, including 891 with albumin infusion, and 1970 without albumin infusion. After PSM, 749 pairs of patients were matched. Albumin infusion was associated with improved 28-day survival (HR 0.72; 95% CI 0.59-0.86; P = 0.002), but it was not difference in 90-day mortality between groups (HR 0.94; 95% CI 0.79-1.12; P = 0.474). Albumin infusion was not associated with the renal function recovery (HR 0.91; 95% CI 0.73-1.13; P = 0.393) in either population. Nevertheless, subgroup analysis showed that albumin infusion was distinctly associated with reduced 28-day mortality in patients with age > 60 years. The results need to be validated in more randomized controlled trials.

S100B/RAGE/Ceramide signaling pathway is involved in sepsis-associated encephalopathy.

AIMS: Sepsis-associated encephalopathy (SAE) is one of the most common complications of sepsis, and it might lead to long-term cognitive dysfunction and disability. This study aimed to explore the role of S100 calcium binding protein B (S100B)/RAGE/ceramide signaling pathway in SAE. MAIN METHODS: FPS-ZM1 (an inhibitor of RAGE), myriocin and GW4869 (an inhibitor of ceramide) were used to explore the role of S100B/RAGE/ceramide in acute brain injury and long-term cognitive impairment in sepsis. In addition, Mdivi-1 (inhibitor of Drp1) and Drp1 siRNA were utilized to assess the effects of C2-ceramide on neuronal mitochondria, and to explore the specific underlying mechanism in C2 ceramide-induced death of HT22 mouse hippocampal neuronal cells. KEY FINDINGS: Western blot analysis showed that sepsis significantly up-regulated S100B and RAGE. Nissl staining and Morris water maze (MWM) test revealed that inhibition of RAGE with FPS-ZM1 markedly attenuated cecal ligation and puncture (CLP)-induced brain damage and cognitive dysfunction. Furthermore, FPS-ZM1 relieved sepsis-induced C2-ceramide accumulation and abnormal mitochondrial dynamics. Moreover, inhibition of ceramide also showed similar protective effects both in vivo and in vitro. Furthermore, Mdivi-1 and Drp1 siRNA significantly reduced C2-ceramide-induced neuronal mitochondrial fragmentation and cell apoptosis in vitro. SIGNIFICANCE: This study confirmed that S100B regulates mitochondrial dynamics through RAGE/ceramide pathway, in addition to the role of this pathway in acute brain injury and long-term cognitive impairment during sepsis.