Introduction: Total hip arthroplasty (THA) is an effective treatment for end-stage hip joint diseases but is frequently associated with postoperative hyperfibrinolysis, which elevates the risks of bleeding and thrombosis. Ginsenosides, the primary active components of Panax ginseng, exhibit a range of pharmacological activities, including anti-inflammatory and anti-apoptotic effects. However, their mechanism of action in counteracting postoperative hyperfibrinolysis after THA remains unclear. Methods Active ginsenoside components were first screened from databases such as TCMSP and BATMAN-TCM on the basis of ADME parameters. Key targets were identified through network pharmacology, followed by the construction of a protein–protein interaction (PPI) network and GO and KEGG enrichment analyses. Meanwhile, venous blood samples were collected from THA patients at 2 hours preoperatively and 24 hours postoperatively for untargeted metabolomics analysis using LC-MS/MS. Multivariate statistical analysis was applied to screen differential metabolites and perform pathway enrichment. Finally, the results of network pharmacology and metabolomics were integrated to construct a “component–target–metabolic pathway” association network. Results A total of 9 active ginsenoside components were obtained, yielding 351 component-related targets and 428 fibrinolysis-related targets, with an intersection of 65 key targets. PPI network analysis identified AKT1, PTGS2, and JUN as core targets. KEGG enrichment analysis revealed significant enrichment in the complement and coagulation cascades, platelet activation, and HIF-1 signaling pathways. Metabolomics identified 292 differential metabolites, mainly enriched in arachidonic acid metabolism, purine metabolism, and glycerophospholipid metabolism. Integrative analysis identified arachidonic acid metabolism and the cGMP-PKG, cAMP, and sphingolipid signaling pathways as common key pathways. Molecular docking of AKT1 with ginsenoside Rh7, JUN with ginsenoside Rg3, PIK3CA with ginsenoside Rh1, and PTGS2 with F2 all demonstrated favorable binding affinity, further supporting the reliability of the network pharmacology predictions. Conclusion This study is the first to systematically elucidate that ginsenosides modulate postoperative fibrinolysis following THA by regulating multiple targets (e.g., AKT1 and PTGS2) and multiple pathways (including arachidonic acid metabolism and the complement and coagulation cascades), thereby providing a new theoretical basis for their perioperative clinical application.

Background:Acute kidney injury (AKI) complicates cardiac valve replacement (CVR) in up to one-third of patients. The triglyceride-glucose-body mass index (TyG-BMI) is a composite marker derived from routine laboratory tests and anthropometric measurements. It reflects the combined burden of insulin resistance and obesity-two interrelated conditions that contribute to chronic low-grade inflammation, oxidative stress, endothelial dysfunction, and increased renal microvascular vulnerability. However, its association with AKI after CVR remains unclear. This study aimed to develop a multivariable clinical prediction model for AKI and evaluate the incremental value of incorporating TyG-BMI into that model. Methods:This single-center retrospective study enrolled consecutive patients aged 18-80 years undergoing first-time elective CVR with cardiopulmonary bypass (CPB) (November 2021-December 2022). Exclusion criteria were pre-existing chronic kidney disease (CKD) [estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2], preoperative AKI, dialysis/kidney transplantation, chronic liver disease, active malignancy, severe infection, infective endocarditis, death within 48 hours, concomitant CABG, or incomplete data. Preoperative blood samples were collected within 24 hours. TyG-BMI was calculated as Ln(TG (mg/dL)×FPG (mg/dL)/2)×BMI (kg/m2). Postoperative AKI was defined per KDIGO criteria (creatinine rise ≥26.5 µmol/L within 48 hours or ≥1.5× baseline within 7 days) and monitored daily for seven days. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors. The incremental predictive value of TyG-BMI was assessed by comparing models with and without it using receiver operating characteristic (ROC) curve analysis. Restricted cubic splines (RCS) were used to explore nonlinear relationships. Results:Among 187 included patients, 64 (34.2%) developed postoperative AKI. Patients who developed AKI had higher preoperative TyG-BMI levels compared to those without [AKI (207.99±27.05) vs. non‑AKI (184.24±23.71); P<0.001]. After adjusting for potential confounders including age, sex, CPB time, aortic cross-clamp time, and preoperative creatinine, TyG-BMI remained independently associated with an increased risk of AKI [odds ratio (OR): 1.050 per unit increase, 95% confidence interval (CI): 1.026-1.076; P<0.001]. The predictive model incorporating TyG-BMI demonstrated a higher area under the curve (AUC) for AKI compared to the model without it (AUC: 0.786 vs. 0.735). RCS analysis showed a significant overall association (P-overall <0.001) but no evidence of nonlinearity (P-nonlinear =0.18). Conclusions:In this limited single-center retrospective cohort, the model with TyG-BMI, age, sex, and CPB time had a modest apparent AUC of 0.786 (optimism-corrected: 0.723). The gain over baseline was small (ΔAUC =0.051). These modest metrics and the retrospective design limit our findings to being preliminary. External validation in larger prospective cohorts is mandatory before clinical application. The weaker association observed in the highest TyG index group also needs independent confirmation.

BackgroundSepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The vascular endothelial cells (VECs) play a pivotal role in the progression of sepsis-induced vascular leakage. While therapeutic strategies targeting pathogen elimination and inflammation exist, direct interventions on the endothelial barrier are limited. The mechanisms of endothelial damage related to mitochondrial dysfunction during sepsis require further elucidation.MethodsThe study utilized a cecal ligation and puncture (CLP) rat model of sepsis and lipopolysaccharide (LPS)-stimulated VECs to investigate vascular leakage mechanisms. These models were utilized to investigate the changes in vascular permeability, mitochondrial function and protein crotonylation in VECs, aiming to identify potential therapeutic targets for sepsis.ResultsIn septic rats, significant lung injury and increased vascular leakage were observed, linked to mitochondrial dysfunction and decreased survival rates. A marked downregulation of Platelet Activating Factor Acetylhydrolase 2 (PAFAH2) in VECs was identified post-sepsis, causing an upregulation of Enoyl-CoA Hydratase, Short Chain 1 (ECHS1), which inhibited crotonylation and compromised mitochondrial function, leading to increased apoptosis of VECs. Restoration experiments showed that modulating PAFAH2 and ECHS1 levels could mitigate these adverse effects. PAFAH2 overexpression alleviated sepsis-induced vascular leakage by downregulating ECHS1 and enhancing crotonylation.ConclusionsThe study identifies the PAFAH2-ECHS1 pathway as a critical axis in sepsis-induced vascular leakage, influencing mitochondrial function and crotonylation, which leads to endothelial apoptosis. These insights could guide the development of new therapies targeting the endothelial barrier for treating sepsis.

Objective:This study aims to assess the effect of using medical waste rubber bung (MWRB) for pin-tract management in patients with open tibial fractures treated with external fixators (EFs). Methods:A retrospective analysis of 91 patients with open tibial fractures admitted to our hospital over a three-year period was conducted to compare and statistically characterize overall PTI incidence, PTI rate across five different pin-tract locations, time (days) to the first occurrence of infection, and Checketts-Otterburn classification. Results:Among the enrolled 91 patients, 88 met the criteria. After excluding deaths and losses to follow-up, they were divided into two study groups, with no significant difference in overall PTI incidence. Group A exhibited a significantly lower rate of severe infection and prolonged time to initial infection compared to Group B (both P < 0.05). Group A also had a significantly lower rate of PTI at the tibial telangiectasia than Group B. Conclusion:The study underscores that compression in EF management is necessary to significantly reduce the incidence of severe PTIs, especially in the tibial metaphysis, and to delay the onset of initial infection among patients with open tibial fractures.

In organisms, non-coding RNAs (ncRNAs) are key regulatory elements that modulate, the expression of genes involved in diverse biological traits. Among them, micro RNAs (miRNAs), small interfering RNAs (siRNAs), and long non-coding RNAs (lncRNAs) have become major research focuses. Wheat, the world’s most widely grown crop, occupies 17% of global cultivated land and supplies ∼55% of the world’s carbohydrates. Understanding the roles, identification, and mechanisms of wheat ncRNAs is essential for both basic research and crop improvement. Through systematic searches of PubMed, Web of Science, and EndNote databases, this study identified 182 publications related to wheat ncRNAs. Based on predefined criteria—research relevance and publication timeframe (2015–2025)—70 high-quality studies were selected for in-depth analysis. This review comprehensively summarizes recent advances in ncRNA research (focusing on lncRNAs and small RNAs) in relation to wheat diseases, pests, and responses to biotic and abiotic stress. By integrating traditional classification with functional characterization, we developed a comprehensive analytical framework encompassing “molecular characteristics-biotic stress–abiotic stress”. Furthermore, this review consolidates multi-omics high-throughput data and online ncRNA databases. The integration of multi-omics technologies aims to provide both a theoretical foundation and novel strategies for wheat genetic improvement.

Fusarium head blight (FHB) is a devastating disease that poses a significant threat to the global wheat production industry. However, there is a limited pool of genes available for genetic enhancement of wheat resistance to FHB, and the mechanism underlying the disease resistance is not yet fully understood. Our previous study identified a late embryogenesis abundant protein, encoded by TaG3LEA-25, which was specifically accumulated in the FHB-resistant wheat varieties. In the current work, the overexpression of TaG3LEA-25 in wheat significantly enhanced resistance to FHB. TaG3LEA-25 may mediate FHB resistance by maintaining the integrity of the plant cell, which was supported by our established wheat protoplast-F. graminearum interaction system and by the experimental evidence that it interacts with tubulin. A single nucleotide polymorphism (SNP) variation in the promoter of TaG3LEA-25 is within the cis-element for MYC2, and correlated significantly with FHB resistance in a panel of breeding varieties. Varieties carrying contrasting alleles at the SNP showed differential responses to jasmonic acid and exhibited distinct phenotypic responses to FHB. This suggests that jasmonic acid may enhance wheat resistance to FHB by modulating the expression of TaG3LEA-25. Our results reveal a novel function for the LEA gene, and TaG3LEA-25 could enrich the genebank for improving FHB resistance in wheat.

Ischemic/hypoxic injury significantly damages vascular function, detrimentally impacting patient outcomes. Changes in mitochondrial structure and function are closely associated with ischemia/hypoxia-induced vascular dysfunction. The mechanism of this process remains elusive. Using rat models of ischemia and hypoxic vascular smooth muscle cells (VSMCs), we combined transmission electron microscopy, super-resolution microscopy, and metabolic analysis to analyze the structure and function change of mitochondrial cristae. Multi-omics approaches revealed arginase 1 (Arg1) upregulation in ischemic VSMCs, confirmed by in vivo and in vitro knockout models showing Arg1’s protective effects on mitochondrial cristae, mitochondrial and vascular function, and limited the release of mtDNA. Mechanistically, Arg1 interacting with Mic10 led to mitochondrial cristae remodeling, together with hypoxia-induced VDAC1 lactylation resulting in the opening of MPTP and release of mtDNA of VSMCs. The released mtDNA led to PANoptosis of VSMCs via activation of the cGAS-STING pathway. ChIP-qPCR results demonstrated that lactate-mediated Arg1 up-regulation was due to H3K18la upregulation. VSMCs targeted nano-material PLGA-PEI-siRNA@PM-α-SMA (NP-siArg1) significantly improved vascular dysfunction. This study uncovers a new mechanism of vascular dysfunction following ischemic/hypoxic injury: a damaging positive feedback loop mediated by lactate-regulated Arg1 expression between the nucleus and mitochondria, leading to mitochondria cristae disorder and mtDNA release, culminating in VSMCs PANoptosis. Targeting VSMCs Arg1 inhibition offers a potential therapeutic strategy to alleviate ischemia/hypoxia-induced vascular impairments.

Postoperative cognitive dysfunction (POCD) negatively impacts patients’ post-surgery recovery, and, in severe cases, raises the risk of mortality. Nonetheless, the underlying mechanism of POCD remains incompletely elucidated, and there is a notable dearth of effective treatment strategies. A randomized allocation was conducted among a total of 90 patients who underwent arthroplasty surgery, with 45 patients assigned to the dexmedetomidine group and 45 patients assigned to the control group. The Dexmedetomidine (DEX) group received an intravenous infusion of 1 µg/kg dexmedetomidine for 10 min, followed by a maintenance dose of 0.4 µg/kg/h for 30 min before surgery completion; the control (CON) group received 0.9

Aim: This study aimed to elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock. Methods: Before definitive hemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg) was administered to uncontrolled hemorrhagic shock (UHS) model rats. Lactate Ringer's solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss; fluid demand; survival time; vital organ function; myocardial mitochondrial structure; mitochondrial function of the heart, liver, kidney, and intestine; and oxidative stress at 1 h after hypotensive resuscitation (50-60 mm Hg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive hemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 h. Results: Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival, and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage, and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney, and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h. Conclusion: Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 h in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.

Observe the effects of dexmedetomidine(Dex) and sevoflurane(Sev) on the optic nerve sheath diameter(ONSD) in patients undergoing microvascular decompression (MVD). Find the most appropriate anesthetic maintenance medication scheme to reduce intracranial pressure (ICP)fluctuation and reduce the incidence of adverse reactions such as postoperative nausea and vomiting(PONV). In this retrospective cohort study, 90 patients undergoing elective MVD surgery were allocated into Groups P, D, and S. Maintenance of anaesthesia: Group P propofol(Propo) 4-12mg/(kg.h) + remifentanil 0.1–0.2ug/(kg.min); Group D Dex 0.4ug/(kg. h) + Propo 4-12mg/(kg.h) + remifentanil 0.1–0.2ug/(kg.min); Group S 1–2 www.chictr.org.cn (07/02/2024,ChiCTR MR-50–24-010856). Questions: Do Dex and Sev have effect on ONSD and PONV in MVD? Findings: Dex has a lower effect on ONSD of MVD during the perioperative phase than Sev, and it can, to a certain extent, reduce the fluctuation of ICP. Dex reduces the incidence of PONV within 24 h after MVD and acts as a protective factor against PONV. Meaning: The usage of 0.4ug/(kg.h) Dex was a protective factor for PONV in MVD.

During thoracoscopic surgery with one-lung ventilation (OLV), achieving lung collapse is critical for providing surgeons with a good visibility of the surgical field and to minimise tissue compression. The aim of this study was to evaluate the efficacy of both the disconnection technique and preemptive one-lung ventilation in facilitating lung collapse during thoracoscopic surgery using a double-lumen tube (DLT). Ninety-seven eligible patients were included and randomly divided into three groups. Control group: OLV was initiated when the surgeon started the skin incision and exposed the operative side. Disconnection group: OLV was started two minutes after the DLT was disconnected, this procedure started when the surgeon performed the skin incision. Preemptive group: OLV was initiated promptly after the patient was turned to the lateral position, and the bronchial tube port was clamped on the operative side at the lateral position for no less than 6 min until the pleura was opened. The primary outcome was the time to achieve satisfactory lung collapse, defined as the time required to reach a lung collapse score of eight points. The secondary outcomes included the lung collapse scores at different time points, Pleural opening times, OLV times, blood gas analysis results and the incidence of hypoxemia and pulmonary complications. The hypothesis formulated before data collection was that both the disconnection technique and preemptive OLV decrease the time to satisfactory lung collapse. Compared to the control group, both the disconnection and the preemptive group had a shorter time to satisfactory lung collapse (P < 0.001), lung collapse in the preemptive group was superior to that in the disconnection group at one minute (P = 0.045), no significant differences were found among the three groups in terms of other outcomes. Both the disconnection technique and preemptive OLV decrease the time to satisfactory lung collapse. However, preemptive OLV results in superior early lung collapse and is therefore may more suitable for clinical application than the disconnection technique. The protocol of this study was registered at www. chictr. org. cn (29/07/2022, ChiCTR2200062199).

BackgroundPostmenopausal women are more prone to develop muscle weakness, which is strongly associated with impairment of mitochondrial function in skeletal muscle. This study aimed to examine the impact of a passive exercise modality, whole-body vibration training (WBVT), on muscle mitochondrial function in ovariectomized (OVX) mice, in comparison with 17β-estradiol (E2) replacement.MethodsFemale C57BL/6J mice were assigned to four groups: sham operation control group (Sham), ovariectomized group (OVX), OVX with E2 supplement group (OVX+E), and OVX with WBVT group (OVX+W). The estrous cycle, body weight, body composition, and muscle strength of the mice were monitored after the operation. Serum E2 level was assessed by enzyme-linked immunosorbent assay (ELISA). The ATP levels were determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was evaluated using high-resolution respirometry (O2K). Expression levels of oxidative phosphorylation (OXPHOS), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and mitochondrial transcription factor A (TFAM) were detected using western blotting.ResultsWe observed decreased muscle strength and impaired mitochondrial function in the skeletal muscle of OVX mice. The vibration training alleviated these impairments as much as the E2 supplement. In addition, the vibration training was superior to the ovariectomy and the estradiol replacement regarding the protein expression of PGC-1α and TFAM.ConclusionWBVT improves the OVX-induced decline in muscle strength and impairment of mitochondrial function in the skeletal muscle. This passive exercise strategy may be useful as an alternative to E2 replacement for preventing menopausal muscular weakness. Further studies are needed to understand the effects of WBVT on various physiological systems, and precautions should be taken when implementing it in patient treatment.

Myocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.

Uncontrolled and persistent inflammation is closely related to numerous acute and chronic diseases. However, effective targeting delivery systems remain to be developed for precision therapy of inflammatory diseases. Herein we report a novel strategy for engineering inflammation-accumulation nanoparticles via phenolic functionalization. Different phenol-functionalized nanoparticles were first developed, which can undergo in situ aggregation upon triggering by the inflammatory/oxidative microenvironment. Phenolic compound-decorated poly (lactide-co-glycolide) nanoparticles, in particular tyramine (Tyr)-coated nanoparticles, showed significantly enhanced accumulation at inflammatory sites in mouse models of colitis, acute liver injury, and acute lung injury, mainly resulting from in situ cross-linking and tissue anchoring of nanoparticles triggered by local myeloperoxidase and reactive oxygen species. By combining a cyclodextrin-derived bioactive material with Tyr decoration, a multifunctional nanotherapy (TTN) was further developed, which displayed enhanced cellular uptake, anti-inflammatory activities, and inflammatory tissue accumulation, thereby affording amplified therapeutic effects in mice with colitis or acute liver injury. Moreover, TTN can serve as a bioactive and inflammation-targeting nanoplatform for site-specifically delivering a therapeutic peptide to the inflamed colon post oral administration, leading to considerably potentiated in vivo efficacies. Preliminary studies also revealed good safety of orally delivered TTN. Consequently, Tyr-based functionalization is promising for inflammation targeting amplification and therapeutic potentiation of nanotherapies.

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent and severe form of organ dysfunction with elusive underlying mechanisms and limited treatment options.In this study, the cecal ligation and puncture and lipopolysaccharide (LPS) were used to reproduce sepsis model in vitro and vivo.The level of voltage-dependent anion channel 2 (VDAC2) malonylation and myocardial malonyl-CoA were detected by mass spectrometry and LC-MS-based metabolomics.Role of VDAC2 malonylation on cardiomyocytes ferroptosis and treatment effect of mitochondrial targeting nano material TPP-AAV were observed.The results showed that VDAC2 lysine malonylation was significantly elevated after sepsis.In addition, the regulation of VDAC2 lysine 46 (K46) malonylation by K46E and K46Q mutation affected mitochondrial-related ferroptosis and myocardial injury.The molecular dynamic simulation and circular dichroism further demonstrated that VDAC2 malonylation altered the N-terminus structure of the VDAC2 channel, causing mitochondrial dysfunction, increasing mitochondrial ROS levels, and leading to ferroptosis.Malonyl-CoA was identified as the primary inducer of VDAC2 malonylation.Furthermore, the inhibition of malonyl-CoA using ND-630 or ACC2 knock-down significantly reduced the malonylation of VDAC2, decreased the occurrence of ferroptosis in cardiomyocytes, and alleviated SIMD.The study also found that the inhibition of VDAC2 malonylation by synthesizing mitochondria targeting nano material TPP-AAV could further alleviate ferroptosis and myocardial dysfunction following sepsis.In summary, our findings indicated that VDAC2 malonylation plays a crucial role in SIMD and that targeting VDAC2 malonylation could be a potential treatment strategy for SIMD.

High potency and safe therapies are still required for ischemic stroke, which is a leading cause of global death and disability. Herein, a reactive oxygen species (ROS)-responsive, transformable, and triple-targeting dl-3-n-butylphthalide (NBP) nanotherapy was developed for ischemic stroke. To this end, a ROS-responsive nanovehicle (OCN) was first constructed using a cyclodextrin-derived material, which showed considerably enhanced cellular uptake in brain endothelial cells due to notably reduced particle size, morphological transformation, and surface chemistry switching upon triggering via pathological signals. Compared to a nonresponsive nanovehicle, this ROS-responsive and transformable nanoplatform OCN exhibited a significantly higher brain accumulation in a mouse model of ischemic stroke, thereby affording notably potentiated therapeutic effects for the nanotherapy derived from NBP-containing OCN. For OCN decorated with a stroke-homing peptide (SHp), we found significantly increased transferrin receptor-mediated endocytosis, in addition to the previously recognized targeting capability to activated neurons. Consistently, the engineered transformable and triple-targeting nanoplatform, i.e., SHp-decorated OCN (SON), displayed a more efficient distribution in the injured brain in mice with ischemic stroke, showing considerable localization in endothelial cells and neurons. Furthermore, the finally formulated ROS-responsive transformable and triple-targeting nanotherapy (NBP-loaded SON) demonstrated highly potent neuroprotective activity in mice, which outperformed the SHp-deficient nanotherapy at a 5-fold higher dose. Mechanistically, our bioresponsive, transformable, and triple-targeting nanotherapy attenuated the ischemia/reperfusion-induced endothelial permeability and improved dendritic remodeling and synaptic plasticity of neurons in the injured brain tissue, thereby promoting much better functional recovery, which were achieved by efficiently enhancing NBP delivery to the ischemic brain tissue, targeting injured endothelial cells and activated neurons/microglial cells, and normalizing the pathological microenvironment. Moreover, preliminary studies indicated that the ROS-responsive NBP nanotherapy displayed a good safety profile. Consequently, the developed triple-targeting NBP nanotherapy with desirable targeting efficiency, spatiotemporally controlled drug release performance, and high translational potential holds great promise for precision therapy of ischemic stroke and other brain diseases.

Objective To investigate the effect and mechanism of propofol on myocardial systolic dysfunction in sepsis. Methods Cecal ligation and puncture (CLP) was used to induce a septic rat model. Twenty-four adult SD rats were randomly divided into sham group, sepsis group (the samples were taken 12 h after CLP modeling) and propofol group (10 mg/kg propofol was injected intraperitoneally in 0 and 12 h after CLP modeling, and the samples were taken 3 h after the second injection of propofol). Sarcomere length and intracellular calcium fluorescence intensity of myocardial cells were measured by cell microtensiometer. Further, acute isolated cardiomyocytes from the propofol group were incubated with inositol 1, 4, 5-triphosphate receptor (IP3R) inhibitor 2-aminoethyl diphenylborinate (2-APB), sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor 2, 5-di-t-butyl-1, 4-benzohydroquinone (BHQ), ryanodine receptor (RyRs) inhibitor azumolene, and large conductance calcium-activated potassium channel (BKCa) inhibitor paxiline, respectively. Then sarcomere length and intracellular calcium fluorescence intensity of myocardial cells were measured again. Results Compared with the sham group, the contractile function and calcium transient amplitude of myocardial cells were significantly decreased in the sepsis group, while propofol treatment obviously restored the contractile function and calcium release ability of myocardial cells in sepsis, with a maximum contractile amplitude restoration of 27.6% (P < 0.05) and a maximum calcium transient amplitude restoration of 41.2% (P < 0.05). However, 2-APB and BHQ notably suppressed the improvement of contractile function of cardiomyocytes induced by propofol, with an inhibitory rate of 62.61% (P < 0.05) and 42.15% (P < 0.05), respectively. However, azumolene had no significant effect on contractile function. Further studies showed that azumolene, 2-APB and BHQ had inhibitory effects on calcium transients with different extent. Among the 3 inhibitors, azumolene showed the mildest inhibitory effect, with a rate of 46.94% (P < 0.05), and the rate was 65.28% (P < 0.05) and 65.33% (P < 0.05), respectively for 2-APB and BHQ. Paxiline had no statistical effect on propofol improving myocardial contractile function and calcium transients. Conclusion Propofol improves the contractile function of myocardial cells in sepsis, which may be related to the regulation of calcium concentration through IP3R and SERCA.

Asthma is a serious global public health concern. Airway neutrophilic inflammation is closely related to severe asthma, for which effective and safe therapies remain to be developed. Here we report nanotherapies capable of simultaneously regulating multiple target cells relevant to the pathogenesis of neutrophilic asthma. A nanotherapy LaCD NP based on a cyclic oligosaccharide-derived bioactive material was engineered. LaCD NP effectively accumulated in the injured lungs of asthmatic mice and mainly distributed in neutrophils, macrophages, and airway epithelial cells after intravenous or inhalation delivery, thereby ameliorating asthmatic symptoms and attenuating pulmonary neutrophilic inflammation as well as reducing airway hyperresponsiveness, remodeling, and mucus production. Surface engineering via neutrophil cell membrane further enhanced targeting and therapeutic effects of LaCD NP. Mechanistically, LaCD NP can inhibit the recruitment and activation of neutrophils, especially reducing the neutrophil extracellular traps formation and NLRP3 inflammasome activation in neutrophils. Also, LaCD NP can suppress macrophage-mediated pro-inflammatory responses and prevent airway epithelial cell death and smooth muscle cell proliferation, by mitigating neutrophilic inflammation and its direct effects on relevant cells. Importantly, LaCD NP showed good safety performance. Consequently, LaCD-derived multi-bioactive nanotherapies are promising for effective treatment of neutrophilic asthma and other neutrophil-associated diseases.

The outbreak of Fusarium head blight (FHB) poses a serious threat to wheat production as it leads to both significant yield losses and accumulation of several mycotoxins including deoxynivalenol (DON) in the grains, which are harmful to human and livestock. To date, hundreds of FHB-resistance-related quantitative trait loci (QTLs) have been reported, but only a few of them have been cloned and used for breeding. Small interfering RNAs (siRNA) have been reported in plants to mediate host defense against pathogens, but they have rarely been reported in wheat-FHB interaction. In order to identify the key siRNAs that can potentially be used in the improvement of resistance to FHB, siRNAs from the spikes of an FHB-resistant variety Sumai 3 and an FHB-susceptible variety of Chinese Spring (CS) were sequenced after F. graminearum infection and mock inoculation, respectively. The expression patterns of the siRNAs of interest were analyzed. A total of 4019 siRNAs of high-confidence were identified, with 131 being CS-specific, 309 Sumai 3-specific and 3071 being common in both varieties. More than 87% of these siRNAs were 24 nt in length. An overall down-regulation trend was found for siRNAs in the spikes of both varieties after being infected with F. graminearum. The expression patterns for Triticum aestivum Dicer-like 3 (TaDCL3) that synthesizes 24 nt siRNAs were validated by qRT-PCR, which were positively correlated with those of the siRNAs. A total of 85% of the differentially expressed genes putatively targeted by the siRNAs were significantly up-regulated after infection, showing a negative correlation with the overall down-regulated expression of siRNAs. Interestingly, the majority of the up-regulated genes are annotated as disease resistance. These results suggested that the inhibition of siRNA by F. graminearum up-regulated the disease resistance genes, which were putatively suppressed by siRNAs through RNA-directed DNA methylation (RdDM). Consequently, the resistant capability to F. graminearum infection was enhanced. This study provides novel clues for investigating the function of siRNA in wheat-F. graminearum interaction.