Targeted Modulation of Redox and Immune Homeostasis in Acute Lung Injury Using a Thioether-Functionalized Dendrimer.

Acute lung injury (ALI) is the pathophysiological precursor of acute respiratory distress syndrome. It is characterized by increased oxidative stress and exaggerated inflammatory response that disrupts redox reactions and immune homeostasis in the lungs, thereby posing significant clinical challenges. In this study, an internally functionalized thioether-enriched dendrimer Sr-G4-PEG is developed, to scavenge both proinflammatory cytokines and reactive oxygen species (ROS) and restore homeostasis during ALI treatment. The dendrimers are synthesized using an efficient and orthogonal thiol-ene "click" chemistry approach that involves incorporating thioether moieties within the dendritic architectures to neutralize the ROS. The ROS scavenging of Sr-G4-PEG manifests in its capacity to sequester proinflammatory cytokines. The synergistic effects of scavenging ROS and sequestering inflammatory cytokines by Sr-G4-PEG contribute to redox remodeling and immune homeostasis, along with the modulation of the NLRP3-pyroptosis pathway. Treatment with Sr-G4-PEG enhances the therapeutic efficacy of ALIs by alleviating alveolar bleeding, reducing inflammatory cell infiltration, and suppressing the release of inflammatory cytokines. These results suggest that Sr-G4-PEG is a potent nanotechnological candidate for remodeling redox and immune homeostasis in the treatment of ALIs, demonstrating the great potential of dendrimer-based nanomedicine for the treatment of respiratory pathologies.

Melatonin regulates circadian clock proteins expression in allergic airway inflammation.

Asthma demonstrates a strong circadian rhythm with disrupted molecular clock. Melatonin which can directly regulate circadian rhythm has been reported to alleviate asthma, but whether this effect is related to its regulation on circadian clock has not yet been known. Here, female C57BL/6 mice were challenged with ovalbumin (OVA) to establish allergic airway inflammation, and were treated with melatonin or Luzindole to investigate whether the expressions of circadian clock proteins were changed in response to OVA and were affected by exogenous/endogenous melatonin. Airway inflammation, mucus secretion, protein expressions of circadian proteins (Bmal1, Per1, Clock, Timeless, Cry1 and Cry2), melatonin biosynthetase (ASMT, AANAT) and melatonin receptor (Mel-1A/B-R) were analyzed accordingly. The results showed that in the successfully established allergic airway inflammation model, inflammatory cells infiltration, expressions of circadian clock proteins in the lung tissues of OVA-challenged mice were all notably up-regulated as compared to that of the vehicle mice. Meanwhile, the protein expression of ASMT and the level of melatonin in the lung tissues were reduced in allergic mice, while the expression of melatonin receptor Mel-1A/B-R was markedly increased. After addition of exogenous melatonin, the OVA-induced airway inflammation was pronouncedly ameliorated, while simultaneously the OVA-induced expressions of Per1 and Clock were further increased. However, a melatonin receptor antagonist Luzindole further augmented the OVA-induced airway inflammation, accompanied with remarkably decreased expressions of Per1, Bmal1, Cry1 and Cry2 but notably increased expression of Timeless. Collectively, our results demonstrated that the expression of circadian clock proteins was increased in the lungs during allergic airway inflammation, and Per1 was a clock protein that can be regulated by both exogenous and endogenous melatonin, suggesting Per1 may be an important potential circadian clock target for melatonin as a negative regulatory factor against Th2-type airway inflammation.

Dexamethasone protects against asthma via regulating Hif-1α-glycolysis-lactate axis and protein lactylation.

PURPOSE: Asthma can not be eradicated till now and its control primarily relies on the application of corticosteroids. Recently, glycolytic reprogramming has been reportedly contributed to asthma, this study aimed to reveal whether the effect of corticosteroids on asthma control is related to their regulation of glycolysis and glycolysis-dependent protein lactylation. METHODS: Ovalbumin (OVA) aeroallergen was used to challenge mice and stimulate human macrophage cell line THP-1 following dexamethasone (DEX) treatment. Airway hyperresponsiveness, airway inflammation, the expressions of key glycolytic enzymes and pyroptosis markers, the level of lactic acid, real-time glycolysis and oxidative phosphorylation (OXPHOS), and protein lactylation were analyzed. RESULTS: DEX significantly attenuated OVA-induced eosinophilic airway inflammation, including airway hyperresponsiveness, leukocyte infiltration, goblet cell hyperplasia, Th2 cytokines production and pyroptosis markers expression. Meanwhile, OVA-induced Hif-1α-glycolysis axis was substantially downregulated by DEX, which resulted in low level of lactic acid. Besides, key glycolytic enzymes in the lungs of asthmatic mice were notably co-localized with F4/80-positive macrophages, indicating metabolic shift to glycolysis in lung macrophages during asthma. This was confirmed in OVA-stimulated THP-1 cells that DEX treatment resulted in reductions in pyroptosis, glycolysis and lactic acid level. Finally, protein lactylation was found significantly increased in the lungs of asthmatic mice and OVA-stimulated THP-1 cells, which were both inhibited by DEX. CONCLUSION: Our present study revealed that the effect of DEX on asthma control was associated with its suppressing of Hif-1α-glycolysis-lactateaxis and subsequent protein lactylation, which may open new avenues for the therapy of eosinophilic asthma.

The characteristics of brain network in patient with post-stroke depression under cognitive task condition.

Objectives: Post-stroke depression (PSD) may be associated with the altered brain network property. This study aimed at exploring the brain network characteristics of PSD under the classic cognitive task, i.e., the oddball task, in order to promote our understanding of the pathogenesis and the diagnosis of PSD. Methods: Nineteen stroke survivors with PSD and 18 stroke survivors with no PSD (non-PSD) were recruited. The functional near-infrared spectroscopy (fNIRS) covering the dorsolateral prefrontal cortex was recorded during the oddball task state and the resting state. The brain network characteristics were extracted using the graph theory and compared between the PSD and the non-PSD subjects. In addition, the classification performance between the PSD and non-PSD subjects was evaluated using features in the resting and the task state, respectively. Results: Compared with the resting state, more brain network characteristics in the task state showed significant differences between the PSD and non-PSD groups, resulting in better classification performance. In the task state, the assortativity, clustering coefficient, characteristic path length, and local efficiency of the PSD subjects was larger compared with the non-PSD subjects while the global efficiency of the PSD subjects was smaller than that of the non-PSD subjects. Conclusion: The altered brain network properties associated with PSD in the cognitive task state were more distinct compared with the resting state, and the ability of the brain network to resist attack and transmit information was reduced in PSD patients in the task state. Significance: This study demonstrated the feasibility and superiority of investigating brain network properties in the task state for the exploration of the pathogenesis and new diagnosis methods for PSD.

TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation.

As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2-/- mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1α stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2-/- mice, indicating TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2-/- mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1α expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2-/- AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2-/- mice abolished while transfer of TLR2-/- resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1α-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1α-glycolysis axis in resident AMs may be a novel therapeutic target for AAI.

Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation.

Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1-/- mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs' immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.

Task-State Cortical Motor Network Characteristics by Functional Near-Infrared Spectroscopy in Subacute Stroke Show Hemispheric Dominance.

Background: There was a reorganization of the brain network after stroke. Some studies have compared the characteristics of activation or functional connectivity (FC) of cortical and subcortical regions between the dominant and non-dominant hemisphere stroke. Objectives: To analyze hemispheric dominance differences in task-state motor network properties in subacute stroke by functional near-infrared spectroscopy (fNIRS). Materials and Methods: Patients with first ischemic stroke in the basal ganglia within 1-3 months after onset and age- and sex-matched right-handed healthy subjects (HS) were enrolled. fNIRS with 29 channels was used to detect the oxyhemoglobin concentration changes when performing the hand grasping task. Activation patterns of motor cortex and two macroscale and two mesoscale brain network indicators based on graph theory were compared between dominant and non-dominant hemisphere stroke. Results: We enrolled 17 subjects in each of left hemisphere stroke (LHS), right hemisphere stroke (RHS), and HS groups. Both patient groups showed bilateral activation. The average weighted clustering coefficient and global efficiency of patients were lower than those of healthy people, and the inter-density was higher than that of the HS group, but the significance was different between LHS and RHS groups. The intra-density changes in the RHS group were opposite to those in the LHS group. The correlation between mesoscale indicators and motor function differed between dominant and non-dominant hemisphere stroke. Conclusion: The changes in macroscale cortical network indicators were similar between the two patient groups, while those of the mesoscale indicators were different. The mesoscale brain network characteristics were affected by the severity of dysfunction to varying degrees in the LHS and RHS patients.

Effect of BCI-Controlled Pedaling Training System With Multiple Modalities of Feedback on Motor and Cognitive Function Rehabilitation of Early Subacute Stroke Patients.

Brain-computer interfaces (BCIs) are currently integrated into traditional rehabilitation interventions after stroke. Although BCIs bring many benefits to the rehabilitation process, their effects are limited since many patients cannot concentrate during training. Despite this outcome post-stroke motor-attention dual-task training using BCIs has remained mostly unexplored. This study was a randomized placebo-controlled blinded-endpoint clinical trial to investigate the effects of a BCI-controlled pedaling training system (BCI-PT) on the motor and cognitive function of stroke patients during rehabilitation. A total of 30 early subacute ischemic stroke patients with hemiplegia and cognitive impairment were randomly assigned to the BCI-PT or traditional pedaling training. We used single-channel Fp1 to collect electroencephalography data and analyze the attention index. The BCI-PT system timely provided visual, auditory, and somatosensory feedback to enhance the patient's participation to pedaling based on the real-time attention index. After 24 training sessions, the attention index of the experimental group was significantly higher than that of the control group. The lower limbs motor function (FMA-L) increased by an average of 4.5 points in the BCI-PT group and 2.1 points in the control group (P = 0.022) after treatments. The difference was still significant after adjusting for the baseline indicators ( ß = 2.41 , 95%CI: 0.48-4.34, P = 0.024). We found that BCI-PT significantly improved the patient's lower limb motor function by increasing the patient's participation. (clinicaltrials.gov: NCT04612426).

[Spatial structural characteristics of natural Populus davidiana - Betula platyphylla secondary forest].

This paper analyzed the spatial structural characteristics of natural Populus davidiana - Betula platyphylla secondary forest in a 4 hm2 plot of Mulan Paddock, based on the diameter distribution and the spatial structure parameters mingling degree, neighborhood comparison, and angle index. In the forest, the diameter distribution of the stands presented as an inverse 'J' curve, the average mingling degree was 0.4, with the individuals at weak and zero mingling degree reached 51.6%, and the average mingling degree of P. davidiana and B. platyphylla was 0.25 and 0.39, respectively. The neighborhood comparison based on the diameter at breast height (DBH) and tree height was almost the same, suggesting that the P. davidiana and B. platyphylla were in the transition state from subdominant to middle. The horizontal distribution pattern had a close relation to the minimum measured DBH, being clustered when the DBH was > or = 1 cm and < 6 cm, and random when the DBH was > or = 6 cm.