A novel strategy for spinal cord reconstruction via vascularized allogeneic spinal cord transplantation combine spinal cord fusion.

AIMS: Spinal cord injuries (SCI) pose persistent challenges in clinical practice due to the secondary injury. Drawing from our experience in spinal cord fusion (SCF), we propose vascularized allogeneic spinal cord transplantation (vASCT) as a novel approach for SCI, much like organ transplantation has revolutionized organ failure treatment and vascularized composite-tissue allotransplantation has addressed limb defects. MATERIALS AND METHODS: In this study, 24 dogs were paired and underwent vASCT, with donor spinal cord grafts and polyethylene glycol (PEG) application for SCF. The experimental group (n = 8) received tacrolimus and methylprednisolone, while the control group (n = 4) received only methylprednisolone. Safety and efficacy of vASCT were evaluated through electrophysiology, imaging, and 6-month follow-up. RESULTS: The experimental group showed substantial recovery in hind limb motor function. Imaging revealed robust survival of spinal cord grafts and restoration of spinal cord continuity. In contrast, the control group maintained hind limb paralysis, with imaging confirming spinal cord graft necrosis and extensive defects. Electrophysiologically, the experimental group exhibited restored motor evoked potential signal conduction postoperatively, unlike the control group. Notably, PEG application during vASCT led to signal conduction recovery in intraoperative spinal cord evoked potential examinations for all dogs. CONCLUSION: In the vASCT surgical model, the combination of PEG with tacrolimus has demonstrated the ability to reconstruct spinal cord continuity and restore hind limb motor function in beagles. Notably, a low dose of tacrolimus has also exhibited an excellent anti-immune rejection effect. These findings highlight vASCT's potential promise as a therapeutic strategy for addressing irreversible SCI.

Dietary silymarin improves performance by altering hepatic lipid metabolism and cecal microbiota function and its metabolites in late laying hens.

BACKGROUND: Liver lipid dysregulation is one of the major factors in the decline of production performance in late-stage laying hens. Silymarin (SIL), a natural flavonolignan extracted from milk thistle, is known for its hepatoprotective and lipid-lowering properties in humans. This study evaluates whether SIL can provide similar benefits to late-stage laying hens. A total of 480 68-week-old Lohmann Pink laying hens were randomly assigned into 5 groups, each group consisting of 6 replicates with 16 hens each. The birds received a basal diet either without silymarin (control) or supplemented with silymarin at concentrations of 250, 500, 750, or 1,000 mg/kg (SIL250, SIL500, SIL750, SIL1000) over a 12-week period. RESULTS: The CON group exhibited a significant decline in laying rates from weeks 9 to 12 compared to the initial 4 weeks (P = 0.042), while SIL supplementation maintained consistent laying rates throughout the study (P > 0.05). Notably, the SIL500 and SIL750 groups showed higher average egg weight than the CON group during weeks 5 to 8 (P = 0.049). The SIL750 group had a significantly higher average daily feed intake across the study period (P < 0.05), and the SIL500 group saw a marked decrease in the feed-to-egg ratio from weeks 5 to 8 (P = 0.003). Furthermore, the SIL500 group demonstrated significant reductions in serum ALT and AST levels (P < 0.05) and a significant decrease in serum triglycerides and total cholesterol at week 12 with increasing doses of SIL (P < 0.05). SIL also positively influenced liver enzyme expression (FASN, ACC, Apo-VLDL II, FXR, and CYP7A1; P < 0.05) and altered the cecal microbiota composition, enhancing species linked to secondary bile acid synthesis. Targeted metabolomics identified 9 metabolites predominantly involved in thiamin metabolism that were significantly different in the SIL groups (P < 0.05). CONCLUSIONS: Our study demonstrated that dietary SIL supplementation could ameliorate egg production rate in late stage laying hens, mechanistically, this effect was via improving hepatic lipid metabolism and cecal microbiota function to achieve. Revealed the potentially of SIL as a feed supplementation to regulate hepatic lipid metabolism dysregulation. Overall, dietary 500 mg/kg SIL had the best effects.

Clara cell 10 (CC10) protein attenuates allergic airway inflammation by modulating lung dendritic cell functions.

Allergic asthma is a complex inflammatory disorder predominantly orchestrated by T helper 2 (Th2) lymphocytes. The anti-inflammatory protein Clara Cell 10-kDa (CC10), also known as secretoglobin family 1A member 1 (SCGB1A1), shows promise in modulating respiratory diseases. However, its precise role in asthma remains unclear. This study examines the potential of CC10 to suppress allergic asthma inflammation, specifically assessing its regulatory effects on Th2 cell responses and dendritic cells (DCs). Lower CC10 levels in asthma were observed and correlated with increased IgE and lymphocytes. Cc10-/- mice exhibited exacerbated allergic airway inflammation marked by increased inflammatory cell infiltration, Th2 cytokines, serum antigen-specific IgE levels, and airway hyperresponsiveness (AHR) in house dust mite (HDM)-induced models. Conversely, recombinant CC10 significantly attenuated these inflammatory responses. Intriguingly, CC10 did not directly inhibit Th cell activation but significantly downregulated the population of CD11b+CD103- DCs subsets in lungs of asthmatic mice and modulated the immune activation functions of DCs through NF-κB signaling pathway. The mixed lymphocyte response assay revealed that DCs mediated the suppressive effect of CC10 on Th2 cell responses. Collectively, CC10 profoundly mitigates Th2-type allergic inflammation in asthma by modulating lung DC phenotype and functions, highlighting its therapeutic potential for inflammatory airway conditions and other related immunological disorders.

Developing preclinical dog models for reconstructive severed spinal cord continuity via spinal cord fusion technique.

Background: Spinal cord injury (SCI) is a severe impairment of the central nervous system, leading to motor, sensory, and autonomic dysfunction. The present study investigates the efficacy of the polyethylene glycol (PEG)-mediated spinal cord fusion (SCF) techniques, demonstrating efficacious in various animal models with complete spinal cord transection at the T10 level. This research focuses on a comparative analysis of three SCF treatment models in beagles: spinal cord transection (SCT), vascular pedicle hemisected spinal cord transplantation (vSCT), and vascularized allograft spinal cord transplantation (vASCT) surgical model. Methods: Seven female beagles were included in the SCT surgical model, while four female dogs were enrolled in the vSCT surgical model. Additionally, twelve female dogs underwent vASCT in a paired donor-recipient setup. Three surgical model were evaluated and compared through electrophysiology, imaging and behavioral recovery. Results: The results showed a progressive recovery in the SCT, vSCT and vASCT surgical models, with no statistically significant differences observed in cBBB scores at both 2-month and 6-month post-operation (both P>0.05). Neuroimaging analysis across the SCT, vSCT and vASCT surgical models revealed spinal cord graft survival and fiber regrowth across transection sites at 6 months postoperatively. Also, positive MEP waveforms were recorded in all three surgical models at 6-month post-surgery. Conclusion: The study underscores the clinical relevance of PEG-mediated SCF techniques in promoting nerve fusion, repair, and motor functional recovery in SCI. SCT, vSCT, and vASCT, tailored to specific clinical characteristics, demonstrated similar effective therapeutic outcomes.

MiR-30a-5p isoform -1|1 promotes the progression of gastric cancer by inhibiting TMEM66 and reducing intratumoral cytotoxic T cells.

Gastric cancer is histologically classified into the intestinal subtype, which forms tubular structures, and the aggressive diffuse subtype, characterized by rapid invasion and poor prognosis. The variety and quantity of miRNA isoforms between different histological subtypes of gastric cancer were unknown. Through systematic filtering, we found that more diverse miR-30a-5p isoforms was present in the diffuse subtype of gastric cancer, and was associated with patients' worse survival independent of tumor stage based on the TCGA miRNA-seq data. Among all nine isoforms of miR-30a-5p, miR-30a-5p -1|1 was more abundant than the archetype of miR-30a-5p. Higher expression of miR-30a-5p -1|1 was observed in patients with advanced tumor stage and poor survival. Furthermore, miR-30a-5p -1|1 could promote the metastasis of gastric cancer cells both in vitro and in vivo by down-regulating TMEM66. In clinical samples, decreased expression of TMEM66 was characteristic of gastric cancer, and the low level of TMEM66 correlated with deceased CD8 positive cells in the tumor microenvironment probably due to decreased cytokines production. In conclusion, the variety of miR-30a-5p isoforms correlates with worse survival in gastric cancer patients. Moreover, miR-30a-5p -1|1 could promote gastric cancer metastasis by inhibiting TMEM66 and the infiltration of intratumoral CD8 positive cells.

Paraquat disrupts KIF5A-mediated axonal mitochondrial transport in midbrain neurons and its antagonism by melatonin.

Paraquat (PQ) is a broad-spectrum herbicide used worldwide and is a hazardous chemical to human health. Cumulative evidence strengthens the association between PQ exposure and the development of Parkinson's disease (PD). However, the underlying mechanism and effective interventions against PQ-induced neurotoxicity remain unclear. In this study, C57BL/6 J mice were treated with PQ (i.p., 10 mg/kg, twice a week) and melatonin (i.g., 20 mg/kg, twice a week) for 8 weeks. Results showed that PQ-induced motor deficits and midbrain dopaminergic neuronal damage in C57BL/6 J mice were protected by melatonin pretreatment. In isolated primary midbrain neurons and SK-N-SH cells, reduction of cell viability, elevation of total ROS levels, axonal mitochondrial transport defects and mitochondrial dysfunction caused by PQ were attenuated by melatonin. After screening of expression of main motors driving axonal mitochondrial transport, data showed that PQ-decreased KIF5A expression in mice midbrain and in SK-N-SH cell was antagonized by melatonin. Using the in vitro KIF5A-overexpression model, it was found that KIF5A overexpression inhibited PQ-caused neurotoxicity and mitochondrial dysfunction in SK-N-SH cells. In addition, application of MTNR1B (MT2) receptor antagonist, 4-P-PDOT, significantly counteracted the protection of melatonin against PQ-induced neurotoxicity. Further, Kif5a-knockdown diminished melatonin-induced alleviation of motor deficits and neuronal damage against PQ in C57BL/6 J mice. The present study establishes a causal link between environmental neurotoxicants exposure and PD etiology and provides effective interventive targets in the pathogenesis of PD.

Effects of increasing sensitizing doses of ovalbumin on airway hyperresponsiveness in asthmatic mice.

BACKGROUND: The dosage of ovalbumin (OVA) during the sensitization stage is considered a crucial factor in the development of airway hyperresponsiveness (AHR). However, the inconsistent dosages of sensitizing OVA used in current studies and the lack of research on their impact on AHR are notable limitations. METHODS: We examined the impact of increasing sensitizing doses of OVA in a murine asthma model, which entailed initial sensitization with OVA followed by repeated exposure to OVA aerosols. BALB/c mice were primed with doses of OVA (0, 10, 20, 50, and 100 µg) plus 1 mg Alum on Days 0 and 7, and were challenged with OVA aerosols (10 mg/mL for 30 min) between Days 14 and 17. Antigen-induced AHR to methacholine (MCh), as well as histological changes, eosinophilic infiltration, and epithelial injury were assessed. RESULTS: The result indicated that there are striking OVA dose-related differences in antigen-induced AHR to MCh. The most intense antigen-induced AHR to MCh was observed with sensitization at 50 µg, while weaker responses were seen at 10, 20, and 100 µg. Meanwhile, there was a significant increase in eosinophil count with sensitization at 50 µg. The changes of AHR were correlated with total cells count, lymphocytes count, eosinophils count, and basophils count in bronchoalveolar lavage fluid; however, it did not correlate with histological changes such as cellular infiltration into bronchovascular bundles and goblet cell hyperplasia of the bronchial epithelium. CONCLUSION: Overall, this study demonstrated that sensitization with 50 µg of OVA resulted in the most significant AHR compared to other dosages. These findings may offer valuable insights for future research on mouse asthma modeling protocols.

Recycling and high-value utilization of polyethylene terephthalate wastes: A review.

Polyethelene terephthalate (PET) is a well-known thermoplastic, and recycling PET waste is important for the natural environment and human health. This study provides a comprehensive overview of the recycling and reuse of PET waste through energy recovery and physical, chemical, and biological recycling. This article summarizes the recycling methods and the high-value products derived from PET waste, specifically detailing the research progress on regenerated PET prepared by the mechanical recycling of fiber/yarn, fabric, and composite materials, and introduces the application of PET nanofibers recycled by physical dissolution and electrospinning in fields such as filtration, adsorption, electronics, and antibacterial materials. This article explains the energy recovery of PET through thermal decomposition and comprehensively discusses various chemical recycling methods, including the reaction mechanisms, catalysts, conversion efficiencies, and reaction products, with a brief introduction to PET biodegradation using hydrolytic enzymes provided. The analysis and comparison of various recycling methods indicated that the mechanical recycling method yielded PET products with a wide range of applications in composite materials. Electrospinning is a highly promising recycling strategy for fabricating recycled PET nanofibers. Compared to other methods, physical recycling has advantages such as low cost, low energy consumption, high value, simple processing, and environmental friendliness, making it the preferred choice for the recycling and high-value utilization of waste PET.

Chronic cadmium exposure induces Parkinson-like syndrome by eliciting sphingolipid disturbance and neuroinflammation in the midbrain of C57BL/6J mice.

Cadmium (Cd) is known as a widespread environmental neurotoxic pollutant. Cd exposure is recently recognized as an etiological factor of Parkinson's disease (PD) in humans. However, the mechanism underlying Cd neurotoxicity in relation to Parkinsonism pathogenesis is unclear. In our present study, C57BL/6 J mice were exposed to 100 mg/L CdCl2 in drinking water for 8 weeks. It was found Cd exposure caused motor deficits, decreased DA neurons and induced neuropathological changes in the midbrain. Non-targeted lipidomic analysis uncovered that Cd exposure altered lipid profile, increased the content of proinflammatory sphingolipid ceramides (Cer), sphingomyelin (SM) and ganglioside (GM3) in the midbrain. In consistency with increased proinflammatory lipids, the mRNA levels of genes encoding sphingolipids biosynthesis in the midbrain were dysregulated by Cd exposure. Neuroinflammation in the midbrain was evinced by the up-regulation of proinflammatory cytokines at mRNA and protein levels. Blood Cd contents and lipid metabolites in Parkinsonism patients by ICP-MS and LC-MS/MS analyses demonstrated that elevated blood Cd concentration and proinflammatory lipid metabolites were positively associated with the score of Unified Parkinson's Disease Rating Scale (UPDRS). 3 ceramide metabolites in the blood showed good specificity as the candidate biomarkers to predict and monitor Parkinsonism and Cd neurotoxicity (AUC>0.7, p < 0.01). In summary, our present study uncovered that perturbed sphingomyelin lipid metabolism is related to the Parkinsonism pathogenesis and Cd neurotoxicity, partially compensated for the deficiency in particular metabolic biomarkers for Parkinsonism in relation to Cd exposure, and emphasized the necessity of reducing Cd exposure at population level.

Cadmium exposure disturbs myocardial lipid signature and induces inflammation in C57BL/6J mice.

Cadmium is a highly ubiquitous environmental pollutant that poses a serious threat to human health. In this study, we assessed the cardiotoxicity of Cd exposure and explored the possible mechanisms by which Cd exerts its toxic effects. The results demonstrated that exposure to Cd via drinking water containing CdCl2 10 mg/dL for eight consecutive weeks induced cardiac injury in C57BL/6J mice. The histopathological changes of myocardial hemolysis, widening of myocardial space, and fracture of myocardial fiber were observed. Meanwhile, elevated levels of cardiac enzyme markers and up-regulation of pro-apoptotic genes also indicated cardiac injury after Cd exposure. Non-targeted lipidomic analysis demonstrated that Cd exposure altered cardiac lipid metabolism, resulted in an increase in pro-inflammatory lipids, and changed lipid distribution abundance. In addition, Cd exposure affected the secretion of inflammatory cytokines by activating the NF-κB signaling pathway, leading to cardiac inflammation in mice. Taken together, results of our present study expand our understanding of Cd cardiotoxicity at the lipidomic level and provide new experimental evidence for uncovering the association of Cd exposure with cardiovascular diseases.

Cadmium exposure impairs skeletal muscle function by altering lipid signature and inducing inflammation in C57BL/6J mice.

Cadmium (Cd) is a well-known environmental pollutant with high toxicity. Despite a variety of studies have demonstrated that Cd exposure induces multiple organ damages in humans, there is still a lack of knowledge of Cd induced skeletal muscle impairment. Exercise is a non-invasive, effective intervention to improve human health and combat diseases. In this study, we aimed to evaluate the toxic effects of Cd exposure on skeletal muscle function and explore the possibility of exercise for attenuating skeletal muscle toxicity of chronic Cd exposure. C57BL/6J mice were exposed to Cd via drinking water containing CdCl2 10 mg/dL for 8 weeks while a moderate exercise was daily induced by a motorized treadmill to mice. It was found that Cd exposure significantly reduced the ratio of gastrocnemius and body weight, decreased mouse exercise capacity, weakened muscle strength, promoted lipid accumulation and up-regulated pro-apoptotic genes in the skeletal muscle. Non-targeted lipidomics analysis indicated that Cd exposure disturbed lipid metabolism, altered lipid signatures and elevated pro-inflammatory lipid species in the skeletal muscle. Moreover, Cd exposure evoked an intense inflammatory response in the skeletal muscle by up-regulating pro-inflammatory cytokine production such as Eotaxin (CCL11), TNF-α, IL-1ß, IL-6, RANTES (CCL5) and so on. Notably, treadmill exercise effectively protected against Cd induced skeletal muscle impairment indicated by the effects of inhibiting lipid metabolism disturbance, suppressing pro-inflammatory cytokine production and preserving skeletal muscle function. These results demonstrated that environment relevant Cd exposure impairs skeletal muscle function and exercise effectively antagonizes the Cd toxicity in the skeletal muscle and preserves skeletal muscle function. This study provided the novel evidence for unraveling Cd toxicity on the skeletal muscle function and highlighted the possibility of considering exercise as a countermeasure for Cd induced skeletal muscle impairment at population level.

Paraquat exposure induces Parkinsonism by altering lipid profile and evoking neuroinflammation in the midbrain.

Paraquat (PQ) is the most widely used herbicide in the world and a well-known potent neurotoxin for humans. PQ exposure has been linked to increase the risk of Parkinson's disease (PD). However, the mechanism underlying its neurotoxic effects in PD pathogenesis is unclear. In our present study, C57BL/6J mice treated with PQ manifested severe motor deficits indicated by the significant reductions in suspension score, latency to fall from rotarod, and grip strength at 8 weeks after PQ exposure. Pathological hallmarks of Parkinsonism in the midbrain such as dopaminergic neuron loss, increased α-synuclein protein, and dysregulated PD-related genes were observed. Non-targeted lipidome analysis demonstrated that PQ exposure alters lipid profile and abundance, increases pro-inflammatory lipids.27 significantly altered subclasses of lipids belonged to 6 different lipid categories. Glycerophospholipids, sphingolipids, and glycerides were the most abundant lipids. Abundance of pro-inflammatory lipids such as Cer, LPC, LPS, and LPI was significantly increased in the midbrain. mRNA expressions of genes regulating ceramide biosynthesis in the midbrain were markedly up-regulated. Moreover, PQ exposure increased serum pro-inflammatory cytokines and provoked neuroinflammation in the midbrain. Pro-inflammatory lipids and cytokines in the midbrain were positively correlated with motor deficits. PQ poisoning in humans significantly also elevated serum pro-inflammatory cytokines and induced an intense systemic inflammation. In summary, we presented initial investigations of PQ induced molecular events related to the PD pathogenesis, capturing aspects of disturbed lipid metabolism, neuroinflammation, impairment of dopaminergic neurons in the midbrain, and an intense systemic inflammation. These neurotoxic effects of PQ exposure may mechanistically contribute to the pathogenesis of PQ induced Parkinsonism. Results of this study also strongly support the hypothesis that ever-increasing prevalence of Parkinson's disease is etiologically linked to the health risk of exposure to neurotoxic environmental pollutants.

Regulation of carbon flux and NADH/NAD+ supply to enhance 2,3-butanediol production in Enterobacter aerogenes.

As a valuable platform chemical, 2,3-Butanediol (2,3-BDO) has a variety of industrial applications, and its microbial production is particularly attractive as an alternative to petroleum-based production. In this study, the regulation of intracellular carbon flux and NADH/NAD+ was used to increase the 2,3-BDO production of Enterobacter aerogenes. The genes encoding lactate dehydrogenase (ldh) and pyruvate formate lyase (pfl) were disrupted using the λ-Red recombination method and CRISPR-Cas9 to reduce the production of several byproducts and the consumption of NADH. Knockout of ldh or pfl increased intracellular NADH/NAD+ by 111 % and 113 %, respectively. Moreover, two important genes in the 2,3-BDO biosynthesis pathway, acetolactate synthase (budB) and acetoin reductase (budC), were overexpressed in E. aerogenes to further amply the metabolic flux toward 2,3-BDO production. And the overexpression of budB or budC increased intracellular NADH/NAD+ by 46 % and 57 %, respectively. In shake-flask cultivation with sucrose as carbon source, the 2,3-BDO titer of the IAM1183-LPBC was 3.55 times that of the wild type. In the 5-L fermenter, the maximal 2,3-BDO production produced by the IAM1183-LPBC was 2.88 times that of the original strain. This work offers new ideas for promoting the biosynthesis of 2,3-BDO for industrial applications.

Cadmium induces ferroptosis mediated inflammation by activating Gpx4/Ager/p65 axis in pancreatic ß-cells.

Cadmium (Cd) is a widely distributed endocrine disruptor and has been reported to be closely correlated to the pathogenesis of diabetes. Since pancreatic ß-cells loss and dysfunction are central to pathogenesis of diabetes, studying Cd toxicity on pancreatic ß-cells and its molecular mechanism is an important scientific issue. However, less attention has been payed to study how Cd induces pancreatic ß-cells death and dysfunction in recent years. Thus, our study aims to explore the toxic mechanism of Cd treatment on pancreatic ß-cells using both cellular and animal models. Firstly, it was confirmed that Cd induced decreased cell viability and insulin secretion in a dose-and time-dependent manner in MIN6 cells. To explore the underlying mechanism, transcriptomic analysis was employed to screen the differentially expressed genes and disturbed metabolic pathways. Go and KEGG analysis showed that Cd exposure triggered ferroptosis process in MIN6 cells. We further validated that Cd led to GSH depletion, Gpx4 reduction, lipid peroxidation, mitochondrial membrane potential loss and ultrastructural damage at mitochondrial level. Since immune system process was also perturbed based on GO analysis, we found that Cd activated Ager/Pkc/p65 inflammatory process. Moreover, ferroptosis inhibitor Fer-1 could effectively antagonized the activation of Ager-mediated immune process. It was also revealed that Cd induced iron accumulation as well as decreased Gpx4 expression in mice islets. We also uncovered that Cd led to systemic and pancreatic inflammation as early as third week after Cd exposure. Our study emphasizes the importance of ferroptotic cell death on Cd-induced systemic chronic inflammation. A novel target is provided to prevent Cd-induced pancreatic ß-cells dysfunction and improve the chronic inflammatory state for prediabetes prevention.

Difference in calcium ion precipitation between free and immobilized Halovibrio mesolongii HMY2.

Biomineralization has become a research focus in wastewater treatment due to its much lower costs compared to traditional methods. However, the low sodium chloride (NaCl)-tolerance of bacteria limits applications to only water with low NaCl concentrations. Here, calcium ions in hypersaline wastewater (10% NaCl) were precipitated by free and immobilized Halovibrio mesolongii HMY2 bacteria and the differences between them were determined. The results show that calcium ions can be transformed into several types of calcium carbonate with a range of morphologies, abundant organic functional groups (C-H, C-O-C, C=O, etc), protein secondary structures (ß-sheet, α-helix, 310 helix, and ß-turn), P=O and S-H indicated by P2p and S2p, and more negative δ13CPDB (‰) values (-16.8‰ to -18.4‰). The optimal conditions for the immobilized bacteria were determined by doing experiments with six factors and five levels and using response surface method. Under the action of two groups of immobilized bacteria prepared under the optimal conditions, by the 10th day, Ca2+ ion precipitation ratios had increased to 79%-89% and 80%-88% with changes in magnesium ion cencentrations. Magnesium ions can significantly inhibit the calcium ion precipitation, and this inhibitory effect can be decreased under the action of immobilized bacteria. Minerals induced by immobilized bacteria always aggregated together, had higher contents of Mg, P, and S, lower stable carbon isotope values and less well-developed protein secondary structures. This study demonstrates an economic and eco-friendly method for recycling calcium ions in hypersaline wastewater, providing an easy step in the process of desalination.

Electroacupuncture at ST36 (Zusanli) Prevents T-Cell Lymphopenia and Improves Survival in Septic Mice.

Purpose: Sepsis is the main cause of death in intensive care unit. Maladaptive cytokine storm and T-cell lymphopenia are critical prognosis predictors of sepsis. Electroacupuncture (EA) is expected to be an effective intervention to prevent sepsis. This study aims to determine the potential of EA at ST36 (Zusanli) to prevent experimental septic mice. Methods: Mice were randomly assigned into PBS, LPS, or EA+LPS group. EA (0.1 mA, continuous wave, 10 Hz) was performed stimulating the ST36 for 30 min, once a day for 3 days. After the third day, all mice were challenged with PBS or LPS (4 mg/kg) simultaneously. Mice were evaluated for survival, ear temperature, and other clinical symptoms. Lung and small intestine tissue injuries were analyzed by hematoxylin and eosin staining. Bio-Plex cytokine assay was used to analyze the concentration of cytokines. T lymphocytes were analyzed by flow cytometry and Western blot assays. The role of T cells in preventing sepsis by EA was analyzed by using nude mice lacking T lymphocytes. Results: EA at ST36 improved survival, symptom scores, and ear temperature of endotoxemic mice. EA also improved dramatically pulmonary and intestinal injury by over 50% as compared to untreated mice. EA blunted the inflammatory cytokine storm by inducing a lasting inhibition of the production of major inflammatory factors (TNF-α, IL-1ß, IL-5, IL-6, IL-10, IL-17A, eotaxin, IFN-γ, MIP-1ß and KC). Flow cytometry and Western blot analyses showed EA significantly reduced T-lymphocyte apoptosis and pyroptosis. Furthermore, T lymphocytes were critical for the effects of EA at ST36 stimulation blunted serum TNF-α levels in wild-type but not in nude mice. Conclusion: EA halted systemic inflammation and improved survival in endotoxemic mice. These effects are associated with the protective effect of EA on T lymphocytes, and T cells are required in the anti-inflammatory effects of EA in sepsis.

Inhibitory Effect of S100A11 on Airway Smooth Muscle Contraction and Airway Hyperresponsiveness.

OBJECTIVE: S100A11 is a member of the S100 calcium-binding protein family and has intracellular and extracellular regulatory activities. We previously reported that S100A11 was differentially expressed in the respiratory tracts of asthmatic rats as compared with normal controls. Here, we aimed to analyze the potential of S100A11 to regulate both allergen-induced airway hyperresponsiveness (AHR) as well as acetylcholine (ACh)-induced hypercontractility of airway smooth muscle (ASM) and contraction of ASM cells (ASMCs). METHODS: Purified recombinant rat S100A11 protein (rS100A11) was administered to OVA-sensitized and challenged rats and then the AHR of animals was measured. The relaxation effects of rS100A11 on ASM were detected using isolated tracheal rings and primary ASMCs. The expression levels of un-phosphorylated myosin light chain (MLC) and phosphorylated MLC in ASMCs were analyzed using Western blotting. RESULTS: Treatment with rS100A11 attenuated AHR in the rats. ASM contraction assays showed that rS100A11 reduced the contractile responses of isolated tracheal rings and primary ASMCs treated with ACh. In addition, rS100A11 markedly decreased the ACh-induced phosphorylation of the myosin light chain in ASMCs. Moreover, rS100A11 also suppressed the contractile response of tracheal rings in calcium-free buffer medium. CONCLUSION: These results indicate that S100A11 protein can relieve AHR by relaxing ASM independently of extracellular calcium. Our data support the idea that S100A11 is a potential therapeutic target for reducing airway resistance in asthma patients.

SOX2 modulated astrocytic process plasticity is involved in arsenic-induced metabolic disorders.

Metabolic disorders induced by arsenic exposure have attracted great public concern. However, it remains unclear whether hypothalamus-based central regulation mechanisms are involved in this process. Here, we exposed mice to 100 µg/L arsenic in drinking water and established a chronic arsenic exposure model. Our study revealed that chronic arsenic exposure caused metabolic disorders in mice including impaired glucose metabolism and decreased energy expenditure. Arsenic exposure also impaired glucose sensing and the activation of proopiomelanocortin (POMC) neurons in the hypothalamus. In particular, arsenic exposure damaged the plasticity of hypothalamic astrocytic process. Further research revealed that arsenic exposure inhibited the expression of sex-determining region Y-Box 2 (SOX2), which decreased the expression level of insulin receptors (INSRs) and the phosphorylation of AKT. The conditional deletion of astrocytic SOX2 exacerbated arsenic-induced effects on metabolic disorders, the impairment of hypothalamic astrocytic processes, and the inhibition of INSR/AKT signaling. Furthermore, the arsenic-induced impairment of astrocytic processes and inhibitory effects on INSR/AKT signaling were reversed by SOX2 overexpression in primary hypothalamic astrocytes. Together, we demonstrated here that chronic arsenic exposure caused metabolic disorders by impairing SOX2-modulated hypothalamic astrocytic process plasticity in mice. Our study provides evidence of novel central regulatory mechanisms underlying arsenic-induced metabolic disorders and emphasizes the crucial role of SOX2 in regulating the process plasticity of adult astrocytes.

[Research progress of lung natural killer cells and their roles in pulmonary diseases].

Lung natural killer (NK) cells can be classified into tissue-resident NK (trNK) cells and conventional NK (cNK) cells. Both trNK and cNK are composed of multiple subsets with unique phenotypes and functional characteristics. However, the phenotypic and functional differences between the two captured less attention. The features of trNK and cNK in the development, phenotypes and functions are sorted, and the interactions between NK cells and other immune cells in the lung are presented. Moreover, the latest research progress of lung NK cells in lung infections, tumors, transplantation, asthma and other diseases is particularly highlighted. It suggests that trNK cells may play a significant role, although lung NK cells are mainly composed of cNK. Further investigations of lung trNK and cNK cells will provide new insights into NK cell-based disease research.