Abstract Chronic pain and sleep disorders frequently co-occur and exacerbate each other, yet the neural mechanisms underlying this comorbidity remain poorly understood. Here, we found that hyperactivity of GABAergic neurons in the dorsal division of the lateral septum (LS GABA ) drives both pain-like behavior and sleep disruption induced by spared nerve injury (SNI) in male mice. We showed that systemic or local application of dexmedetomidine (DEX), with known sedative and analgesic properties, reduces LS GABA hyperactivity via α 2 A adrenergic receptor activation, alleviating pain-like behavior and sleep disruption. LS GABA can project onto the glutamatergic and GABAergic neurons in the lateral preoptic area (LPO), respectively. The LS GABA →LPO Glu circuit and the LS GABA → LPO GABA circuit contribute to mechanical allodynia and sleep disruption, respectively. Furthermore, LS α 2 A adrenergic receptor plays an important role in DEX-regulated activity of LPO GABA and LPO Glu . Taken together, these findings reveal a shared neural substrate for chronic pain and sleep disorders and establish DEX as a potential treatment for this comorbidity through selective modulation of LS GABA -driven circuits.

BACKGROUND:With obesity as a risk factor for atherosclerotic disease, recent research suggests that adipose tissue in obese animal models and humans can generate endocrine-like molecules that affect arterial health. Previous studies showed that microRNA-30e (miR-30e) levels are elevated in atherosclerosis and solute carrier family 7 member 11 (SLC7A11), a cystine/glutamate transporter, is involved in atherogenesis. However, whether an endocrine-like link between the adipose-derived miR-30e-5p and SLC7A11 in the vascular endothelium can lead to obesity-caused atherosclerosis is unknown. METHODS:miRNA data mining and reverse transcription-polymerase chain reaction validations were used to demonstrate the positive association among serum levels of miR-30e-5p, obesity, and coronary arterial disease in human patients. Transcriptomics (bulk RNA sequencing and single-nucleus RNA sequencing), metabolomics, and in silico analysis were used to establish a miR-30e-5p-SLC7A11 regulation of central carbon metabolism, mitochondrial and endothelial cell (EC) function. Mouse models with EC-specific Slc7a11 knockout (EC-Slc7a11-/-) and gain- or loss-of- function of miR-30e-5p were used to elucidate the detrimental role of this endocrine-like axis in obesity-related atherosclerosis. RESULTS:The level of adipocyte-derived miR-30e-5p was significantly upregulated in obese human patients with coronary artery disease and in obese and atherosclerotic mice. Mediated through serum exosomes, the adipocyte-generated miR-30e-5p targeted SLC7A11 mRNA in vascular ECs. SLC7A11 deficiency due to miR-30e-5p targeting dysregulated glutamate/cystine metabolism, increased glycolysis, reduced oxidative phosphorylation, and impaired mitochondrial function. The EC dysfunction could be rectified by SLC7A11 overexpression or miR-30e-5p antagonism. Administration of exogenous miR-30e-5p or white adipose tissue-derived exosomes phenocopied the increased atherosclerosis in EC-Slc7a11-/- mice. In contrast, miR-30e-5p antagomir or GW4869 treatment reduced atherosclerosis in Apoe-/- and ob/ob mice. CONCLUSIONS:Our multiomics approaches demonstrate that the adipose-derived miR-30e-5p downregulated SLC7A11 mRNA in ECs via tissue crosstalk. The resulting EC dysfunction led to obesity-related atherosclerosis in mice. These findings underscore a causality between obesity and atherosclerosis in the context of cardiovascular-kidney-metabolic syndrome.

BackgroundThe association between glycated hemoglobin (HbA1c) and in-stent restenosis (ISR) in coronary artery disease (CAD) patients following percutaneous coronary intervention (PCI) is not well understood. We examined the association between HbA1c levels and ISR risk among CAD patients after PCI.MethodsWe conducted a retrospective study of 6297 CAD patients following PCI. Patients were stratified into three groups based on admission HbA1c levels. The primary outcome was the incidence of ISR. Adjusted logistic regression models were used to assess the association between HbA1c levels and ISR. We employed the generalized additive model (GAM) to examine potential relationships, with subsequent stratified analyses to evaluate the robustness of the main results and to test for effect modification by additional clinical variables.ResultsAmong this study participants, a total of 1305 individuals were diagnosed with ISR, representing 20.72% of the cohort. The distribution of participants across HbA1c categories, along with corresponding sample sizes and proportions, was as follows: HbA1c <5.7%, 914 individuals (14.51%). HbA1c ≥5.7% to <6.5%, 2783 individuals (44.20%). HbA1c ≥6.5%, 2600 individuals (41.29%). After controlling for confounders, higher HbA1c levels were significantly linked to a greater risk of ISR [OR:1.18, 95%CI (1.09–1.27), p <0.0001]. Specifically, individuals with HbA1c ≥6.5% exhibited a substantially higher risk [OR:1.70, 95% CI (1.26–2.29), p =0.0005]. The GAM analysis revealed a non-linear association between HbA1c levels and the risk of ISR. The threshold effect analysis revealed a turning point at an HbA1c level of 7.8%. Below this threshold, the association between HbA1c and ISR risk was more pronounced.ConclusionThis study showed a non-linear relationship between increased HbA1c levels and the risk of ISR in CAD patients post-PCI.

Preclinical studies have shown that Lactiplantibacillus plantarum J26 (J26) improves metabolic syndrome (MetS)-related parameters, but clinical evidence remains limited. We therefore conducted a 12-week randomized, double-blind, placebo-controlled trial in 110 adults with MetS, who received J26 (5 × 10⁹ CFU/day) or placebo (ChiCTR2400088192). Compared with placebo, J26 significantly reduced body weight (−0.75 kg, P = 0.021), BMI (−0.29 kg/m², P = 0.021), waist circumference (−1.92 cm, P = 0.023), and body fat (−0.87%, P = 0.003), and enriched Lactobacillus and Bifidobacterium, which partially mediated reductions in adiposity-related outcomes. Although effects on blood pressure, glycemic, and lipid parameters were limited, exploratory clustering identified heterogeneous metabolic responses; responders showed greater metabolic improvements, enrichment of Lactobacillus, Bacteroides, and Anaerobutyricum, and higher baseline dietary quality than non-responders. However, these exploratory, hypothesis-generating findings require further validation. J26 may improve adiposity-related outcomes partly through gut microbiota remodeling, while baseline dietary quality may contribute to heterogeneity in broader metabolic benefits.

ABSTRACT Perfluorodecanoic acid (PFDA) is a pervasive food chemical contaminant which is readily absorbed and accumulated in the liver. This study aimed to investigate the adverse effects of PFDA exposure on metabolic dysfunction‐associated steatotic liver (MASL) and to explore the potential protective role of dietary folic acid. Utilizing data from the National Health and Nutrition Examination Survey, we first observed that PFDA exposure exhibited the strongest association with metabolic dysfunction‐associated steatotic liver disease (MASLD) risk among all detected perfluoroalkyl and polyfluoroalkyl substances in the general population, whereas high folic acid consumption could potentially mitigate this risk. Further in vivo experiments indicated that PFDA exposure‐induced MASL in C57BL/6 mice, characterized by elevated serum and hepatic levels of TC, TG, LDL‐c, and HDL‐c, as well as an increased LDL‐c/HDL‐c ratio. In vitro experiments demonstrated that PFDA exposure induced cellular steatosis by promoting lipogenesis and oxidative stress in hepatocytes. Mechanistically, PFDA exposure reduced the m6A modification of IL18 mRNA by upregulating FTO, thereby shielding it from YTHDF2‐mediated degradation. Elevated IL18, in turn, promoted lipogenesis by upregulating ADIRF. Ultimately, folic acid supplementation mitigated PFDA‐induced MASL both in vivo and in vitro. Collectively, these findings suggest that PFDA induces MASL via FTO/m6A/IL18/ADIRF‐mediated lipogenesis, and that adequate dietary folic acid supplementation may be a promising strategy to counteract this foodborne toxicity.

INTRODUCTION:Clonal hematopoiesis of indeterminate potential (CHIP), driven by somatic mutations (e.g., TET2), is an independent risk factor for atherosclerosis (AS). CHIP-mutant macrophages promote plaque inflammation, but targeted therapies are lacking. Crucially, whether these clones acquire immunogenic neoantigens-enabling immune clearance-remains unexplored. OBJECTIVE:To investigate if Tet2-mutant cells in CHIP-associated AS develop immunogenic neoantigens and evaluate a neoantigen-targeting vaccine strategy. METHODS:Tet2 was edited in hematopoietic cells via CRISPR/Cas9 and transplanted into Ldlr-/- mice fed a high-fat diet to model CHIP-accelerated AS. DNA and RNA sequencing of Tet2-mutant macrophages identified nonsynonymous mutations. Neoantigen immunogenicity was predicted in NetMHCpan. A therapeutic vaccine (GelVax) encapsulating mutant cell lysates (neoantigen source), GM-CSF (DC recruitment), and R848 (TLR agonist) within a biocompatible hydrogel was developed. Efficacy was assessed in the AS model. RESULTS:Tet2 deficiency exacerbated atherosclerosis (+72% plaque area) and systemic inflammation.  DNA and RNA sequencing results identified 2 mutations showing high MHC-I binding affinity, suggesting neoantigenicity. GelVax vaccination reduced aortic plaque burden by 45%, selectively cleared Tet2-mutant macrophages in plaques, attenuated systemic cytokines (TNF-α, IL-1β) and improved plaque stability (↓ necrotic core, ↑ collagen). The protection was primarily CD8+ T-cell dependent. CONCLUSION:Tet2-mutant cells in CHIP-associated AS acquire immunogenic neoantigens. Leveraging these antigens via a hydrogel vaccine induces clone-specific CD8+ T cell responses, clears pathogenic macrophages, and ameliorates atherosclerosis. This validates mutant neoantigens as actionable targets for CHIP-driven cardiovascular disease.

Dyslipidemia is an important risk factor for coronary artery disease (CAD). However, the relationship between high-density lipoprotein (HDL) antioxidant function and plasma lipid profile has not been fully investigated. Lipid-lowering therapy is recommended in patients with CAD. The relationship between HDL antioxidant function and lipid-lowering therapy remains unclear. This study aimed to analyze the association between HDL antioxidant function, lipid profiles, and lipid-lowering therapy in patients with CAD. To investigate this, we recruited 1,000 patients with CAD and 200 healthy subjects. HDL lipid peroxide content was measured and normalized by HDL cholesterol (HDL-C) levels to represent HDL antioxidant function (nHDLox). nHDLox levels were compared across different CAD severities. The association between nHDLox and lipid profiles was also analyzed. The difference in nHDLox between patients who received lipid-lowering therapy and those who did not was analyzed. A correlation analysis was performed to investigate the association between nHDLox and fasting blood glucose and inflammatory markers. Results demonstrated that nHDLox levels were elevated in patients with CAD compared to healthy subjects, and were also higher in patients with acute coronary syndrome and CAD combined with three-vessel disease. Receiver operating characteristic curve analysis showed that nHDLox was better than triglyceride-glucose index and HDL-C levels in predicting CAD. nHDLox positively correlated with total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels. Further analysis showed an approximately "L"-shaped relationship between nHDLox and HDL-C levels. Moreover, among CAD patients with LDL-C < 3.0 mmol/L, nHDLox was significantly reduced in the lipid-lowering therapy group compared to that in the group without lipid-lowering therapy. Furthermore, nHDLox positively correlated with fasting blood glucose levels and inflammatory markers. In conclusion, HDL antioxidant function is associated with lipid profiles. Lipid-lowering therapy improves HDL antioxidant function in patients with CAD, and nHDLox may serve as an indicator for the efficacy of such treatment.

Background Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). As a major risk factor for atherosclerotic cardiovascular disease (ASCVD), hyperlipidemia is a common sequela of CKD, which is linked to increased lipid synthesis, impaired lipoprotein clearance, and maladapted reverse cholesterol transport. Because exosomes can transport miRNAs to modulate intercellular and tissue communication, we hypothesized that exosomal miRNAs can act as endocrine-like molecules to modulate the CKD-associated hyperlipidemia and ASCVD. Methods Small RNA-seq and qPCR were used to determine the differential plasma level of exosomal miR-148a-3p in ASCVD patients with and without CKD. RNA-seq and in silico analysis were used to establish the regulation of lipid metabolism via miR-148a-3p/salt-inducible kinase 1 (SIK1)/AMP-activated protein kinase alpha 1 subunit (AMPKα1) in the liver. Inhibition of miR-148a-3p or overexpression of SIK1/AMPKα1 in ApoE-/- mice with 5/6 nephrectomy was used to elucidate the role of the miR-148a-3p/SIK1/AMPKα1 axis in CKD-related hyperlipidemia and atherosclerosis. Results The plasma level of exosomal miR-148a-3p was significantly elevated in patients with ASCVD and CKD (ASCVD/CKD) and ApoE-/- mice with 5/6 nephrectomy. Via circulating exosomes, kidney-generated miR-148a-3p was delivered to the liver, where it targeted SIK1 / AMPKα1 transcripts, thereby upregulating SREBP2/PCSK9 and reciprocally downregulating LDLR. Levels of SIK1 and AMPKα1 were decreased in hepatocytes transfected with miR-148a-3p or treated with plasma exosomes from ASCVD/CKD patients, with attendant SREBP2 activation and attenuated LDL-C binding. The decreased LDL-C binding was rectified by SIK1/AMPKα1 or LNA-miR-148a-3p overexpression. LNA-miR-148a-3p or AAV8- SIK1 / AMPKα administration in 5/6 nephrectomy/ApoE-/- mice significantly ameliorated hyperlipidemia and atherosclerosis. Conclusion In ASCVD/CKD patients and nephrectomy/ApoE-/- mice, kidney-originating miR-148a-3p targeted hepatic SIK1 / AMPKα1 mRNA. This exosome-mediated endocrine effect upregulated SREBP2/PCSK9 and reciprocally reduced LDLR level, which elevated plasma LDL-C level and exacerbated ASCVD. These findings underscore a kidney-liver-artery axis involved in cardiovascular-kidney-metabolic syndrome. ### Competing Interest Statement The authors have declared no competing interest. * 3’-UTR : 3’ untranslated region AAV8 : adeno-associated virus serotype 8 AMPKα1 : AMP-activated protein kinase alpha 1 subunit ASCVD : atherosclerotic cardiovascular disease CKD : chronic kidney disease CKM : cardiovascular-kidney-metabolic eGFR : estimated glomerular filtration rate FISH : fluorescence in situ hybridization HDL-C : high-density lipoprotein cholesterol HFD : high fat diet LDL-C : low-density lipoprotein cholesterol LDLR : low-density lipoprotein receptor miRISCs : miRNA-induced silencing complexes NTA nanoparticle tracking analysis PCSK9 : proprotein convertase subtilisin/kexin type 9 SIK1 : salt-inducible kinase 1 SREBP-1c : sterol regulatory element binding protein-1c SREBP2 : sterol regulatory element binding protein 2 TC : total cholesterol TEM : transmission electron microscopy TG : triglycerides

Sex differences in the pathogenesis of a variety of diseases have drawn increasing attention. However, it remains unclear whether such differences exist in chemotherapy-induced neuropathic pain. Here, we conducted a retrospective analysis of clinical case data and found that peripheral sensory disorders occurred earlier in females than in males following bortezomib (BTZ) treatment in patients with multiple myeloma. BTZ treatment led to an early elevation of intercellular adhesion molecule-1, which triggered the infiltration of peripheral monocytes into the perivascular region of the spinal cord in female mice. The CC-chemokine ligand 1 released by infiltrating macrophages directly activated neurons or indirectly activated neurons by enhancing the astrocyte activity, ultimately leading to the earlier onset of BTZ-induced neuropathic pain in females. Together, clarifying the mechanism underlying the earlier onset of BTZ-induced neuropathic pain will contribute to the precise treatment of multiple myeloma in females.

BACKGROUND:Chronic neuropathic pain generally has a poor response to treatment with conventional drugs. Sympathectomy can alleviate neuropathic pain in some patients, suggesting that abnormal sympathetic-somatosensory signaling interactions might underlie some forms of neuropathic pain. The molecular mechanisms underlying sympathetic-somatosensory interactions in neuropathic pain remain obscure. METHODS:Lumbar sympathectomy was performed in spared nerve injury (SNI) mice or rats, and the up-down method was used to measure the mechanical paw withdrawal threshold. Dorsal root ganglia (DRG) injection and perfusion were used to deliver virus or drugs. Methylated RNA immunoprecipitation sequencing, RNA-sequencing, and immunoelectron microscopy were used to identify neurotransmitters. RESULTS:We found that sprouting tyrosine hydroxylase-positive sympathetic fibres in DRG mediated the maintenance of mechanical allodynia after SNI (day 28, P<0.001). We further found that SNI significantly increased the N6-methyladenosine level of CXCL16 messenger RNA (day 28, P<0.001), which was attributable to the reduced N6-methyladenosine demethylase fat mass and obesity-associated protein (P=0.002) and increased interaction with YTHDF1 (P=0.013) in the sympathetic ganglion. Enhanced expression of CXCL16 in the sympathetic ganglia can lead to increases release into the DRG and act synergistically with norepinephrine from sympathetic terminals to enhance DRG neuronal excitability. CONCLUSIONS:Norepinephrine and CXCL16 co-released from sympathetic nerve terminals in the DRG synergistically contribute to maintenance of neuropathic pain in a rodent model.

Background Angiogenesis plays a crucial role in organ development. However, aberrant blood vessel growth is involved in various diseases, including tumors and neovascular eye diseases. Angiotensin-converting enzyme 2 (ACE2) is a critical enzyme regulating the health of cardiovascular system, and its post-translational modifications (PTMs) are crucial to determine ACE2 expression level and activity. Here, we studied how the PTM of ACE2 in vascular endothelial cells (ECs) affect pathological retinal neovascularization and tumor angiogenesis. Methods The angiogenic capabilities of ECs were assessed by tube formation, sprouting assays, and 5-ethynyl-2-deoxyuridine (EdU) and filopodia staining. EC angiogenesis was examined by poteome profiler array and aortic ring assays in vitro and by the oxygen-induced retinopathy (OIR) and tumor angiogenesis models in vivo. High-throughput screening involving data from RNA-seq, ATAC-seq, and ChIP-seq were used to explore the epigenetic and transcriptional regulations of pro-angiogenic genes regualtged by ACE2 PTMs. Results ACE2 Ser-680 dephosphorylation in connection with Lys-788 ubiquitination increased EC angiogenic phenotype, which were manifested by aberrant vascularization in mouse OIR and tumor models. ACE2 Ser-680 dephosphorylation led to the activation of activator protein-1 (AP-1), which transactivated multiple genes involved in angiogenesis. AP- 1 inhibition mitigated such angiogenesis in vivo. Conclusion Our findings show a novel PTM mechanism of ACE2 involved in pathological angiogeneis. Specifically, ACE2 Ser-680 dephosphorylation facilitated AP-1 transactivation of the downstream pro-angiogenic genes in ECs. ### Competing Interest Statement The authors have declared no competing interest. * ACE2 : angiotensin-converting enzyme 2 Ad- : adenovirus AMPK : AMP-activated protein kinase AP-1 : activator protein-1 AT1R : Ang II type 1 receptor ATAC-seq : assay for transposase-accessible chromatin with high-throughput sequencing ChIP-seq : chromatin immunoprecipitation sequencing DEG : differentially expressed gene ECs : endothelial cells EdU : 5-ethynyl-2-deoxyuridine EMSA : electrophoretic mobility shift assay HUVECs : human umbilical vein endothelial cells MDM2 : murine double minute 2 OIR : oxygen-induced retinopathy PTMs : post-translational modifications PVP : polyvinylpyrrolidone RAS : renin-angiotensin system ROP : retinopathy of prematurity TFs : transcription factors

OBJECTIVE:The aim of this research was to investigate the effects of cardiovascular health (CVH), genetic predisposition, and their interactions on new-onset type 2 diabetes (T2D) and cardiovascular diseases (CVD) among individuals with prediabetes. METHOD:We assessed 26,962 individuals with prediabetes from the UK Biobank. Life's Essential 8 (LE8) was utilized to measure CVH. LE8 score encompasses 4 health behaviors (diet, physical activity, nicotine exposure, sleep) and 4 health factors (body mass index, blood lipids, blood glucose, blood pressure). Polygenic risk score (PRS) was utilized to evaluate genetic predisposition. Cox regression analyses were applied to explore the associations of LE8 score and PRS with new-onset T2D, CVD, myocardial infarction (MI), and stroke. RESULTS:Higher LE8 score was associated with lower risk of adverse outcomes (hazard ratios [HRs] ranging from 0.26 to 0.72) after multivariate adjustment. Even a 1-point increment in LE8 score was significantly linked to decreased risk of adverse outcomes in participants with prediabetes (HRs ranging from 0.97 to 0.99). A substantial proportion of incident T2D (70.47%) and CVD (45.12%) cases could be attributable to low LE8 score. Higher PRS was significantly associated with higher risk of adverse outcomes (HRs ranging from 1.38 to 3.68). Compared with those who had a low LE8 score and high PRS, participants with a high LE8 score and low PRS had lower risk of T2D, CVD, MI, and stroke. Participants with low PRS benefited more from adherence to LE8 concerning incident T2D. Besides, further analysis suggested that BMI, blood pressure, and nicotine exposure have the greatest contribution to incident T2D and CVD during the prediabetes stage. CONCLUSIONS:Ideal CVH was associated with lower risk of incident T2D and CVD among individuals with prediabetes, irrespective of their genetic predisposition. If all metrics could not be improved at once, achieving ideal status of BMI and blood pressure and avoiding nicotine exposure should be prioritized.

Cognitive impairment resulting from insufficient sleep poses a significant public health concern, particularly in children. The effects and mechanisms of choline on cognitive impairment caused by sleep deprivation are unknown. Chronic sleep deprivation is induced in young mice in this study, followed by feeding diet containing 11.36 g/kg choline bitartrate. Choline supplementation significantly improves spatial learning ability. Functional MRI results reveal the hippocampus as a key region affected by sleep deprivation, where choline supplementation notably preserves hippocampal structural integrity and enhanced connectivity. Additionally, choline ameliorates hippocampal pathological injury, reduces blood-brain barrier permeability and serum brain injury biomarkers. Choline also reduces inflammation and oxidative stress biomarkers, and mitigates microglial activation in the hippocampus, which preserves synaptic plasticity. A key finding is the changes of hippocampal phospholipidomic profile along with cognitive function, and a total of 313 phospholipid molecules are identified. Choline increases the levels of total phospholipid and sub-classes (particularly PC), which are strongly correlated with reduced neuroinflammation and oxidative stress biomarkers, as well as improved cognitive outcomes. Furthermore, there are similar findings in some phospholipid molecules such as PC 36:1, PC O-33:0, PC p-38:3, PE 36:3, PE p-42:4 and PS 44:12. These findings highlight that choline alleviates cognitive impairment in sleep deprivation via reducing neuroinflammation and oxidative stress as well as altering phospholipidomic profile. This study suggests that choline could develop into functional food or medicine ingredient to prevent and treat cognitive impairment by sleep disturbances, particularly children and adolescents.

BACKGROUND:The hypotension prediction index (HPI) is an algorithm designed to predict hypotension. Some studies have reported that HPI-guided hemodynamic management strategies decrease intraoperative hypotension and complications; however, the effect of HPI on reducing perioperative complications is controversial. This meta-analysis aimed to assess the efficacy of the HPI in reducing major complications and intraoperative hypotension. METHODS:We conducted this meta-analysis according to the PRISMA statement and Cochrane Handbook guidelines. A comprehensive literature review was conducted to identify studies focusing on the efficacy of HPI-guided management in reducing intraoperative hypotension and postoperative complications. The PubMed, Embase, Scopus, and Web of Science databases were searched, and the resulting data were combined to calculate the pooled mean differences or risk ratios (RRs) with 95% CIs of both randomized controlled trials (RCTs) and retrospective studies, as appropriate. Heterogeneity and potential publication bias were also assessed. RESULTS:Nineteen articles (12 RCTs and 7 retrospective studies) with 2570 recruited patients were included in this meta-analysis. The critical evaluation of the study quality revealed a low risk of bias in the included RCTs. Among the non-randomized trials, one was rated 7, two were rated 8, and the remaining four were rated 9 on the Newcastle-Ottawa Scale, indicating high quality and a low risk of bias. HPI-guided management significantly reduced intraoperative hypotension and associated major complications (RR = 0.79, 95% CI [0.69-0.90], I2 = 0, P < 0.001). Blood loss and length of hospital stay were comparable between the groups. CONCLUSIONS:HPI-guided management significantly reduced intraoperative hypotension and major complications.

Ischaemic stroke, characterized with sterile brain tissue injury, can lead to acute pneumonia and pulmonary dysfunction, which are the primary causes of death in ischaemic stroke patients. The association of neural and molecular mechanisms between the infarcted brain area and the development of pneumonia and pulmonary dysfunction are not understood. We used whole-body plethysmography, the respiratory patterns test and arterial blood gas analysis to examine pulmonary function. In addition, Holter monitoring, electrophysiological recordings, chemogenetic manipulation, fibre photometry, ELISA, immunofluorescence, western blotting, reverse transcription-qPCR, haematoxylin and eosin staining, TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-nick end labelling) staining and viral-mediated manipulations were used to address our questions. Here, we observed significant pneumonia (immune cell infiltration and increased inflammatory cytokines) and pulmonary dysfunction in middle cerebral artery occlusion rats. A decrease in parasympathetic nerve function and activity was observed in clinical patients and rodent models with acute ischaemic stroke. Mechanistically, ischaemic stroke leads to the apoptosis of glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVNCaMKII) that innervate acetylcholine neurons in the dorsal motor nucleus of the vagus (DMVACh) and subsequently decreases the activity of DMVACh neurons. The reduced DMVACh neuron activity, via the α7 nicotinic acetylcholine receptor (α7nAChR), upregulates high mobility group box 1 (HMGB1) expression in the pulmonary parasympathetic ganglia neurons, which increases the expression of tumour necrosis factor-α and interleukin-1β in various immune cells via toll-like receptor 4 or the receptor for advanced glycation end products (RAGE). Meanwhile, the activation of circuit from DMVACh neurons to pulmonary parasympathetic ganglia neurons improved pneumonia and pulmonary dysfunction. These results dissect a novel neuroimmune framework that acute ischaemic stroke induces the apoptosis of DMVACh-innervating PVNCaMKII neurons, and subsequently promotes immune cell infiltration and increases in inflammatory cytokines via the α7nAChR-HMGB1 pathway in the pulmonary ganglion neurons, which leads to pulmonary dysfunction. These results provide a novel insight into the pathogenesis of pneumonia and pulmonary dysfunction after acute ischaemic stroke.

Accurate detection and evaluation of carotid plaque in ultrasound images is of great help in clinical diagnosis, operation implementation, and treatment plan design. However, accurate segmentation of carotid plaques is a challenging task, as the shape and size of plaque vary greatly reason from different scanning positions, and existing methods can't address well these out-of-order issues. Here, a dual branch multi-directional and multiscale cross-feature fusion integrated network (PDCS-Net) is proposed, which encodes collaboratively to extract the shared features of plaques and blood vessels and decodes using a dual branch to decouple category-specific features from common features. Besides, the cross-attention feature fusion module (CAFF) is designed, which fully utilizes the positional relationship between plaques and blood vessels to constrain and locate plaque segmentation. To achieve more accurate segmentation of plaques of different sizes and shapes, we constructed the multi-directional multi-scale feature fusion module (MSFF). The proposed method is evaluated on a carotid plaque segmentation dataset with high-qualicriticalty labels of carotid plaques and blood vessels. The experimental results show that our method attains outstanding segmentation performance varying significantly in size, shape and scanning position, which outperforms state-of-the-art algorithms across various evaluation metrics. Furthermore, the generalizability of our method is validated by its performance on plaques and blood vessels from 7 ultrasonic equipments. Specifically, the Dice of plaque and vessel segmentation are 80.26 % and 93.77 % respectively, and the IoU are 70.28 % and 88.96 % respectively. In addition, we conducted corresponding comparative experiments on a kidney tumor dataset to demonstrate the robustness and generalization of the model. The code for the proposed model is available at https://github.com/Peppa-ing/PDCS-Net.

Abstract Background With the increasing prevalence of colorectal cancer (CRC), optimizing perioperative management is of paramount importance. This study investigates the potential of stellate ganglion block (SGB), known for its stress response-mediating effects, in improving postoperative recovery. We postulate that preoperative SGB may enhance the postoperative recovery of patients undergoing laparoscopic CRC surgery. Methods We conducted a randomized controlled trial of 57 patients undergoing laparoscopic colorectal cancer surgery at a single center. Patients, aged 18–70 years, were randomly assigned to receive either preoperative SGB or standard care. SGB group patients received 10 mL of 0.2% ropivacaine under ultrasound guidance prior to surgery. Primary outcome was time to flatus, with secondary outcomes encompassing time to defecation, lying in bed time, visual analog scale (VAS) pain score, hospital stays, patient costs, intraoperative and postoperative complications, and 3-year mortality. A per-protocol analysis was used. Results Twenty-nine patients in the SGB group and 28 patients in the control group were analyzed. The SGB group exhibited a significantly shorter time to flatus (mean [SD] hour, 20.52 [9.18] vs. 27.93 [11.69]; p = 0.012), accompanied by decreased plasma cortisol levels (mean [SD], postoperatively, 4.01 [3.42] vs 7.75 [3.13], p = 0.02). Notably, postoperative pain was effectively managed, evident by lower VAS scores at 6 h post-surgery in SGB-treated patients (mean [SD], 4.70 [0.91] vs 5.35 [1.32]; p = 0.040). Furthermore, patients in the SGB group experienced reduced hospital stay length (mean [SD], day, 6.61 [1.57] vs 8.72 [5.13], p = 0.042). Conclusions Preoperative SGB emerges as a promising approach to enhance the postoperative recovery of patients undergoing laparoscopic CRC surgery. Clinical trial registration ChiCTR1900028404, Principal investigator: Xia Feng, Date of registration: 12/20/2019.

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

Vascular microenvironment is found to be closely related to immunotherapy efficacy. Identification and ultrasound imaging of the unique vascular characteristics, able to predict immune microenvironment, is important for immunotherapy decision-making. Herein, it is proved that high CD93 expression in the tumor vessels is closely related to the poor immune response of prostate cancer. For ultrasound molecular imaging of CD93, CD93-targeted microbubbles (MBs) consist a gaseous core and the MMRN2 (Multimerin-2) containing cell membrane (CM) /lipid hybrid membrane is then synthesized. In vitro and in vivo assays demonstrate that these MBs can recognize CD93 efficiently and then accumulate within tumor regions highly expressing CD93. Contrast-enhanced ultrasound (CEUS) imaging with CD93-targeted MBs demonstrates that targeted ultrasound intensity is negatively related to inflammatory tumor immune microenvironment (TIME) and cytotoxic T cell infiltration. Together, endothelial expression of CD93 in tumor is a unique predictor of immunosuppressive microenvironment and CD93-targeted MBs have a great potential to evaluate tumor immune status.