Objective: To characterize perioperative dynamic changes in immune-cell phenotypes and inflammatory cytokines in patients undergoing CPB (cardiopulmonary bypass) cardiac surgery, and to explore their associations with postoperative outcomes. Methods: In this prospective cohort study, 120 adult patients who underwent elective cardiac surgery under CPB at West China Hospital from May 2022 to March 2023 were enrolled. Perioperative immune-cell phenotypes and concentrations of 40 inflammation-related cytokines were measured. The primary outcomes were the sequential organ failure assessment (SOFA) score at 24 h after surgery and ΔSOFA (the peak SOFA score within 48 h after surgery minus the preoperative SOFA score). Secondary outcomes included major adverse cardiovascular events (MACE), acute kidney injury (AKI), respiratory failure, severe liver injury, and infection. Results: The mean age of enrolled patients was 57±10 years. Of these, 52% (62/120) were male and 90% (108/120) underwent valve surgery. During the rewarming to the end of CPB, neutrophil counts rapidly increased (7.39×10 /L vs preoperative 3.07×10 /L, P<0.001), with significant upregulation of CD11b (7.30×10 /L vs preoperative 3.05×10 /L, P<0.001) and CD54 (7.15×10 /L vs preoperative 2.99×10 /L, P<0.001). Lymphocyte counts increased at the end of CPB (1.75×10 /L vs preoperative 1.12×10 /L, P<0.001) but decreased significantly at 24 h after surgery (0.59×10 /L vs preoperative 1.12×10 /L, P<0.001). Plasma analysis showed that multiple pro-inflammatory cytokines increased during CPB and remained elevated up to 24 h after surgery; five chemokines and the anti-inflammatory cytokine IL-10 peaked at the end of CPB. The SOFA score increased from 1 (1, 2) preoperatively to 7 (5, 10) at 24 h after surgery, with a ΔSOFA of 6 (4, 8). Within 30 days after surgery, 48 patients (40.0%) developed AKI, 17 (14.2%) developed infection, 4 (3.3%) developed severe liver injury, 3 (2.5%) developed respiratory failure, and 3 (2.5%) experienced MACE. During the 2-year follow-up, 8 patients (6.7%) experienced MACE and 5 (4.2%) died. Conclusion: Multi-organ dysfunction is common after cardiac surgery under CPB (median ΔSOFA, 6), accompanied by perioperative activation of multiple immune-cell subsets and upregulation of pro-inflammatory, anti-inflammatory, and chemotactic mediators. This study provides data-driven evidence and research clues for further investigation of the associations between CPB-related immune perturbations and postoperative organ dysfunction and clinical outcomes.

Cyclic GMP-AMP synthase (cGAS), a pivotal molecule in innate immunity, has emerged as a keypoint in interdisciplinary research at the intersection of basic immunology and tumor biology. As a cytosolic nucleic acid sensor, cGAS is primarily characterized by its capacity to recognize double-stranded DNA (dsDNA) in the cytosol. Upon binding to dsDNA, cGAS undergoes a conformational change that promotes its dimerization and subsequent enzymatic activation. Once activated, it catalyzes the synthesis of the second messenger 2',3'-cGAMP from ATP and GTP. cGAMP then binds to the adaptor protein STING, which resides on the endoplasmic reticulum (ER) membrane. The binding process triggers STING to traffic from the ER to the Golgi apparatus, where it is phosphorylated by the kinase TBK1. Phosphorylated STING serves as a docking site for the transcription factor IRF3, facilitating its phosphorylation by TBK1. Once phosphorylated, IRF3 forms dimers and translocates to the nucleus, where it drives the expression of type I interferons and pro-inflammatory cytokines, initiating a potent antimicrobial state. The DNA-sensing mechanism of cGAS is inherently non-selective regarding the origin of its ligand. It readily detects exogenous DNA from invading pathogens, thereby playing an indispensable role in host defense against microbial infections. However, this same mechanism also enables cGAS to recognize self-DNA that leaks from the nucleus or mitochondria into the cytosol under various cellular stress conditions. While critical for immunity, the recognition of self-dsDNA by cGAS can disrupt cellular homeostasis and trigger aberrant inflammatory responses. The loss of self-tolerance can precipitate or exacerbate the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), highlighting the dual role of cGAS as both a sentinel for infection and a potential driver of autoimmune pathology. Notably, the subcellular localization of cGAS is not still. Increasing recent researches have revealed that cGAS is also abundant within the nucleus, challenging the traditional view of it solely as a cytosolic nucleic acid sensor. Within the nucleus, cGAS exhibits non-canonical functions that are distinct from its canonical immunological role. First, cGAS exists in a state of stringent immunological silence in the nucleus, with mechanisms involving its competitive binding to histones and its post-translational modifications which block the activation of cGAS enzymatic activity, thus, effectively preventing it from mounting an autoimmune attack on genomic DNA. Second, cGAS plays a critical role in maintaining genomic stability. Upon DNA damage, cGAS is rapidly recruited to the lesion site and participates in the DNA damage repair process. Moreover, under conditions of DNA replication stress, cGAS contributes to the stabilization of replication forks, preventing the cell from entering a state of uncontrolled hyper-replication. Consequently, in light of the dual role of cGAS in both immune regulation and tumor development, the development of small-molecule drugs targeting cGAS holds significant therapeutic promise. This review summarizes the structural characteristics of cGAS and its canonical function as a pattern recognition receptor in the cytosol, including the types of pathogens it recognizes and the autoimmune responses resulting from erroneous recognition of self-DNA. It then focuses on its emerging non-canonical functions within the nucleus, detailing its nucleocytoplasmic shuttling, the mechanisms underlying its nuclear immune quiescence, and its role in mediating DNA damage repair and replication fork stabilization. Finally, the review discusses the progress and application prospects of small-molecule drugs targeting cGAS for the treatment of autoimmune diseases and cancer.

Cyclic GMP-AMP synthase (cGAS), a pivotal molecule in innate immunity, has emerged as a keypoint in interdisciplinary research at the intersection of basic immunology and tumor biology. As a cytosolic nucleic acid sensor, cGAS is primarily characterized by its capacity to recognize double-stranded DNA (dsDNA) in the cytosol. Upon binding to dsDNA, cGAS undergoes a conformational change that promotes its dimerization and subsequent enzymatic activation. Once activated, it catalyzes the synthesis of the second messenger 2',3'-cGAMP from ATP and GTP. cGAMP then binds to the adaptor protein STING, which resides on the endoplasmic reticulum (ER) membrane. The binding process triggers STING to traffic from the ER to the Golgi apparatus, where it is phosphorylated by the kinase TBK1. Phosphorylated STING serves as a docking site for the transcription factor IRF3, facilitating its phosphorylation by TBK1. Once phosphorylated, IRF3 forms dimers and translocates to the nucleus, where it drives the expression of type I interferons and pro-inflammatory cytokines, initiating a potent antimicrobial state. The DNA-sensing mechanism of cGAS is inherently non-selective regarding the origin of its ligand. It readily detects exogenous DNA from invading pathogens, thereby playing an indispensable role in host defense against microbial infections. However, this same mechanism also enables cGAS to recognize self-DNA that leaks from the nucleus or mitochondria into the cytosol under various cellular stress conditions. While critical for immunity, the recognition of self-dsDNA by cGAS can disrupt cellular homeostasis and trigger aberrant inflammatory responses. The loss of self-tolerance can precipitate or exacerbate the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and Aicardi-Goutières syndrome (AGS), highlighting the dual role of cGAS as both a sentinel for infection and a potential driver of autoimmune pathology. Notably, the subcellular localization of cGAS is not still. Increasing recent researches have revealed that cGAS is also abundant within the nucleus, challenging the traditional view of it solely as a cytosolic nucleic acid sensor. Within the nucleus, cGAS exhibits non-canonical functions that are distinct from its canonical immunological role. First, cGAS exists in a state of stringent immunological silence in the nucleus, with mechanisms involving its competitive binding to histones and its post-translational modifications which block the activation of cGAS enzymatic activity, thus, effectively preventing it from mounting an autoimmune attack on genomic DNA. Second, cGAS plays a critical role in maintaining genomic stability. Upon DNA damage, cGAS is rapidly recruited to the lesion site and participates in the DNA damage repair process. Moreover, under conditions of DNA replication stress, cGAS contributes to the stabilization of replication forks, preventing the cell from entering a state of uncontrolled hyper-replication. Consequently, in light of the dual role of cGAS in both immune regulation and tumor development, the development of small-molecule drugs targeting cGAS holds significant therapeutic promise. This review summarizes the structural characteristics of cGAS and its canonical function as a pattern recognition receptor in the cytosol, including the types of pathogens it recognizes and the autoimmune responses resulting from erroneous recognition of self-DNA. It then focuses on its emerging non-canonical functions within the nucleus, detailing its nucleocytoplasmic shuttling, the mechanisms underlying its nuclear immune quiescence, and its role in mediating DNA damage repair and replication fork stabilization. Finally, the review discusses the progress and application prospects of small-molecule drugs targeting cGAS for the treatment of autoimmune diseases and cancer.

OBJECTIVE To explore the in vitro and in vivo inhibitory effects and mechanism of metformin on the malignant biological behavior of esophageal squamous cell carcinoma （ESCC） cells by the hypoxia inducible factor-1α （HIF-1α）/interleukin-8 （IL-8） signaling pathway. METHODS Human ESCC TE1 cells were assigned into blank group， metformin low-， medium-， and high-dose groups （0.5， 1， 2 mmol/L）， IDF-11774 （HIF-1α inhibitor） group （20 μmol/L）， and high-dose metformin+HIF-1α activator dimethyloxalylglycine （DMOG） group. After 24 h treatment， cell proliferation [measured by the positive rate of 5-ethynyl- 2′-deoxyuridine （EdU） and optical density at 450 nm （OD450 value）]， apoptosis， invasion and migration as well as mRNA expressions of proliferating cell nuclear antigen （PCNA）， Bcl-2 interacting mediator of cell death （Bim）， migration and invasion enhancer 1 （MIEN1）， and matrix metalloproteinase-9 （MMP-9）， and protein expressions of HIF-1α and IL-8 in the cells were detected. The xenograft tumor model of nude mice was established. Thirty nude mice were randomly divided into blank group， metformin low-， medium-， and high-dose groups （i.g. administration of metformin 62.5， 125， 250 mg/kg+i.p. administration of equal volume of normal saline）， IDF-11774 group （i.g. administration of 50 mg/kg IDF-11774+i.p. administration of equal volume of normal saline） and high-dose metformin+DMOG group （i.g. administration of metformin 250 mg/kg+i.p. administration of DMOG 250 mg/kg）， with 5 mice in each group. They were given relevant medicine， once a day， for 4 consecutive weeks； the mass and volume of the tumor and protein expressions of HIF-1α and IL-8 in the tumor tissue were determined. RESULTS The EdU positive rate， OD450 value， cell invasion number， scratch healing rate， mRNA expressions of PCNA， MIEN1 and MMP-9， protein expressions of HIF-1α and IL-8， as well as the mass and volume of transplanted tumors and protein expressions of HIF-1α and IL-8 in tumor tissues were decreased by metformin in concentration/dose-dependent manner （P＜0.05）. Additionally，metformin increased the apoptosis rate and mRNA expression of Bim in cells （P＜0.05）. The trend of changes in corresponding indicators in the IDF-11774 group was consistent with that in the metformin groups， whereas DMOG could significantly attenuate the aforementioned effects of high-concentration/high-dose metformin （P＜0.05）. CONCLUSIONS Metformin can inhibit the proliferation， invasion， migration of TE1 cells， and tumor growth of nude mice， and induce cell apoptosis， the mechanism of which may be related to the inhibition of HIF-1α/IL-8 signaling pathway.

ObjectiveTo multidimensionally analyze the clinical effects of Qianyang Yuyin granules on elderly hypertensive patients through an "energy-inflammation-aging" network. MethodsRelevant datasets were retrieved from the GEO database. Gene set enrichment analysis （GSEA） was performed on the gene expression profiles of peripheral blood cells from patients with essential hypertension in dataset GSE24752. The GSEA referenced "GO gene sets" and "KEGG gene sets" to identify significantly enriched gene sets. A clinical trial was conducted using a randomized controlled study design. A total of 40 patients meeting the inclusion criteria were enrolled. The control group received standard antihypertensive treatment with angiotensin receptor blockers （ARBs） or combined calcium channel blockers （CCBs）. In contrast，the treatment group received Qianyang Yuyin Granules in addition to the standard treatment for 12 weeks. Blood pressure levels and clinical efficacy were observed，and changes in energy metabolism indicators，DNA damage markers，and senescence-associated secretory phenotype （SASP） in blood were measured using ELISA before and after treatment. ResultsGSEA results indicated significant energy metabolism dysregulation in hypertensive patients. Clinical findings showed that both groups achieved blood pressure control without significant intergroup differences. In terms of clinical efficacy，the treatment group had a significantly higher effective rate compared to the control group （95% vs 65%，P0.05）. After treatment，the treatment group showed a significant increase in NAD⁺ levels （P0.01），with higher levels compared to the control group （P0.05）. The treatment group also exhibited a greater reduction in DNA damage marker 8-OHdG （P0.01） and cell adhesion factors ICAM-1 and VCAM-1 （P0.01） compared to the control group. Pro-inflammatory cytokines IL-1β and IL-6 were significantly reduced in the treatment group （P0.01），with greater reductions compared to the control group （P0.05，P0.01）. Anti-inflammatory cytokines IFN-α，IL-4，and IL-10 were significantly elevated in the treatment group （P0.01），with higher levels compared to the control group （P0.01）. No significant adverse reactions were reported in either group. ConclusionThe "energy- inflammation- aging" network plays an important role in the pathological mechanism of hypertension patients. Qianyang Yuyin granules may delay the aging process by increasing patients' energy metabolism levels，reducing DNA oxidative damage，and maintaining the balance of inflammatory factors.

OBJECTIVE: To observe the effect of heat-sensitive moxibustion at "Feishu" (BL13) on immunoinflammatory response in rats with allergic rhinitis (AR) based on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, so as to explore its underlying mechanism. METHODS: Thirty-two male SD rats were randomly divided into a blank group (6 rats) and a modeling group (26 rats). In the modeling group, AR model was prepared using systemic and local attack sensitization method with ovalbumin. The successfully-modeled rats were randomized into a model group (6 rats), a medication group (6 rats) and a moxibustion group (14 rats). In the moxibustion group, the suspending moxibustion was operated at bilateral "Feishu" (BL13), 40 min each time, once daily, for 21 consecutive days; during which, the temperature of the body and tail was recorded. During intervention, if the temperature of the body and tail increased by >1 ℃, the heat-sensitive reaction at the point was determined in the rats of the moxibustion group, and these rats were collected in a heat-sensitive moxibustion group (8 rats involved and 6 rats of them were randomly collected to ensure the sample-size consistency); and those without heat-sensitive moxibustion reaction were assigned to a traditional moxibustion group (6 rats). In the medication group, fluticasone propionate nasal spray was applied, 8 μL on each side, once daily and for 21 days. The behavioral score for AR symptoms after modeling and intervention, and the content of serum immunoglobulin E (IgE) after modeling were observed. After intervention, the histological morphology of the nasal mucosa was observed using HE staining, the positive expression of thymic stromal lymphopoietin (TSLP) in the nasal mucosa was detected using immunohistochemistry, the levels of IgE, interleukin (IL)-4, IL-5, IL-13 and interferon-γ (IFN-γ) were detected by ELISA, and the protein expression of the member 4 of tumor necrosis factor receptor superfamily (OX40), phosphorylated protein kinase B (p-AKT), phosphorylated phosphatidylinositol 3-kinase (p-PI3K) in nasal mucosa was detected by Western blotting. RESULTS: After modeling, the behavioral score of AR symptoms and serum IgE level in the modeling group were higher than those of the blank group (P<0.01), suggesting the success of AR modeling. After intervention, compared with the blank group, the behavioral score of AR symptoms was increased (P<0.01)；the nasal mucosa structure was disordered, the inflammatory infiltration was severe; the positive expression of TSLP in the nasal mucosa increased (P<0.01), the levels of serum IgE, IL-4, IL-5, and IL-13 elevated (P<0.01), and the level of IFN-γ decreased (P<0.01); and the protein expression of OX40, p-AKT, and p-PI3K in the nasal mucosa increased (P<0.05) in the model group. Compared with the model group, the behavioral score of AR symptoms was reduced (P<0.01); the nasal mucosa structure, inflammatory infiltration, and vascular dilation were ameliorated to varying degrees; the positive expression of TSLP in the nasal mucosa decreased (P<0.01); the content of serum IgE, IL-4, IL-5, and IL-13 decreased (P<0.05), and that of IFN-γ increased (P<0.05) in the medication, traditional moxibustion, and heat-sensitive moxibustion groups. Compared with the model group, the protein expression of p-AKT was reduced in the medication and traditional moxibustion groups (P<0.05), the protein expression of OX40, p-AKT, and p-PI3K in the nasal mucosa decreased in the heat-sensitive moxibustion group (P<0.05). When compared with the medication group, the positive expression of TSLP in the nasal mucosa was reduced (P<0.05) in the heat-sensitive moxibustion group. In comparison with the traditional moxibustion group, the content of serum IL-13 was reduced and the content of IFN-γ elevated in the heat-sensitive moxibustion and the medication groups (P<0.05), the protein expression of p-PI3K reduced in the medication group (P<0.05), and the positive expression of TSLP and the protein expression of OX40 and p-PI3K in the nasal mucosa were reduced in the heat-sensitive moxibustion group (P<0.05). CONCLUSION Heat-sensitive moxibustion at "Feishu" (BL13) can alleviate the symptoms of AR rats, ameliorate the inflammatory infiltration and telangiectasia of nasal mucosa, and inhibit immunoinflammatory response, which may be obtained by regulating PI3K/AKT signal pathway.
Animals ; Moxibustion ; Male ; Rats ; Signal Transduction ; Rats, Sprague-Dawley ; Rhinitis, Allergic/genetics* ; Proto-Oncogene Proteins c-akt/immunology* ; Acupuncture Points ; Humans ; Phosphatidylinositol 3-Kinases/immunology* ; Phosphatidylinositol 3-Kinase/immunology*

Objective:To explore the prognostic factors of seroma after endoscopic thyroidectomy by breast ap-proach,and construct a nomogram to predict the possibility of cervical seroma.Methods:Data of patients undergoing endoscopic thyroid surgery in Dongguan Tungwah Hospital from January 2022 to May 2024 and Dongguan Songshan Lake Tungwah Hospital from May 2023 to August 2024 were retrospectively analyzed,and 1493 patients meeting the in-clusion criteria were selected.Among them,there were 1048 patients in Dongguan Tungwah Hospital as the training co-hort,1015 patients without seroma group and 33 patients with seroma group.There were 445 patients in Dongguan Songshan Lake Tungwah Hospital as the verification cohort,including 424 patients without seroma and 21 patients with seroma.Multivariate logistic regression analysis was used to obtain relevant independent prognostic factors,and R soft-ware established a nomogram model.Calibration curves,Hosmer-Lemeshow goodness of fit,ROC curves were used to evaluate the calibrability of the nomogram model,and clinical utility was assessed by clinical decision curves.Results:Multivariate logistic regression analysis showed that central lymph node dissection,diabetes,hyperthyroidism,and nod-ule size were independent prognostic factors related to seroma.Based on the prognostic factors,the nomogram of se-roma after ETBA was constructed.The calibration curves of the training and the verification group were in good agree-ment with the observed results,and the Hosmer-Lemeshow goodness of fit test was good,with the training cohort P=0.244 and the verification cohort P=0.803.The ROC curve of the training cohort showed that the area under the curve was 0.810(95%CI:0.740～0.879),and the ROC curve of the verification cohort showed that the area under the curve was 0.815(95%CI:0.722～0.909).Conclusion:The nomogram model based on the relevant prognostic factors ob-tained by multivariate logistic regression analysis has a good prediction effect on the seroma after ETBA,and can provide reasonable and individualized treatment plan for patients.

BACKGROUND:The development of calcium phosphate bone cement is limited due to its poor mechanical properties and weak osteogenic ability.Silicate bioactive glass is highly favored due to its excellent biological activity and osteogenic ability.Simultaneously,fiber structures can enhance the mechanical strength of materials.OBJECTIVE:To investigate the mechanical properties,biocompatibility,and osteogenic effect of silicate bioactive glass fiber composite calcium phosphate bone cement.METHODS:Different mass percentages(0％,10％,and 20％)of silicate bioactive glass fiber were added to the solid phase of calcium phosphate bone cement,mixed with the liquid phase and cured for 48 hours to obtain silicate bioactive glass fiber composite calcium phosphate bone cement.The mechanical properties,setting time,and ion precipitation of the cement were characterized.The three groups of bone cement extracts were co-cultured with MC3T3-E1 cells.The cell compatibility of the materials was evaluated by CCK-8 assay,live/dead staining,and phalloidin staining.After osteogenic induction,the osteogenic induction ability of the materials was evaluated by alkaline phosphatase staining,alizarin red staining,RUNX2 immunofluorescence staining,and RT-PCR.RESULTS AND CONCLUSION:(1)With the increase of silicate bioactive glass fiber content,the compressive strength and flexural strength of bone cement increased,and the setting time was prolonged.When bone cement was immersed in simulated body fluid,the precipitation of silicon ions,calcium ions,and phosphorus ions could be detected.Moreover,with the increase of silicate bioactive glass fiber content,the mass concentration of silicon ions and phosphorus ions released by bone cement increased,and the mass concentration of calcium ions decreased.(2)Live/dead staining and phalloidin staining results exhibited that silicate bioactive glass fiber composite calcium phosphate bone cement had no toxic effect on MC3T3-E1 cells.CCK-8 assay results showed that silicate bioactive glass fiber composite calcium phosphate bone cement could promote the proliferation of MC3T3-E1 cells.(3)With the increase of silicate bioactive glass fiber content in bone cement,the alkaline phosphatase activity and extracellular calcium deposition of MC3T3-E1 cells increased,the expression of RUNX2 protein increased,and the expression of alkaline phosphatase,osteocalcin,osteopontin,and RUNX2 mRNA expression increased.(4)The results indicate that silicate bioactive glass fibers can enhance the mechanical properties and osteogenic induction ability of calcium phosphate bone cement,among which 20％silicate bioactive glass fibers have a more obvious effect.

Objective To explore the influence of hsa_circ_0004535 on type 2 diabetes(T2DM)combined with metabolic-associated fatty liver disease(MAFLD)model mice.Methods Forty-eight healthy SPF grade Balb/c mice were selected for modeling and divided into the following groups(n=6 per group):Control group:normal feed;T2DM group:diabetes model induced by high-glucose and high-fat diet;T2DM combined MAFLD group:non-alcoholic fatty liver high-glucose and high-fat diet-induced diabetes combined with fatty liver model;T2DM combined MAFLD+hsa_circ_NC group:after 4 weeks of modeling,10 nmol hsa_circ_NC injected into the tail vein;T2DM combined MAFLD+hsa_circ_0004535 group:after 4 weeks of modeling,10 nmol circ_0004535 injected into the tail vein;T2DM combined MAFLD+miRNA_NC group:after 4 weeks of modeling,10 nmol miRNA blank control injected into the tail vein;T2DM combined MAFLD+miR-1827 agomir group:after 4 weeks of modeling,10 nmol miR-1827 agomir injected into the tail vein;and T2DM combined MAFLD+miR-1827 antagomir group:after 4 weeks of modeling,10 nmol miR-1827 antagomir injected into the tail vein.Mouse body weight was measured after the interventions and recorded weekly.Glucose and insulin tolerance tests were performed,blood lipids and liver function were measured,the liver and insulin resistance indexes were calculated,and pathological tests(hematoxylin/eosin(HE),oil red O,and Masson staining,immunohistochemistry,terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL))were performed to measure the degree of hepatic inflammation,fat deposition,and fibrosis.Results(1)Body weight,liver weight,liver index,insulin resistance index,and biochemical indexes were all significantly lower in the hsa_circ_0004535 injection group compared with the hsa_circ_NC injection group and the T2DM combined MAFLD group(both P＜0.05).(2)Steatosis vacuoles were reduced and smaller and inflammatory cell infiltration was reduced in the T2DM combined MAFLD+circ_0004535 group,as shown by HE and oil red staining.(3)TUNEL-positive cells were significantly reduced in the T2DM combined MAFLD+hsa_circ_0004535 group(P＜0.05).(4)Collagen fiber deposition was significantly reduced in the T2DM combined MAFLD+hsa_circ_0004535 group,as shown by Masson staining(P＜0.05).Conclusions The expression of hsa_circ_0004535 and miRNA-1827 play important roles in regulating lipid metabolism,insulin sensitivity,inflammatory pathways,hepatocyte apoptosis,and hepatic fibrosis-related pathways in an animal model of T2DM combined with MAFLD.

Objective To explore the effects of heat-sensitive moxibustion intervention on the expression of programmed death re-ceptor-1(PD-1)and its downstream PI3K/Akt/mTOR signaling pathway-related proteins in ovalbumin(OVA)-induced allergic rhinitis(AR)rats,and to elucidate the potential mechanism of its therapeutic treatment of AR.Methods Sixty SD rats were randomly divided into the blank group(n=10)and the modeling group(n=50),and AR models were prepared with normal saline and OVA,re-spectively.After successful modeling,the modeled rats were randomly divided into model group(n=10),moxibustion group(n=20),positive drug group(n=10)and PD-1 inhibitor group(n=10).The blank group had no intervention;the model group and the positive drug group were given normal saline/fluticasone propionate nasal spray nasal drops,8μl/side,once a day for 21 days;the PD-1 inhibitor group was blocked from the intervention for7days before sensitization was stimulated;the moxibustion group was treated with thermal mox-ibustion moxa strips suspended on the"feishu point"(once a day,40minutes each time),and the changes of the body and tail tempera-tures were recorded in the course of the intervention,for a total of 21 days.After the last treatment,the moxibustion group was divided into moxibustion group(n=9)and thermal moxibustion group(n=11)according to the changes in body and tail temperature.After the inter-vention,hematoxylin-eosin staining was used to observe the morphology of nasal mucosa,immunofluorescence and Western blot was used to detect the expressions of PD-1 and PI3K/Akt/mTOR-related proteins,and real-time fluorescence quantitative polymerase chain re-action(RT-qPCR)was used to detect the expression of related genes in spleen tissues.Results Compared with the blank group,the expression of PD-1 and PI3K,Akt,mTOR and their phosphorylation levels were significantly elevated in the rats of model group(P＜0.05).After the intervention of thermal moxibustion,the protein and mRNA expression of PD-1 and PI3K,Akt,mTOR,as well as the ratios of p-PI3K/PI3K,p-Akt/Akt,and p-mTOR/mTOR were significantly decreased compared with that of the model group(P＜0.05),and the down-regulation tendency was similar to that of the moxibustion group,the positive drug group and the PD-1 inhibitor group.Conclusion Thermal moxibustion at the"feishu point"can effectively improve nasal inflammation and tissue damage in AR rats,and its mechanism may be related to the down-regulation of PD-1 expression and the inhibition of downstream PI3 K/Akt/mTOR signa-ling pathway activation.