OBJECTIVE To investigate the effects of subanesthetic dose of esketamine on postoperative anxiety and recovery in patients undergoing laparoscopic cholecystectomy. METHODS A total of 200 patients scheduled for laparoscopic cholecystectomy at Suzhou Ninth Hospital Affiliated to Soochow University from January 2023 to December 2024 were randomly assigned to control group （n＝100） and observation group （n＝100）. One minute before the initiation of anesthesia， patients in the control group received intravenous injections of Propofol emulsion injection， Sufentanil citrate injection， and Succinylcholine chloride injection. On this basis， patients in the observation group received an intravenous injection of Esketamine hydrochloride injection. The anxiety status of patients in both groups was compared， along with their general intraoperative conditions （including sufentanil dosage， duration of pneumoperitoneum， operative time， anesthesia time， and extubation time）， postoperative recovery， incidence of adverse reactions， and the need for dezocine rescue analgesia. Heart rate and mean arterial pressure， entropy index （state entropy and response entropy）， inflammatory marker levels [interleukin-6 （IL-6） and C-reactive protein （CRP）]， numerical rating scale （NRS） for pain intensity were compared between the two groups at different time points. RESULTS No significant differences were found between the two groups in pneumoperitoneum duration， operative time， anesthesia time，extubation time， incidence of postoperative dry mouth， entropy index or length of stay in the post-anesthesia care unit （P＞0.05）. Compared with the control group， the observation group showed significantly lower postoperative STAI-S scores， reduced intraoperative sufentanil consumption， decreased incidence of postoperative nausea， vomiting， and shivering， the need for dezocine rescue analgesia， as well as lower plasma IL-6 and CRP levels at 24 h after surgery， and NRS （P＜0.05）. The heart rate and mean arterial pressure of patients in the observation group at the start of surgery， end of surgery， and during extubation were all significantly higher than those in the control group （P＜0.05）. CONCLUSIONS Subanesthetic dose of esketamine can effectively alleviate postoperative anxiety， reduce intraoperative opioid consumption， suppress postoperative inflammatory response， relieve postoperative pain， and promote recovery in patients undergoing laparoscopic cholecystectomy.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

ObjectiveTo observe the effects of Yifei Tongluo prescription on the NOD-like receptor protein 3 （NLRP3）/Caspase-1/gasdermin D （GSDMD） pathway and epithelial-mesenchymal transition （EMT） in rats with pulmonary fibrosis. MethodsTracheal instillation of bleomycin was conducted to establish a rat model of pulmonary fibrosis. Thirty Sprague-Dawley （SD） rats were randomly divided into a blank group， a model group， a prednisone acetate group （1.17 mg·kg^-1）， and low- and high-dose Yifei Tongluo prescription groups （10.62 and 21.24 g·kg^-1， respectively）. Administration started on the 7th day after modeling， once a day for 28 consecutive days. The lung coefficient of each group was calculated. The pathological changes of lung tissues in each group were observed by hematoxylin-eosin （HE） staining and Masson staining. The expression of α-smooth muscle actin （α-SMA） and vimentin in rat lung tissues was detected by immunohistochemistry. The expression of NLRP3 inflammasome， E-cadherin （E-cad）， and typeⅠ collagen （ColⅠ） in lung tissues was detected by immunofluorescence. The content of hydroxyproline （HYP）， tumor necrosis factor （TNF）-α， interleukin （IL）-18， and IL-1β in rat serum was detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expression levels of NLRP3， apoptosis-associated speck-like protein containing a CARD （ASC）， IL-1β， and transforming growth factor （TGF）-β₁ in rat lung tissues were determined by real-time quantitative polymerase chain reaction （Real-time PCR）. The protein expression levels of NLRP3， GSDMD， ASC， and Caspase-1 in rat lung tissues were determined by Western blot. ResultsCompared with the blank group， the model group exhibited a significantly increased lung coefficient （P<0.01） and significantly increased range of pulmonary interstitial inflammation and collagen deposition. In addition， the levels of α-SMA， Vimentin， E-cad， and ColⅠ in lung tissues were significantly increased （P<0.01）. The levels of fibrosis- and inflammation-related factors HYP， TNF-α， IL-18， and IL-1β in serum were significantly upregulated （P<0.01）. The levels of factors related to the activation of NLRP3 inflammasome in lung tissues， including NLRP3， GSDMD， ASC， Caspase-1， IL-1β， and TGF-β₁， were significantly upregulated （P<0.01）. Compared with the model group， the Yifei Tongluo prescription groups showed improved lung coefficients. Additionally， the extent of lung inflammation and collagen deposition was significantly reduced. The expression of α-SMA， Vimentin， E-cad， and ColⅠ in lung tissue was significantly decreased （P<0.01）. The levels of HYP， TNF-α， IL-18， and IL-1β in serum were significantly reduced （P<0.01）. The expression levels of NLRP3， GSDMD， ASC， Caspase-1， IL-1β， and TGF-β₁ in lung tissue were also significantly decreased （P<0.01）. ConclusionYifei Tongluo prescription can regulate the NLRP3/Caspase-1/GSDMD pathway， down-regulate release of pro-inflammatory and pro-fibrotic cytokines， alleviate NLRP3 inflammasome-mediated pyroptosis and EMT， and thereby improve pulmonary fibrosis in rats.

ObjectiveTo investigate the effect and mechanism of modified Sini San in ameliorating intestinal mucosal barrier by observing its effects on short chain fatty acids （SCFAs） and high mobility group protein B1 （HMGB1）/receptor of advanced glycation end products （RAGE） signaling pathways in chronic stress rats. MethodsThe 50 male SD rats were randomly divided into control group，model group，low-dose modified Sini San group （7.34 g·kg^-1·d^-1），high-dose modified Sini San group （14.68 g·kg^-1·d^-1），and Fructo-oligosaccharides group （3.15 g·kg^-1·d^-1），with 10 rats in each group. Except for the control group，all other groups were subjected to chronic unpredictable stress/social isolation to create a chronic stress model for 6 weeks. After 4 weeks of modeling，each treatment group was given corresponding drugs by gavage for 2 weeks while modeling. The control group and model group were given the same volume of physiological saline. The effects of Modified Sini San on behaviors，body weight，Bristol score in feces and fecal moisture content in chronic stress rats were observed. Hematoxylin and eosin （HE） staining was used to observe the pathological changes in the cecum. The content of SCFAs in the cecal contents of rats were detected by Gas chromatography-mass spectrometry （GC-MS）. Immunohistochemistry and Western blot were used to detect the expression of HMGB1/RAGE pathway related proteins in cecal tissue. The levels of ZO-1，Occludin，and Claudin-1 in the cecal tissue were detected by enzyme linked immunosorbent assay （ELISA）. ResultsCompared with the model group，the sucrose preference rate，total distance traveled and the number of grid crossings in the open field test of rats in the low-dose modified Sini San group were obviously increased （P<0.05， P<0.01），and the immobility time in the open field test and the immobility time in the forced swimming test of rats in the low-dose and high-dose modified Sini San groups were obviously reduced （P<0.05， P<0.01）. Meanwhile，the Bristol score and fecal moisture content of rats in the low and high dose groups of modified Sini San were obviously increased （P<0.05）. The low-dose group of modified Sini San had intact mucosal layer structure in the cecal tissue and reduced infiltration of inflammatory cells. The content of SCFAs in the cecal contents increased，with a obviously increase in the content of acetic acid，propionic acid，butyric acid，and isovaleric acid （P<0.05， P<0.01） and the expression levels of HMGB1，RAGE，Toll-like receptor 2（TLR2），Toll-like receptor 4（TLR4），tumor necrosis factor-α（TNF-α），and nuclear factor kappa-B p65（NF-κB p65） proteins in cecal tissue were significantly decreased （P<0.05， P<0.01） in low-dose group of modified Sini San. Meanwhile，the contents of ZO-1，Occludin，and Claudin-1 in the cecal tissue were obviously increased （P<0.01） in low-dose group of modified Sini San. ConclusionModified Sini San can improve the function of intestinal mucosal barrier in chronic stress rats by increasing the content of SCFAs in the intestine and inhibiting the HMGB1/RAGE pathway.

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.

AIM: To investigate the genetic association and potential causal relationship between diabetic nephropathy(DN)and diabetic retinopathy(DR), and to elucidate their shared molecular mechanisms through differential gene expression analysis and Mendelian randomization(MR).METHODS: Transcriptomic data of DN and DR were obtained from the Gene Expression Omnibus(GEO)database and analyzed for differentially expressed genes(DEGs). Genes meeting the significance threshold(log2FC>1, P<0.05)were identified, followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis to explore shared biological pathways. Using genome-wide association study(GWAS)summary statistics for DN and DR, two-sample MR analysis was performed, with DN as the exposure and DR as the outcome. The causal effect was primarily estimated with the inverse-variance weighted(IVW)method, and sensitivity analyses were conducted to assess robustness.RESULTS: MR analysis revealed that DN significantly increased the risk of DR. IVW estimates indicated that the odds ratio(OR)for non-proliferative DR(NPDR)was 3.23(95% CI: 2.12-4.95, P<0.001), and the OR for proliferative DR(PDR)was 1.10(95% CI: 1.06-1.15, P<0.001). DEG analysis identified several key genes, including FN1, COL1A2, and THBS2. FN1 and COL1A2 are involved in extracellular matrix remodeling and fibrosis, contributing to vascular permeability alterations and microvascular damage in diabetic complications. THBS2 is closely associated with angiogenesis and vascular homeostasis, suggesting its potential role in DR. KEGG enrichment analysis showed that these DEGs were mainly enriched in advanced glycation end products(AGEs)-RAGE signaling, extracellular matrix degradation, and oxidative stress pathways, all of which are highly relevant to the pathogenesis of DN and DR.CONCLUSION: This study demonstrates the genetic association between DN and DR using MR and DEGs analyses. The shared mechanisms, particularly involving extracellular matrix remodeling, inflammatory response, and angiogenesis, may serve as novel therapeutic targets and provide a theoretical basis for the early diagnosis and targeted treatment of diabetic complications.

OBJECTIVE: To observe the effects of point-moxibustion with Zhuang medicinal thread on differentially expressed genes (DEGs) in the dorsal root ganglion (DRG), tissue morphology, and the expression of Fc epsilon RI (FcεRI) pathway proteins spleen tyrosine kinase (Syk) and membrane spanning 4-domain A2 (MS4A2) in rat model of postherpetic neuralgia (PHN), and to explore the potential mechanism by which this therapy alleviates pain sensitization. METHODS: Thirty-nine male Sprague-Dawley (SD) rats were randomly divided into a control group, a model group, and a moxibustion group, with 13 rats in each group. The PHN model was established in the model and moxibustion groups by intraperitoneal injection of resiniferatoxin. In the moxibustion group, bilateral L₄-L₆ "Jiaji" (EX-B2) points were treated with point-moxibustion with Zhuang medicinal thread from day 7 post-modeling, with two cones per acupoint per session, every other day for a total of 10 sessions. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured at 1 day before modeling and on days 1, 4, 7, 13, 19, and 25 after modeling. After intervention, HE staining was used to observe DRG morphology. RNA sequencing was performed to analyze DEGs in DRG and conduct bioinformatics analysis. The expression of Syk and MS4A2 mRNA and proteins in the FcεRI pathway in DRG was detected by quantitative PCR and Western blot. RESULTS: Compared with the control group, the model group exhibited decreased MWT (P<0.05) and increased TWL (P<0.05); histopathological analysis revealed neuronal atrophy, nuclear displacement, and intracellular vacuoles, with a slightly loose arrangement; the RNA-Seq identified 3,207 DEGs (1,997 upregulated and 1,210 downregulated); the mRNA and protein expression levels of Syk and MS4A2 were significantly increased (P<0.01). Compared with the model group, the moxibustion group showed increased MWT (P<0.05) and decreased TWL (P<0.05), with relatively normal neuronal morphology; the RNA-Seq identified 426 DEGs (250 upregulated and 176 downregulated); the mRNA and protein expression levels of Syk and MS4A2 were significantly decreased (P<0.05). Venn diagram analysis identified 156 DEGs that showed a reversal in expression trends after treatment, including Syk and MS4A2, which are associated with pain sensitization. KEGG pathway analysis indicated that these DEGs were primarily enriched in the FcεRI pathway. CONCLUSION Point-moxibustion with Zhuang medicinal thread could alleviate pain sensitization in PHN rats, possibly by inhibiting the FcεRI signaling pathway and downregulating the expression of Syk and MS4A2.
Animals ; Rats, Sprague-Dawley ; Male ; Rats ; Moxibustion ; Neuralgia, Postherpetic/physiopathology* ; Syk Kinase/metabolism* ; Acupuncture Points ; Humans ; Ganglia, Spinal/metabolism* ; Signal Transduction

OBJECTIVE: To investigate the clinical therapeutic effect of Rendu Tongtiao acupuncture (acupuncture for regulating and improving the circulation of the conception and governor vessels) on hyperandrogenism (HA) in polycystic ovary syndrome (PCOS) with kidney-yin deficiency induced fire hyperactivity. METHODS: A total of 80 PCOS-HA patients were selected and randomly divided into an observation group and a control group, 40 cases in each group. In the control group, ethinylestradiol and cyproterone acetate tablets were administered orally,2 mg each time, once daily and for 21 consecutive days as one menstrual cycle. In the observation group, Rendu Tongtiao acupuncture was delivered at Qihai (CV6), Zhongwan (CV12), Guanyuan (CV4), Zhongji (CV3), Mingmen (GV4), Yaoyangguan (GV3), etc. once daily till ovulation, which was taken as the treatment session of one menstrual cycle. The treatment was completed after 3 menstrual cycles in each group. Before and after treatment, the serum levels of testosterone (T), dihydrotestosterone (DHT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), sex hormone-binding globulin (SHBG), and the scores of acne and hirsutism were compared in the two groups; besides, menstrual recovery rate, ovulation recovery rate, basic body temperature (BBT) biphasic rate and clinical effect were compared between the two groups. RESULTS: Compared with those before treatment, the levels of T, DHT, LH and PRL, as well as the scores of acne and hirsutism were reduced in the two groups after treatment (P<0.05), and the levels of FSH and SHBG were increased (P<0.05). After treatment, the levels of T, DHT, LH and PRL, as well as the scores of acne and hirsutism in the observation group were lower than those in the control group (P<0.05); and FSH and SHBG were higher (P<0.05). After treatment, the menstrual recovery rate and ovulation recovery rate, as well as BBT biphasic rate in the observation group increased in comparison with the control group (P<0.05). The total effective rate was 97.5% (39/40) in the observation group, which was higher than 82.4% (33/40) of the control group (P<0.05). CONCLUSION Rendu Tongtiao acupuncture can effectively regulate the secretion of hormones, alleviate the clinical symptoms of HA, and accelerate the recovery of menstruation and natural ovulation in patients with PCOS-HA of kidney-yin deficiency induced fire hyperactivity .
Humans ; Female ; Polycystic Ovary Syndrome/complications* ; Acupuncture Therapy ; Adult ; Young Adult ; Hyperandrogenism/blood* ; Yin Deficiency/therapy* ; Kidney/physiopathology* ; Acupuncture Points ; Testosterone/blood* ; Luteinizing Hormone/blood* ; Follicle Stimulating Hormone/blood* ; Adolescent