Thyroid dysfunction(TD)is a prevalent disorder of the endocrine system.Owing to its non-specific clinical symptoms and the limitations inherent in current diagnostic approaches,there is a pressing need to further investigate its underlying pathogenesis and identify novel biomarkers.As a pivotal component of systems biology,omics technologies offer a promising avenue for uncovering the molecular mechanisms of TD by integrating high-throughput data.This thesis presents a comprehensive review of recent advancements in genomics,transcriptomics,proteomics,metabolomics,lipidomics,and multi-omics research related to TD.It examines genetic variations and epigenetic regulatory mechanisms from multiple molecular levels,including DNA,RNA,proteins,and metabolites.Furthermore,it elucidates the metabolic disturbances associated with TD and the modes of action of relevant therapeutic agents,contributing to the development of potential biomarkers and drug targets for early detection and intervention.By synthesizing findings across various omics platforms,this thesis aims to delineate the complex network interactions underlying TD and to provide valuable insights and strategies for future clinical management,as well as personalized diagnosis and treatment.

Thyroid dysfunction(TD)is a prevalent disorder of the endocrine system.Owing to its non-specific clinical symptoms and the limitations inherent in current diagnostic approaches,there is a pressing need to further investigate its underlying pathogenesis and identify novel biomarkers.As a pivotal component of systems biology,omics technologies offer a promising avenue for uncovering the molecular mechanisms of TD by integrating high-throughput data.This thesis presents a comprehensive review of recent advancements in genomics,transcriptomics,proteomics,metabolomics,lipidomics,and multi-omics research related to TD.It examines genetic variations and epigenetic regulatory mechanisms from multiple molecular levels,including DNA,RNA,proteins,and metabolites.Furthermore,it elucidates the metabolic disturbances associated with TD and the modes of action of relevant therapeutic agents,contributing to the development of potential biomarkers and drug targets for early detection and intervention.By synthesizing findings across various omics platforms,this thesis aims to delineate the complex network interactions underlying TD and to provide valuable insights and strategies for future clinical management,as well as personalized diagnosis and treatment.

Intervertebral disc degeneration (IDD) is largely attributed to impaired endogenous repair. Nucleus pulposus-derived stem cells (NPSCs) senescence leads to endogenous repair failure. Small extracellular vesicles/exosomes derived from mesenchymal stem cells (mExo) have shown great therapeutic potential in IDD, while whether mExo could alleviate NPSCs senescence and its mechanisms remained unknown. We established a compression-induced NPSCs senescence model and rat IDD models to evaluate the therapeutic efficiency of mExo and investigate the mechanisms. We found that mExo significantly alleviated NPSCs senescence and promoted disc regeneration while knocking down thioredoxin (TXN) impaired the protective effects of mExo. TXN was bound to various endosomal sorting complex required for transport (ESCRT) proteins. Autocrine motility factor receptor (AMFR) mediated TXN K63 ubiquitination to promote the binding of TXN on ESCRT proteins and sorting of TXN into mExo. Knocking down exosomal TXN inhibited the transcriptional activity of nuclear factor erythroid 2-related factor 2 (NRF2) and activator protein 1 (AP-1). NRF2 and AP-1 inhibition reduced endogenous TXN production that was promoted by exosomal TXN. Inhibition of NRF2 in vivo diminished the anti-senescence and regenerative effects of mExo. Conclusively, AMFR-mediated TXN ubiquitination promoted the sorting of TXN into mExo, allowing exosomal TXN to promote endogenous TXN production in NPSCs via TXN/NRF2/AP-1 feed-forward circuit to alleviate NPSCs senescence and disc degeneration.

Objective:To investigate the relationship between collateral circulation and viable myocardium (VM) in patients with coronary chronic total occlusion (CTO).Methods:A total of 88 patients (76 males, 12 females, age (61.0±9.8) years) with coronary CTO were retrospectively analyzed. All patients underwent both 99Tc m-methoxyisobutylisonitrile (MIBI) SPECT myocardial perfusion imaging and 18F-FDG PET myocardial metabolism imaging for evaluation of VM at the First People′s Hospital of Changzhou between September 2012 and June 2023, and they were scheduled to receive coronary revascularization. The perfusion/metabolism mismatch myocardium was regarded as VM. The VM index within the CTO region was calculated, reflected the quantities of VM: VM index=(summed rest score within the CTO region-summed 18F-FDG uptake score within the CTO region)/reduced perfusion myocardial segments×4×100%. Rentrop grading of collateral circulation was performed based on coronary angiography. The differences of VM index within the CTO region between poor-developed (PD, Rentrop grade 0-1) and well-developed (WD, Rentrop grade 2-3) collateral circulation, and among different Rentrop grades were analyzed by the independent-sample t test or Kruskal-Wallis rank sum test. The linear regression analysis was used to evaluate the relationship between Rentrop grading and VM index within the CTO region. The ROC curve was constructed to analyze the predictive value of Rentrop grading for VM within the CTO region. Results:The VM index within the CTO region was significantly higher in WD patients ( n=54) compared to those in PD patients ( n=34): (45.8±16.3)% vs (21.3±16.7)% ( t=-6.79, P<0.001). Moreover, the VM index within the CTO region increased with increased Rentrop grade, and there was a significant difference among 4 groups ( H=30.22, P<0.001). Multiple linear regression analysis showed that only the Rentrop grading was an independent influencing factor for the VM index within the CTO region ( β=9.29, 95% CI: 5.91-12.67, P<0.001). ROC curve showed that the sensitivity and specificity of Rentrop grading score≥2 for predicting the presence or absence of VM within the CTO region were 65.8%(52/79) and 7/9, with the AUC of 0.724(95% CI: 0.619-0.814). Conclusions:In CTO patients who are scheduled for revascularization and evaluation of VM, as the Rentrop grading increases, the VM index within the CTO region also increases. The presence of VM within the CTO region can be predicted with Rentrop grading score ≥2.

Objective:To investigate the relationship between collateral circulation and viable myocardium (VM) in patients with coronary chronic total occlusion (CTO).Methods:A total of 88 patients (76 males, 12 females, age (61.0±9.8) years) with coronary CTO were retrospectively analyzed. All patients underwent both 99Tc m-methoxyisobutylisonitrile (MIBI) SPECT myocardial perfusion imaging and 18F-FDG PET myocardial metabolism imaging for evaluation of VM at the First People′s Hospital of Changzhou between September 2012 and June 2023, and they were scheduled to receive coronary revascularization. The perfusion/metabolism mismatch myocardium was regarded as VM. The VM index within the CTO region was calculated, reflected the quantities of VM: VM index=(summed rest score within the CTO region-summed 18F-FDG uptake score within the CTO region)/reduced perfusion myocardial segments×4×100%. Rentrop grading of collateral circulation was performed based on coronary angiography. The differences of VM index within the CTO region between poor-developed (PD, Rentrop grade 0-1) and well-developed (WD, Rentrop grade 2-3) collateral circulation, and among different Rentrop grades were analyzed by the independent-sample t test or Kruskal-Wallis rank sum test. The linear regression analysis was used to evaluate the relationship between Rentrop grading and VM index within the CTO region. The ROC curve was constructed to analyze the predictive value of Rentrop grading for VM within the CTO region. Results:The VM index within the CTO region was significantly higher in WD patients ( n=54) compared to those in PD patients ( n=34): (45.8±16.3)% vs (21.3±16.7)% ( t=-6.79, P<0.001). Moreover, the VM index within the CTO region increased with increased Rentrop grade, and there was a significant difference among 4 groups ( H=30.22, P<0.001). Multiple linear regression analysis showed that only the Rentrop grading was an independent influencing factor for the VM index within the CTO region ( β=9.29, 95% CI: 5.91-12.67, P<0.001). ROC curve showed that the sensitivity and specificity of Rentrop grading score≥2 for predicting the presence or absence of VM within the CTO region were 65.8%(52/79) and 7/9, with the AUC of 0.724(95% CI: 0.619-0.814). Conclusions:In CTO patients who are scheduled for revascularization and evaluation of VM, as the Rentrop grading increases, the VM index within the CTO region also increases. The presence of VM within the CTO region can be predicted with Rentrop grading score ≥2.

Objective:To assess the prevalence of exercise addiction among college students and explore its relationship with negative emotion and exercise frequency.Methods:A total of 837 college students were enrolled from January 1, 2022 to December 31, 2022. The cross-sectional survey was administered using the exercise dependence scale revised(EDS-R) and the depression, anxiety, and stress scale 21 items (DASS-21). Data analysis was conducted with SPSS 26.0 software, including partial correlation analysis and hierarchical regression.Results:Among college students, the students in the group with risk and symptoms of exercise addiction accounted for 4.9%(EDS-R score (110.32±11.51), DASS-21-depression score 21.00(10.50, 25.00), DASS-21-anxiety score 21.00(11.50, 24.00), DASS-21-stress score 42.00(22.00, 47.50)). The students in the group without risk but with symptoms accounted for 42.53%(EDS-R score (60.02±12.91), DASS-21-depression score 8.00(1.00, 14.00), DASS-21-anxiety score 8.00(3.00, 14.00), DASS-21-stress score 15.00(4.00, 28.00)), and the students in the group without risk and symptoms accounted for 52.57%(EDS-R score (31.57±7.51), DASS-21-depression score 8.00(5.00, 12.00), DASS-21-anxiety score 7.00(3.00, 10.00), DASS-21-stress score 15.00(6.00, 21.00)). Exercise addiction scores were positively correlated with stress ( r=0.303, P<0.001), anxiety ( r=0.327, P<0.001), and depression ( r=0.259, P<0.001). The results of the hierarchical regression analysis also showed that the main risk variables were anxiety (△ R2=0.175, F=60.954) and exercise frequency (△ R2=0.044, F=21.401). Additionally, male college students had a higher risk of exercise addiction than female( P<0.01), but there was no gender difference in negative emotions( P>0.05). Conclusion:The college students were susceptible to developing an exercise addiction, especially among individuals with high exercise frequency and anxiety symptoms.It provides robust behavioral evidence in support of early detection and treatment of high-risk exercise addiction groups.

Objective To explore the clinical efficacy of prone position ventilation(PPV)in improving hypoxemia in patients with severe brain damage.Methods A retrospective research method was conducted,140 patients with severe brain damage who were admitted to the department of critical care medicine of the First Affiliated Hospital,Zhejiang University School of Medicine from August 2020 to August 2021 were selected as subject objected.According to the inclusion and exclusion criteria,20 patients with oxygenation index≤200 mmHg(1 mmHg≈0.133 kPa)who were treated with PPV were statistically analyzed.The patients'blood gas analysis related indicators[including arterial partial pressure of oxygen(PaO2),fractional of inspired oxygen(FiO2),oxygenation index,arterial oxygen saturation(SaO2),arterial partial pressure of carbon dioxide(PaCO2),pH value],ventilator-related parameters[including peak inspiratory pressure(PIP),positive end-expiratory pressure(PEEP),tidal volume(VT),lung dynamic compliance(Cdyn),etc.],and mean arterial pressure(MAP),heart rate(HR)were compared before PPV,12 hours after PPV,and 12 hours after reverting to supine position.At the same time,the related complications of patients during PPV were recorded.Results There were 15 males and 5 females,the mean age of the patients was(46.10±17.22)years old,the average PPV time was(22.20±5.94)hours.Compared with before PPV,patients showed significant increases in PaO2,oxygenation index,SaO2,VT,and Cdyn at 12 hours after PPV and 12 hours after recovery from supine position[PaO2(mmHg):98.35±21.85,98.45±17.90 vs.72.15±10.14,oxygenation index(mmHg):198.82±40.51,202.27±46.39 vs.133.20±33.95,SaO2:0.97±0.02,0.97±0.01 vs.0.94±0.03,VT(mL):558.42±111.23,580.29±119.44 vs.484.82±123.77,Cdyn(mL/cmH2O):26.11±5.42,27.90±5.80 vs.24.15±6.13,all P<0.05];Compared with 12 hours after PPV,the Cdyn of the patient still showed a significant increase after 12 hours of recovery from supine position(P<0.05).There were no statistical differences in the FiO2,PaCO2,pH value,PIP,PEEP,HR,and MAP of patients at various time points before and after PPV(all P>0.05).Five patients developed redness and swelling at the skin compression site mainly on the face after PPV,which gradually improved after returning to a supine position.During this period,there was no occurrence of catheter detachment,malignant arrhythmia,or significant hemodynamic instability.Conclusion PPV has a certain clinical effect on improving hypoxemia in patients with severe brain damage.

Objective:To investigate the role and molecular mechanism of sensory neuron-derived exosomes (nExo) in mediating intervertebral disc degeneration (IDD).Methods:A rat IDD model was constructed, with nExo injected into the intervertebral disc. After 4 weeks, the degenerative grades of operated discs were evaluated using histological staining, while the senescent phenotype of nucleus pulposus stem cells (NPSC) in the tissue was evaluated using immunofluorescence staining. For in vitro experiments, 24 hours after the treatment of nExo to NPSC, immunoblotting, flow cytometry, or senescence-associated β-galactosidase staining was applied to evaluate the senescent phenotype of NPSC. Transcriptomics analysis was applied to identify the key molecules that mediate nExo-induced cells senescence. After 4 weeks of injecting nExo and TXN into the rat tail disc degeneration model.Results:nExo increased the degenerative grades of IDD and increased the proportion of TEK +p16 + and TEK +p21 + cells (from 36.32% ±4.04%, 33.69% ±4.56% in IDD group to 56.41% ±5.26%, 50.14% ±8.49% in IDD+nExo group, respectively; t=7.420, P<0.001; t=4.184, P<0.0019, respectively) in the disc tissue. Besides, nExo promoted the expression of p16 and p21 in NPSC and increased the percentage of cells with positive senescence-associated β-galactosidase staining (from 7.32%±1.73% to 58.22%±11.38%, t=7.658, P=0.002), while the percentage of G2/M cells was downregulated (from 18.10%±1.32% to 1.60%±0.67%, t=19.290, P<0.001). Transcriptomic analysis showed that the differential genes of CTRL vs. nExo were closely related to cell senescence, and TXN was screened by intersecting the differential gene set with the cellular senescence gene sets from the published database. Furthermore, we verified that nExo decreased the content of TXN in NPSC, while exogenous TXN downregulated the expression of p16 and p21 in NPSC, reduced the positive cell rate of senescence-associated β-galactosidase staining (from 58.84%±3.99% to 21.68%±8.16%, t=7.048, P=0.021), increased the percentage of G2/M cells (from 1.21%±0.34% to 15.26%±2.60%, t=9.259, P=0.001). TXN significantly reduced the grade of disc tissue degeneration (histological score: 14.33±0.82 in the nExo group; 8.17±1.17 in the nExo+TXN group, t=10.590, P<0.001), significantly increased the content of extracellular matrix (from 10.94±4.35 μg/mg to 50.55±12.16 μg/mg, t=7.512, P<0.001), and reduced the proportion of TEK +p16 + and TEK +p21 + double-positive cells (from 54.92%±4.21% and 60.31%±9.02% to 27.93%±3.26% and 33.75%±8.07%, respectively; t=12.430, P<0.001; t=5.375, P<0.001, respectively). Conclusion:nExo promotes cell senescence and IDD by downregulating TXN in NPSC.

Objective:To evaluate early residual myocardial ischemia after successful percutaneous coronary intervention (PCI) in patients with coronary artery disease by using myocardial perfusion imaging (MPI) and investigate independent influencing factors of early residual myocardial ischemia.Methods:From January 2020 to December 2022, 127 patients (107 males, 20 females; age (60.3±9.6) years) with coronary artery disease who underwent PCI complete revascularization at the First People′s Hospital of Changzhou were consecutively enrolled prospectively. All patients underwent rest and stress MPI within 1-3 months after PCI. Reversible myocardial perfusion defect in the blood supply area of the culprit vessels in stress and rest MPI was defined as early residual myocardial ischemia after PCI. Accordingly, the culprit vessels undergoing PCI were divided into residual ischemic group and non-ischemic group. Differences of cardiovascular examination between two groups were compared ( χ2 test), such as proportion of culprit vessels with severe stenosis (≥90%), proportion of bifurcation lesions, and proportion of diffuse coronary disease. Logistic regression analyses were performed to identify influencing factors for early residual myocardial ischemia. Results:Among 148 culprit vessels undergoing PCI in 127 patients, early residual myocardial ischemia was present in 49 vessels (33.1%, 49/148). The proportion of culprit vessels with severe stenosis before PCI in residual ischemia group was higher than that in non-ischemia group (69.4%(34/49) and 49.5%(49/99); χ2=5.27, P=0.022). The proportion of bifurcation lesions in residual ischemic group was also higher than that in non-ischemic group (28.6%(14/49) and 10.1%(10/99); χ2=8.23, P=0.004), with a slightly higher proportion of diffuse coronary disease compared to non-ischemic group (14.3%(7/49) and 4.0%(4/99); χ2=3.62, P=0.057). Multivariate logistic regression analysis showed that bifurcation lesion (odds ratio ( OR)=4.087, 95% CI: 1.615-10.344, P=0.003) and diffuse coronary disease ( OR=4.208, 95% CI: 1.115-15.878, P=0.034) were independent influencing factors for early residual myocardial ischemia. Conclusions:Early residual myocardial ischemia is still present in about 1/3 of the culprit vessels after PCI complete revascularization. Bifurcation lesion and diffuse coronary disease are independent influencing factors for early residual myocardial ischemia in culprit vessels.

Objective:To evaluate inflammation early in the infarct zone and its dynamic changes after acute myocardial infarction (AMI) using 18F-FDG PET imaging, and analyze its relationship with left ventricular remodeling progression (LVRP). Methods:Sixteen Bama miniature pigs (4-6 months old, 8 females) were selected. AMI models were established by balloon occlusion of the left anterior descending artery. 18F-FDG PET imaging was performed before AMI and at days 1, 5, 8, and 14 post-AMI to evaluate the regional inflammation response. 18F-FDG SUV ratio (SUVR) and the percentage of uptake area of left ventricle (F-extent) in the infarct zone, and the SUVRs of the spleen and bone marrow, were measured. Echocardiography and 99Tc m-methoxyisobutylisonitrile(MIBI) SPECT myocardial perfusion imaging (MPI) were performed at the above time points and on day 28 post-AMI to assess left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), and myocardial perfusion defect extent. The degree of LVRP at day 28 post-AMI was defined as ΔLVESV(%)=(LVESV AMI 28 d-LVESV AMI 1 d)/LVESV AMI 1 d×100%. Data were analyzed using repeated measures analysis of variance, Kruskal-Wallis rank sum test and Pearson correlation analysis. Results:Twelve pigs were successfully modeled and completed the study. Inflammation in the infarct zone persisted until day 14 post-AMI. The SUVR of the infarct zone pre-AMI and at days 1, 5, 8, and 14 post-AMI were 1.03±0.08, 3.49±1.06, 2.93±0.90, 2.38±0.76, and 1.63±0.62, respectively ( F=49.31, P<0.001). The F-extent values in the infarct zone pre-AMI and at days 1, 5, 8, and 14 post-AMI were 0, (40.08±12.46)%, (40.00±12.76)%, (31.08±12.82)%, and 16.50%(7.25%, 22.00%), respectively ( H=37.61, P=0.001). There were no significant differences in the SUVRs of bone marrow and spleen before and after AMI ( F values: 0.69 and 0.77, both P>0.05). At day 1 post-AMI, both SUVR and F-extent in the infarct zone were significantly correlated with LVRP ( r values: 0.82 and 0.70, P values: 0.001 and 0.035). Conclusions:18F-FDG PET imaging can be used to evaluate inflammation in the infarct area and its dynamic changes after AMI. Inflammation in the infarct area is severe at day 1, and then gradually decreases. The extent and severity of inflammation visible on 18F-FDG PET imaging 1 d after AMI are closely related to LVRP.