ObjectiveThis paper aims to find the identified and validated clinical biomarker data building upon a clinical study of early-phase phase Ⅱ and investigate the correlation analysis of Huanglian Jiedu Wan on syndrome improvement and clinical biomarkers in the treatment of "excess heat-toxicity" based on a machine learning model. Additionally， the effective prediction of clinical biomarker values for the main symptoms of the "excess heat-toxicity" syndrome was assessed. MethodsA total of 229 patients meeting the inclusion criteria for "excess heat-toxicity" syndrome were randomly divided into the Huanglian Jiedu Wan group and the placebo group. Syndrome score transition matrices were constructed for the Huanglian Jiedu Wan group and the placebo group based on three main symptoms of "excess heat-toxicity" syndrome， such as oral ulcers， sore throat， and gum swelling and pain. Data from the patients with these three syndromes were also integrated for an overall analysis. The corresponding syndrome score transition matrices were further constructed to visualize symptom change trends of the patients in the two groups via heatmaps. Based on the identified and validated clinical biomarkers related to inflammation， oxidative stress， and energy metabolism in the early phase， Spearman correlation analysis was employed to analyze and evaluate the associations between clinical biomarkers and syndrome improvement. Key clinical biomarkers reflecting the effect of Huanglian Jiedu Wan were screened through the comparison of differences between groups. An extreme gradient boosting （XGBoost） algorithm was used to develop a prediction model for main symptom classification， with classification performance evaluated through 10-fold cross-validation. Feature importance analysis was applied to identify variables with the greatest contribution to the prediction result. ResultsThe syndrome transition matrix results indicated that the Huanglian Jiedu Wan group showed a superior effect to the placebo group in improving oral ulcers， sore throat， and overall symptoms， with significant effects observed especially in sore throat and overall symptom analyses （P<0.01）. Spearman correlation analysis revealed that several clinical biomarkers positively correlated with "excess heat-toxicity" syndrome and its main symptom improvement， were also called "heat-related biomarkers"， including succinic acid， α-ketoglutaric acid， glycine， lactic acid， adenosine monophosphate （AMP）， tumor necrosis factor-α （TNF-α）， interferon-γ （IFN-γ）， interleukin-1β （IL-1β）， interleukin-4 （IL-4）， interleukin-6 （IL-6）， interleukin-8 （IL-8）， interleukin-10 （IL-10）， and so on. Conversely， clinical biomarkers negatively correlated with symptom severity， were also called "heat-clearing related biomarkers" after administration of Huanglian Jiedu Wan， including malic acid， fumaric acid， cis-aconitic acid， adrenocorticotropic hormone （ACTH）， IL-1β， IL-4， IL-8， succinic acid， and citric acid. The XGBoost classification model using all 52 biomarkers as variables achieved an average test accuracy of 0.754 and an average F1 score of 0.777. Feature importance analysis identified the scores of glutamic acid in saliva and IL-6 were the highest in all the variables， with importance scores of 0.081 and 0.080， respectively. After screening out 14 key variables and optimizing the parameters， model performance improved to an average accuracy of 0.758 and an F1 score of 0.798. Feature importance analysis further determined that the glutamic acid in saliva and IL-6 showed obvious changes after screening the variables， confirming the good syndrome prediction ability of the model constructed by these key clinical biomarkers. ConclusionThis study systematically elucidates the correlation between syndrome improvement and clinical biomarkers of Huanglian Jiedu Wan in the treatment of "excess heat-toxicity" syndrome. An XGBoost classification model based on key clinical biomarkers is successfully established， achieving effective prediction of the symptoms related to the "excess heat-toxicity" syndrome such as oral ulcers and sore throat and providing a new insight for objective identification of traditional Chinese medicine syndromes.

ObjectiveThis paper aims to find the identified and validated clinical biomarker data building upon a clinical study of early-phase phase Ⅱ and investigate the correlation analysis of Huanglian Jiedu Wan on syndrome improvement and clinical biomarkers in the treatment of "excess heat-toxicity" based on a machine learning model. Additionally， the effective prediction of clinical biomarker values for the main symptoms of the "excess heat-toxicity" syndrome was assessed. MethodsA total of 229 patients meeting the inclusion criteria for "excess heat-toxicity" syndrome were randomly divided into the Huanglian Jiedu Wan group and the placebo group. Syndrome score transition matrices were constructed for the Huanglian Jiedu Wan group and the placebo group based on three main symptoms of "excess heat-toxicity" syndrome， such as oral ulcers， sore throat， and gum swelling and pain. Data from the patients with these three syndromes were also integrated for an overall analysis. The corresponding syndrome score transition matrices were further constructed to visualize symptom change trends of the patients in the two groups via heatmaps. Based on the identified and validated clinical biomarkers related to inflammation， oxidative stress， and energy metabolism in the early phase， Spearman correlation analysis was employed to analyze and evaluate the associations between clinical biomarkers and syndrome improvement. Key clinical biomarkers reflecting the effect of Huanglian Jiedu Wan were screened through the comparison of differences between groups. An extreme gradient boosting （XGBoost） algorithm was used to develop a prediction model for main symptom classification， with classification performance evaluated through 10-fold cross-validation. Feature importance analysis was applied to identify variables with the greatest contribution to the prediction result. ResultsThe syndrome transition matrix results indicated that the Huanglian Jiedu Wan group showed a superior effect to the placebo group in improving oral ulcers， sore throat， and overall symptoms， with significant effects observed especially in sore throat and overall symptom analyses （P<0.01）. Spearman correlation analysis revealed that several clinical biomarkers positively correlated with "excess heat-toxicity" syndrome and its main symptom improvement， were also called "heat-related biomarkers"， including succinic acid， α-ketoglutaric acid， glycine， lactic acid， adenosine monophosphate （AMP）， tumor necrosis factor-α （TNF-α）， interferon-γ （IFN-γ）， interleukin-1β （IL-1β）， interleukin-4 （IL-4）， interleukin-6 （IL-6）， interleukin-8 （IL-8）， interleukin-10 （IL-10）， and so on. Conversely， clinical biomarkers negatively correlated with symptom severity， were also called "heat-clearing related biomarkers" after administration of Huanglian Jiedu Wan， including malic acid， fumaric acid， cis-aconitic acid， adrenocorticotropic hormone （ACTH）， IL-1β， IL-4， IL-8， succinic acid， and citric acid. The XGBoost classification model using all 52 biomarkers as variables achieved an average test accuracy of 0.754 and an average F1 score of 0.777. Feature importance analysis identified the scores of glutamic acid in saliva and IL-6 were the highest in all the variables， with importance scores of 0.081 and 0.080， respectively. After screening out 14 key variables and optimizing the parameters， model performance improved to an average accuracy of 0.758 and an F1 score of 0.798. Feature importance analysis further determined that the glutamic acid in saliva and IL-6 showed obvious changes after screening the variables， confirming the good syndrome prediction ability of the model constructed by these key clinical biomarkers. ConclusionThis study systematically elucidates the correlation between syndrome improvement and clinical biomarkers of Huanglian Jiedu Wan in the treatment of "excess heat-toxicity" syndrome. An XGBoost classification model based on key clinical biomarkers is successfully established， achieving effective prediction of the symptoms related to the "excess heat-toxicity" syndrome such as oral ulcers and sore throat and providing a new insight for objective identification of traditional Chinese medicine syndromes.

ObjectiveTo observe the clinical efficacy and safety of Tangning Tongluo tablets in the treatment of nonproliferative diabetic retinopathy （DR）. MethodsFourteen research centers participated in this study， which spanned a time interval from September 2021 to May 2023. A total of 240 patients with nonproliferative DR were included and randomly assigned into an observation group （120 cases） and a control group （120 cases）. The observation group was treated with Tangning Tongluo tablets， and the control group with calcium dobesilate capsules. Both groups were treated for 24 consecutive weeks. The vision， DR progression rate， retinal microhemangioma， hemorrhage area， exudation area， glycosylated hemoglobin （HbA1c） level， and TCM syndrome score were assessed before and after treatment， and the safety was observed. ResultsThe vision changed in both groups after treatment （P<0.05）， and the observation group showed higher best corrected visual acuity （BCVA） than the control group （P<0.05）. The DR progression was slow with similar rates in the two groups. The fundus hemorrhage area and exudation area did not change significantly after treatment in both groups， while the observation group outperformed the control group in reducing the fundus hemorrhage area and exudation area. There was no significant difference in the number of microhemangiomas between the two groups before treatment. After treatment， the number of microhemangiomas decreased in both the observation group （Z=-1.437， P<0.05） and the control group （Z=-2.238， P<0.05）， and it showed no significant difference between the two groups. As the treatment time prolonged， the number of microhemangiomas gradually decreased in both groups. There was no significant difference in the HbA1c level between the two groups before treatment. After treatment， the decline in the HbA1c level showed no significant difference between the two groups. The TCM syndrome score did not have a statistically significant difference between the two groups before treatment. After treatment， neither the TCM syndrome score nor the response rate had significant difference between the two groups. With the extension of the treatment time， both groups showed amelioration of TCM syndrome compared with the baseline. ConclusionTangning Tongluo tablets are safe and effective in the treatment of nonproliferative DR， being capable of improving vision and reducing hemorrhage and exudation in the fundus.

Extensive evidence has demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can ameliorate obesity. Our previous studies revealed that (Ex-4)₂-Fc, a long-acting GLP-1RA we developed, depends on the leptin pathway to treat obesity. However, the mechanisms linking (Ex-4)₂-Fc and leptin resistance remain largely unclear. To address this question, we explored the mechanism of GLP-1RAs from the perspective of the gut microbiota, as increasing evidence indicates an important link between the gut microbiota and obesity. This study aimed to explore the potential role of the gut microbiota in the treatment of GLP-1RAs. We found that (Ex-4)₂-Fc treatment reshaped obesity-induced gut microbiota disturbances and substantially increased the abundance of Akkermansia muciniphila (Am). In addition, (Ex-4)₂-Fc did not respond well in antibiotic-treated (ATB) Obese mice. Subsequent studies have shown that this defect can be overcome by gavage with Am. In addition, we found that Am enhanced (Ex-4)₂-Fc therapy by producing the metabolite inosine. Inosine regulates the macrophage adenosine A2A receptor (A2A) pathway to indirectly reduce leptin levels in adipocytes Thus, elucidating the role of metabolites in regulating the leptin pathway will provide new insights into GLP-1RAs therapy and may lead to more effective strategies for guiding the clinical use of antidiabetic agents.

ObjectiveTo observe the therapeutic effect of BD-77 by nebulized inhalation on animal models of various respiratory viral infections and investigate the mechanism of broad-spectrum antiviral action of BD-77 using proteomics. MethodThe influenza virus H1N1/FM1 experiment used ICR mice and divided them into a normal group， model group， Tamiflu group， and BD-77 groups of 75 and 37.5 g·L^-1 for inhalation of 20 min and 25 min. Human coronavirus 229E and OC43 experiment divided the BALB/c mice into a normal group， model group， chloroquine phosphate group， and BD-77 groups of 75， 37.5， 18.75， and 9.375 g·L^-1， with 10 mice in each group. Influenza virus H1N1/FM1 and human coronaviruses 229E and OC43 infection-induced pneumonia models were used to detect mouse lung index， and real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the viral load in lung tissue. Enzyme-linked immunosorbent assay （ELISA） was used to detect related inflammatory factors in lung tissue， and proteomics analysis was performed on the lung tissue of OC43-infected mice. ResultCompared with that in the normal group， the lung index of mice in each infection group was significantly increased （P<0.01）， and viral nucleic acid could be detected in the lung tissue of mice infected with human coronaviruses 229E and OC43. The levels of interleukin-6 （IL-6）， IL-10， and tumor necrosis factor-α （TNF-α） in the lung tissue of mice infected with human coronavirus 229E were all significantly increased （P<0.01）. BD-77 could significantly reduce the lung index of mice infected with influenza virus H1N1/FM1 and human coronaviruses 229E and OC43 （P<0.05， P<0.01）， cut down the viral load in the lungs of mice infected with human coronaviruses 229E and OC43 （P<0.01）， and lower the contents of IL-6， IL-10， and TNF-α in the lung tissue of mice infected with human coronavirus 229E （P<0.01）. Proteomics analysis of the lung tissue of OC43-infected mice showed that BD-77 regulated the AMPK signaling pathway， TNF signaling pathway， NOD-like signaling pathway， IL-17 signaling pathway， Forkhead box protein O （FoxO） signaling pathway， transforming growth factor-β （TGF-β） signaling pathway， and other signaling pathways. ConclusionNebulized inhalation of BD-77 is effective in treating pneumonia caused by influenza virus H1N1/FM1 and human coronaviruses 229E and OC43 infection in mice and may exert its antiviral effects by regulating the balance of cellular metabolism， enhancing the immune function of the host， and attenuating inflammatory responses.

Objective To analyze the clinical efficacy of transcatheter tricuspid valve replacement (TTVR) in cardiac implantable electronic lead-related tricuspid regurgitation (TR). Methods The patients with severe TR who underwent LuX-Valve TTVR in 9 Chinese medical centers from June 2020 to August 2021 were retrospectively enrolled. They were divided into a cardiac implantable electronic device (CIED) group and a non-CIED group based on whether they had pre-existing CIED implantation. Success of the procedure was defined as safe implantation of the LuX-Valve and complete withdrawal of the delivery system. Prognostic improvement was defined as a decrease of TR grade to≤2+ and an improvement of cardiac function by≥2 grades. Surgical success and postoperative prognosis were compared between the two groups. Results A total of 190 patients were collected, including 50 males and 140 females with a mean age of 66.2±7.8 years. There were 29 patients in the CIED group, and 161 patients in the non-CIED group. In the CIED group, 28 patients were implanted with a permanent pacemaker and 1 patient with a cardioverter-defibrillator. Preoperative New York Heart Association (NYHA) cardiac function class, TR degree, left ventricular ejection fraction, tricuspid annular plane systolic excusion, and cardiac risk scores were comparable between the two groups (P>0.05). Postoperative TR was reduced to≤2+ in all patients, and there was no statistical difference in the incidence of perivalvular leakage between the two groups (P=0.270). Postoperative CT of CIED patients showed the valve was in place, and the lead was not extruded, twisted, or deflected. The in-hospital mortality of the two groups were 10.3% and 1.9%, respectively, and the difference was statistically significant (P=0.047). In addition, there was no statistical difference between the two groups in terms of postoperative improvement of cardiac function and mortality in the 1- and 2-year follow-up. Conclusion TTVR is feasible, safe, and effective in patients with CIED implantation, and the pre-existing lead has no significant effect on the clinical efficacy.

cAMP response element binding protein (CREB) is an eukaryotic intranuclear protein widely expressed in a variety of organs, and its activation increases the transcriptional activity of downstream genes and promotes the expression of related genes. The neuronal function of CREB is related to many intracellular processes, such as proliferation, differentiation, survival, long-term synaptic potentials, neurogenesis and neuronal plasticity. Increasing evidence has demonstrated that CREB plays an important role in the stroke development and therefore, it may serve as a potential target for stroke therapy. Since some herbal medicines as well as their active ingredients regulate the CREB signaling, this article will summarize the role of CREB signaling pathway in stroke pathophysiology. The research progress of traditional Chinese medicine and its active ingredients modulating CREB activity will also be discussed, with the aim of providing the basis and reference for the future research and development of natural medicines against stroke.

Objective To investigate the modulatory effect of Yulian Pills(composed of Coptidis Rhizoma and Euodiae Fructus)on splenic memory follicular T helper cell(mTfh)in mice with dextran sodium sulfate(DSS)-induced ulcerative colitis.Methods Forty BALB/c mice were randomly divided into normal group,model group,Yulian Pills group(0.5 g·kg-1)and Mesalazine group(0.3 g·kg-1),10 mice in each group.The mouse model of ulcerative colitis was induced by ad libitum drinking 3%DSS solution for 7 days.During the experiment,the mental state,faecal characteristics,blood in stool and body mass of the mice were recorded daily,and the length and mass of the colon were measured and the colon mass index was calculated;HE staining was used to observe the pathological and morphological changes of the colon tissue;ELISA was used to determine the expression levels of interleukin(IL)-6 and IL-15 in the colon tissues;flow cytometry was used to determine the mTfh cell subpopulation in the spleen tissue expression;Western Blot was used to determine the protein expression levels of Roquin-1,AMPK-α,p-AMPK-α in colon tissues.Results Compared with the normal group,the mice in the model group showed a significant decrease in body mass(P＜0.01),a significant shortening of colon length(P＜0.01),significant increase in colon mass(P＜0.05)and colon mass index(P＜0.01),and severe pathological damage to colon tissues;the expression levels of the pro-inflammatory cytokines IL-6 and IL-15 in the colon tissues were significantly increased(P＜0.01);cell expression levels of CD4+CCR7-CXCR5+CD62L+,CD4+CCR7+CXCR5+ GL7+,CD4+CCR7-CXCR5+GL7+ were significantly increased in spleen tissues(P＜0.01),whereas the expression level of CD4+CCR7+CXCR5+CD62L+ cell was significantly decreased(P＜0.01);and protein expression levels of Roquin-1,AMPK-α,p-AMPK-α were significantly reduced in the colonic tissues(P＜0.05).Compared with the model group,mice in the Yulian Pills group and Mesalazine group showed a significant increase in body mass(P＜0.05),a significant extension of colon length(P＜0.01),a significant reduction in colon mass(P＜0.05),a significant decrease in the colon mass index(P＜0.01),and a more obvious improvement in pathological damage of the colon tissues;a significant decrease in the expression levels of IL-6 and IL-15 in the colon tissues(P＜0.01);cell expression levels of CD4+CCR7-CXCR5+CD62L+,CD4+CCR7+CXCR5+GL7+,CD4+CCR7-CXCR5+GL7+ in splenic tissues was significantly reduced(P＜0.01),whereas the expression level of CD4+CCR7+CXCR5+CD62L+ cell was significantly increased(P＜0.01);the protein expression levels of Roquin-1,AMPK-α,and p-AMPK-α were significantly increased in colon tissues(P＜0.05,P＜0.01).Conclusion The therapeutic effect of Yulian Pills on DSS-induced ulcerative colitis mice can ameliorate the histopathological damage of colon,which may be related to the activation of the Roquin-1/MPK-α signalling pathway,the down-regulation of the expressions of inflammatory cytokines IL-6 and IL-15,and the modulation of the homeostasis of the mTfh cell subpopulation.

Objective To investigate the risk factors for postoperative gastrointestinal bleeding (GIB) in patients with type A aortic dissection, and further discuss its prevention and treatment. Methods The clinical data of patients with type A aortic dissection admitted to the Department of Cardiovascular Surgery of the First Affiliated Hospital of Naval Medical University from 2017 to 2021 were retrospectively analyzed. Patients were divided into a GIB group and a non-GIB group based on the presence of GIB after surgery. The variables with statistical differences between two groups in univariate analysis were included into a multivariate logistic regression model to analyze the risk factors for postoperative GIB in patients with type A aortic dissection. Results There were 18 patients in the GIB group including 12 males and 6 females, aged 60.11±10.63 years, while 511 patients in the non-GIB group including 384 males and 127 females, aged 49.81±12.88 years. In the univariate analysis, there were statistical differences in age, preoperative percutaneous arterial oxygen saturation (SpO2)<95%, intraoperative circulatory arrest time, postoperative low cardiac output syndrome, ventilator withdrawal time>72 hours, postoperative FiO2≥50%, continuous renal replacement therapy (CRRT) rate, extracorporeal membrane oxygenation (ECMO) rate, infection rate, length of hospital stay and ICU stay, and in-hospital mortality (all P<0.05). In the multivariate logistic regression analysis, preoperative SpO2<95% (OR=10.845, 95%CI 2.038-57.703), ventilator withdrawal time>72 hours (OR=0.004, 95%CI 0.001-0.016), CRRT (OR=6.822, 95%CI 1.778-26.171) were risk factors for postoperative GIB in patients (P≤0.005). In the intra-group analysis of GIB, non-occlusive mesenteric ischemia (NOMI) accounted for 38.9% (7/18) and was the main disease type for postoperative GIB in patients with type A aortic dissection. Conclusion In addition to patients with entrapment involving the superior mesenteric artery who are prone to postoperative GIB, preoperative SpO2<95%, ventilator withdrawal time>72 hours, and CRRT are independent risk factors for postoperative GIB in patients with type A aortic dissection. NOMI is a major disease category for GIB, and timely diagnosis and aggressive treatment are effective ways to reduce mortality. Awareness of its risk factors and treatment are also ways to reduce its incidence.

Objective To analyze the postoperative therapeutic effect of prokinetic agents in patients after tricuspid valve replacement （TVR） under cardiopulmonary bypass. Methods Patients received TVR under cardiopulmonary bypass （during June 2010 to December 2021） in the department of Cardiovascular Surgery of the First Affiliated Hospital of Naval Medical University were selected as the subjects of our study. The data of basic characteristics, first postoperative defecation time and postoperative recovery condition were collected and retrospectively analyzed in the patients taking prokinetic agents within three days after surgery （prevention group） and patients not taking prokinetic agents within three days after surgery （control group）. Results A total of 184 patients were selected, including 101 in the prevention group and 83 in the control group. The first defecation time of patients in the prevention group was significantly earlier than that in the control group （P<0.05）. The incidences of abdominal distension and pulmonary infection in the prevention group were significantly lower than that in the control group. The length of time in ICU, postoperative mechanical ventilation and nasogastric tube decompression in the prevention group were significantly shorter than that in the control group （P<0.05）. Conclusion Taking prokinetic agents within three days after TVR under cardiopulmonary bypass could effectively improve the prognosis of patients.