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.

Objective:To prepare 89Zr-labeled anti-human podoplanin (PDPN) monoclonal antibody SZ168 and evaluate its feasibility for melanoma immunoPET imaging. Methods:89Zr-desferrioxamine (DFO)-SZ168 was prepared by conjugating p-isothiocyanatobenzyl (SCN-Bn)-DFO with SZ168 and chelating with 89Zr. Quality control analyses were conducted, including labeling rate, radiochemical purity, and in vitro stability. Melanoma mouse models were created, with experimental group ( n=3) and control group ( n=3) receiving tail vein injections of 89Zr-DFO-SZ168 and 89Zr-DFO-immunoglobulin (Ig)G solutions (3.7MBq) respectively. The experimental group underwent microPET/CT imaging at 12, 24, 48 and 72h post-injection, while the control group underwent imaging at 48h post-injection. Tumor and organ radioactivity uptake was analyzed using the ROI method. Mice were sacrificed at 7d post-injection to assess the ex vivo biodistribution of 89Zr-DFO-SZ168 and 89Zr-DFO-IgG. Independent-sample t test was used to analyze the data. Results:The pH value of the 89Zr-DFO-SZ168 solution was approximately 7.0, with a labeling rate >60%, radiochemical purity >95% after PD10 column purification, and good stability after 72h in vitro. Series microPET/CT imagings showed significant tumor visualization in tumor-bearing mice. Radioactivity uptake in tumors peaked at 48h post-injection, while the tumor was not clearly detected by 89Zr-DFO-IgG microPET/CT imaging. Ex vivo biodistribution indicated that 89Zr-DFO-SZ168 mainly accumulated in tumors, liver, and bones, with tumor uptake significantly higher than that of 89Zr-DFO-IgG ((29.36±7.29) percentage activity of injection dose per gram of tissue (%ID/g) vs (8.78±1.63) %ID/g; t=4.77, P=0.009). Immunohistochemistry of tumor specimens showed high expression of PDPN in tumor tissues. Conclusions:The probe 89Zr-DFO-SZ168 is successfully prepared, showing potential for specific molecular imaging diagnosis of melanoma. This lays a basis for developing PDPN molecular target-based immuno-PET diagnosis and integrated diagnosis and treatment for melanoma.

Objective:To evaluate the changes in cortical electroencephalogram (EEG) burst suppression rate (BSR) during sevoflurane anesthesia in septic mice and the correlation with cerebral blood perfusion.Methods:Forty SPF male C57BL/6J mice, aged 8-10 weeks, weighing 22-25 g, were divided into 2 groups ( n=20 each) by the random number table method: sham operation group (Sham group) and cecal ligation perforation group (CLP group). The sepsis model was established by cecal ligation and puncture in anesthetized animals. Mice in both groups inhaled 2% sevoflurane for 2 h. During sevoflurane anesthesia, BSR (30 min as an epoch) on electroencephalogram was recorded, and the cortical cerebral blood perfusion was recorded using the laser speckle flow imaging at 30, 60, 90 and 120 min of anesthesia. Results:Compared with Sham group, the cortical EEG BSR was significantly increased, and the cortical cerebral blood perfusion was decreased during sevoflurane anesthesia in CLP group ( P<0.05). Cortical EEG BSR was negatively correlated with cortical cerebral blood perfusion ( P<0.05). Conclusions:Cortical EEG BSR increases during sevoflurane anesthesia in septic mice, which may be related to decreased cortical cerebral blood perfusion.

Objective:To explore the short-term clinical effects of deep cervical lymph node-venous anastomosis in the treatment of Alzheimer’s disease (AD).Methods:A prospective exploratory study was conducted on the treatment of AD patients using the cervical deep lymph node-venous anastomosis technique in Scar and Wound Treatment Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, from September to October 2024. The patients underwent high-frequency ultrasound to locate deep cervical lymph nodes and the external jugular vein. Under general anesthesia, bilateral deep cervical lymph node-venous anastomoses were performed. Indocyanine green (ICG) lymphography was conducted via subcutaneous injection behind the ear to visualize lymph nodes in levels Ⅱ and Ⅲ. After making a skin incision along the posterior margin of the sternocleidomastoid muscle, the external jugular vein, internal jugular veins, and associated lymph nodes were exposed. Adjacent veins were selected for anastomosis of lymph node. Using microsurgical techniques, end-to-side or end-to-end anastomosis was completed for lymph nodes in levels Ⅱ and Ⅲ. Preoperative assessments included the mini-mental state examination (MMSE, a higher score indicates better cognitive function), Alzheimer’s disease assessment scale-cognitive subscale (ADAS-Cog, a higher score indicates greater impairment of cognitive function), Alzheimer’s disease cooperative study scale for activities of daily living (ADCS-ADL, a higher score indicates better ability to perform daily activity), and neuropsychiatric inventory (NPI, a higher score indicates more severe behavioral and emotional symptom). Postoperative follow-up included the same scales to observe changes in cognitive function, activities of daily living, and emotional communication.Results:Four patients (1 male, 3 females, aged 58-79 years) with AD were included. All were diagnosed based on cerebrospinal fluid biomarkers. All patients successfully underwent bilateral deep cervical lymph node-venous anastomoses. On average, 4.3 (2-7 per person) anastomoses were performed per patient. Surgical procedures lasted an average of 6.5 h (5.5-8.5 h) with minimal blood loss (less than 50 ml). Patients resumed normal activity within 6 hours postoperatively and were discharged after an average of 4.1 d (3.5-5.0 d). Postoperative complications included one case each of aspiration pneumonia, lower limb venous thrombosis, and transient delirium, all of whom resolved without long-term effects. Clinical symptoms, including memory decline, mood swings, and anxiety, showed varying degrees of improvement. Patients reported enhanced quality of life, emotional stability, and social engagement, confirming the procedure’s safety and potential cognitive benefits. At one month postoperatively, the MMSE scores of the four patients increased by an average of 0.8 points compared to preoperative levels. Additionally, the two patients who completed the ADAS-Cog assessments showed a decrease in their scores (reduced by 1.0 points and 11.3 points, respectively, compared to preoperative scores), indicating a certain degree of improvement in cognitive function during this period. The ADCS-ADL and NPI scores of four patients varied significantly, without showing any clear pattern.Conclusion:Lymphovenous anastomosis of the deep cervical lymph node-venous anastomosis may provide a new surgical intervention approach for AD, but further large-scale studies and long-term follow-up are needed to validate its safety and effectiveness.

Objective To evaluate the value of color Doppler echocardiography and electrocardiography in assessing cardiac function and disease severity in patients with hypertensive heart disease.Methods A retrospective analysis was conducted on 205 patients with hypertensive heart disease who were categorized into 3 groups based on the New York Heart Association(NYHA)criteria:class Ⅱ(n=62),class Ⅲ(n=89)and class Ⅳ(n=54).The demographic characteristics(including gender and age)and the results of color Doppler echocardiography and electrocardiography were extracted from the hospital's medical record system for analyzing the relationships of the diagnostic findings from color Doppler echocardiography and electrocardiography with cardiac function and disease severity.Results Electrocardiography revealed statistically significant intergroup differences in QTc interval,QRS voltage,and QRS duration across 3 groups(P<0.05).Among 3 groups,class Ⅳ group exhibited the most pronounced abnormalities with prolonged QTc interval and QRS duration,along with reduced QRS voltage(P<0.05).Compared with class Ⅱ group,class Ⅲ group had longer QTc interval and QRS duration,alongside lower QRS voltage(P<0.05).Color Doppler echocardiography showed that left ventricular systolic diameter,left ventricular diastolic diameter,left atrial diameter,left ventricular posterior wall thickness,interventricular septum thickness,left ventricular ejection fraction,and E/A ratio differed significantly across 3 groups(P<0.05).Class Ⅳ group exhibited the largest left ventricular systolic diameter,left ventricular diastolic diameter and left atrial diameter,the thickest left ventricular posterior wall and interventricular septum,and the lowest left ventricular ejection fraction and E/A ratio(P<0.05).Compared with class Ⅱ group,class Ⅲ group had enlarged left ventricular systolic diameter,left ventricular diastolic diameter and left atrial diameter,thicker left ventricular posterior wall and interventricular septum,and reduced left ventricular ejection fraction and E/A ratio(P<0.05).Spearman correlation analysis found that QTc interval,QRS duration,left ventricular systolic diameter,left ventricular diastolic diameter,left atrial diameter,left ventricular posterior wall thickness,and interventricular septum thickness were positively correlated with cardiac functional impairments in patients with hypertensive heart disease,while QRS voltage,left ventricular ejection fraction,and E/A ratio were negatively correlated with cardiac functional impairments in patients with hypertensive heart disease(P<0.05).Multiple linear regression analysis identified QTc interval,QRS duration,left ventricular end-systolic diameter,left ventricular end-diastolic diameter,left atrial diameter,left ventricular posterior wall thickness,ventricular septum thickness,QRS voltage,left ventricular ejection fraction,and E/A ratio as critical factors for assessment of cardiac function(P<0.05).Conclusion Color Doppler echocardiography and electrocardiography demonstrate significant clinical utility in evaluating cardiac function and disease severity in patients with hypertensive heart disease.

Objective To evaluate the quality of ketoconazole lotion produced by different domestic companies.Methods Legal standards and exploratory research were used to conduct a comprehensive evaluation of 45 batches(40 batch numbers)of ketoconazole lotion for national drug sampling inspection in 2024,including related substances,antioxidant content,packaging oxygen permeability,in vitro permeation test,and viscosity,antibacterial efficacy,irritation,microstructure,etc.Results The legal standard inspection pass rate was 100.0%.Correlation analysis found that the main factors affecting the quality of this product are prescription technology and packaging.Conclusion It is recommended that manufacturers optimize the prescription process as soon as possible,and pay attention to choose suitable packaging materials,effectively improve the quality of ketoconazole lotion.

Objective:To evaluate the changes in cortical electroencephalogram (EEG) burst suppression rate (BSR) during sevoflurane anesthesia in septic mice and the correlation with cerebral blood perfusion.Methods:Forty SPF male C57BL/6J mice, aged 8-10 weeks, weighing 22-25 g, were divided into 2 groups ( n=20 each) by the random number table method: sham operation group (Sham group) and cecal ligation perforation group (CLP group). The sepsis model was established by cecal ligation and puncture in anesthetized animals. Mice in both groups inhaled 2% sevoflurane for 2 h. During sevoflurane anesthesia, BSR (30 min as an epoch) on electroencephalogram was recorded, and the cortical cerebral blood perfusion was recorded using the laser speckle flow imaging at 30, 60, 90 and 120 min of anesthesia. Results:Compared with Sham group, the cortical EEG BSR was significantly increased, and the cortical cerebral blood perfusion was decreased during sevoflurane anesthesia in CLP group ( P<0.05). Cortical EEG BSR was negatively correlated with cortical cerebral blood perfusion ( P<0.05). Conclusions:Cortical EEG BSR increases during sevoflurane anesthesia in septic mice, which may be related to decreased cortical cerebral blood perfusion.

Objective To evaluate the value of color Doppler echocardiography and electrocardiography in assessing cardiac function and disease severity in patients with hypertensive heart disease.Methods A retrospective analysis was conducted on 205 patients with hypertensive heart disease who were categorized into 3 groups based on the New York Heart Association(NYHA)criteria:class Ⅱ(n=62),class Ⅲ(n=89)and class Ⅳ(n=54).The demographic characteristics(including gender and age)and the results of color Doppler echocardiography and electrocardiography were extracted from the hospital's medical record system for analyzing the relationships of the diagnostic findings from color Doppler echocardiography and electrocardiography with cardiac function and disease severity.Results Electrocardiography revealed statistically significant intergroup differences in QTc interval,QRS voltage,and QRS duration across 3 groups(P<0.05).Among 3 groups,class Ⅳ group exhibited the most pronounced abnormalities with prolonged QTc interval and QRS duration,along with reduced QRS voltage(P<0.05).Compared with class Ⅱ group,class Ⅲ group had longer QTc interval and QRS duration,alongside lower QRS voltage(P<0.05).Color Doppler echocardiography showed that left ventricular systolic diameter,left ventricular diastolic diameter,left atrial diameter,left ventricular posterior wall thickness,interventricular septum thickness,left ventricular ejection fraction,and E/A ratio differed significantly across 3 groups(P<0.05).Class Ⅳ group exhibited the largest left ventricular systolic diameter,left ventricular diastolic diameter and left atrial diameter,the thickest left ventricular posterior wall and interventricular septum,and the lowest left ventricular ejection fraction and E/A ratio(P<0.05).Compared with class Ⅱ group,class Ⅲ group had enlarged left ventricular systolic diameter,left ventricular diastolic diameter and left atrial diameter,thicker left ventricular posterior wall and interventricular septum,and reduced left ventricular ejection fraction and E/A ratio(P<0.05).Spearman correlation analysis found that QTc interval,QRS duration,left ventricular systolic diameter,left ventricular diastolic diameter,left atrial diameter,left ventricular posterior wall thickness,and interventricular septum thickness were positively correlated with cardiac functional impairments in patients with hypertensive heart disease,while QRS voltage,left ventricular ejection fraction,and E/A ratio were negatively correlated with cardiac functional impairments in patients with hypertensive heart disease(P<0.05).Multiple linear regression analysis identified QTc interval,QRS duration,left ventricular end-systolic diameter,left ventricular end-diastolic diameter,left atrial diameter,left ventricular posterior wall thickness,ventricular septum thickness,QRS voltage,left ventricular ejection fraction,and E/A ratio as critical factors for assessment of cardiac function(P<0.05).Conclusion Color Doppler echocardiography and electrocardiography demonstrate significant clinical utility in evaluating cardiac function and disease severity in patients with hypertensive heart disease.

Objective To evaluate the quality of ketoconazole lotion produced by different domestic companies.Methods Legal standards and exploratory research were used to conduct a comprehensive evaluation of 45 batches(40 batch numbers)of ketoconazole lotion for national drug sampling inspection in 2024,including related substances,antioxidant content,packaging oxygen permeability,in vitro permeation test,and viscosity,antibacterial efficacy,irritation,microstructure,etc.Results The legal standard inspection pass rate was 100.0%.Correlation analysis found that the main factors affecting the quality of this product are prescription technology and packaging.Conclusion It is recommended that manufacturers optimize the prescription process as soon as possible,and pay attention to choose suitable packaging materials,effectively improve the quality of ketoconazole lotion.

Objective:To prepare 89Zr-labeled anti-human podoplanin (PDPN) monoclonal antibody SZ168 and evaluate its feasibility for melanoma immunoPET imaging. Methods:89Zr-desferrioxamine (DFO)-SZ168 was prepared by conjugating p-isothiocyanatobenzyl (SCN-Bn)-DFO with SZ168 and chelating with 89Zr. Quality control analyses were conducted, including labeling rate, radiochemical purity, and in vitro stability. Melanoma mouse models were created, with experimental group ( n=3) and control group ( n=3) receiving tail vein injections of 89Zr-DFO-SZ168 and 89Zr-DFO-immunoglobulin (Ig)G solutions (3.7MBq) respectively. The experimental group underwent microPET/CT imaging at 12, 24, 48 and 72h post-injection, while the control group underwent imaging at 48h post-injection. Tumor and organ radioactivity uptake was analyzed using the ROI method. Mice were sacrificed at 7d post-injection to assess the ex vivo biodistribution of 89Zr-DFO-SZ168 and 89Zr-DFO-IgG. Independent-sample t test was used to analyze the data. Results:The pH value of the 89Zr-DFO-SZ168 solution was approximately 7.0, with a labeling rate >60%, radiochemical purity >95% after PD10 column purification, and good stability after 72h in vitro. Series microPET/CT imagings showed significant tumor visualization in tumor-bearing mice. Radioactivity uptake in tumors peaked at 48h post-injection, while the tumor was not clearly detected by 89Zr-DFO-IgG microPET/CT imaging. Ex vivo biodistribution indicated that 89Zr-DFO-SZ168 mainly accumulated in tumors, liver, and bones, with tumor uptake significantly higher than that of 89Zr-DFO-IgG ((29.36±7.29) percentage activity of injection dose per gram of tissue (%ID/g) vs (8.78±1.63) %ID/g; t=4.77, P=0.009). Immunohistochemistry of tumor specimens showed high expression of PDPN in tumor tissues. Conclusions:The probe 89Zr-DFO-SZ168 is successfully prepared, showing potential for specific molecular imaging diagnosis of melanoma. This lays a basis for developing PDPN molecular target-based immuno-PET diagnosis and integrated diagnosis and treatment for melanoma.