This study elucidated the structure-activity relationships (SAR) of three distinct opioid ligand series at the μ-opioid receptor (μ-OR) and investigated the ligand-dependent role of arrestin in downstream signaling. Radioligand binding assays across 13 compounds revealed that high-affinity μ-OR binding is not restricted to a single chemical scaffold. For fentanyl analogs, SAR analysis identified four key structural determinants: the N-phenethyl group (R1) is essential for μ-OR binding, the piperidine 4-position (R2) is sterically constrained and tolerates only small substituents such as carbomethoxy, the acyl side chain (R3) tolerates diverse chemical modifications including alkyl, alkoxy, and heteroaryl groups without substantial loss of affinity, and para-substitution on the phenethyl ring (R4) with electron-withdrawing groups like fluorine is well-tolerated. Analysis of non-fentanyl scaffolds (2-Methyl AP-237, W-15, and brorphine) demonstrated that specific side-chain functionalization, rather than core scaffold architecture, primarily determines binding potency. Comparison of classical opioids further revealed that structural flexibility, exemplified by methadone, can confer superior binding affinity compared to the rigid morphine scaffold. Consistent with this structural diversity, the contribution of arrestins to ERK activation varied substantially across compounds, suggesting that μ-OR-biased signaling is not dictated exclusively by intrinsic receptor properties but emerges from the interplay between receptor conformation and ligandspecific structural features. Collectively, our results provide a molecular framework for understanding opioid pharmacology with important implications for rational drug design aimed at minimizing adverse effects while maintaining analgesic efficacy.

Objective To investigate the correlation between the triglyceride-glucose(TyG)index,its derivatives in combination with obesity indicators and the risk of albuminuria in patients with type 2diabetes mellitus(T2DM).Methods T2DM inpatients who were hospitalized in the Department of Endocrinology from January 2020 to March 2023 were consecutively collected as study subjects,and divided into the group with no albuminuria(n=246)and the group with albuminuria(n=221).Spearman correlation analysis was used to analyze the correlation between TyG index,its derivative index and clinical indicators,and multivariate Logistic regression was used to analyze the correlation between TyG index,its derivative indexes and albuminuria.Results The TyG index and its derived indices[TyG-body mass index(TyG-BMI),TyG-waist-to-hip ratio(TyG-WHR),TyG-waist-to-height ratio(TyG-WtHR)]were significantly higher in the albuminuric group of patients with T2DM than in the group without albuminuria(all P＜0.001).The inci-dence of albuminuria gradually increased with increasing tertile groupings of all four indicators(all P＜0.001).In multivariate Logistic regression analysis,after correcting for screened risk factors,the TyG index(OR=1.50,95％CI:1.07-2.08,P=0.019),TyG-BMI(OR=1.01,95％CI:1.00-1.01,P=0.009),TyG-WHR(OR=1.45,95％CI:1.12-1.88,P=0.005),and TyG-WtHR(OR=1.39,95％CI:1.00-1.91,P=0.048)were the independent risk factors for albuminuria.For categorical variables,using the 1st quartile group(Q1)as a control group,the 3rd quartile group(Q3)of all four indices were all risk factors for albuminuria,whereas the Q3group of TyG-WHR was more significantly associated with albuminuria compared to the TyG index alone and the other de-rived indices(OR=2.55,95％CI:1.44-4.51,P=0.002).Conclusion In patients with T2DM,both TyG index and its derivatives combined with obesity indicators were significantly associated with albuminuria,and in patients with higher index levels,the risk of albu-minuria was higher in patients with high levels of TyG-WHR compared with single TyG index and other derivatives.Therefore,TyG-WHR may be a novel biological indicator to predict the development of DKD in T2DM patients.

Chronic eczema is clinically characterized by pruritus and skin lesions such as macules,exudation,desquamation,and lichenification.Traditional Chinese medicine(TCM)typically attributes its pathogenesis to wind,dampness,and heat pathogens,and TCM treatment for chronic eczema focused on dispelling wind,eliminating dampness,and clearing heat.However,there were fewer reports about the treatment of accompanying emotional changes and sleep disturbances in chronic eczema patients.This paper integrated the physique-qi-spirit trinity life view with zang-fu organ differentiation,and proposed that the disorder of spleen transportation and transformation contributed to the pathological foundation of chronic eczema,while the dysfunction of heart and liver was the factor that significantly influenced disease progression after analyzing the clinical features of chronic eczema.For the treatment of chronic eczema,the establishment of strategies should consider clinical characteristics,duration of disease,and skin lesion patterns.The combination of physique-qi-spirit regulation with heart-liver-spleen treatment approaches aims to alleviate clinical symptoms,improve quality of life,and enhance therapeutic efficacy for chronic eczema patients.

Objective To evaluate the application of shear wave elastography(SWE)in the diagnosis of peripheral neuropathy in patients with diabetes.Methods Totally 85 patients with type 2 diabetes(T2DM)were selected from the Chengdu Office Hospital of People's Government of Tibetan Autonomous Region,including 46 patients with peripheral neuropathy(DPN)and 39 patients without peripheral neuropathy(NDPN).Compared for clinical data(gender,age,disease duration),cross-sectional area of the median nerve measured by high-frequency ultra-sound(CSA)and shear wave elastography(SWE)parameters(mean Young's modulus value,Emean)and shear wave velocity(SWV)between two groups of patients.Multifactor Logistic regression analysis was carried out on the indicators between the above groups to screen independent predictors in the diagnosis of peripheral neuropathy in diabetes patients,and a combined model was constructed.The area under the operating characteristic curve(AUC),sensitivity and specificity of the subjects were used to evaluate the diagnostic efficacy of the single model and com?bined model of the quantitative parameters(CSA,Emean,SWV)measured by clinical data,high?frequency ultra?sound and SWE in the diagnosis of peripheral neuropathy in diabetes patients.Results Age,course of disease,Emean,SWV and CSA were statistically significant in the diagnosis of peripheral neuropathy in diabetes patients(all P<0.05).AUC was 0.658,0.754,0.839,0.822 and 0.736,respectively.The combination model based on disease course,CSA and SWV showed the highest diagnostic efficiency,with AUC,sensitivity,and specificity of 0.887(0.800-0.946),80.43％,and 84.62％,respectively.Conclusions The combined model based on the course of disease,CSA and SWV have a high diagnostic efficiency in peripheral neuropathy of diabetes patients,and has good clinical application value.

Objective To investigate the correlation between the triglyceride-glucose(TyG)index,its derivatives in combination with obesity indicators and the risk of albuminuria in patients with type 2diabetes mellitus(T2DM).Methods T2DM inpatients who were hospitalized in the Department of Endocrinology from January 2020 to March 2023 were consecutively collected as study subjects,and divided into the group with no albuminuria(n=246)and the group with albuminuria(n=221).Spearman correlation analysis was used to analyze the correlation between TyG index,its derivative index and clinical indicators,and multivariate Logistic regression was used to analyze the correlation between TyG index,its derivative indexes and albuminuria.Results The TyG index and its derived indices[TyG-body mass index(TyG-BMI),TyG-waist-to-hip ratio(TyG-WHR),TyG-waist-to-height ratio(TyG-WtHR)]were significantly higher in the albuminuric group of patients with T2DM than in the group without albuminuria(all P＜0.001).The inci-dence of albuminuria gradually increased with increasing tertile groupings of all four indicators(all P＜0.001).In multivariate Logistic regression analysis,after correcting for screened risk factors,the TyG index(OR=1.50,95％CI:1.07-2.08,P=0.019),TyG-BMI(OR=1.01,95％CI:1.00-1.01,P=0.009),TyG-WHR(OR=1.45,95％CI:1.12-1.88,P=0.005),and TyG-WtHR(OR=1.39,95％CI:1.00-1.91,P=0.048)were the independent risk factors for albuminuria.For categorical variables,using the 1st quartile group(Q1)as a control group,the 3rd quartile group(Q3)of all four indices were all risk factors for albuminuria,whereas the Q3group of TyG-WHR was more significantly associated with albuminuria compared to the TyG index alone and the other de-rived indices(OR=2.55,95％CI:1.44-4.51,P=0.002).Conclusion In patients with T2DM,both TyG index and its derivatives combined with obesity indicators were significantly associated with albuminuria,and in patients with higher index levels,the risk of albu-minuria was higher in patients with high levels of TyG-WHR compared with single TyG index and other derivatives.Therefore,TyG-WHR may be a novel biological indicator to predict the development of DKD in T2DM patients.

Objective To investigate the role of Toll-like receptor 4(TLR4)in the regulation of homocys-teine(Hcy)-induced ferroptosis in macrophages.Methods Mouse macrophage cells RAW264.7 were cultured and divided into control group,Hcy intervention group(Hcy group),and Hcy plus ferroptosis inhibitor group(Hcy+Fer-1 group).After transfection with interference fragments,macrophages were treated with Hcy,and then divided into control group,Hcy intervention group(Hcy group),TLR4 interference negative control plus Hcy intervention group(si-NC+Hcy group),and TLR4 interference plus Hcy intervention group(si-TLR4+Hcy group).Macrophages were transfected with overexpression lentivirus and treated with Hcy,then were divided into control group,Hcy intervention group(Hcy group),a TLR4 overexpression negative control plus Hcy intervention group(OE-NC+Hcy group),and a TLR4 overexpression plus Hcy intervention group(OE-TLR4+Hcy group).After 48 hours of intervention,real-time fluorescent quantitative PCR and western blot were used to detect the expression levels of TLR4 in macrophages treated with Hcy;western blot was used to detect the expression levels of ferroptosis-related proteins ACSL4,GPX4,and FTH1 in macrophages,and ferrous ion assay kit to detect the concentration of Fe2+in macrophages;reactive oxygen species(ROS)assay kit and laser confocal microscopy were used to detect the content of intracellular reactive oxygen species.Results Compared with those in the control group,the expression level of the pro-ferroptosis protein ACSL4 was increased in the Hcy group(P<0.05),while the expression levels of anti-ferroptosis proteins GPX4 and FTH1 were decreased(P<0.05);the concentration of Fe2+was increased(P<0.05),and the content of ROS was increased.Meanwhile,the protein and mRNA expres-sion levels of TLR4 were both increased in the Hcy group(P<0.05).After macrophages were transfected with TLR4 interference fragments,compared with those in the si-NC+Hcy group,the expression levels of GPX4 and FTH1 were increased(P<0.05);the expression level of ACSL4 was decreased(P<0.05);the concentration of Fe2+was decreased(P<0.05),and the content of ROS was reduced in the si-TLR4+Hcy group.After macro-phages were transfected with TLR4 overexpression lentivirus,compared with those in the OE-NC+Hcy group,the expression levels of GPX4 and FTH1 were decreased(P<0.05),and the expression level of ACSL4 was increased(P<0.05)in the OE-TLR4+Hcy group.Conclusion Hcy induces the occurrence of ferroptosis in macrophages,and Toll-like receptor 4 has a positive feedback regulatory effect on ferroptosis in macrophages.

Objective To investigate the role of Toll-like receptor 4(TLR4)in the regulation of homocys-teine(Hcy)-induced ferroptosis in macrophages.Methods Mouse macrophage cells RAW264.7 were cultured and divided into control group,Hcy intervention group(Hcy group),and Hcy plus ferroptosis inhibitor group(Hcy+Fer-1 group).After transfection with interference fragments,macrophages were treated with Hcy,and then divided into control group,Hcy intervention group(Hcy group),TLR4 interference negative control plus Hcy intervention group(si-NC+Hcy group),and TLR4 interference plus Hcy intervention group(si-TLR4+Hcy group).Macrophages were transfected with overexpression lentivirus and treated with Hcy,then were divided into control group,Hcy intervention group(Hcy group),a TLR4 overexpression negative control plus Hcy intervention group(OE-NC+Hcy group),and a TLR4 overexpression plus Hcy intervention group(OE-TLR4+Hcy group).After 48 hours of intervention,real-time fluorescent quantitative PCR and western blot were used to detect the expression levels of TLR4 in macrophages treated with Hcy;western blot was used to detect the expression levels of ferroptosis-related proteins ACSL4,GPX4,and FTH1 in macrophages,and ferrous ion assay kit to detect the concentration of Fe2+in macrophages;reactive oxygen species(ROS)assay kit and laser confocal microscopy were used to detect the content of intracellular reactive oxygen species.Results Compared with those in the control group,the expression level of the pro-ferroptosis protein ACSL4 was increased in the Hcy group(P<0.05),while the expression levels of anti-ferroptosis proteins GPX4 and FTH1 were decreased(P<0.05);the concentration of Fe2+was increased(P<0.05),and the content of ROS was increased.Meanwhile,the protein and mRNA expres-sion levels of TLR4 were both increased in the Hcy group(P<0.05).After macrophages were transfected with TLR4 interference fragments,compared with those in the si-NC+Hcy group,the expression levels of GPX4 and FTH1 were increased(P<0.05);the expression level of ACSL4 was decreased(P<0.05);the concentration of Fe2+was decreased(P<0.05),and the content of ROS was reduced in the si-TLR4+Hcy group.After macro-phages were transfected with TLR4 overexpression lentivirus,compared with those in the OE-NC+Hcy group,the expression levels of GPX4 and FTH1 were decreased(P<0.05),and the expression level of ACSL4 was increased(P<0.05)in the OE-TLR4+Hcy group.Conclusion Hcy induces the occurrence of ferroptosis in macrophages,and Toll-like receptor 4 has a positive feedback regulatory effect on ferroptosis in macrophages.

Objective:To investigate the changes of directional connections of auditory and non-auditory in patients with noise-induced deafness (NID) by degree centrality (DC) and Granger causality analysis (GCA), and to explore the mode of brain function remodeling after NID.Methods:In October 2023, a total of 58 patients diagnosed with NID by the Occupational Diseases Department of Yantaishan Hospital of Yantai from 2014 to 2022 were collected as case group (NID group), and 42 healthy volunteers matched by gender, age and education level were selected as the control group (HC group). Resting state-functional magnetic resonance imaging (Rs-fMRI) was perfomed and PC analysis was performed. The brain regions with statistically significant differences in DC values between groups and the bilateral Heschl regions were extracted as regions of interest (ROI) for voxel-based whole brain GCA and correlation analysis.Results:Compared with HC group, the SOG.L DC value of NID group was lower, the connectivity values of SFGdor.L to SOG.L was increased, the connectivity value of PCL.L to SOG.L was decreased, the connectivity values of ORBmid.L, PCG.R and CUN. L/R to HES.L were increased, the connectivity value of SFGdor.L to HES.L was decreased, the connectivity value of HES.L to PCUN.L was decreased, the connectivity values of ORBsup.L and PCG.R to HES.R were increased, the connectivity value of HES.R to CUN.L was decreased ( P voxel level<0.01, P cluster level<0.05). The connectivity value of PCL.L to SOG.L was negatively correlated with the weighted value of the better whisper frequency ( P<0.05) . Conclusion:The NID patients have abnormal directional connectivity activity in multiple brain regions, such as auditory vision, executive control, somatosensory movement, and default mode network. It is suggested that hearing loss may cause complex neural remodeling between auditory and non-auditory centers.

Objective:To investigate the changes of directional connections of auditory and non-auditory in patients with noise-induced deafness (NID) by degree centrality (DC) and Granger causality analysis (GCA), and to explore the mode of brain function remodeling after NID.Methods:In October 2023, a total of 58 patients diagnosed with NID by the Occupational Diseases Department of Yantaishan Hospital of Yantai from 2014 to 2022 were collected as case group (NID group), and 42 healthy volunteers matched by gender, age and education level were selected as the control group (HC group). Resting state-functional magnetic resonance imaging (Rs-fMRI) was perfomed and PC analysis was performed. The brain regions with statistically significant differences in DC values between groups and the bilateral Heschl regions were extracted as regions of interest (ROI) for voxel-based whole brain GCA and correlation analysis.Results:Compared with HC group, the SOG.L DC value of NID group was lower, the connectivity values of SFGdor.L to SOG.L was increased, the connectivity value of PCL.L to SOG.L was decreased, the connectivity values of ORBmid.L, PCG.R and CUN. L/R to HES.L were increased, the connectivity value of SFGdor.L to HES.L was decreased, the connectivity value of HES.L to PCUN.L was decreased, the connectivity values of ORBsup.L and PCG.R to HES.R were increased, the connectivity value of HES.R to CUN.L was decreased ( P voxel level<0.01, P cluster level<0.05). The connectivity value of PCL.L to SOG.L was negatively correlated with the weighted value of the better whisper frequency ( P<0.05) . Conclusion:The NID patients have abnormal directional connectivity activity in multiple brain regions, such as auditory vision, executive control, somatosensory movement, and default mode network. It is suggested that hearing loss may cause complex neural remodeling between auditory and non-auditory centers.

【Objective】 To explore the learning curve of single-surgeon robot-assisted laparoscopic radical prostatectomy (RARP), which provides a reference for physicians who intend to carry out RARP. 【Methods】 The clinical data of 65 prostate cancer patients who underwent RARP in our hospital during Sep.2022 and Dec.2023 were retrospectively analyzed.The patients’ median age was 67.5(58.1-82.4) years, median total prostate-specific antigen (PSA) was 15.6 (6.7-98.4) ng/mL, median body mass index (BMI) was 20.8(17.4-27.3) and preoperative clinical stage of tumor was T2aN0M0-T3bN1M0.The cumulative sum (CUSUM) method was used to fit the learning curves of machine installation time and operation time.According to the inflection points, the learning curves were divided into different learning stages, and the clinical data of patients at different learning stages were compared. 【Results】 The learning curve of RARP was 12 cases.The 65 cases were divided into three stages: 1st-12th cases in the learning stage, 13rd-43rd cases in the mastery stage, and 44th-65th cases in the proficiency stage.With the increase of the number of surgical cases, the median operation time [191(100-360) min vs. 116(83-165) min vs. 90(75-105) min] and median intraoperative blood loss [403(180-900) mL vs. 236(180-305) mL vs. 94(30-200) mL] in the three stages showed a gradual downward trend (P<0.05).The median machines installation time of the learning stage was significantly longer than that in the mastery stage and the proficiency stage [25(21-28) min vs. 12(11-15) min vs. 12(11-14) min] (P<0.05).The positive surgical marginrate (PSM) in the learning stage was significantly higher than that in the mastery stage and proficiency stage (41.7% vs.22.6% vs.22.7%) (P<0.05). 【Conclusion】 For surgeons with rich experience in traditional laparoscopic surgery, the learning curve of RARP is about 12 cases, and after 43 cases, the operation time and intraoperative blood loss can be further reduced.