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.

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.

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.

Female acquired urinary incontinence is a clinical challenge. This article reported a female patient who had urinary incontinence after excessive urethral caruncle resection. Urodynamics showed effective urethral length was 1.6 cm and maximal urethral pressure was 41 cm cmH 2O(1 cmH 2O=0.133 kPa). Urethroscopy showed urethral length was about 2 cm, urethral sphincter function was good, and urethral stricture was absent. The patient has undergone robot-assisted modified Leadbetter bladder neck reconstruction. The surgery was successfully completed without intraoperative complications. Urinary catheter was removed at 4 weeks after surgery, and the patient has complete urinary continence with unobstructed voiding. After 3 months of follow-up, the patient still has unobstructed voiding and urinary continence.

Objective:To evaluate the efficacy of robot-assisted Y-V plasty (RAYV) and laparoscopic Y-V plasty (LYV) in the treatment of refractory bladder neck contracture (BNC) after BPH surgery.Methods:A retrospective analysis was performed for the clinical data of 42 patients with refractory BNC after BPH surgery from January 2020 to July 2023, including 18 RAYV and 24 LYV. There were no significant differences between both groups( P>0.05) in term of median age [68(62, 81) years vs. 70(61, 76) years], median body mass index [20.7(17.6, 26.1) kg/m 2 vs. 19.8(16.3, 25.3) kg/m 2], median Q max [9.4(5.6, 13.2) ml/s vs. 8.9(6.2, 12.2)ml/s], median IPSS [20.5(15, 23) vs. 21.1(17, 23)], median QOL score [4.6 (4, 6) points vs. 4.8 (4, 6) points] and median postvoid residual volume [84.7(58, 125)ml vs. 78.3(50, 120)ml]. Preoperative examination of one patient in the RAYV group showed no contractile function of the external urethral sphincter.The surgical procedure was basically the same for both groups: entering into the retropubic space, and incision of the anterior wall of bladder and prostate urethra was performed in an inverted Y-shaped. After excising the scar around the anterior wall of bladder neck, the apex of inverted V-shaped bladder wall flap is brought to the base of the Y-shaped incision using two 3-0 running suture. The catheter was removed 2 weeks after surgery. Perioperative and follow-up data were compared between the two groups. Results:All surgeries were successfully completed without complications. The difference between RAYV and the LYV group in operation time [71.8(50, 98)min vs. 105.9(71, 143)min] and postoperative drainage removal time [2.7(2, 4)d vs. 4.5(3, 7)d] was statistically significant ( P<0.05). There was no significant difference between both groups in term of intraoperative blood loss [50.4(20, 100) ml vs. 60.8(40, 150) ml] and postoperative hospital stay [4.1(3, 5)d vs. 4.6(3, 7)d]( P>0.05). All patients were followed up with a median follow-up of 16.5(2, 41) months. There was no significant difference between RAYV and LYV in term of postoperative Q max [27.9(11.7, 37.6) ml/s vs. 22.4(12.3, 31.5)ml/s], IPSS[5.1(4, 9) points vs. 4.8(4, 10) points], QOL[1.6(1, 3) points vs. 1.5(1, 3) points] and postvoid residual volume [5.6(0, 15) ml vs. 7.2(5, 20) ml] ( P>0.05). The postoperative bladder neck patency rates in the RAYV group and the LYV group were 94.4%(17/18) and 95.8%(23/24), respectively, with no significant difference( P>0.05). In terms of urinary continence, 1 patient in the RAYV group had no contractile function of the external urethral sphincter before surgery, and none of the 41 patients with good preoperative continence had urinary incontinence after surgery. Conclusions:The effect of RAYV in the treatment of refractory BNC after BPH surgery is comparable to that of LYV, but RAYV can shorten the operation time and postoperative drainage time.

Pelvic fracture urethral injury (PFUI) may result in loss of external urethral sphincter function, and traditional transurethral resection of the prostate may increase risk of permanent urinary incontinence after surgery in patients with benign prostatic hyperplasia (BPH) with a history of PFUI reconstruction. In the study, hulium laser enucleation-resection of prostate(ThuLERP) with bladder neck preservation was used to treat 4 patients with BPH with a history of PFUI reconstruction. All operations were conducted smoothly, and all patients had unobstructed voiding and no permanent urinary incontinence at 3 months after surgery. ThuLERP with bladder neck preservation was safe and effective treatment of BPH with a history of PFUI reconstruction, and avoided the risk of permanent urinary incontinence.