Bombesin receptor subtype-3 (BRS3) is an orphan G protein-coupled receptor (GPCR) that plays critical roles in energy homeostasis, glucose metabolism, and insulin secretion. Recent structural studies have elucidated BRS3 signaling mechanisms using synthetic ligands, including BA1 and MK-5046. However, the molecular basis of BRS3 activation by bioactive natural compounds and their derivatives, particularly those derived from traditional Chinese medicine, remains unclear. Here, we present high-resolution cryogenic electron microscopy (cryo-EM) structures of the human BRS3-G_q complex in both unliganded and active states bound by two herb-derived compounds (DSO-5a and oridonin), at resolutions of 2.9, 2.8, and 2.9 Å, respectively. These structures display distinct ligand recognition patterns between DSO-5a and oridonin. Although both compounds bind to the orthosteric pocket, they differentially engage the interaction network of BRS3, as demonstrated by mutagenesis studies assessing calcium mobilization and inositol phosphate 1 (IP1) accumulation. These findings enhance our understanding of BRS3 activation and provide valuable insights into the development of small-molecule BRS3 modulators with therapeutic potential.

Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis. Conventional chemo-radiotherapy demonstrates limited therapeutic efficacy and is often accompanied by significant side effects, largely due to factors such as drug resistance, radiation resistance, the presence of the blood-brain barrier (BBB), and the activation of DNA damage repair mechanisms. There is a pressing need to enhance treatment efficacy, with BRD4 identified as a promising target for increasing GBM sensitivity to therapy. Lacking small molecule inhibitors, BRD4 can be degraded using PROteolysis Targeting Chimera (PROTAC), thereby inhibiting DNA damage repair. To deliver PROTAC, SIAIS171142 (SIS) effectively, we designed a responsive nanocapsule, MPL_(SS)P@SIS, featuring GBM-targeting and GSH-responsive drug release. Modified with 1-methyl-l-tryptophan (MLT), nanocapsules facilitate targeted delivery of SIS, downregulating BRD4 and sensitizing GBM cells to radiotherapy and chemotherapy. After intravenous administration, MPL_(SS)P@SIS selectively accumulates in tumor tissue, enhancing the effects of radiotherapy and temozolomide (TMZ) by increasing DNA damage and oxidative stress. GSH activates the nanocapsules, triggering BRD4 degradation and hindering DNA repair. In mouse models, the nanosensitizer, combined with TMZ and X-ray irradiation, efficiently inhibited the growth of GBM. These findings demonstrate a novel PROTAC-based sensitization strategy targeting BRD4, offering a promising approach for effective GBM therapy.

Eight new diterpenoids, Isodons A-H (1-8), comprising seco-abietane and abietane-type structures, together with 13 known analogues (9-21), were isolated from Isodon lophanthoides (Buch.-Ham. ex D. Don) Hara. The compounds (+)-3/(-)-3, (+)-4/(-)-4, and (+)-5/(-)-5 were identified as three enantiomeric pairs. The planar structures and absolute configurations of 1-8 were determined through high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), 1D & 2D nuclear magnetic resonance (NMR) spectroscopy, electronic circular dichroism (ECD) calculations, and X-ray diffraction crystallography. A cholesterol 7α-hydroxylase (Cyp7a1) luciferase reporter assay revealed significant anti-cholestatic activities for compounds 1, (+)-4, 6, 7, 12-14, and 16. Additionally, compound 6 demonstrated anti-cholestatic effects through the farnesoid X receptor (FXR)-associated signaling pathways in vitro and in vivo. These findings suggest potential applications for I. Lophanthoides in pharmaceutical development.
Abietanes/pharmacology* ; Molecular Structure ; Animals ; Isodon/chemistry* ; Humans ; Diterpenes/pharmacology* ; Plant Extracts/chemistry*

Objective : To explore the expression profile of core 1 β1,3-galactosyltransferase 1(C1GALT1) in glioblastoma(GBM) and to elucidate its impact on the initiation and progression of GBM. Methods : The expression levels and prognostic significance of C1GALT1 in GBM were analyzed using the GEPIA and CGGA databases. Two representative glioblastoma cells(U251 and LN18) were selected to construct C1GALT1-knockdown cell lines and performed in vitro experiments. The Cell Counting Kit-8(CCK-8) and Transwell assays were employed to evaluate the impact of C1GALT1 on proliferation, migration and invasion of GBM cells. Transcriptome data were analyzed to identify potential signaling pathways. Senescence β-Galactosidase Staining Kit was used to detect β-galactosidase activity. Results : nalysis of GEPIA and CGGA databases revealed that C1GALT1 was significantly upregulated in GBM tissues compared to adjacent non-cancerous tissues (P < 0. 05) , and its high expression was associated with poor prognosis of patients (P < 0. 000 1) . The CCK-8 experiment demonstrated a significant reduction in prolifera- tion rate following C1GALT1 knockdown (P < 0. 05) . Transwell assay showed that cell migration and invasion de- creased after C1GALT1 was knocked down ( P < 0. 001) . Transcriptome sequencing and senescence β-galactosi- dase staining showed that C1GALT1 was involved in the cellular senescence signaling pathway , and the activity of β-galactosidase associated with cellular senescence significantly increased after C1GALT1 was knocked down(P < 0. 05) . Conclusion C1GALT1 is overexpressed in GBM tissues and may promote the proliferation , migration and invasion of GBM cells by inhibiting cellular senescence .

Objective To observe the efficacy of percutaneous mechanical thrombectomy(PMT)for treating different traditional Chinese medicine(TCM)syndrome type lower extremity arterial thromboses.Methods Forty patients with lower extremity arterial thromboses who underwent PMT were retrospectively enrolled and divided into dampness-heat syndrome group(n=18)and blood stasis syndrome group(n=22)according to TCM syndrome types.The technical success rate,ankle-brachial index(ABI),Rutherford grade and vascular patency rate 12 months after PMT were compared between groups.Perioperative complications and adverse events during follow-up were recorded.Results The technical success rate of PMT in dampness-heat syndrome group and blood stasis syndrome group was 94.44%(17/18)and 100%(22/22),respectively.Twelve months after PMT,ABI was 0.45±0.11 and 0.52±0.14,and vascular patency rate was 94.44%(17/18)and 81.82%(18/22)in dampness-heat syndrome group and blood stasis syndrome group,respectively,both not significantly different between groups(all P＞0.05).No significant difference of Rutherford grade before treatment was found between groups(P＞0.05),while 12 months after PMT,Rutherford grade in dampness-heat syndrome group was higher than in blood stasis syndrome group(P＜0.05).During perioperative period,false aneurysm of brachial artery occurred in 1 case in dampness-heat syndrome group,while osteofascial compartment syndrome and atrial fibrillation occurred each in 1 case in blood stasis syndrome group,both relieved after treatments.No serious adverse event such as amputation nor death occurred during follow-up.Conclusion PMT was effective and safe for treating different TCM syndrome type lower extremity arterial thromboses.The prognosis of patients with blood stasis syndrome type lower extremity arterial thromboses was better than that of those with dampness-heat syndrome.

Objective By investigating the retention and fatigue performance of polyetheretherketone(PEEK)clasps with increased proportions of clasp arm engaging the undercut,an innovative method to improve PEEK clasps'performance was proposed and verified.Methods Three groups of PEEK clasps(n=10/group)with the terminal 1/3,2/3 and whole of their retentive arms engaging the 0.75 mm undercut were designed and fabricated respectively along with a group of cobalt-chrome clasps(n=10)with their terminal 1/3 of retentive arms engaging the 0.25 mm undercut.Retentive forces were recorded initially and every 1 500 cycles for a total of 15 000 in-sertion and removal fatigue cycles.Optical scanning and software analysis were applied to evaluate the deformation of the clasps by root mean square(RMS)after fatigue test.The inner surface morphology of clasps'arms was observed by scanning electron microscopy.Re-sults PEEK clasps with the whole of their retentive arms engaging the undercut exhibited highest mean retentive force(9.24±1.78)Namong other PEKK clasps,which was slightly lower than that of cobalt-chrome clasps(11.88±2.05)N.The retentive force of each group turned out to be reduced after fatigue cycles and cobalt-chrome clasps showed the greatest reduction(38.38%).The RMS of the PEEK clasps groups were of no statistical difference(P=0.111)and were lower than that of cobalt-chrome clasps(105.47±10.82)μm.Evidence of surface abrasion was observed on all groups of clasps especially on the section that engaged the undercut.Conclusion Increasing the proportion of PEEK clasp arm engaging the undercut effectively improved the retentive force and satisfied clinical re-quirements after fatigue cycles.PEEK clasps exhibited greater retention stability than cobalt-chrome clasps.It is feasible to improve the performance of PEEK clasps by increasing the proportion of clasp arm engaging the undercut.

Objective To establish the animal model of comorbidity of knee osteoarthritis(KOA)and hypertension with pattern of liver and kidney deficiency and evaluate its characteristics of comorbidity and pattern.Methods Wistar-Kyoto(WKY)rats and spontaneously hypertensive rats(SHR)were assigned to the WKY control group(control group),hypertension combined with KOA sham-operation group(sham-operation group),hypertension combined with KOA group(model group),hypertension combined with KOA and liver-kidney deficiency pattern group(LKD group).The animal model of KOA combined with hypertension was prepared by anterior cruciate ligament transection(ACLT)in spontaneously hypertensive rats.ACLT combined with intramuscular injection of hydrocortisone was performed to prepare an animal model of KOA with liver-kidney deficiency(LKD)pattern type,combined with hypertension.Then,the related indexes of LKD syndrome were detected in turn,including the contents of thyroid stimulating hormone(TSH),testosterone(T),corticosterone(CORT),adrenocorticotropic hormone(ACTH)in serum,and enzyme activities of alanine transaminase(ALT),aspartate transaminase(AST),and alkaline phosphatase(ALP)in serum,the mass ratio of liver,kidney,spleen,thymus to the brain,body weight,anal temperature,activity situation,and emotion.Systolic blood pressure,diastolic blood pressure,and other blood pressure-related indices were also detected.The levels of serum tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β),plantar mechanical pain sensitivity threshold,weight difference score of both hind limbs,hind limb joint swelling,and quadruped gait parameters were also measured.Furthermore,hematoxylin-eosin,safranine-fast green,and Masson staining were performed to observe pathological changes,cartilage degeneration,and bone destruction of the knee joint,and the microstructure parameters of the tibia were detected by Micro-CT imaging.Results Compared to the model group,the contents of serum TSH,ACTH,T,CORT and the mass ratio of the kidney,spleen,and thymus to the brain in the LKD group decreased(P<0.05).Compared to the control group,the systolic blood pressure and diastolic blood pressure of the other three groups increased significantly(P<0.05).Compared to the sham-operation group,serum TNF-α and IL-1β levels increased,plantar mechanical pain threshold decreased,weight difference score of both hind limbs and joint swelling of the affected limb increased(P<0.05),and gait parameters(e.g.,gait length and standing time of the affected limbs)became abnormal in the model and LKD groups.Simultaneously,the cartilage surface defect of the rat knee joint was severe,the arrangement of the surface chondrocytes was altered,the cartilage layer became thinner,the muscle fibers increased,and the cartilage ossification was severe.Furthermore,the relative volume,thickness,and number of trabeculae of the knee joint decreased significantly(P<0.05).Conclusion The rat model established in this study is consistent with the clinical characteristics of integrated traditional Chinese and Western medicine in patients with comorbidities of hypertension and KOA with liver and kidney deficiency pattern.This rat model can characterize the typical symptoms of liver and kidney deficiency pattern.It has typical pathological changes in knee cartilage and subchondral bone tissues and can maintain a stable range of high systolic and diastolic blood pressure.It also explore the scientific connotation of simultaneous treatment of different diseases in traditional Chinese medicine,revealing the therapeutic mechanism and developing new drugs.

The correspondence between prescription and syndrome is the advantage and characteristic of traditional Chinese medicine(TCM)treatment.However,the pathogenesis of clinical diseases is complex and the condition is changeable,and the clinical application is difficult to achieve the maximum effect under the existing cognition of the correspondence between prescription and syndrome.In this paper,the five categories of physiological characteristics,pathological characteristics,constitution,syndrome,and disease of the longitudinal classification of"TCM state"are introduced into the correspondence of prescription and syndrome.Under the vertical perspective of"TCM state",the theoretical connotation of the correspondence between prescription and syndrome is interpreted as"correspondence between prescription and state",namely correspondence of"prescription-physiological characteristics",correspondence of"prescription-pathological characteristics",correspondence of"prescription-constitution",correspondence of"prescription-syndrome",and correspondence of"prescription-disease".It is hoped to accurately grasp the corresponding connotation of the correspondence between prescription and syndrome,in order to deepen the clinical thinking mode of TCM.

Objective To establish normal reference values for left ventricular trabecular and papillary muscle mass(TPMM)in Chinese adults using MRI and to explore its impact factors.Methods A total of 168 healthy Chinese adults were retrospectively included,and compacted and total left ventricular myocardial mass(LVM)were measured using traditional and dedicated methods,respectively.TPMM was calculated from the difference between total and compacted LVM.Independent sample t-tests and analysis of variance were used to explore the differences in TPMM among genders and age groups,while multiple linear regression was used to explore the independent correlation between TPMM and age,gender,heart rate,systolic blood pressure(SBP),fasting blood glucose(FBG),and body mass index(BMI).Results TPMM for men was significantly larger than that for female(P<0.001).TPMM in the elderly group was significantly larger in female(P<0.05),but not in men.Multiple linear regression showed that BMI and SBP were both independently positively correlated with TPMM,and female and heart rate were independently negatively correlated with TPMM(P<0.05).Conclusion This study provides age-and gender-specific normal reference values for TPMM in Chinese adults.Gender,heart rate,BMI,and SBP are all independently associated with TPMM.

Objective This study aimed to investigate the differential effects of sevoflurane and propofol on perioperative HIF-1α levels and postoperative recovery in patients undergoing bariatric surgery.Methods A total of 40 obese patients(BMI≥44 kg/m2)were randomly allocated into two groups:sevoflurane(n=21)group and propofol(n=19)group.The quantitative measurement of HIF-1α levels in human serum at different time points was conducted using ELISA.The assessment of redness,swelling,pain,exudation,and prognosis-related indicators of the patient's umbilical incision was performed at 24 and 48 hours after surgery.Results On the day following surgery,there was a significant increase in HIF-1α levels in the sevoflurane group and a significant decrease in the propofol group.The frequency and type of opioid analgesics used in the sevoflurane group were signifi-cantly lower than those used in the propofol group after surgery.Conclusions Compared with propofol,sevoflurane is more suitable for maintaining anesthesia in obese patients undergoing bariatric surgery.Sevoflurane can promote enhanced recovery after surgery by reducing postoperative analgesic consumption and upregulating HIF-1α levels.