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.

OBJECTIVES: To assess the therapeutic effect of aucubin in mice with knee osteoarthritis (KOA) and investigate the underlying mechanism. METHODS: Sixty C57BL/6J mice were randomized equally into sham operation group, KOA model group, glucosamine (positive control) treatment group, and low-, medium-, and high-dose aucubin treatment groups (2, 4, and 8 mg/kg, respectively). KOA mouse models were established by transection of the anterior cruciate ligament (ACL), and the treatment was initiated on day 1 postoperatively and administered weekly for 8 weeks. Safranin O-fast green staining, immunohistochemistry, and microCT were used to evaluate the changes in cartilage pathology, inflammatory protein expression, and subchondral bone volume fraction (BV/TV). The expression levesl of COL2, SOX9, p-P65, IL-1β and MMP13 proteins in the cartilage tissues were detected using Western blotting. In a chondrocyte model with IL-1β treatment for mimicking KOA, the effect of aucubin on chondrogenic differentiation was observed with Alcian blue and Safranin O staining, and cellular COL2, SOX9 and TNF‑α mRNA expressions were detected with RT-qPCR. RESULTS: Compared with those in the model group, the mouse models receiving aucubin treatment showed significantly upregulated COL2 and SOX9 protein levels and downregulated p-P65, IL-1β and MMP13 expressions in the cartilage tissues. In the IL-1β-induced chondrocyte model, aucubin treatment significantly upregulated the mRNA expressions of SOX9 and COL2 but lowered the mRNA expression of TNF-α. Alcian blue and Safranin O staining confirmed that aucubin promoted the synthesis of cartilage extracellular matrix and enhanced chondrogenic differentiation of the cells. CONCLUSIONS Aucubin can effectively alleviate KOA in mice by inhibiting NF‑κB-mediated cartilage inflammation, promoting cartilage matrix synthesis, and improving subchondral bone microstructure.
Animals ; Mice, Inbred C57BL ; Mice ; Osteoarthritis, Knee/drug therapy* ; Signal Transduction/drug effects* ; NF-kappa B/metabolism* ; Iridoid Glucosides/therapeutic use* ; SOX9 Transcription Factor/metabolism* ; Chondrocytes/drug effects* ; Male ; Interleukin-1beta/metabolism* ; Matrix Metalloproteinase 13/metabolism* ; Collagen Type II/metabolism* ; Disease Models, Animal

OBJECTIVE: Asthma imposes a significant global health burden. This study examines changes in the asthma-related disease burden from 1990 to 2021 and projects future burdens for 2050 under different scenarios. METHODS: Using data from the Global Burden of Disease 2021 study, we analyzed asthma incidence, prevalence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2021. We projected the disease burden for 2050 based on current trends and hypothetical scenarios in which all risk factors are controlled. Temporal trends in age-standardized incidence, prevalence, mortality, and DALY rates were explored using Annual Percent Change. RESULTS: In 2021, the age-standardized rates for asthma incidence, prevalence, mortality, and DALYs in China were 364.17 per 100,000 (95% uncertainty interval [ UI]: 283.22-494.10), 1,956.49 per 100,000 (95% UI: 1,566.68-2,491.87), 1.47 per 100,000 (95% UI: 1.15-1.79), and 103.76 per 100,000 (95% UI: 72.50-145.46), respectively. A higher disease burden was observed among Chinese men and individuals aged 70 years or older. Compared to the current trend, a combined scenario involving improvements in environmental factors, behavioral and metabolic health, child nutrition, and vaccination resulted in a greater reduction in the disease burden caused by asthma. CONCLUSION Addressing modifiable risk factors is essential for further reducing the asthma-related disease burden.
Humans ; Asthma/mortality* ; China/epidemiology* ; Male ; Female ; Adult ; Middle Aged ; Aged ; Child ; Adolescent ; Global Burden of Disease/trends* ; Child, Preschool ; Young Adult ; Infant ; Cost of Illness ; Disability-Adjusted Life Years ; Prevalence ; Incidence ; Infant, Newborn ; Aged, 80 and over ; Risk Factors

OBJECTIVE: This study aims to analyze the burden of lower respiratory infections in Chinese elderly people aged 70 and above. METHODS: This study utilized Global Burden of Disease (GBD) 1990-2050 prediction data to analyze changes in mortality rates and disability-adjusted life year (DALY) rates for lower respiratory infections in the elderly population (aged 70 and above) in China from 1990 to 2050. It also discusses future trends in the burden of lower respiratory infections (LRI) in China under different scenarios. RESULTS: According to GBD predictions, the burden of lower respiratory infections in the elderly aged 70 years and above in China is lower than the global average. The burden has been decreasing from 1990 to 2020, but is projected to increase from 2020 to 2050. Scenario-based predictions suggest that, under scenarios involving improvements in nutrition and vaccination, the burden of lower respiratory infections in the elderly in China is expected to be the lowest in 2050. CONCLUSION This study indicates that the burden of lower respiratory infections in elderly people aged 70 years and above in China remains a significant public health issue and may worsen. The government should consider strengthening the preventive measures and management strategies for respiratory infections in the elderly population.
Humans ; China/epidemiology* ; Aged ; Respiratory Tract Infections/mortality* ; Aged, 80 and over ; Male ; Female ; Forecasting ; Disability-Adjusted Life Years ; Global Burden of Disease ; Cost of Illness

OBJECTIVE: To analyze the prevalence and burden of headache disorders in China and its provinces from 1990 to 2021. METHODS: Using data from the Global Burden of Disease Study (GBD) 2021, the number of prevalent cases, prevalence rate, disability-adjusted life years (DALYs), and age-standardized DALY rates were analyzed by sex, age group, and province for headache disorders and their subtypes (migraine and tension-type headache [TTH]) between 1990 and 2021. Percentage changes during this period were also estimated. RESULTS: In 2021, approximately 426 million individuals in China were affected by headache disorders, with an age-standardized prevalence rate of 27,582.61/100,000. The age-standardized DALY rate for all headache disorders was 487.15/100,000. Between 1990 and 2021, the number of prevalent cases increased by 37.78%, while the prevalence of all headache disorders, migraine, and TTH increased by 6.92%, 7.57%, and 7.86%, respectively. The highest prevalence was observed in the 30-34 age group (39,520.60/100,000). Migraine accounted for a larger proportion of DALYs attributable to headache disorders, whereas TTH has a greater impact on its prevalence. In 2021, the highest age-standardized DALY rates for headache disorders were observed in Heilongjiang (617.85/100,000) and Shanghai (542.86/100,000). CONCLUSION The prevalence of headache disorders is increasing in China. Effective health education, improve diagnosis and treatment are essential, particularly for middle-aged working populations and women of childbearing age.
Humans ; China/epidemiology* ; Female ; Male ; Adult ; Middle Aged ; Prevalence ; Young Adult ; Adolescent ; Aged ; Child ; Headache Disorders/epidemiology* ; Disability-Adjusted Life Years ; Child, Preschool ; Cost of Illness ; Infant ; Aged, 80 and over

ObjectiveTo establish a vaginal self-sampling HPV cervical cancer screening model in Hainan Province, to analyze the application of p16 protein detection in HPV positive and non-HPV16 /18 shunt screening. MethodsFrom January 2019 to September 2022, a total of 200 women from the targeted population was randomly selected for vaginal self-sampling HPV typing test to screen cervical cancer using randomized numeric table method, followed by cervical cytology sampling for cytology p16 protein detection. Postoperative pathological examination was used as the gold standard. Multivariate logistic regression analysis was used to analyze the influencing factors of HPV positive detection rate in cervical lesions, and the nomogram model was constructed simultaneously. The receiver operating characteristic(ROC) curve and calibration curve were used for evaluating the accuracy of the nomogram model. Differences in the distribution of self-sampled HPV-positive and HPV infected genotypes were recorded, and the application of p16 protein detection in HPV-positive and non-HPV16/18 shunt screening was analyzed. ResultsAged ≥40 years, BMI ≥28.00 kg·m^-2, number of sexual partners ≥2, frequency of sexual life ≥10 times·month^-1, bleeding from sexual intercourse, and age of first sexual intercourse <22 years were the risk factors for HPV positive of cervical lesions (all P<0.001). The results of ROC curve and calibration curve showed that the area under ROC curve (AUC) was 0.874 (95%CI: 0.823‒0.907, P<0.05), the sensitivity was 0.835, the specificity was 0.847, and the Youden index was 0.672, indicating a good fit of the model. Results of vaginal self-sampling HPV test showed that the positive rate of HPV was 86.50% (173/200). HPV high-risk infection types mainly included HPV16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, 68, 73, and 82. Single HPV infection accounted for 95.95% (166/173), 2.89% (5/173) were infected with two types of HPV, and 1.16% (2/173) were infected with three or more types of HPV. Colposcopic pathologic diagnosis was used as the gold standard, and the results showed that the accuracy of p16 protein detection in the diagnosis of cervical cancer was 93.50% (187/200), with a sensitivity of 96.53% (167/173), and a specificity of 74.07% (20/27). The negative and positive predictive value were 76.92% (20/26) and 95.98% (167/174), respectively. The results of shunt screening showed that there were 80 cases infected with HPV16, 79 cases infected with HPV18 and 41 cases of non-HPV16/18, with a sensitivity of 90.91%, 90.32% and 86.67%, a specificity of 71.43%, 64.71% and 72.73%, a negative predictive value of 62.50%, 64.71% and 66.67%, a positive predictive value of 93.75%, 90.32% and 89.66%, and an accuracy of 87.50%, 84.81% and 82.93%, respectively. The specificity and accuracy of p16 positive screening for cervical cancer were significantly higher than that of HPV positive detection, but the false positive rate was significantly lower than that of HPV positive detection. The AUCs of HPV positive, p16 positive and combination of the two detection methods for cervical cancer were 0.603, 0.822 and 0.907, respectively. ConclusionVaginal self-sampling HPV testing is a widely accepted mode for cervical cancer screening. Cervical cytology p16 protein detection is important for self-sampled HPV positive and shunt screening of non-HPV16/18.

Objective To investigate the role of bone marrow mesenchymal stem cells derived from diabetic mice and their paracrine roles in inducing insulin resistance(IR).Methods The mouse model of diabetes mellitus was established,bone marrow mesenchymal stem cells(BMSC)were extracted and cultured,and the culture supernatant(M-BMSC-CS)was collected.(1)Cell experiment:HepG2 hepatocytes were divided into normal low-glycemic culture group[cultured with low-glycemic DMEM(5.55 mmol·L-1)],M-BMSC-CS experimental group(M-BMSC-CS 75 μL),and high-glycemic and high-lipid control group(given 25 mmol·L-1 high-glycemic DMEM+0.25 mmol·L-1 palmitic acid);(2)Animal experiments:Mice were divided into normal mice group(0.9％NaCl by intraperitoneal injection)and M-BMSC-CS-m group(M-BMSC-CS by intraperitoneal injection of normal mice(injection dose 0.2 mL/10 g)].Glucose intake was measured by glucose oxidase method.The fluorescence intensity of Glut2 protein was detected by immunofluorescence.The expression of insulin signaling pathway protein was detected by Western blot.Test oral glucose tolerance(OGTT)and insulin tolerance(ITT).Results The glucose intakes of the normal low-glucose culture group,the M-BMSC-CS experimental group and the high-glucose and high-lipid control group were(2.96±0.05),(1.64±0.28)and(1.42±0.32)mmol·L-1,respectively;the fluorescence expressions of glucose transporter 2(Glut2)were 53.21±2.70,30.95±3.39 and 34.96±7.60,respectively;the protein expression levels of phosphorylated insulin receptor substrate 1-ser307(p-IRS-1ser307)were 0.46±0.21,1.09±0.24 and 0.91±0.16,respectively;phosphorylated protein kinase(p-AKT)protein expression levels were 0.94±0.05,0.59±0.06 and 0.53±0.05;Glut2 protein expression levels were 1.08±0.14,0.58±0.14 and 0.62±0.09,respectively.The above indexes in M-BMSC-CS experimental group were statistically significant compared with those in normal low-glycemic culture group(all P＜0.05).Fasting blood glucose levels in the normal group and M-BMSC-CS-m group were(5.23±0.57)and(9.30±1.14)mmol·L-1;p-AKT protein expression level were 1.27±0.21 and 0.51±0.19;Glut2 protein expression level were 1.17±0.17 and 0.79±0.09,respectively.The above indexes in M-BMSC-CS-m group were significantly different from those in normal mouse group(P＜0.05).Conclusion BMSC culture supernatant from diabetic mice induced insulin resistance of normal HepG2 hepatocytes in vitro and normal mice in vivo.

OBJECTIVE To establish a method for the determination of the concentrations of anti-tumor lead compounds purine benzamides PLB-E and PLB-P in rat plasma by HPLC and apply to study pharmacokinetics. METHODS The established HPLC was used to determine the plasma drug concentrations of rats at different time points after intravenous administration of 5, 10, 20 mg·kg–1 (low, medium, high doses) of PLB-E and PLB-P, and the pharmacokinetic parameters of each compound were calculated using DAS 3.3.0 software. RESULTS PLB-E and PLB-P had good linear relationship in the range of 2–120, 3–60 μg·mL–1, respectively(r2>0.999). The RSD of inter-day and intra-day precision were <15%. The extraction recoveries were 87.48%–92.84% and 88.24%–92.60%, respectively. The main pharmacokinetic parameters of PLB-E and PLB-P after a single intravenous injection of 5, 10, 20 mg·kg–1 were as follows, the average Cmax was (20.30±2.39), (40.63±3.40), (63.62±7.55)mg·L–1 and (13.21±1.40), (24.87±1.33), (32.83±0.65)mg·L–1, respectively. AUC(0-∞) were (104.67±48.39), (177.42±84.11), (194.32±91.48)mg·h·L–1 and (106.75±54.21), (179.90±93.59), (253.56±126.17)mg·h·L–1, respectively. Tmax of each dose was 0.08 h. CONCLUSION The HPLC method established in this study meets the requirements for the determination of biological samples through methodological verification, which is applicable to the determination of the concentration of PLB-E and PLB-P in rat plasma and the pharmacokinetic study. The pharmacokinetic process of PLB-E and PLB-P in rats conforms to the two-compartment model, and conforms to the nonlinear kinetic elimination.