Grounded in the theory of "all marrows dominated by brain", this study explored the therapeutic mechanism of Zuogui Pills in modulating the oxytocin(OXT)/oxytocin receptor(OXTR) feed-forward loop in the treatment of postmenopausal osteoporosis(PMOP). A PMOP rat model was established using ovariectomy, and 70 Sprague-Dawley female rats were randomly divided into the following groups: sham operation group, model group, estradiol group(17β-estradiol, 0.05 mg·kg~(-1)·d~(-1)), Zuogui Pills low, medium, and high dose groups(0.2, 0.4, 0.8 g·kg~(-1)·d~(-1), respectively), and an antagonist group(atosiban 0.9 mg·kg~(-1)·d~(-1) + 17β-estradiol 0.05 mg·kg~(-1)·d~(-1) + Zuogui Pills 0.4 g·kg~(-1)·d~(-1)). After 12 weeks of model establishment, treatment was administered by gavage once daily for another 12 weeks, followed by sample collection. Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of estrogen(E_2), OXT, tartrate-resistant acid phosphatase(TRACP-5b), and bone alkaline phosphatase(BALP). Histopathological changes in the left distal femur were observed through hematoxylin and eosin(HE) staining. Micro-computed tomography(micro-CT) was used to analyze the microstructure of the right distal femur. Western blot was employed to detect the expression levels of OXTR, small GTP-binding protein Ras, Raf1 proto-oncogene(Raf1), mitogen-activated protein kinase kinase 1/2(MEK1/2), and extracellular signal-regulated kinase 1/2(ERK1/2), and their phosphorylated forms in tibial tissues. Compared with the model group, the Zuogui Pills medium and high dose groups showed significantly increased levels of E_2, OXT, and BALP, with a notable decrease in TRACP-5b levels. Morphologically, the trabeculae in the left distal femur were more tightly arranged. The fibrous structure in the right distal femur was significantly improved in the Zuogui Pills high dose group. Additionally, the expression of OXTR, Ras, p-Raf1, p-MEK1/2, and p-ERK1/2 proteins in tibial tissues was significantly increased. The therapeutic effect of the Zuogui Pills high dose group was partially inhibited when an OXTR antagonist was administered. These findings suggest that Zuogui Pills can regulate the OXT/OXTR feed-forward loop, activate the phosphorylation of the downstream Ras/Raf1/MEK/ERK signaling pathway, and ultimately improve bone mineral density, thereby exerting therapeutic effects in PMOP.
Animals ; Rats, Sprague-Dawley ; Rats ; Female ; Drugs, Chinese Herbal/administration & dosage* ; Oxytocin/genetics* ; Receptors, Oxytocin/genetics* ; Humans ; Osteoporosis, Postmenopausal/genetics* ; Bone and Bones/drug effects* ; Brain/drug effects* ; Bone Marrow/drug effects*

Anemia of chronic disease (ACD) is the most frequent clinical issue in patients with chronic disease. ACD is usually secondary to chronic kidney disease (CKD), cancer, and chronic infection, which is associated with poor health outcomes, increased morbidity and mortality, and substantial economic costs. Current treatment options for ACD are very limited. The discovery of the hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) pathway made it possible to develop novel therapeutic agents (such as hypoxia-inducible factor-prolyl hydroxylase inhibitor, HIF-PHI) to treat ACD by stabilizing HIF and subsequently promoting endogenous erythropoietin (EPO) production and iron absorption and utilization. Thus, HIF-PHIs appear to open a new door for the treatment of ACD patients with a novel mechanism. Here, we comprehensively reviewed the latest advancements in the application of HIF-PHIs in ACD. Specifically, we highlighted the key features of HIF-PHIs on ACD, such as stimulation of endogenous EPO, handling iron metabolism, inflammation-independent, and prolonging lifespan of red blood cells. In conclusion, the success of HIF-PHIs in the treatment of ACD may expand the therapeutic opportunity for other types of anemia beyond renal anemia.
Humans ; Anemia/metabolism* ; Chronic Disease ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism* ; Erythropoietin/metabolism* ; Prolyl-Hydroxylase Inhibitors/therapeutic use* ; Animals ; Renal Insufficiency, Chronic

Objective:To explore the clinical efficacy of the sixth generation CyberKnife (M6) in treating patients with brain metastases, and analyze clinical characteristics and dosimetric factors.Methods:Clinical data of patients with brain metastases who received CyberKnife treatment at Sichuan Cancer Hospital from April 2023 to March 2024 were retrospectively analyzed. All patients were treated with CyberKnife with 6 MV X-ray. According to the maximum diameter of brain metastases, the radiation prescription dose of brain metastases was adjusted. The tumor remission, recurrence, 6-month and 1-year overall survival (OS), local control (LC) of intracranial target lesions, progression-free survival (PFS), distant metastasis-free survival (DMFS) of intracranial brain metastases and adverse reactions were evaluated. According to the median biological dose, the survival difference between the groups was compared. Survival analysis was conducted by Kaplan-Meier method. Survival differences among different groups were analyzed by log-rank test.Results:A total of 63 eligible patients with brain metastases were enrolled, with a median age of 59 years (rang: 36-80 years). Among them, 47 patients were diagnosed with primary tumors originating from the lungs, 16 patients with primary tumors originating from other organs; 44 patients with single brain metastases, and 19 patients with 2-3 lesions, respectively. The median biological dose was 67.2 Gy (rang: 47.4-86.4 Gy), and the median single dose was 8 Gy/F (rang: 4-24 Gy/F). The follow-up was conducted until July 15, 2024. The median follow-up time for the entire group was 9 months (rang: 2-15 months). Among the 87 target lesions treated with CyberKnife, 11 patients corresponding to 14 target lesions experienced local recurrence. And the 6-month and 1-year LC rates were 92.5% and 70.9%, respectively. Ten patients corresponding to 16 target lesions died. And the 6-month and 1-year OS rates were 92.7% and 74.8%, respectively. Thirty-five patients corresponding to 50 target lesions experienced disease progression. And the 6-month and 1-year PFS rates were 64.3% and 25.5%, respectively. Thirty-three patients corresponding to 48 target lesions showed distant metastasis outside the target lesions, with a 6-month DMFS of 67.0% and a 1-year DMFS of 33.9%. Group comparison showed that 43 target lesions in the group receiving ≤67.2 Gy irradiation and 44 in the group receiving >67.2 Gy irradiation. The 6-month LC, OS, PFS, and DMFS rates between two groups were 89.8% vs. 97.7% ( P=0.127), 89.8% vs. 95.4% ( P=0.305), 65.4% vs. 68.5% ( P=0.514), 65.4% vs. 68.5% ( P=0.516), respectively. The 1-year LC, OS, PFS, and DMFS rates between two groups were 54.1% vs. 89.5% ( P=0.003), 67.3% vs. 82.9% ( P=0.219), 19.2% vs. 32.7% ( P=0.370) and 23.3% vs. 33.0% ( P=0.533). During the follow-up, only 2 patients (3.2%) were found to have grade 1-2 radiation-induced brain injury (asymptomatic brain injury) by MRI examination, and there were no other radiotherapy related adverse reactions. Conclusions:CyberKnife therapy is clinically effective for brain metastases, with mild adverse reactions. Increasing the tumor irradiation dose can improve local tumor control and is expected to further improve the OS of patients.

Objective:To explore the clinical efficacy of the sixth generation CyberKnife (M6) in treating patients with brain metastases, and analyze clinical characteristics and dosimetric factors.Methods:Clinical data of patients with brain metastases who received CyberKnife treatment at Sichuan Cancer Hospital from April 2023 to March 2024 were retrospectively analyzed. All patients were treated with CyberKnife with 6 MV X-ray. According to the maximum diameter of brain metastases, the radiation prescription dose of brain metastases was adjusted. The tumor remission, recurrence, 6-month and 1-year overall survival (OS), local control (LC) of intracranial target lesions, progression-free survival (PFS), distant metastasis-free survival (DMFS) of intracranial brain metastases and adverse reactions were evaluated. According to the median biological dose, the survival difference between the groups was compared. Survival analysis was conducted by Kaplan-Meier method. Survival differences among different groups were analyzed by log-rank test.Results:A total of 63 eligible patients with brain metastases were enrolled, with a median age of 59 years (rang: 36-80 years). Among them, 47 patients were diagnosed with primary tumors originating from the lungs, 16 patients with primary tumors originating from other organs; 44 patients with single brain metastases, and 19 patients with 2-3 lesions, respectively. The median biological dose was 67.2 Gy (rang: 47.4-86.4 Gy), and the median single dose was 8 Gy/F (rang: 4-24 Gy/F). The follow-up was conducted until July 15, 2024. The median follow-up time for the entire group was 9 months (rang: 2-15 months). Among the 87 target lesions treated with CyberKnife, 11 patients corresponding to 14 target lesions experienced local recurrence. And the 6-month and 1-year LC rates were 92.5% and 70.9%, respectively. Ten patients corresponding to 16 target lesions died. And the 6-month and 1-year OS rates were 92.7% and 74.8%, respectively. Thirty-five patients corresponding to 50 target lesions experienced disease progression. And the 6-month and 1-year PFS rates were 64.3% and 25.5%, respectively. Thirty-three patients corresponding to 48 target lesions showed distant metastasis outside the target lesions, with a 6-month DMFS of 67.0% and a 1-year DMFS of 33.9%. Group comparison showed that 43 target lesions in the group receiving ≤67.2 Gy irradiation and 44 in the group receiving >67.2 Gy irradiation. The 6-month LC, OS, PFS, and DMFS rates between two groups were 89.8% vs. 97.7% ( P=0.127), 89.8% vs. 95.4% ( P=0.305), 65.4% vs. 68.5% ( P=0.514), 65.4% vs. 68.5% ( P=0.516), respectively. The 1-year LC, OS, PFS, and DMFS rates between two groups were 54.1% vs. 89.5% ( P=0.003), 67.3% vs. 82.9% ( P=0.219), 19.2% vs. 32.7% ( P=0.370) and 23.3% vs. 33.0% ( P=0.533). During the follow-up, only 2 patients (3.2%) were found to have grade 1-2 radiation-induced brain injury (asymptomatic brain injury) by MRI examination, and there were no other radiotherapy related adverse reactions. Conclusions:CyberKnife therapy is clinically effective for brain metastases, with mild adverse reactions. Increasing the tumor irradiation dose can improve local tumor control and is expected to further improve the OS of patients.

Objective To investigate the nutritional status of children with cystic fibrosis(CF)and understand the correlation between malnutrition and clinical characteristics as well as lung function.Methods A retrospective analysis was performed on clinical data of CF children admitted from January 2016 to June 2023.Clinical characteristics of CF children with different nutritional statuses were compared,and the correlation between malnutrition and lung function was analyzed.Results A total of 52 CF children were included,comprising 25 boys(48％)and 27 girls(52％),aged between 7 months and 17 years.Respiratory symptoms were the predominant clinical manifestations(96％,50/52).The prevalence of malnutrition was 65％(34/52),with moderate/severe malnutrition being the most common(65％,22/34).The malnutrition group had a longer duration of illness,higher proportion of digestive system symptoms,and lower levels of serum albumin(P＜0.05).Pulmonary function parameters,including forced expiratory volume in one second as a percentage of the predicted value,ratio of forced expiratory volume in one second to forced vital capacity,forced expiratory flow at 25％of forced vital capacity exhaled,forced expiratory flow at 50％of forced vital capacity exhaled,forced expiratory flow at 75％of forced vital capacity exhaled,and maximum mid-expiratory flow as a percentage of the predicted value,were lower in the malnutrition group compared to the normal nutrition group(P＜0.05).Correlation analysis showed body mass index Z-score was positively correlated with the above six pulmonary function parameters(P＜0.05).Conclusions The prevalence of malnutrition is high in CF children and is associated with decreased lung function.CF children with higher body mass index have better lung function.Therefore,screening and evaluation of nutritional status as well as appropriate nutritional intervention should be emphasized in CF children.[Chinese Journal of Contemporary Pediatrics,2024,26(3):275-281]

Objective To investigate the mechanism of salidroside on abnormal proliferation and extracellular matrix deposition of keloid(KD)fibroblasts.Methods The primary KD fibroblasts were randomly divided into model group(normal culture),experimental-L group(50 μmol·L-1 salidroside),experimental-H group(100 μmol·L-1 salidroside),Vector group(100 μmol·L-1 salidroside+Vector),ubiquitin C-terminal hydrolase L1(UCHL1)group(100 μmol·L-1 salidroside+overexpression UCHL1);The mRNA expression level of UCHL1 was detected by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR);flow cytometry was used to detect apoptosis;Western blot assay was used to detect the expression levels of Collagen Ⅰ,glutathione peroxidase 4(GPX4)and α-smooth muscle actin(α-SMA);the reactive oxygen species(ROS)levels was detected by DCFH-DA method.Results The relative expression levels of UCHL1 mRNA in model group,experimental-L,experimental-H,vector group and UCHL1 group were 1.01±0.11,0.71±0.07,0.49±0.05,0.50±0.05 and 2.36±0.13,respectively;the apoptosis rates were(4.59±0.56)％,(12.11±0.80)％,(22.16±3.21)％,(23.54±2.08)％,(9.04±0.72)％,respectively;Collagen Ⅰ protein expression levels were 0.97±0.06,0.82±0.07,0.53±0.04,0.54±0.07 and 0.91±0.11,respectively;α-SMA protein expression levels were 1.11±0.07,0.79±0.06,0.61±0.08,0.60±0.04,0.96±0.11,respectively;GPX4 protein expression levels were 0.93±0.06,0.66±0.04,0.41±0.03,0.43±0.03,0.78±0.04,respectively;ROS levels were(100.00±5.03)％,(127.18±10.15)％,(146.09±10.15)％,(144.75±10.95)％,(106.57±11.28)％,respectively.Compared with the model group,the above indexes in the experimental-L,-H groups were statistically significant(all P＜0.05).Compared with the Vector group,the above indexes in the UCHL1 group were statistically significant(all P＜0.05).Conclusion Salidroside can induce iron death,promote fibroblast apoptosis,inhibit excessive extracellular matrix deposition,and slow down KD progression,which may be related to the inhibition of UCHL1 expression.

Jumonji domain-containing protein D3(JMJD3)is a 2-oxoglutarate-dependent dioxygenase that specif-ically removes transcriptional repression marks di-and tri-methylated groups from lysine 27 on histone 3(H3K27me2/3).The erasure of these marks leads to the activation of some associated genes,thereby influencing various biological processes,such as development,differentiation,and immune response.However,comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking.Here,we provide a comprehensive overview of JMJD3,including its structure,functions,and involvement in inflammatory pathways.In addition,we summarize the evidence supporting JMJD3's role in several inflammatory diseases,as well as the potential therapeutic applications of JMJD3 inhibitors.Additionally,we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases.

Objective To study the pharmacokinetic characteristics of buspirone hydrochloride tablets in healthy adult populations under conditions of fasting and postprandial administration.Methods A single-center,randomized,three-cycle partially repeated crossover trial design was adopted,and 36 subjects were enrolled on fasting/postprandial,one tablet of the test preparation was taken in one cycle,one tablet of reference preparation(5 mg of buspirone tablets)was taken once in each of 2 cycles,the drug concentration of buspirone in plasma was determined by liquid chromatography-tandem mass spectrometry,and the pharmacokinetic parameters were calculated by WinNonlin software.Results Main pharmacokinetics of buspirone after oral administration of test and reference preparations in fasting group,the Cmax was(285.72±286.08)and(308.94±341.03)pg·mL-1;AUC0-t were(577.09±491.10)and(618.62±642.56)pg·mL-1·h;AUC0-∞ were(586.85±510.04)and(655.92±687.95)pg·mL-1·h;tmax was 0.75(0.33-4.00)and 0.75(0.33-1.75)h.Main pharmacokinetics of buspirone after oral administration of test and reference preparations in the postprandial group,the Cmax were(676.36±603.64)and(760.33±610.27)pg·mL-1;AUC0-t were(1 755.58±1 001.69)and(1 743.00±1 073.33)pg·h·mL-1;AUC0-∞ were(1 839.97±1 044.60)and(1 818.00±1 106.95)pg·mL-1·h;tmax was 1.25(0.25-4.50)and 1.00(0.25-3.50)h.The 90％confidence intervals of the AUC0-t and AUC0-∞ geometric mean ratios of the test preparation and the reference preparation in the fasting test and the postprandial test all fell between 80.00％and 125.00％,and the 95％upper confidence limit of of Cmax was ≤0 and geometric mean ratios point estimates fall between 80.00％and 125.00％.Conclusion Two kinds of buspirone hydrochloride are bioequivalent in Chinese healthy adult subject.

Objective To establish and validate a method for simultaneous determination of 9 sedative-hypnotics in human plasma,and to explore the preliminary clinical application.Methods Plasma samples were precipitated with acetonitrile and determined by high performance liquid chromatography tandem mass spectrometry.The column was Agilent Poroshell 120 EC-C18(2.1 mm × 50.0 mm,2.7μm)and eluted with acetonitrile water containing 0.1％formic acid in an equal degree program at a flow rate of 0.3 mL·min-1.The column temperature was 20 ℃ and injection volume was 5 μL.The deprotonated ions of analytes were ionized by positive ion,electron spray ionization and multiple reaction monitoring mode.The specificity,standard curve and lower limit of quantification,precision and recovery,matrix effect,stability and dilution effect of the method were investigated.Results Excellent linear relationship with correlation coefficient of r2 ≥ 0.997 7 was obtained.The linear of esazolam,alprazolam,oxazepam,clonazepam,lorazepam,triazolam,midazolam,diazepam and zolpidem were 18-1 800,4.5-450,25-2 500,3.5-350,25-2 500,1.5-150,5.5-550,35-3 500,4-400 ng·mL-1,respectively.The lower limit of quantification were 18,4.5,25,3.5,25,1.5,5.5,35,4 ng·mL-1.The method was accurate and precise with acceptable intra-day and inter-day precisions(relative standard deviations were less than 20％for a lower limit of quantification and less than 15％for other quality control samples)and an accuracy of 86.21％-112.38％.The extraction recovery rate were 93.07％-110.50％.The matrix factors normalized by internal standard were 86.61％-108.41％,relative standard deviations were less than 15％.Plasma samples remained stable under various storage conditions.The precision and accuracy of plasma samples were acceptable after dilution.Conclusion The method is simple,rapid,sensitive and specific,and it can be used for simultaneous detection of the 9 sedative-hypnotics in human plasma.

Objective To analyze the active components and mechanism of action of Houttuyniae Herba-Leonuri Herba in treating systemic lupus erythematosus(SLE).Methods The main chemical components of Houttuyniae Herba-Leonuri Herba and their targets through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)were obtained,and the active components of the Chinese medicine according to ADME were screened;the potential therapeutic targets of SLE through Genecards database were obtained.The protein-protein interactions(PPI)network was constructed by using the STRING 12.0 database,and the potential protein functional modules in the network was mined.The molecular docking technique was used to further validate the action mechanism of components and targets which played a therapeutic role.Results A total of 198 Houttuyniae Herba-Leonuri Herba-SLE intersection targets were obtained.Core active ingredients such as isothermalone,iso-preleoheterin,kaempferol,and quercetin and core targets such as IL6,AKT1,SRC,STAT3 and EGFR were screened out.A total of 1 001 entries were screened by Gene Ontology(GO)functional enrichment analysis,which were mainly related to the reaction of proteins and their kinases,and inflammation,etc..A total of 166 pathways were enriched in Kyoto Encyclopedia of Genes and Genomes(KEGG),including cancer pathway,PI3K-Akt signaling pathway,neuroactive ligand-receptor pathway,and so on.Molecular docking results showed that the core active components of Houttuyniae Herba-Leonuri Herba had great binding activities with their core targets,which preliminarily verified the above network pharmacology results.Conclusion Houttuyniae Herba-Leonuri Herba may exerts a therapeutic effect on SLE through core ingredients such as isothermalone acting on core targets such as IL6,AKT1,SRC,STAT3 and EGFR,and regulating cancer pathway,PI3K-Akt signaling pathway and neuroactive ligand-receptor interaction.