BACKGROUND: Early control of low-density lipoprotein cholesterol (LDL-C) is crucial for reducing the progress of cardiovascular disease. However, its additional role to the risk of primary osteoporosis in men with coronary heart disease was inconclusive. Our study aims to determine the association of LDL-C and its trajectories for osteoporosis risk in the middle-aged and aged men of China. METHODS: The retrospective cohort study of 1546 men aged 69.74 ± 11.30 years conducted in Beijing, China from 2015 to 2022. And the incidence of primary osteoporosis was annually recorded. LDL-C trajectories were further identified by latent class growth model using repeated measurements of LDL-C. The association of baseline LDL-C for osteoporosis was estimated using hazard ratio (HR) with 95% CI in Cox proportional hazard model, while mean level and trajectories of LDL-C for osteoporosis were evaluated using odds ratio (OR) with 95% CI in logistic regression model. RESULTS: During the median 6.2-year follow-up period, 70 men developed primary osteoporosis. The higher level of baseline LDL-C (HR = 1.539, 95% CI: 1.012-2.342) and mean LDL-C (OR = 2.190, 95% CI: 1.443-3.324) were associated with higher risk of osteoporosis in men with coronary heart disease after adjusted for covariates. Compared with those in the LDL-C trajectory of low-stable decrease, participants with medium-fluctuant trajectory, whose longitudinal LDL-C started with a medium LDL-C level and appeared an increase and then decrease, were negatively associated with osteoporosis risk (OR = 2.451, 95% CI: 1.152-5.216). And participants with initially high LDL-C level and then a rapid decrease demonstrated a tendency towards reduced risk (OR = 0.718, 95% CI: 0.212-2.437). CONCLUSIONS Elevated LDL-C level and its long-term fluctuation may increase the risk of primary osteoporosis in men. Early controlling a stable level of LDL-C is also essential for bone health.

Objective:To establish a mouse model of liver cancer resistant to PD-1 monoclonal antibody and analyze the changes in its metabolomics to explore the potential mechanism of drug resistance.Methods:BALB/c mice were randomly divided into control and treatment groups after being loaded with tumor,and a normal group was additionally set up.The normal and control groups were injected with saline,and the treatment group was injected with PD-1 monoclonal antibody,after which the mice in the treatment group were screened for drug resistant and response groups.Observed the drug-resistant situation,body mass,tumor growth and survival rate of mice in each group,calculate the spleen index.The pathological features of tumor tissues were observed by HE staining method.Serum metabolites were detected by non-targeted metabolomics.Finally,a bivariate Pearson correlation analysis was conducted between the differential serum metabolites and tumor size.Results:The tumor-bearing mouse model with PD-1 monoclonal antibody resistance was successfully established,and the drug resistance rate of the mice was 50％.Compared with the normal and response groups,mice in the resistant group showed an increase in body weight,a significant increase in tumor volume,a decrease in survival rate,and a significant increase in splenic index.There was less lymphocyte infiltration in the tumor tissue.Metabolomics analysis showed that the serum levels of glutamic acid and aspartic acid increased and malic acid decreased in the resistant mice compared with the response group,and these changes were closely related to the arginine biosynthesis pathway.Conclusions:The tumor-bearing mouse model with PD-1 monoclonal antibody resistance was successfully established.The changes in its peripheral serum metabolomics mainly involve arginine metabolism and the related changes of aspartate,malate and glutamate.

Central nervous system(CNS)degenerative disorders refer to a spectrum of pathological alterations triggered by struc-tural damage to cerebral neural tissues,clinically manifested as diverse neurological dysfunction syndromes,including multiple sclerosis(MS),neurodegenerative diseases(NDs),and ische-mic stroke.The hallmark pathological features of these disorders involve irreversible neuronal damage and decompensation of functional neural networks,ultimately leading to progressive neurological deficits.Notably,with the accelerating global popu-lation aging,the incidence of these diseases has surged signifi-cantly.According to WHO statistics,they now rank among the top three global causes of disability and mortality.Current re-search has confirmed that the pathogenesis of CNS degenerative disorders exhibits high heterogeneity,encompassing multifaceted pathophysiological processes such as genetic predisposition,oxi-dative stress,protein misfolding,and metabolic dysregulation.This intricate pathogenic network not only complicates clinical differential diagnosis but also poses substantial challenges to the development of precision therapeutic strategies.Importantly,re-cent studies have revealed that mitochondrial homeostasis disrup-tion-induced inflammatory cascades(termed mitochondrial in-flammation)play a pivotal regulatory role in neurodegenerative progression.Key molecular mechanisms include impaired mito-phagy,aberrant mitochondrial DNA(mtDNA)release and NL-RP3 inflammasome activation.This review systematically deci-phers the molecular regulatory network of mitochondrial inflam-mation,with a focus on its biological effects in critical pathologi-cal events such as blood-brain barrier disruption,microglial hy-peractivation and neuronal apoptosis.The overarching aim is to provide a theoretical foundation for developing innovative thera-peutic strategies targeting mitochondrial homeostasis restoration.

Central nervous system(CNS)degenerative disorders refer to a spectrum of pathological alterations triggered by struc-tural damage to cerebral neural tissues,clinically manifested as diverse neurological dysfunction syndromes,including multiple sclerosis(MS),neurodegenerative diseases(NDs),and ische-mic stroke.The hallmark pathological features of these disorders involve irreversible neuronal damage and decompensation of functional neural networks,ultimately leading to progressive neurological deficits.Notably,with the accelerating global popu-lation aging,the incidence of these diseases has surged signifi-cantly.According to WHO statistics,they now rank among the top three global causes of disability and mortality.Current re-search has confirmed that the pathogenesis of CNS degenerative disorders exhibits high heterogeneity,encompassing multifaceted pathophysiological processes such as genetic predisposition,oxi-dative stress,protein misfolding,and metabolic dysregulation.This intricate pathogenic network not only complicates clinical differential diagnosis but also poses substantial challenges to the development of precision therapeutic strategies.Importantly,re-cent studies have revealed that mitochondrial homeostasis disrup-tion-induced inflammatory cascades(termed mitochondrial in-flammation)play a pivotal regulatory role in neurodegenerative progression.Key molecular mechanisms include impaired mito-phagy,aberrant mitochondrial DNA(mtDNA)release and NL-RP3 inflammasome activation.This review systematically deci-phers the molecular regulatory network of mitochondrial inflam-mation,with a focus on its biological effects in critical pathologi-cal events such as blood-brain barrier disruption,microglial hy-peractivation and neuronal apoptosis.The overarching aim is to provide a theoretical foundation for developing innovative thera-peutic strategies targeting mitochondrial homeostasis restoration.

Objective:To establish a mouse model of liver cancer resistant to PD-1 monoclonal antibody and analyze the changes in its metabolomics to explore the potential mechanism of drug resistance.Methods:BALB/c mice were randomly divided into control and treatment groups after being loaded with tumor,and a normal group was additionally set up.The normal and control groups were injected with saline,and the treatment group was injected with PD-1 monoclonal antibody,after which the mice in the treatment group were screened for drug resistant and response groups.Observed the drug-resistant situation,body mass,tumor growth and survival rate of mice in each group,calculate the spleen index.The pathological features of tumor tissues were observed by HE staining method.Serum metabolites were detected by non-targeted metabolomics.Finally,a bivariate Pearson correlation analysis was conducted between the differential serum metabolites and tumor size.Results:The tumor-bearing mouse model with PD-1 monoclonal antibody resistance was successfully established,and the drug resistance rate of the mice was 50％.Compared with the normal and response groups,mice in the resistant group showed an increase in body weight,a significant increase in tumor volume,a decrease in survival rate,and a significant increase in splenic index.There was less lymphocyte infiltration in the tumor tissue.Metabolomics analysis showed that the serum levels of glutamic acid and aspartic acid increased and malic acid decreased in the resistant mice compared with the response group,and these changes were closely related to the arginine biosynthesis pathway.Conclusions:The tumor-bearing mouse model with PD-1 monoclonal antibody resistance was successfully established.The changes in its peripheral serum metabolomics mainly involve arginine metabolism and the related changes of aspartate,malate and glutamate.

AIM To investigate the variation rules of main secondary metabolites in Hedysari Radix before and after rubbing strip.METHODS UPLC-MS/MS was adopted in the content determination of formononetin,ononin,calycosin,calycosin-7-glucoside,medicarpin,genistein,luteolin,liquiritigenin,isoliquiritigenin,vanillic acid,ferulic acid,γ-aminobutyric acid,adenosine and betaine,after which cluster analysis,principal component analysis and orthogonal partial least squares discriminant analysis were used for chemical pattern recognition to explore differential components.RESULTS After rubbing strip,formononetin,calycosin,liquiritigenin and γ-aminobutynic acid demonstrated increased contents,along with decreased contents of ononin,calycosin-7-glucoside and vanillic acid.The samples with and without rubbing strip were clustered into two types,calycosin-7-glucoside,formononetin,γ-aminobutynic acid,vanillic acid,calycosin-7-glucoside and formononetin were differential components.CONCLUSION This experiment clarifies the differences of chemical constituents in Hedysari Radix before and after rubbing strip,which can provide a reference for the research on rubbing strip mechanism of other medicinal materials.

Objective To compare the effects of 20 mg qd and 10 mg bidadministration of iprrazole enteric-coated tablets on the control of gastric acid in healthy subjects.Methods A randomized,single-center,parallel controlled trial was designed to include 8 healthy subjects.Randomly divided into 2 groups,20 mg qd administration group:20 mg enteric-coated tablets of iprrazole in the morning;10 mg bid administration group:10 mg enteric-coated tablets of iprrazole in the morning and 10 mg in the evening.The pH values in the stomach of the subjects before and 24 h after administration were monitored by pH meter.The plasma concentration of iprazole after administration was determined by HPLC-MS/MS.The main pharmacokinetic parameters were calculated by Phoenix WinNonlin(V8.0)software.Results The PK parameters of iprrazole enteric-coated tablets and reference preparations in fasting group were as follows:The Cmax of 20 mg qd group and 10 mg bid group were(595.75±131.15)and(283.50±96.98)ng·mL-1;AUC0-t were(5 531.94±784.35)and(4 686.67±898.23)h·ng·mL-1;AUC0-∞ were(6 003.19±538.59)and(7 361.48±1 816.77)h·ng·mL-1,respectively.The mean time percentage of gastric pH＞3 after 20 mg qd and 10 mg bid were 82.64％and 61.92％,and the median gastric pH within 24 h were 6.25±1.49 and 3.53±2.05,respectively.The mean gastric pH values within 24 h were 5.71±1.36 and 4.23±1.45,respectively.The correlation analysis of pharmacokinetic/pharmacodynamics showed that there was no significant correlation between the peak concentration of drug in plasma and the inhibitory effect of acid.Conclusion Compared with the 20 mg qd group and the 10 mg bid group,the acid inhibition effect is better,the administration times are less,and the safety of the two administration regimes is good.

This study investigated the drug delivery performance of oral co-loaded puerarin(PUE) and daidzein(DAZ) mixed micelles(PUE/DAZ-FS/PMMs) from the perspectives of pharmacokinetics, pharmacodynamics, and tissue distribution. The changes in PUE plasma concentration in rats were evaluated based on PUE suspension, single drug-loaded micelles(PUE-FS/PMMs), and co-loaded micelles(PUE/DAZ-FS/PMMs). Spontaneously hypertensive rats(SHR) were used to monitor systolic blood pressure, diastolic blood pressure, and mean arterial pressure for 10 weeks after administration by tail volume manometry. The content of PUE in the heart, liver, spleen, lung, kidney, brain, and testes was determined using LC-MS/MS. The results showed that compared with PUE suspension and PUE-FS/PMMs, PUE/DAZ-FS/PMMs significantly increased C_(max) in rats(P<0.01) and had a relative bioavailability of 122%. The C_(max), AUC_(0-t), AUC_(0-∞), t_(1/2), and MRT of PUE/DAZ-FS/PMMs were 1.77, 1.22, 1.22, 1.17, and 1.13 times higher than those of PUE suspension, and 1.76, 1.16, 1.08, 0.84, and 0.78 times higher than those of PUE-FS/PMMs, respectively. Compared with the model control group, PUE/DAZ-FS/PMMs significantly reduced systolic blood pressure, diastolic blood pressure, and mean arterial pressure in SHR rats(P<0.05). The antihypertensive effect of PUE/DAZ-FS/PMMs was greater than that of PUE suspension, and even greater than that of PUE-FS/PMMs at high doses. Additionally, the distribution of PMMs in various tissues showed dose dependency. The distribution of PMMs in the kidney and liver, which are metabolically related tissues, was lower than that in the suspension group, while the distribution in the brain was higher than that in the conventional dose group. In conclusion, PUE/DAZ-FS/PMMs not only improved the bioavailability of PUE and synergistically enhanced its therapeutic effect but also prolonged the elimination of the drug to some extent. Furthermore, the micelles facilitated drug penetration through the blood-brain barrier. This study provides a foundation for the development of co-loaded mixed micelles containing homologous components.
Rats ; Animals ; Micelles ; Tissue Distribution ; Chromatography, Liquid ; Tandem Mass Spectrometry ; Rats, Inbred SHR ; Isoflavones/pharmacology*

Aim To investigate the differences in the role of different purinergic receptor subtypes at different sites in postoperative-hyperalgesic priming in mice. Methods A postoperative-hyperalgesic priming model was constructed by injecting PGE

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.
Female ; Humans ; Male ; Aged ; Middle Aged ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Prognosis ; Lymphoma, B-Cell ; Immunohistochemistry ; Immunoglobulin Heavy Chains/therapeutic use*