Objective To develop a physiological pharmacokinetic(PBPK)model of ritonavir,simulate ritonavir-mediated drug interactions,and provide future predictions for ritonavir pharmacokinetics(PK)and drug-drug interaction(DDI).Methods The PBPK model of ritonavir was constructed by searching relevant databases,collecting data on the physicochemical properties,PK,DDI related parameters and clinical studies of ritonavir,and using PK-Sim software to optimize and validate the parameters of the model to evaluate the performance of the constructed PBPK model in describing the PK characteristics and predicting the DDI of ritonavir.Results The ritonavir PBPK model demonstrated good performance,and by calculating the geometric mean folded error(GMFE)between the Sim and actual Obs values,the GMFEs of ritonavir AUC and Cmax were 1.11 and 1.16,respectively,and the GMFEs of ritonavir AUC and Cmax after combination with ritonavir were 1.24 and 1.26,respectively.Conclusion The PBPK model of ritonavir has been successfully constructed,and the effect of ritonavir on the metabolic enzyme cytochrome P450 3A4 is significant.Therefore,when ritonavir is combined with the victim drugs,individualized dosing can be guided according to the PBPK model.

Zilucoplan is a novel subcutaneous self-administered macrocyclic peptide inhibitor of complement component 5.It was approved by the FDA in October 2023 for the treatment of adults with generalized myasthenia gravis(gMG)who are positive for acetylcholine receptor(AChR)antibodies.This article reviews its pharmacological action,pharmacokinetics,clinical evaluation and safety.

Objective To evaluate the pharmacokinetics(PK)of tenofovir alafenamide Fumarate tablets(25 mg)in healthy Chinese subjects after single oral administration to provide a basis for bioequivalence evaluation.Methods Using a single-dose,randomized,open-lable,two-period,two-way crossover design under fasting condition,while three-way crossover design under fed condition,42 healthy subjects respectively for fasting and fed study were enrolled,and randomized into two groups to receive a single dose of test product(T)or reference product(R)25 mg.Plasma concentration of tenofovir alafenamide and tenofovir were determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS)method.The pharmacokinetic parameters were calculated by WinNonlin software(8.1 version)using non-compartmental model,and bioequivalence evaluation was performed for the two preparations.Relevant safety evaluations were performed during the trial.Results The test product and the reference product under fasting study,the main PK parameters of tenofovir alafenamide were as follows:Cmax were(215.17±94.24)and(199.30±71.11)ng·mL-1;AUC0-t were(135.44±71.60)and(123.91±53.82)h·ng·mL-1;the main PK parameters of tenofovir were as follows:Cmax were(7.30±2.27)and(7.12±1.74)ng·mL-1,AUC0-t of tenofovir were(237.16±47.09)and(230.06±43.41)h·ng·mL-1,respectively.The test product and the reference product under fed study,the main PK parameters of tenofovir were as follows:Cmax were(197.69±82.19)and(197.10±110.54)ng·mL-1;AUC0-t were(197.69±82.19)and(197.10±110.54)h·ng·mL-1;the main PK parameters of tenofovir were as follows:CMax were(2.57±1.37)and(2.58±1.31)ng·mL-1;AUC0-t were(227.08±74.33)and(238.51±128.30)h·ng·mL-1,respectively.The 90％confidence interval for geometric mean ratio of Cmax,AUC0-tof T and R under fed condition were between 80.00％-125.00％,respectively.The incidence of adverse events in fasting and fed tests was 21.43％and 30.95％,respectively,and no serious adverse event was reported.Conclusion The test formulation and reference formulation of tenofovir alafenamide fumarate tablets were equivalent and was safe.

Liver is the main organ of glucose and lipid metabolism, and persistent hyperglycemia is a common cause of liver injury. Panax notoginsenosides (PNS) is the main active ingredient in Panax notoginseng, which have anti-inflammatory and antioxidant effects. In this study, quantitative proteomics combined with experimental verification was used to explore the protective effect of PNS on liver injury in type 2 diabetes mellitus (T2DM) mice and its potential mechanism. All experiments were approved by the Ethical Committee Experimental Animal Center of North Sichuan Medical College (NSMC2022023). Hematoxylin-eosin (H&E) staining and transmission electron microscopy were used to observe the effect of PNS on the histopathological changes of liver in T2DM mice. TdT-mediated dUTP Nick-end labeling (TUNEL) staining was used to analyze the effect of PNS on hepatocyte apoptosis in T2DM mice. Reactive oxygen species (ROS) and malonaldehyde (MDA) kits were used to detect the effect of PNS on oxidative damage of liver in T2DM mice. Subsequently, proteomics profiling of mice in T2DM and T2DM+PNS groups were investigated based on quantitative proteomics. Differentially expressed proteins were screened out according to fold change and significance level in T2DM and T2DM+PNS groups, respectively. Pathway enrichment analysis of these differential proteins was done using GeneAnalytics database. Gene ontology analysis was conducted by Metascape database. Protein-protein interaction networks were constructed based on STRING database. Western blot was used to detect protein expression. These results showed that PNS could improve liver abnormalities, inhibit hepatocyte apoptosis, and improve the morphology of mitochondria and endoplasmic reticulum in T2DM mice. Proteome data demonstrated that 489 genes expression changed significantly in liver of T2DM mice compared with normal, and 42 ones were significantly reversed after PNS treatment and returned to normal levels. Pathway analysis showed that sterol hormone biosynthesis, adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathway, oxidative stress, insulin signaling, phosphatidylinositol pathway, tumor necrosis factor-α (TNF-α) mediated inflammation, insulin resistance, and mTOR signaling pathway exhibited notable changes based on pathway enrichment ratio and significance level. It is worth noting that PNS could improve the abnormal changes of AMPK, TNF-α, apoptosis and insulin pathways. Western blot manifested that PNS inhibit the expression of Bax, Grp78 and Chop, reduce ratio of cleaved casp6/casp6, increase the levels of pAMPKα, HO-1 and Nu-Nrf2 in the liver of T2DM mice. These results suggested that PNS may play protective roles in the liver of T2DM mice by inhibiting apoptosis via activating AMPK/Nrf2/HO-1 signaling pathway, alleviating oxidative stress and endoplasmic reticulum stress.

Objective:To discuss the clinical characteristics,diagnosis processes,and treatment methods of one patient with congenital intrabdominal hernia,and to summarize the potential misconceptions during the diagnostic and treatment processes,and to improve the clinicians'awareness of this disease.Methods:The clinical data and auxiliary examination results of one patient with congenital intrabdominal hernia were collected and analyzed,and the related literatures were reviewed.Results:The patient,a 65-year-old male,sought care at the local hospital due to upper abdominal pain before 2 d;there were no significant abnormalities in the examination results at the cocal hospital;blood glucose>25 mmol·L-1.After receiving hypoglycemic,rehydration,and blood purification treatment,the condition of the patient was worsened,presenting with confusion,hypotension,and respiratory distress;the patient admitted in our hospital for further diagnosis and treatment.After admission,the patient was given despite fluid resuscitation,mechanical ventilation,and supportive treatment,but there was no improvement in the symptoms;interventional radiology was performed angiography of the abdominal artery and right femoral vein,which showed no significant vascular abnormalities in the abdomen.An abdominal paracentesis yielded a mixed bloody fluid,suggesting the concealed intraperitoneal disease;exploratory laparotomy was performed.During operation,the intrabdominal hernia with small intestine necrosis and septic shock were diagnosed,and partial small intestine resection,anastomosis,adhesiolysis,and abdominal irrigation and drainage were carried out.The patient had a good recovery and was discharged on the 14th day after operation.Conclusion:Congenital intrabdominal hernia is a very rare cause of intestinal obstruction in the adults,and high suspicion for intrabdominal hernia is one of the differential diagnosis for atypical acute abdomen;early multidisciplinary intervention can be lifesaving for the patients.

Objective:To explore the role of combined detection of cell free BMPR1A and PLAC8 gene methylation in plasma in predicting postoperative recurrence of hepatocellular carcinoma.Methods:Case series study. Patients with stage Ⅰ-Ⅳ hepatocellular carcinoma who were treated at the Third Affiliated Hospital of Sun-Yat-sen University from January 2022 to July 2023 were selected. All enrolled patients underwent alpha fetoprotein (AFP) and imaging assessments 1 month, 3 months, 6 months, 9 months, and 12 months after treatment. Simultaneously, peripheral blood of patients was extracted for plasma circulating tumor DNA (ctDNA) methylation detection, and the results of free BMPR1A and PLAC8 gene methylation detection in patients′ plasma after treatment were compared with the positive rate of traditional tumor marker AFP detection. Draw the receiver operating characteristic curve (ROC) of the subjects to demonstrate the effectiveness of this method in predicting the recurrence of hepatocellular carcinoma. Based on the results of cell free DNA methylation and whether AFP is more than 7 μg/L, hepatocellular carcinoma patients were divided into high-risk methylation group (12 cases), low-risk methylation group (21 cases), high-risk AFP group (15 cases), and Kaplan Meier survival analysis was performed on them.Results:The sensitivity and specificity of combined detection of free BMPR1A PLAC8 gene methylation in plasma for predicting liver cancer recurrence were 66.7% and 88.9%, respectively. The area under curve (AUC) of BMPR1A PLAC8 gene methylation detection for liver cancer recurrence were 0.770 and 0.778, and the AFP was 0.522 in ROC curve analysis. Compared to imaging examinations, cell free DNA methylation detection can detect the recurrence of hepatocellular carcinoma on average by 58.3 days in advance(53.8 days vs 112.1 days). The progression free survival rate of the high-risk group based on free DNA methylation prediction at 400 days was 22.2%, significantly lower than the low-risk group (76.2%, P<0.001). Conclusion:Compared to AFP, detecting the methylation of BMPR1A and PLAC8 genes can predict the recurrence of hepatocellular carcinoma more accurately, making it a practical method for monitoring liver cancer recurrence.

The Republic of China period （1912—1949） was an important stage of transition from traditional herbalism to clinical Chinese materia medica. The clinical application of Chinese materia medica became the focus of academic attention. During the Republic of China period， the research objectives， methods， and content of clinical Chinese materia medica were clarified， and the basic framework of Chinese materia medica was established through efficacy classification and item description. Based on the historical background at that time， striving for survival in adversity were the internal factors driving the construction of clinical Chinese materia medica， and the rise of academic education and the popularity of traditional Chinese medicine journals provided favorable conditions for the development of clinical Chinese materia medica. The clinical Chinese materia medica during the Republic of China period gradually formed a theoretical structure and core content that was distinctly different from that of traditional herbal medicine， which was integrated with the scientific research of Chinese materia medica and promoted the continuous development of Chinese materia medica together with other subdisciplines， presenting distinctive characteristics of the times and important academic significance.

Using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the plasma level of Lyso-GL3 in patients with Fabry disease and to analyze the clinical application of the method.

Cells not only contain membrane-bound organelles (MBOs), but also membraneless organelles (MLOs) formed by condensation of many biomacromolecules. Examples include RNA-protein granules such as nucleoli and PML nuclear bodies (PML-NBs) in the nucleus, as well as stress granules and P-bodies in the cytoplasm. Phase separation is the basic organizing principle of the form of the condensates or membraneless organelles (MLOs) of biomacromolecules including proteins and nucleic acids. In particular, liquid-liquid phase separation (LLPS) compartmentalises and concentrates biological macromolecules into liquid condensates. It has been found that phase separation of biomacromolecules requires some typical intrinsic characteristics, such as intrinsically disordered regions, modular domains and multivalent interactions. The phase separation of biomacromolecules plays a key role in many important cell activities. In recent years, the phase separation of biomacromolecules phase has become a focus of research in gene transcriptional regulation. Transcriptional regulatory elements such as RNA polymerases, transcription factors (TFs), and super enhancers (SEs) all play important roles through phase separation. Our group has previously reported for the first time that long-term inactivation or absence of assembly factors leads to the formation of condensates of RNA polymerase II (RNAPII) subunits in the cytoplasm, and this process is reversible, suggesting a novel regulatory model of eukaryotic transcription machinery. The phase separation of biomacromolecules provides a biophysical understanding for the rapid transmission of transcriptional signals by a large number of TFs. Moreover, phase separation during transcriptional regulation is closely related to the occurrence of cancer. For example, the activation of oncogenes is usually associated with the formation of phase separation condensates at the SEs. In this review, the intrinsic characteristics of the formation of biomacromolecules phase separation and the important role of phase separation in transcriptional regulation are reviewed, which will provide reference for understanding basic cell activities and gene regulation in cancer.

BACKGROUND:Quercetin plays an important role in the proliferation and differentiation of bone marrow mesenchymal stem cells,but less research has been done on its mechanism of promoting the migration of bone marrow mesenchymal stem cells. OBJECTIVE:To study the effect of quercetin on the migration of human bone marrow mesenchymal stem cells through in vitro experiments,and to explore the regulatory role of CCR1 and CXCR4. METHODS:Human bone marrow mesenchymal stem cells were selected as experimental subjects.CCK8 assay was used to detect the effect of quercetin on the proliferative activity of human bone marrow mesenchymal stem cells.Cell scratch assay and Transwell assay were used to detect the in vitro invasive and migratory abilities of human bone marrow mesenchymal stem cells after quercetin treatment,respectively.The role of quercetin in relation to CCR1 and CXCR4 was demonstrated with the help of molecular docking technology.Western blot assay and real-time fluorescence quantitative PCR were used to detect the migration-related chemokine expression after quercetin treatment. RESULTS AND CONCLUSION:(1)5 and 10 μmol/L quercetin could significantly promote the proliferation of human bone marrow mesenchymal stem cells,and the drug concentration of 10 μmol/L resulted in the highest cell proliferation efficiency.(2)To better explore the dose-effect relationship of quercetin affecting the migration of human bone marrow mesenchymal stem cells,5 and 10 μmol/L quercetin were selected for the subsequent experiments,and ligustrazine was used as the positive control drug,and the experiments were divided into blank control group,5 μmol/L quercetin group,10 μmol/L quercetin group,and 100 μmol/L ligustrazine group.(3)In vitro migration and invasion ability of human bone marrow mesenchymal stem cells were elevated in a concentration-dependent manner after quercetin treatment,and the migration effect of 10 μmol/L quercetin group was better than that of ligustrazine group.(4)The molecular docking results suggested that there was a strong interaction between quercetin and CCR1 and CXCR4.(5)Quercetin could up-regulate the expression of CCR1 and CXCR4 proteins and mRNA.(6)This study confirmed at the cellular level that quercetin could promote the migration of human bone marrow mesenchymal stem cells by targeting CCR1 and CXCR4.