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 describe the clinical features of patients with primary sclerosing cholangitis(PSC)in China based on a nationwide multicenter patient cohort,and to investigate the risk factors for prognosis.Methods A retrospective cohort study was conducted among the patients with a confirmed diagnosis of PSC based on the electronic medical record system of seven grade A tertiary hospitals across the country,and related data were extracted.The Mann-Whitney U test was used for comparison of continuous data between groups,and the chi-square test was used for comparison of categorical data between groups.The Kaplan-Meier method was used to estimate liver transplant-free survival,and the log-rank test was used for comparison of survival rate between PSC patients with different features.The Cox regression model was used to identify independent risk factors for the prognosis of PSC patients and the interactions between key factors.Results A total of 107 patients were enrolled,among whom 55.6%(55/99)had large-duct PSC and 29.0%(31/107)had comorbidity with inflammatory bowel disease(IBD).The positivity rate of anti-neutrophil cytoplasmic antibody(ANCA)was 32.9%(24/73),and 50.0%(40/80)of the patients had an increase in IgG/IgM.The median symptom-to-diagnosis interval was 1 year(<1-4.0),and 38.3%(41/107)of the patients had progressed to decompensated cirrhosis at the time of diagnosis.The median liver transplant-free survival time was 114 months(95%confidence interval[CI]:62-166),with a 5-year survival rate of 65.7%.The multivariate analysis showed that an increase in total bile acid(TBA)(hazard ratio[HR]=1.006,95%CI:1.002-1.010,P=0.001)and a prolonged symptom-to-diagnosis interval(HR=1.252,95%CI:1.059-1.480,P=0.009)were independent risk factors for prognosis.The interaction analysis showed that compared with the female patients with TBA<50 μmol/L,both male and female patients with TBA≥50 μmol/L had a significant increase in the risk of liver transplantation or death(male:HR=16.563,95%CI:2.103-130.449,P<0.001;female:HR=17.009,95%CI:2.113-136.934,P<0.001),and compared with the patients with an age of<45 years and a TBA level of<50 μmol/L,the patients with an age of≥45 years and a TBA level of≥50 μmol/L had a significant increase in the risk of liver transplantation or death(HR=10.729,95%CI:1.325-86.859,P=0.026).Compared with the female patients with an symptom-to-diagnosis interval of≤2 years,the male patients with a symptom-to-diagnosis interval of>2 years had an increased risk of liver transplantation or death(HR=4.825,95%CI:1.725-13.644,P=0.003),and compared with the patients with an age of<45 years and a symptom-to-diagnosis interval of≤2 years,the patients with an age of<45 years and a symptom-to-diagnosis interval of>2 years had an increased risk of liver transplantation or death(HR=4.983,95%CI:1.366-18.173,P=0.015).Conclusion Compared with the reports from Western countries,large-duct PSC is also the main type of PSC in China,but with a relatively low proportion,and there is also a relatively low proportion of patients with IBD or positive ANCA.An increase in TBA and a prolonged symptom-to-diagnosis interval are independent risk factors for prognosis,with significant interactions with age and sex.This suggests that early screening and intervention should be enhanced to improve prognosis.

Objective:To summarize the clinicopathologic characteristics of malignant hypertension (MHT) patients with acute kidney injury (AKI) and application of renin-angiotensin-aldosterone system inhibitor (RAASi).Methods:It was a retrospective cohort study. The adult patients with MHT and AKI admitted to Peking University First Hospital from January 1, 2012 to July 14, 2022. The patients were categorized into RAASi group and non-RAASi group based on RAASi administration from AKI onset to discharge. The clinicopathological data between the two groups were compared, and application of RAASi was analyzed.Results:A total of 179 patients were enrolled with age of 31 (26, 37) years and 148 males (82.7%). Ninety-five patients (53.1%) received dialysis treatment. The common causes of MHT were essential hypertension (125 patients, 69.8%), renal hypertension (39 patients, 21.8%) and endocrine hypertension (7 patients, 3.9%). AKI severity distribution showed 41 patients (22.9%) in stage 1, 1 patient (0.5%) in stage 2 and 137 patients (76.5%) in stage 3. Among MHT patients, 94 patients (52.5%) had been treated with RAASi before AKI, and 13 patients (7.3%) discontinued RAASi after AKI. Among 85 patients (47.5%) without receiving RAASi treatment before AKI, 68 new patients (38.0%) received RAASi treatment after AKI, and 40 patients (22.3%) were treated with the support of dialysis. Compared with non-RAASI group ( n=30), proportions of chronic kidney disease ( χ2=6.324, P=0.012) and post-AKI hyperkalemia ( χ2=4.048, P=0.044) in RAASi group ( n=149) were lower, and the proportion of dialysis treatment ( χ2=5.638, P=0.018), admission diastolic blood pressure ( Z=-3.609, P<0.001) and maximum diastolic blood pressure during hospitalization ( Z=-1.978, P=0.048) were higher. There were no statistically significant differences in the rates of target blood pressure control and renal function recovery between the two groups during hospitalization (all P>0.05). During hospitalization, 64 patients received renal biopsies, of which 50 patients (78.1%) had typical MHT vascular lesions such as "onion skin" in renal arterioles. Twenty-seven patients (42.2%) were complicated with glomerular diseases, and IgA nephropathy was the most common type (85.2%, 23/27). The proportions of glomerular ischemia and sclerosis, endothelial cell proliferation and acute renal tubular injury in RAASi group ( n=54) were lower than those in non-RAASi group ( n=10), and proportions of thrombosis and "onion skin" change were higher than those in RAASi group ( n=10), but the differences were not statistically significant (all P>0.05). Renal function recovery occurred in 47 patients (26.3%) by discharge. Among 95 dialysis patients, 26 patients (27.4%) achieved dialysis independence at discharge. Conclusions:MHT patients with AKI exhibit severe renal pathology and short-term poor prognosis. RAASi is primarily prescribed to those with relatively better kidney function or those receiving dialysis support.

Objective:To investigate the correlation between statins and contrast-induced acute kidney injury (CI-AKI) and provide a reference basis for clinical practice.Methods:It was a retrospective cohort study. The adult patients were admitted to Peking University First Hospital from January 1, 2018, to December 31, 2020, and received at least one intravascular iodinated contrast administration during hospitalization. The clinical data of the patients were collected. The enrolled patients were divided into statin group and non-statin group according to statin exposure. The exposure of statins was defined as use of any type of statins within 48 hours before iodinated contrast administration. The primary outcome was in-hospital AKI defined as AKI developed after contrast administration and before discharge, with 30 days as the endpoint observation time, and the secondary outcome was post-contrast AKI (PC-AKI) defined as AKI onset within 72 hours after contrast administration. Cox regression model was applied to investigate the correlation between statin prescription prior to contrast administration and clinical outcomes. Pre-specified interaction analysis was conducted to examine modification effect of age, gender, baseline estimated glomerular filtration rate (eGFR), diabetes and the injection method of contrast.Results:Among 10 321 enrolled patients, the age was 63 (54, 71) years old, and 6 274 (60.8%) patients were males. There were 2 372 (23.0%) patients taking statins before the use of iodinated contrast agents, and the person-time incidence rate of in-hospital AKI was 2.5 per 1 000 person-days. The person-time incidence rate of statin users and statin non-users was 3.2 and 2.4 per 1 000 person-days, respectively. Compared with the non-statin group, age, serum creatinine and the proportions of males, admitted to the intensive care unit, lipid metabolism disorder, hypertension, diabetes, cerebrovascular diseases, cardiovascular diseases, using renin-angiotensin- aldosterone inhibitors, using diuretics, using non-steroidal anti-inflammatory drugs, using proton pump inhibitors, iodinated contrast administration via artery, eGFR<60 ml·min -1·(1.73 m 2) -1 were higher, while the proportions of general anesthesia surgery, severe liver diseases and tumors, and eGFR were lower in the statin group (all P<0.05). Among 10 321 patients, 5 867 patients had serum creatinine measurement within 72 hours after iodinated contrast administration, among which 70 patients (4.0 per 1 000 person-days) developed PC-AKI. Multivariate Cox regression analysis showed that statin use was an independent protective factor for in-hospital AKI ( HR=0.65, 95% CI 0.45?0.93, P=0.017) and PC-AKI ( HR=0.44, 95% CI 0.22?0.88, P=0.020). Subgroup analysis showed the significant interaction between diabetes and statin use ( P for interaction=0.039), and the protective effect of statins against in-hospital AKI was only observed in non-diabetic group ( HR=0.45, 95% CI 0.26?0.77). There were no significant differences in subgroups stratified by age, sex, baseline eGFR and the injection method of contrast (all P for interaction>0.05). Conclusions:Statin use prior to iodinated contrast administration is correlated with reduced risks of in-hospital AKI and PC-AKI in hospitalized patients, and the correlation between statin use and in-hospital AKI is more significant in non-diabetic patients. It is suggested that statin use before the application of iodinated contrast agents in hospitalized patients may prevent the occurrence of AKI.

Objective:To investigate the serum sodium level and its fluctuation in patients with hospitalized acquired acute kidney injury (AKI) and explore their impacts on in-hospital mortality.Methods:It was a single-center retrospective study. The adult patients developing hospital-acquired AKI and receiving at least twice serum sodium tests admitted to Peking University First Hospital from January 1, 2018, to December 31, 2020 were included. Dysnatremia included hyponatremia (< 135 mmol/L) and hypernatremia (>145 mmol/L). The patients were divided into hyponatremia group, normal serum sodium group and hypernatremia group, and the differences of clinical data among the three groups were compared. The fluctuation of serum sodium level was evaluated by coefficient of variation. A restricted cubic spline was applied to investigate the association between serum sodium level at AKI onset and mortality. Poisson regression analysis was used to explore the mortality risk of dysnatremia at AKI onset, dysnatremia at admission, and coefficient of variation of serum sodium, respectively.Results:Among the enrolled 1 475 AKI patients, the age was 66.0 (55.0, 78.0) years, and 850 patients (57.6%) were males. The estimated glomerular filtration rate was 77.3 (50.4, 97.6) ml·min -1·(1.73 m 2) -1. The time from admission to AKI onset was 8 (4, 15) days. The incidence of hyponatremia and hypernatremia at admission were 19.6% (289/1 475) and 2.6% (39/1 475), respectively, while the incidence at AKI onset was 24.0% (354/1 475) and 12.7% (188/1 475), respectively. There was statistically significant difference in terms of age, the initial classification distribution of AKI, serum sodium at admission, serum sodium at the occurrence of AKI, the lowest serum sodium at hospitalization, the highest serum sodium at hospitalization, the coefficient of variation of serum sodium, and the proportions of heart failure, stroke, disseminated intravascular coagulation, sepsis, acute respiratory distress syndrome, shock, prerenal causes, circle diuretics and aldosterone antagonists among hyponatremia group, normal serum sodium group and hypernatremia group (all P<0.05). The restricted cubic spline analysis showed a "U"-shaped correlation between serum sodium level at AKI onset and in-hospital mortality. Poisson regression analysis showed that after adjusting for age, gender, number of chronic comorbidities, initial classification of AKI, basal estimated glomerular filtration rate and number of acute disease state, with normal serum sodium as the reference, hyponatremia ( RR=1.56, 95% CI 1.14-2.13) and hypernatremia ( RR=1.71, 95% CI 1.23-2.39) at AKI onset were correlated with an increased risk of in-hospital mortality. Hyponatremia at admission was correlated with an increased risk of in-hospital mortality ( RR=2.13, 95% CI 1.62-2.79), while there was no statistically significant association between hypernatremia and in-hospital mortality ( RR=1.22, 95% CI 0.62-2.44). After further adjusting serum sodium levels at admission and at the occurrence of AKI, the coefficient of variation of serum sodium level was still correlated with an increased risk of in-hospital mortality ( RR=1.23, 95% CI 1.14-1.33). Conclusions:Dysnatremia is common in patients with hospital-acquired AKI. The serum sodium level at AKI onset is correlated with in-hospital death in a "U" shape. Dysnatremia and serum sodium fluctuation are associated with an increased risk of in-hospital mortality.

Traumatic brain injury (TBI) is intricately linked to the most severe clinical manifestations of brain damage. It encompasses dynamic pathological mechanisms, including hemodynamic disorders, excitotoxic injury, oxidative stress, mitochondrial dysfunction, inflammation, and neuronal death. This review provides a comprehensive analysis and summary of biomaterial-based tissue engineering scaffolds and nano-drug delivery systems. As an example of functionalized biomaterials, nano-drug delivery systems alter the pharmacokinetic properties of drugs. They provide multiple targeting strategies relying on factors such as morphology and scale, magnetic fields, pH, photosensitivity, and enzymes to facilitate the transport of therapeutics across the blood-brain barrier and to promote selective accumulation at the injury site. Furthermore, therapeutic agents can be incorporated into bioscaffolds to interact with the biochemical and biophysical environment of the brain. Bioscaffolds can mimic the extracellular matrix environment, regulate cellular interactions, and increase the effectiveness of local treatments following surgical interventions. Additionally, stem cell-based and exosome-dominated extracellular vesicle carriers exhibit high bioreactivity and low immunogenicity and can be used to design therapeutic agents with high bioactivity. This review also examines the utilization of endogenous bioactive materials in the treatment of TBI.

Objective To explore and evaluate the association between mitotic spindle organizing protein 2A(MZT2A)and survival prognosis and immunotherapy response of skin cutaneous melanoma(SKCM),based on multiomics data mining.Methods The expression difference and survival prognosis of MZT2A in SKCM were analyzed by the Cancer Genome Atlas database,Genotype-tissue Expression Data,Human Protein Atlas,SUMMER database.The biological function of MZT2A and related enriched pathways were analyzed by David2.The differences of immune infiltrating cells,immune therapy response and immune escape ability between high-and low-MZT2A groups were analyzed and compared by using Tumor Immune Estimation Resource,Tumor Immune Single-cell Hub,Tumor-immune System Interactions database,the Cancer Imaging Archive and Tumor Immune Dysfunction and Exclusion databases.Results The expression of MZT2A gene elevated in a variety of cancers,especially in SKCM.SKCM samples with high expression of MZT2A had a poor overall survival.The expression of MZT2A was negatively correlated with the infiltration of CD8+T cells,CD4+T cells,macrophages,neutrophils and dendritic cells in SKCM tissues.In addition,the higher the expression of MZT2A,the therapeutic response of SKCM were worse to immune checkpoint inhibitors(ICI).Conclusion MZT2A is a novel survival prediction target of SKCM.SKCM patients with high expression of MZT2A have poor response to ICI treatment,which provides a theoretical basis for predicting the survival prognosis and guiding immune targeted therapy of SKCM.

OBJECTIVE To establish the fingerprint of Bushen ningshen ointment， determine the contents of its major constituents， and investigate its in vitro antioxidant activity. METHODS High performance liquid chromatography （HPLC） fingerprints of 10 batches of Bushen ningshen ointment were established. Similarity evaluation and identification of common peaks were subsequently performed. The contents of 10 components such as salidroside were determined using the same HPLC method. Using the scavenging rates against 2，2′-azino bis（3-ethylbenzothiazoline-6-sulfonic acid） （ABTS） and 1，1-diphenyl-2- picrylhydrazyl （DPPH） radicals， as well as ferric ion reducing antioxidant power （FRAP） as indicators， the anti-oxidant activity of the ointment was evaluated； grey relational analysis and partial least squares regression were conducted using SIMCA 14.1 software to establish the spectrum-effect relationship. RESULTS The fingerprint chromatogram of 10 batches of Bushen ningshen ointment contained 24 common peaks， with similarity values all exceeding 0.96. Eleven peaks were identified as adenosine （peak 1）， salidroside （peak 4）， morroniside （peak 6）， catechin （peak 7）， paeoniflorin （peak 10）， spinosin （peak 11）， ferulic acid （peak 12）， isoquercitrin （peak 13）， E-mail：wli1743@163.com verbascoside （peak 14）， paeonol （peak 23）， and emodin （peak 24）. Content determination results showed that the average contents of salidroside， morroniside， catechin， paeoniflorin， spinosin， ferulic acid， isoquercitrin， verbascoside， paeonol， and emodin were 0.725， 1.962， 0.214， 3.395， 0.124， 0.107， 0.286， 0.019， 0.034 and 0.067 mg/g， respectively. The antioxidant potency composite index （APC） for the 10 batches ranged from 85.08% to 96.35%. Spectrum-effect relationship analysis indicated that all 24 common peaks were positively correlated with the antioxidant capacity. Seventeen peaks had variable importance in projection values ＞1， specitically peaks 2， 5， 6， 7， 9， 10， 13- 21， 23， and 24. CONCLUSIONS This study successfully established the HPLC fingerprint and content determination method for Bushen ningshen ointment. The compounds represented by the 17 common peaks such as morroniside may be the active components contributing to its antioxidant effects.

Objective:To provide a scoping review of domestic and international studies on the influencing factors of frailty in stroke inpatients, and to provide guidance for interventional studies on debility in stroke inpatients in China.Methods:A systematic search of domestic and international literature databases, including China National Knowledge Infrastructure, WanFang, VIP, China Biomedical Literature Database, PubMed, Web of Science, Embase, Cochrane Library, CINAHL was conducted about the status and its influencing factors of frailty in stroke inpatients. The retrieval time limit was from database establishment to November 23, 2023. The included literature was extracted, analyzed, and summarized according to the reporting specifications of the scope review guidelines.Results:Thirty-six articles were included, all of the 36 papers reported the prevalence of frailty in patients with stroke. The top three countries with the highest prevalence were China (15.3%-86.9%), the United Kingdom (28%-78%), and Italy (31.37%). The risk factors of stroke frailty were categorized mainly into 4 themes: social demographic factors, physical health factors, disease-related factors, and psychological and social background factors.Conclusions:The confidence of frailty in stroke patients of a higher level at home and abroad, and the risk factors involved are complex and diverse. It is suggested that future studies need to conduct large-sample, multicenter longitudinal studies to clarify the causal relationship, strengthen the exploration of controversial factors of stroke debility, and carry out more targeted intervention studies, so as to reduce the incidence of frailty and improve the recovery process of patients.

Objective To describe the clinical features of patients with primary sclerosing cholangitis(PSC)in China based on a nationwide multicenter patient cohort,and to investigate the risk factors for prognosis.Methods A retrospective cohort study was conducted among the patients with a confirmed diagnosis of PSC based on the electronic medical record system of seven grade A tertiary hospitals across the country,and related data were extracted.The Mann-Whitney U test was used for comparison of continuous data between groups,and the chi-square test was used for comparison of categorical data between groups.The Kaplan-Meier method was used to estimate liver transplant-free survival,and the log-rank test was used for comparison of survival rate between PSC patients with different features.The Cox regression model was used to identify independent risk factors for the prognosis of PSC patients and the interactions between key factors.Results A total of 107 patients were enrolled,among whom 55.6%(55/99)had large-duct PSC and 29.0%(31/107)had comorbidity with inflammatory bowel disease(IBD).The positivity rate of anti-neutrophil cytoplasmic antibody(ANCA)was 32.9%(24/73),and 50.0%(40/80)of the patients had an increase in IgG/IgM.The median symptom-to-diagnosis interval was 1 year(<1-4.0),and 38.3%(41/107)of the patients had progressed to decompensated cirrhosis at the time of diagnosis.The median liver transplant-free survival time was 114 months(95%confidence interval[CI]:62-166),with a 5-year survival rate of 65.7%.The multivariate analysis showed that an increase in total bile acid(TBA)(hazard ratio[HR]=1.006,95%CI:1.002-1.010,P=0.001)and a prolonged symptom-to-diagnosis interval(HR=1.252,95%CI:1.059-1.480,P=0.009)were independent risk factors for prognosis.The interaction analysis showed that compared with the female patients with TBA<50 μmol/L,both male and female patients with TBA≥50 μmol/L had a significant increase in the risk of liver transplantation or death(male:HR=16.563,95%CI:2.103-130.449,P<0.001;female:HR=17.009,95%CI:2.113-136.934,P<0.001),and compared with the patients with an age of<45 years and a TBA level of<50 μmol/L,the patients with an age of≥45 years and a TBA level of≥50 μmol/L had a significant increase in the risk of liver transplantation or death(HR=10.729,95%CI:1.325-86.859,P=0.026).Compared with the female patients with an symptom-to-diagnosis interval of≤2 years,the male patients with a symptom-to-diagnosis interval of>2 years had an increased risk of liver transplantation or death(HR=4.825,95%CI:1.725-13.644,P=0.003),and compared with the patients with an age of<45 years and a symptom-to-diagnosis interval of≤2 years,the patients with an age of<45 years and a symptom-to-diagnosis interval of>2 years had an increased risk of liver transplantation or death(HR=4.983,95%CI:1.366-18.173,P=0.015).Conclusion Compared with the reports from Western countries,large-duct PSC is also the main type of PSC in China,but with a relatively low proportion,and there is also a relatively low proportion of patients with IBD or positive ANCA.An increase in TBA and a prolonged symptom-to-diagnosis interval are independent risk factors for prognosis,with significant interactions with age and sex.This suggests that early screening and intervention should be enhanced to improve prognosis.