This paper explored the specific mechanism of ginsenoside Rg_1 in regulating mitochondrial fusion through the neurogenic gene Notch homologous protein 1(Notch1) pathway to alleviate hypoxia/reoxygenation(H/R) injury in HL-1 cells. The relative viability of HL-1 cells after six hours of hypoxia and two hours of reoxygenation was detected by cell counting kit-8(CCK-8). The lactate dehydrogenase(LDH) activity in the cell supernatant was detected by the lactate substrate method. The content of adenosine triphosphate(ATP) was detected by the luciferin method. Fluorescence probes were used to detect intracellular reactive oxygen species(Cyto-ROS) levels and mitochondrial membrane potential(ΔΨ_m). Mito-Tracker and Actin were co-imaged to detect the number of mitochondria in cells. Fluorescence quantitative polymerase chain reaction and Western blot were used to detect the mRNA and protein expression levels of Notch1, mitochondrial fusion protein 2(Mfn2), and mitochondrial fusion protein 1(Mfn1). The results showed that compared with that of the control group, the cell activity of the model group decreased, and the LDH released into the cell culture supernatant increased. The level of Cyto-ROS increased, and the content of ATP decreased. Compared with that of the model group, the cell activity of the ginsenoside Rg_1 group increased, and the LDH released into the cell culture supernatant decreased. The level of Cyto-ROS decreased, and the ATP content increased. Ginsenoside Rg_1 elevated ΔΨ_m and increased mitochondrial quantity in HL-1 cells with H/R injury and had good protection for mitochondria. After H/R injury, the mRNA and protein expression levels of Notch1 and Mfn1 decreased, while the mRNA and protein expression levels of Mfn2 increased. Ginsenoside Rg_1 increased the mRNA and protein levels of Notch1 and Mfn1, and decreased the mRNA and protein levels of Mfn2. Silencing Notch1 inhibited the action of ginsenoside Rg_1, decreased the mRNA and protein levels of Notch1 and Mfn1, and increased the mRNA and protein levels of Mfn2. In summary, ginsenoside Rg_1 regulated mitochondrial fusion through the Notch1 pathway to alleviate H/R injury in HL-1 cells.
Ginsenosides/pharmacology* ; Receptor, Notch1/genetics* ; Signal Transduction/drug effects* ; Mice ; Animals ; Mitochondrial Dynamics/drug effects* ; Mitochondria/metabolism* ; Cell Line ; Reactive Oxygen Species/metabolism* ; Oxygen/metabolism* ; Cell Hypoxia/drug effects* ; Cell Survival/drug effects* ; Membrane Potential, Mitochondrial/drug effects* ; Humans

In this study, the pharmacodynamic components and potential pharmacological functions of Danzhi Xiaoyao Formula in treating nervous system diseases were investigated by hippocampal component characterization and network pharmacology. After rats were administrated with Danzhi Xiaoyao Formula by gavage, high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(HPLC-Q-TOF-MS/MS) was employed to explore the components in the hippocampus of rats. Fifty-seven components were identified in the hippocampus of rats by comparing the extract of Danzhi Xiaoyao Formula, herbal components in the hippocampus after administration, and blank samples. KEGG and GO analyses predicted 74 core targets including GSK3B, MAPK1, AKT, IL6. These targets were involved in PI3K/Akt, NF-κB, MAPK, JAK/STAT, Wnt, and other signaling pathways. The results indicated that Danzhi Xiaoyao Formula may ameliorate other nervous system diseases enriched in DO, such as neurodegenerative diseases, cerebrovascular diseases, and mental and emotional disorders by mediating target pathways, inhibiting inflammation, reducing neuronal damage, and alleviating hippocampal atrophy. The relevant activities exhibited by this formula in nervous system diseases such as Alzheimer's disease, Parkinson's disease, and diabetic neuropathy have extremely high development value and are worthy of further in-depth research. This study provides a theoretical basis and practical guidance for expanding the application of Danzhi Xiaoyao Formula in the treatment of nervous system diseases.
Drugs, Chinese Herbal/administration & dosage* ; Animals ; Rats ; Hippocampus/metabolism* ; Network Pharmacology ; Chromatography, High Pressure Liquid ; Tandem Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; Nervous System Diseases/genetics* ; Humans ; Signal Transduction/drug effects*

OBJECTIVE: To investigate chronic hepatitis C virus (HCV) infection's effect on gestational liver function, pregnancy and delivery complications, and neonatal development. METHODS: A total of 157 HCV antibody-positive (anti-HCV[+]) and HCV RNA(+) patients (Group C) and 121 anti-HCV(+) and HCV RNA(-) patients (Group B) were included as study participants, while 142 anti-HCV(-) and HCV RNA(-) patients (Group A) were the control group. Data on biochemical indices during pregnancy, pregnancy complications, delivery-related information, and neonatal complications were also collected. RESULTS: Elevated alanine aminotransferase (ALT) rates in Group C during early, middle, and late pregnancy were 59.87%, 43.95%, and 42.04%, respectively-significantly higher than Groups B (26.45%, 15.70%, 10.74%) and A (23.94%, 19.01%, 6.34%) ( P < 0.05). Median ALT levels in Group C were significantly higher than in Groups A and B at all pregnancy stages ( P < 0.05). No significant differences were found in neonatal malformation rates across groups ( P > 0.05). However, neonatal jaundice incidence was significantly greater in Group C (75.16%) compared to Groups A (42.25%) and B (57.02%) ( χ ² = 33.552, P < 0.001). HCV RNA positivity during pregnancy was an independent risk factor for neonatal jaundice ( OR = 2.111, 95% CI 1.242-3.588, P = 0.006). CONCLUSIONS Chronic HCV infection can affect the liver function of pregnant women, but does not increase the pregnancy or delivery complication risks. HCV RNA(+) is an independent risk factor for neonatal jaundice.
Humans ; Female ; Pregnancy ; Adult ; Pregnancy Complications, Infectious/epidemiology* ; Retrospective Studies ; Pregnancy Outcome ; Infant, Newborn ; Viremia/virology* ; Hepatitis C ; Hepacivirus/physiology* ; Hepatitis C, Chronic/virology* ; Young Adult ; Alanine Transaminase/blood*

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Objective To compare the early clinical effects of unilateral biportal endoscopic lumbar in-terbody fusion(ULIF)and minimally invasive transforaminal lumbar interbody fusion(MIS-TLIF)in the treatment of single lumbar degenerative disease(LDD).Methods The patients with LDD treated with ULIF(ULIF group,n=32)and MIS-TLIF(MIS-TLIF group,n=36)in this hospital from January 2020 to Novem-ber 2022 were selected as the study subjects.The perioperative conditions were compared between the two groups,including the postoperative drainage volume,postoperative ground activity time,hospitalization dura-tion,total hospitalization expenses,laboratory hematological indexes including Hb,HCT,CRP and CK levels.The clinical effects were compared between the two groups,including the visual analogue scale(VAS)score of waist and leg pain,Oswestry dysfunction index(ODI),operation excellence rate,vertebral fusion rate and op-eration related complications.Results Compared with the MIS-TLIF group,the ULIF group had less postop-erative drainage,earlier ground activity time,short hospitalization duration,but the operation time was longer and hospitalization costs were higher,and the differences were statistically significant(P<0.05).Compared with the MIS-TLIF group,the Hb and HCT levels on postoperative 3 d in the ULIF group were higher,the CRP and CK levels on postoperative 1,3,5 d were lower,and the differences were statistically significant(P<0.05).The waist and leg pain VAS score and ODI at each postoperative follow up time points in the two groups were significantly improved compared with before operation(P<0.05).The intergroup comparison showed that the VAS score in postoperative 1 week and 1 month,and ODI in postoperative 1 month in the ULIF group were lower than those in the MIS-TLIF group(P<0.05).In postoperative 12 months,the opera-tion excellence rate and intervertebral fusion rate in the ULIF group were 93.75%and 96.88%respectively,which in the MIS-TLIF group were 88.89%and 91.67%respectively,but the difference between the two groups were not statistically significant(P>0.05).Conclusion Adopting ULIF in the treatment of single LDD could obtain the similar clinical effectt of MIS-TLIF,moreover ULIF has less tissue damage,less bleed-ing,less inflammatory reaction and faster postoperative recovery.

OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Peptide-based radiopharmaceuticals targeting integrin α5β1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target α5β1 demonstrate inadequate in vivo performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an α5β1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for α5β1-overexpressing tumors.

Abstract The construction of autism spectrum disorders (ASD) specialty cohorts in China is still in its infancy, and the cost effectiveness is insufficient when relying on diagnostic and treatment processes of child health care to collect ample and high quality data. After 2000, the United States Simons Foundation s ASD Research Initiative, the Early ASD Risk Longitudinal Investigation (EARLI), and the British ASD Study of Infant Siblings (BASIS), which have been built based on Internet recruitment, have provided new insight for the construction of large sample ASD specialty cohorts in China. Future research can further explore and optimize the methods of Internet recruitment, and establish a more comprehensive and accurate ASD specialty cohorts.

ObjectiveTo investigate the effects of Yiqi Wenyang Huoxue Lishui components on the cardiac function and mitochondrial energy metabolism in the rat model of chronic heart failure （CHF） and explore the underlying mechanism. MethodsThe rat model of CHF was prepared by transverse aortic constriction （TAC）. Eight of the 50 SD rats were randomly selected as the sham group， and the remaining 42 underwent TAC surgery. The 24 SD rats successfully modeled were randomized into model， trimetazidine （6.3 mg·kg^-1）， and Yiqi Wenyang Huoxue Lishui components （60 mg·kg^-1 total saponins of Astragali Radix， 10 mg·kg^-1 total phenolic acids of Salviae Miltiorrhizae Radix et Rhizoma， 190 mg·kg^-1 aqueous extract of Lepidii Semen， and 100 mg·kg^-1 cinnamaldehyde） groups. The rats were administrated with corresponding agents by gavage， and those in the sham and model groups were administrated with the same amount of normal saline at a dose of 10 mL·kg^-1 for 8 weeks. Echocardiography was used to examine the cardiac function in rats. Enzyme-linked immunosorbent assay was employed to determine the serum levels of N-terminal pro-B-type natriuretic peptide （NT-ProBNP）， hypersensitive troponin（cTnI）， creatine kinase （CK）， lactate dehydrogenase （LD）， free fatty acids （FFA）， superoxide dismutase （SOD）， and malondialdehyde （MDA）. The colorimetric assay was employed to measure the levels of adenosine triphosphate （ATP）， adenosine diphosphate （ADP）， and adenosine monophosphate （AMP） in the myocardial tissue. The pathological changes in the myocardial tissue were observed by hematoxylin-eosin staining and Masson staining. The Na⁺-K⁺-ATPase and Ca²⁺-Mg²⁺-ATPase activities in the myocardial tissue were determined by the colorimetric assay. The ultrastructural changes of myocardial mitochondria were observed by transmission electron microscopy. Western blot was employed to determine the protein levels of ATP synthase subunit delta （ATP5D）， glucose transporter 4 （GLUT4）， and carnitine palmitoyltransferase-1 （CPT-1）. The mitochondrial complex assay kits were used to determine the activities of mitochondrial complexes Ⅰ， Ⅱ， Ⅲ， and Ⅳ. ResultsCompared with the sham group， the model group showed a loosening arrangement of cardiac fibers， fracture and necrosis of partial cardiac fibers， inflammatory cells in necrotic areas， massive blue fibrotic tissue in the myocardial interstitium， increased collagen fiber area and myocardial fibrosis， destroyed mitochondria， myofibril disarrangement， sparse myofilaments， and fractured and reduced cristae. In addition， the rats in the model group showed declined ejection fraction （EF） and fractional shortening （FS）， risen left ventricular end-diastolic diameter （LVIDd）， left ventricular end-systolic diameter （LVIDs）， left ventricular end-diastolic posterior wall thickness （LVPWd）， left ventricular end-systolic posterior wall thickness （LVPWs）， left ventricular end-diastolic volume （LVVOLd）， and left ventricular end-systolic volume （LVVOLs）， elevated levels of NT-ProBNP， cTnI， CK， MDA， FFA， and LD， lowered level of SOD， down-regulated protein levels of GLUT4 and CPT-1， decreased activities of Na⁺-K⁺-ATPase， Ca²⁺-Mg²⁺-ATPase， and respiratory complexes Ⅰ-Ⅳ， and declined levels of ATP5D， ATP， ADP， and AMP （P<0.05， P<0.01）. Compared with the model group， the Yiqi Wenyang Huoxue Lishui components and trimetazidine groups showed alleviated pathological damage of the mitochondria and mycardial tissue， risen EF and FS， declined LVIDd， LVIDs， LVPWd， LVPWs， LVVOLd， and LVVOLs， lowered levels of NT-ProBNP， cTnI， CK， MDA， FFA， and LD， elevated level of SOD， up-regulated protein levels of GLUT4 and CPT-1， increased activities of Na⁺-K⁺-ATPase， Ca²⁺-Mg²⁺-ATPase， and respiratory complexes Ⅰ-Ⅳ， and elevated levels of ATP5D， ATP， ADP， and AMP （P<0.05， P<0.01）. ConclusionYiqi Wenyang Huoxue Lishui components can improve the cardiac function， reduce myocardial injury， regulate glucose and lipid metabolism， optimize the utilization of substrates， and alleviate the damage of mitochondrial structure and function， thus improving the energy metabolism of the myocardium in the rat model of CHF.