ObjectiveTo investigate the mechanism by which Notoginsenoside R1 （NGR1） ameliorates hypoxia/reoxygenation （H/R）-induced injury in AC16 human cardiomyocyte cell lines through the regulation of mitophagy. MethodsCommon genes linked to hypoxia/reoxygenation injury and mitophagy were identified by intersecting data from GeneCards and MitoCarta databases. AC16 cell viability was assessed via CCK-8 assay under varying NGR1 concentrations （0， 6.25， 12.5， 25， 50， 100， 200， 300， 400， 500 μmol/L）. AC16 cells were divided into the following groups： control group （Control）， model group （H/R）， and treatment groups （H/R + NGR1 at 100， 200 and 300 μmol/L）. Mitochondrial membrane potential （ΔΨm） was measured using 5，5'，6，6'-tetrachloro-1，1'，3，3'-tetraethylbenzimidazolylcarbocyanine iodide （JC-1） staining. Transcriptional levels of mitophagy-related genes （Parkin， Pink1， P62） were quantified by reverse transcription-quantitative PCR （RT-qPCR）. Protein expression of mitophagy-related markers （Parkin， Pink1， P62， and LC3BⅡ） was evaluated via Western blot analysis. Mitochondrial ultrastructure was visualized by transmission electron microscopy （TEM）. ResultsCompared to the control group， cell viability in the H/R group significantly decreased （P<0.01）. Treatment with NGR1 at concentrations above 100 μmol/L significantly enhanced the cell viability of AC16 cells compared to the H/R group （P<0.01）. H/R induced a significant decrease in mitochondrial membrane potential （P<0.01）， which was restored by NGR1 treatment （P<0.01）. The mRNA levels of Parkin， Pink1， and P62 in the H/R group were upregulated compared to the control group （P<0.05）， while NGR1 intervention downregulated their expression （P<0.05）. Protein expression levels of Parkin， Pink1， and LC3BⅡ in the H/R group significantly increased， while P62 expression decreased compared to the control group （P<0.01）. In contrast， different doses of NGR1 treatment significantly reduced the expression of Parkin， Pink1， and LC3BⅡ while increasing P62 expression （P<0.05）. TEM revealed that the mitochondrial structure in the H/R group was severely disrupted， with fragmented and disorganized cristae， which was alleviated by NGR1. ConclusionNGR1 ameliorates H/R-induced AC16 cell injury， and its mechanism may be associated with modulating the Pink1/Parkin pathway to suppress excessive mitophagy.

ObjectiveTo investigate the efficacy and safety of Babaodan Capsule （BBD） in the treatment of patients with chronic hepatitis B virus （HBV） infection with damp-heat in the liver and gallbladder comorbid with gallbladder polyps. MethodsA randomized， double-blinded， placebo-controlled single-center trial was conducted among 120 patients with chronic HBV infection who were admitted to Beijing YouAn Hospital， Capital Medical University， from August 2020 to April 2023， and they were divided into treatment group （BBD） and control group （placebo）， with 60 patients in each group. The course of treatment was 24 weeks， and follow-up assessments were conducted every 4 weeks. The primary outcome measures were the number and maximum diameter of gallbladder polyps （assessed by ultrasound）， and the secondary outcome measures included traditional Chinese medicine （TCM） syndrome score， blood lipid levels， and liver function parameters. The independent-samples t test or the Wilcoxon rank-sum test was used for comparison of continuous data between two groups， and the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups； the Wilcoxon rank-sum test was used for comparison of ranked data between two groups； the generalized estimating equation was used to analyze repeated measures data. ResultsAfter 8 weeks of treatment， the treatment group had a significantly smaller diameter of polyps and a significantly lower number of polyps than the control group （Z=-1.76 and -1.80， both P<0.05）， and after 24 weeks of treatment， the treatment group had a significantly higher polyp reduction rate than the control group （30.51% vs 10.91%， P<0.05）. The subgroup analysis showed that patients receiving combined antiviral therapy， male patients， patients with a diameter of polyps of <5 mm， and patients with multiple polyps tended to achieve significantly greater benefits. At week 8 of treatment， the treatment group had a significantly better TCM syndrome score than the control group （Z=-2.35， P<0.05）； after treatment， compared with the control group， the treatment group had a significantly greater increase in high-density lipoprotein （Z=-1.85， P<0.05） and significantly lower levels of alanine aminotransferase （Z=-2.06， P <0.05）， aspartate aminotransferase （Z=-2.13， P<0.05）， total bilirubin （Z=-2.12， P<0.05）， and direct bilirubin （Z=-3.09， P<0.05）. No serious adverse events were reported in either group. ConclusionBBD can effectively reduce the size of gallbladder polyps， improve TCM syndrome score， and reduce the level of bilirubin in patients with chronic HBV infection with damp-heat in the liver and gallbladder， with a favorable safety profile， and it may be more suitable for patients receiving combined antiviral therapy and specific subgroups （male patients， patients with a diameter of polyps of <5 mm， and patients with multiple polyps.

Mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern to activate the stimulator of interferon genes (STING) signaling in macrophages, promoting tissue inflammation. However, its role in acute myocardial infarction (AMI) remains unclear. Macrophage-specific Sting1 knockout mice were used to validate STING's pathological role in AMI. Cardiac and liver mtDNA were used to activate macrophages in co-culture systems with cardiomyocytes to assess fibrosis and hypertrophy. Panaxatriol saponin (PTS) was tested for its ability to block mtDNA-driven macrophage activation and subsequent cardiomyocyte damage. STING-PTS binding ability was analyzed. AMI rats received PTS to evaluate its effects on myocardial inflammation and ventricular remodeling. In vivo, macrophage-specific Sting1 knockout reduced myocardial inflammation and injury after AMI. In vitro, mtDNA-activated macrophages induced cardiomyocyte fibrosis and hypertrophy through STING signaling. PTS suppressed mtDNA-driven macrophage activation by directly binding STING, thereby blocking inflammatory cascades. In AMI rats, PTS treatment attenuated acute inflammation and reversed ventricular remodeling. These findings establish the mtDNA-STING axis in macrophages as a critical driver of post-AMI inflammation and identify pharmacological STING inhibition with PTS as a promising therapeutic strategy. The study bridges genetic validation with translational applications, highlighting macrophage STING as a novel target for ischemic heart disease management.

OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

Objective:To explore the advantages of robotic-arm assisted total hip arthroplasty (rTHA) in acetabular component positioning and lower limb length assessment in patients with severe pelvic coronal tilt.Methods:A retrospective analysis was conducted on the data of 122 patients with unilateral end-stage hip disease and coronal pelvic tilt angle >3° who underwent total hip arthroplasty (THA) at the First Medical Center of PLA General Hospital from June 2022 to December 2023. Among them, 44 patients underwent rTHA, and 78 underwent manual THA (mTHA). The rTHA group included 18 males and 26 females, with an average age of 60.5±9.3 years; the mTHA group included 41 males and 37 females, with an average age of 58.5±8.4 years. Compare the differences in the anteversion angle, abduction angle, pelvic tilt angle, leg length discrepancy (LLD) of the acetabular prosthesis, and the proportions of patients with LLD>0.5 cm and >1 cm between the two groups of patients after surgery. Calculate the proportion of outlier rates of acetabular abduction angle (<30° or >45°), and proportions within Callanan's safe zone. The early efficacy of the hip joint was evaluated by using the modified Harris score and joint range of motion.Results:All patients were followed up for 6 to 12 months, with an average of 8 months. All the surgical incisions of the patients achieved primary healing. Postoperative comparisons showed no statistically significant differences in acetabular abduction angle (39.5°±3.3° vs. 38.4°±7.3°) or anteversion angle (20.7°±1.6° vs. 19.7°±1.6°) between rTHA and mTHA groups ( P>0.05). However, pelvic tilt angle [2.5° (1.1°, 3.6°) vs. 3.5° (2.3°, 5.9°)] showed a statistically significant difference ( U=4.371, P=0.008). The rTHA group exhibited smaller absolute LLD [0.2 (0.1, 0.4) cm vs. 0.5 (0.2, 0.5) cm] and lower proportions of LLD >0.5 cm [14% (6/44) vs. 49% (38/78)] and >1 cm [2% (1/44) vs. 18% (14/78)], with statistical significance ( P<0.05). The rTHA group had a lower outlier rate for acetabular abduction angle (<30°or >45°) compared to the mTHA group [2% (1/44) vs. 33% (26/78)], with statistical significance (χ 2=10.388, P<0.001). Taking the Callanan safety zone as the standard, the proportion of acetabular cups within the safe zone was significantly higher in the rTHA group (98%, 43/44) compared to the mTHA group (67%, 52/78), with a statistically significant difference (χ 2=13.998, P<0.001). The modified Harris score and hip joint range of motion in the mTHA group increased from 47.6±6.6 points and 83° (73°, 88°) before the operation to 83.5±11.2 points and 118° (110°, 122°) at the last follow-up, respectively. The rTHA group increased from 46.5±9.2 points and 79° (71°, 90°) before the operation to 85.0±12.5 points and 124° (116°, 130°) at the last follow-up. The differences in the modified Harris score and hip joint range of motion between the two groups before the operation and at the last follow-up were statistically significant ( P<0.05). However, there was no statistically significant difference between the groups at the last follow-up ( P>0.05). No THA-related complications occurred during follow-up period. Conclusion:For patients with end-stage hip joint diseases with coronal tilt exceeding 3°, robotic-assisted technology significantly improves the accuracy of acetabular component placement during THA and offers better control of postoperative LLD.

Purpose To evaluate the efficacy of ultra-high field 5.0T MRI combined with histogram analysis for diagnosing prostate cancer and benign prostatic hyperplasia.Materials and Methods This retrospective analysis included data from 63 patients with prostatic diseases at the Chongqing University Three Gorges Hospital from January to May 2024,comprising 31 cases of prostate cancer and 32 cases of benign prostatic hyperplasia.MRI sequences included T2WI,T1WI,diffusion-weighted imaging,intravoxel incoherent motion and T2 mapping.Histogram data of apparent diffusion coefficient,true diffusion coefficient,pseudo-diffusion coefficient,perfusion fraction and T2 relaxation time were calculated,and diagnostic efficacy was assessed using the area under the receiver operating characteristic curve.Results In prostate cancer,the 10th percentile,the 90th percentile,mean,median,and minimum values of histogram parameters from apparent diffusion coefficient,true diffusion coefficient,pseudo-diffusion coefficient,perfusion fraction and T2 mapping were significantly lower than those of benign prostatic hyperplasia(Z=-6.036--3.368,all P<0.05).Notably,the combined model of apparent diffusion coefficient,intravoxel incoherent motion and T2 mapping parameters achieved an the area under the curve of 0.987,with sensitivity and specificity of 96.77%and 96.87%,respectively.Conclusion This study confirms that 5.0T MRI histogram analysis technique demonstrates significant diagnostic efficacy in differentiating prostate cancer from benign prostatic hyperplasia.

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

This study aims to investigate the potential effect of the water extract of fresh Rehmanniae Radix on hypercholesterolemia in mice that was induced by a high-fat and high-cholesterol diet and explore its possible mechanism from bile acid reabsorption. Male C57BL/6 mice were randomly assigned into the following groups: control, model, low-and high-dose(4 and 8 g·kg~(-1), respectively) fresh Rehmanniae Radix, and positive drug(simvastatin, 0.05 g·kg~(-1)). Other groups except the control group were fed with a high-fat and high-cholesterol diet for 6 consecutive weeks to induce hypercholesterolemia. From the 6th week, mice were administrated with corresponding drugs daily via gavage for additional 6 weeks, while continuing to be fed with a high-fat and high-cholesterol diet. Serum levels of total cholesterol(TC), triglycerides(TG), low density lipoprotein-cholesterol(LDL-c), high density lipoprotein-cholesterol(HDL-c), and total bile acid(TBA), as well as liver TC and TG levels and fecal TBA level, were determined by commercial assay kits. Hematoxylin-eosin(HE) staining, oil red O staining, and transmission electron microscopy were performed to observe the pathological changes in the liver. Three livers samples were randomly selected from each of the control, model, and high-dose fresh Rehmanniae Radix groups for high-throughput transcriptome sequencing. Differentially expressed genes were mined and KEGG pathway enrichment analysis was performed to predict the key pathways and target genes of the water extract of fresh Rehmanniae Radix in the treatment of hypercholesterolemia. RT-qPCR was employed to measure the mRNA levels of cholesterol 7α-hydroxylase(CYP7A1) and cholesterol 27α-hydroxylase(CYP27A1) in the liver. Western blot was employed to determine the protein levels of CYP7A1 and CYP27A1 in the liver as well as farnesoid X receptor(FXR), apical sodium-dependent bile acid transporter(ASBT), and ileum bile acid-binding protein(I-BABP) in the ileum. The results showed that the water extract of fresh Rehmanniae Radix significantly lowered the levels of TC and TG in the serum and liver, as well as the level of LDL-c in the serum. Conversely, it elevated the level of HDL-c in the serum and TBA in feces. No significant difference was observed in the level of TBA in the serum among groups. HE staining, oil red O staining, and transmission electron microscopy showed that the water extract reduced the accumulation of lipid droplets in the liver. Further mechanism studies revealed that the water extract of fresh Rehmanniae Radix significantly down-regulated the protein levels of FXR and bile acid reabsorption-related proteins ASBT and I-BABP. Additionally, it enhanced CYP7A1 and CYP27A1, the key enzymes involved in bile acid synthesis. Therefore, it is hypothesized that the water extract of fresh Rehmanniae Radix may exert an anti-hypercholesterolemic effect by regulating FXR/ASBT/I-BABP signaling, inhibiting bile acid reabsorption, and increasing bile acid excretion, thus facilitating the conversion of cholesterol to bile acids.
Animals ; Male ; Bile Acids and Salts/metabolism* ; Mice, Inbred C57BL ; Mice ; Diet, High-Fat/adverse effects* ; Cholesterol/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; Hypercholesterolemia/genetics* ; Receptors, Cytoplasmic and Nuclear/genetics* ; Rehmannia/chemistry* ; Liver/drug effects* ; Humans ; Cholesterol 7-alpha-Hydroxylase/genetics* ; Plant Extracts

OBJECTIVE: To establish foot and ankle models of different lateral collateral ligament injuries of ankle joint, and conduct finite element analysis on, and to explore the force conditions of subtalar articular cartilage during foot inversion movements under different gait stages and under different loads. METHODS: A normal ankle CT scan of a 30-year-old male healthy volunteer (heighted 175 cm and weighted 60 kg) was selected. The CT images were imported into software such as Mimics 21.0, Geomajic 2017, and Solidworks 2017 respectively, extract the normal ankle bone model. Then, the foot and ankle finite element models of different lateral collateral ligament injuries of ankle joint were constructed and divided into anterior talofibular ligament(ATFL) rupture group, ATFL and calcaneo fibular ligament (CFL) rupture group, ATFL, CFL and posterior talofibular ligament (PTFL) rupture group, and control group with intact ligament function by ANSYS 2021. Corresponding horizontal and vertical loads and torques were applied respectively on tibia and talus according to the force conditions of different phases to simulate landing phase, neutral and off-ground phase in walking gait. The changes in stress distribution area and stress peak of subtalar articular cartilage in the loading phase, neutral phase and off-ground phase gaits among four groups were observed. Simulate varus sprain action, apply different loads of 600, 1, 800, and 4, 200 N respectively, and changes in stress distribution area and the stress peak of subtalar articular cartilage among four groups of models were observed. RESULTS: In the gait simulation, the stress results of loading phase in ATFL fracture group, ATFL and CFL fracture groups, ATFL, CFL and PTFL fracture groups, and control group were 0.889 54, 0.960 89, 1.139 20, and 0.722 64 MPa, respectively. The neutral response force results were 1.250 60, 1.358 50, 1.363 70, 1.246 40 MPa respectively;the results of corresponding forces off-ground phase were 1.029 90, 1.138 70, 1.145 90 and 0.832 40 MPa respectively. In the inversion simulation, the stresses of ATFL fracture group, ATFL and CFL fracture groups, ATFL, CFL and PTFL fracture groups, and control group under load of 600 N were 2.191 3, 2.208 5, 2.215 7, and 2.156 6 MPa respectively. The stresses under a load of 1 800 N were 7.134 7, 9.715 2, 10.064 0, and 7.107 0 MPa respectively;the stresses under a load of 4 200 N were 17.435 0, 25.309 0, 26.119 0 and 16.010 0 MPa respectively. CONCLUSION The lateral collateral ligament of ankle joint plays an important role in the stability of the subtalar joint, especially CFL plays an important role in restricting calcaneal varus. If these ligaments are damaged, it will cause instability of the subtalar joint and further lead to lesions in the subtalar articular cartilage. Relevant exercises should be reduced or the ligament injuries should be treated in a timely manner.
Humans ; Finite Element Analysis ; Male ; Adult ; Cartilage, Articular/physiopathology* ; Ankle Injuries/physiopathology* ; Ankle Joint/physiopathology* ; Biomechanical Phenomena ; Subtalar Joint/injuries* ; Tomography, X-Ray Computed

Objective:To explore the advantages of robotic-arm assisted total hip arthroplasty (rTHA) in acetabular component positioning and lower limb length assessment in patients with severe pelvic coronal tilt.Methods:A retrospective analysis was conducted on the data of 122 patients with unilateral end-stage hip disease and coronal pelvic tilt angle >3° who underwent total hip arthroplasty (THA) at the First Medical Center of PLA General Hospital from June 2022 to December 2023. Among them, 44 patients underwent rTHA, and 78 underwent manual THA (mTHA). The rTHA group included 18 males and 26 females, with an average age of 60.5±9.3 years; the mTHA group included 41 males and 37 females, with an average age of 58.5±8.4 years. Compare the differences in the anteversion angle, abduction angle, pelvic tilt angle, leg length discrepancy (LLD) of the acetabular prosthesis, and the proportions of patients with LLD>0.5 cm and >1 cm between the two groups of patients after surgery. Calculate the proportion of outlier rates of acetabular abduction angle (<30° or >45°), and proportions within Callanan's safe zone. The early efficacy of the hip joint was evaluated by using the modified Harris score and joint range of motion.Results:All patients were followed up for 6 to 12 months, with an average of 8 months. All the surgical incisions of the patients achieved primary healing. Postoperative comparisons showed no statistically significant differences in acetabular abduction angle (39.5°±3.3° vs. 38.4°±7.3°) or anteversion angle (20.7°±1.6° vs. 19.7°±1.6°) between rTHA and mTHA groups ( P>0.05). However, pelvic tilt angle [2.5° (1.1°, 3.6°) vs. 3.5° (2.3°, 5.9°)] showed a statistically significant difference ( U=4.371, P=0.008). The rTHA group exhibited smaller absolute LLD [0.2 (0.1, 0.4) cm vs. 0.5 (0.2, 0.5) cm] and lower proportions of LLD >0.5 cm [14% (6/44) vs. 49% (38/78)] and >1 cm [2% (1/44) vs. 18% (14/78)], with statistical significance ( P<0.05). The rTHA group had a lower outlier rate for acetabular abduction angle (<30°or >45°) compared to the mTHA group [2% (1/44) vs. 33% (26/78)], with statistical significance (χ 2=10.388, P<0.001). Taking the Callanan safety zone as the standard, the proportion of acetabular cups within the safe zone was significantly higher in the rTHA group (98%, 43/44) compared to the mTHA group (67%, 52/78), with a statistically significant difference (χ 2=13.998, P<0.001). The modified Harris score and hip joint range of motion in the mTHA group increased from 47.6±6.6 points and 83° (73°, 88°) before the operation to 83.5±11.2 points and 118° (110°, 122°) at the last follow-up, respectively. The rTHA group increased from 46.5±9.2 points and 79° (71°, 90°) before the operation to 85.0±12.5 points and 124° (116°, 130°) at the last follow-up. The differences in the modified Harris score and hip joint range of motion between the two groups before the operation and at the last follow-up were statistically significant ( P<0.05). However, there was no statistically significant difference between the groups at the last follow-up ( P>0.05). No THA-related complications occurred during follow-up period. Conclusion:For patients with end-stage hip joint diseases with coronal tilt exceeding 3°, robotic-assisted technology significantly improves the accuracy of acetabular component placement during THA and offers better control of postoperative LLD.