ObjectiveTo explore the effect of oral sodium butyrate on skeletal muscle atrophy in CT26 tumor mice through the gut microbiota-skeletal muscle axis and its potential mechanism. MethodsSixty SPF BALB/c male mice aged 8 weeks were randomly divided into a normal control group (NC, n=18) and a ABX-depleted group (ABX, n=42). The ABX mice were pretreated with a quadruple antibiotic cocktail via oral gavage (0.2 ml per administration, once daily, 6 d per week, for 2 weeks), whereas NC received an equal volume of sterile water. The quadruple antibiotic cocktail consisted of metronidazole (1 g/L), vancomycin (0.5 g/L), ampicillin (1 g/L), and gentamicin (1 g/L). Following successful pretreatment, six mice from each group were randomly selected for gut microbiota sequencing analysis and designated as the Abx group and the NC0 group, respectively. Theremaining mice in ABX were subcutaneously inoculated in the dorsum with 0.2 ml of CT26 cell suspension (at a cell density of 1×10⁷/ml). Then these mice were randomly allocated into three subgroups: a control tumor bearing model group (0_NaB, n=12), a tumor-bearing model group receiving low-dose oral sodium butyrate (L_NaB, n=12), a tumor-bearing model group receiving high-dose oral sodium butyrate (H_NaB, n=12). And mice in NC were inoculated at the same site with 0.2 ml of normal saline. The administration dose for L_NaB was 0.3 g/(kg·d), that for H_NaB was 0.5 g/(kg·d), while NC and 0_NaB were given the same volume of normal saline (0.2ml per time, once daily, 6 d per week, for 4 weeks). The general condition of mice was monitored, and forelimb grip strength gastrocnemius muscle mass and its muscle fiber cross-sectional area were measured for each group. The structural changes in gut microbiota were assessed by 16S rRNA sequencing of cecal contents. Pathological alterations in the intestinal wall were examined via HE staining. Serum and gastrocnemius muscle levels of TNF‑α, IL-6, IL-1β, and LPS were quantified using ELISA. The protein expression of ZO-1 and occludin in the small intestine, as well as proteins associated with the TLR4/MyD88/NF-κB signaling pathway in the gastrocnemius muscle, were detected by Western blot analysis. Results(1) The alpha-diversity in Abx was significantly lower than that in NC0 (P<0.01), a significant decrease of the mass and muscle fiber cross-sectional area of the gastrocnemius (P<0.01), with the majority of gut microbiota being effectively depleted. (2) Compared with NC, the subcutaneous tumors of mice in 0_NaB were prominent, a significant increase of the mass and muscle fiber cross-sectional area of the gastrocnemius, accompanied by a significant decrease in body weight at the end of the 3th and 4th week (P<0.05), and a significant weakening of the forelimb grasping strength at the 5th and 6th week (P<0.01). Compared with 0_NaB, the tumor mass of mice in L_NaB and H_NaB showed a significant decreasing trend, and the grip strength of the forelimbs significantly increased at the 5th and 6th week (P<0.05, P<0.01). (3) Compared with 0_NaB, the Shannon and Observed species indices in α diversity of L_NaB and H_NaB were significantly increased (P<0.05). At the genus level, compared with 0_NaB, L_NaB exhibited a significant decrease in the relative abundance of Parasutterella (P< 0.01), while H_NaB showed significant reductions in the relative abundances of both Escherichia-Shigella and Parasutterella (P < 0.01). (4) Compared with 0_NaB, the small intestinal tissue structure in L_NaB and H_NaB was more intact, the infiltration of inflammatory cells was significantly reduced, and the capillaries were slightly dilated. The expression levels of ZO-1 and occludin proteins in L_NaB were significantly increased (P<0.01). (5) The LPS concentration in the gastrocnemius muscle and the protein expression levels of TLR4, MyD88, p-IκBα, and p-NF‑κB p65 in L_NaB and H_NaB were significantly lower than those in 0_NaB (P<0.05). The serum TNF‑α concentration in H_NaB and TNF-α concentration in the gastrocnemius muscle of the L_NaB and H_NaB were significantly lower than those in 0_NaB (P<0.05, P<0.01, P<0.01). ConclusionOral administration of NaB can improve gut microbiota α diversity, adjusting its composition, improving intestinal mucosal barrier function, reducing the LPS-induced pro-inflammatory response, and delaying skeletal muscle atrophy. The underlying mechanism may involve down regulation of TLR4/MyD88/NF-κB signaling in skeletal muscle.

Objective To investigate the value of ultrasonographic features combined with immunohistochemistry in predicting axillary lymph node metastasis in middle-aged women with breast cancer.Methods A retrospective analysis was conducted on 827 middle-aged female breast cancer patients who underwent surgical treatment at the Affiliated Hospital of Chengde Medical University from June 2017 to June 2023.Ultrasonographic and immunohistochemical information was collected,and the patients were randomly allocated into a training set(579 patients)and a validation set(248 patients).Univariate and multivariate Logistic regression analyses were performed to identify ultrasonographic and immunohistochemical risk factors associated with axillary lymph node metastasis in these patients,and a nomogram model was developed.Receiver operating characteristic curves and calibration curves were established to evaluate the performance of the nomogram model,and clinical decision curves were built to assess the clinical value of the model.Results The maximum diameter,morphology,boundary,calcification,and expression of human epidermal growth facor receptor 2 and Ki-67 in breast cancer lesions were identified as risk factors for predicting axillary lymph node metastasis in middle-aged women.The areas under the curve of the nomogram model on the training and validation sets were 0.747(0.707-0.787)and 0.714(0.647-0.780),respectively.Calibration curves and clinical decision curves indicated good consistency and performance of the model.Conclusion The nomogram model constructed based on ultrasonographic features and immunohistochemistry of the primary breast cancer lesion demonstrates high value in predicting axillary lymph node metastasis in middle-aged women with breast cancer.
Humans ; Female ; Breast Neoplasms/diagnostic imaging* ; Middle Aged ; Lymphatic Metastasis/diagnostic imaging* ; Axilla ; Retrospective Studies ; Nomograms ; Ultrasonography ; Immunohistochemistry ; Lymph Nodes/diagnostic imaging* ; Risk Factors ; Ki-67 Antigen

China has become the country with the highest global burden of heart failure(HF).Despite the widespread use of prognostic-improving medications today,the mortality rate of HF remains high,reaching 13.7％at one year-particularly among patients with heart failure with reduced ejection fraction(HFrEF).HF interventional device therapy(structural intervention)targets the structural factors underlying HF,including atrial pressure,ventricular remodeling,and valvular intervention.It leverages the heart's intrinsic physiological properties and pathological progression mechanisms to deliver treatments through interventions without external active forces,achieving anatomical or functional repair.This field has emerged as a rapidly growing area and plays an increasingly critical role in HF management.This article provides a comprehensive review and summary of the latest advancements in HF and cardiomyopathy interventional therapy over the past year.It covers various novel technologies and products currently in the research phase,aiming to provide an in-depth analysis of the current status and future directions of HF interventional therapy,and further advance the development of this discipline.

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 explore the functional roles and underlying mechanisms of neferine in the context of angiotensin II (Ang II)-induced hypertension and vascular dysfunction. METHODS: Male mice were infused with Ang II to induce hypertension and randomly divided into treatment groups receiving neferine or a control vehicle based on baseline blood pressure using a random number table method. The hypertensive mouse model was constructed by infusing Ang II via a micro-osmotic pump (500 ng/kg per minute), and neferine (0.1, 1, or 10 mg/kg), valsartan (10 mg/kg), or double distilled water was administered intragastrically once daily for 6 weeks. A non-invasive blood pressure system, ultrasound, and hematoxylin and eosin staining were performed to assess blood pressure and vascular changes. RNA sequencing and network pharmacology were employed to identify differentially expressed transcripts (DETs) and pathways. Vascular ring tension assay was used to test vascular function. A7R5 cells were incubated with neferine for 24 h and then treated with Ang II to record the real-time Ca²⁺ concentration by confocal microscope. Immunohistochemistry (IHC) and Western blot were used to evaluate vasorelaxation, calcium, and the extracellular signal-regulated kinase (ERK)1/2 pathway. RESULTS: Neferine treatment effectively mitigated the elevation in blood pressure, pulse wave velocity, aortic thickening in the abdominal aorta of Ang II-infused mice (P<0.05). RNA sequencing and network pharmacology analysis identified 355 DETs that were significantly reversed by neferine treatment, along with 25 potential target genes, which were further enriched in multiple pathways and biological processes, such as ERK1 and ERK2 cascade regulation, calcium pathway, and vascular smooth muscle contraction. Further investigation revealed that neferine treatment enhanced vasorelaxation and reduced Ca²⁺-dependent contraction of abdominal aortic rings, independent of endothelium function (P<0.05). The underlying mechanisms were mediated, at least in part, via suppression of receptor-operated channels, store-operated channels, or voltage-operated calcium channels. Neferine pre-treatment demonstrated a reduction in intracellular Ca²⁺ release in Ang II stimulated A7R5 cells. IHC staining and Western blot confirmed that neferine treatment effectively attenuated the upregulation of p-ERK1/2 both in vivo and in vitro, which was similar with treatment of ERK1/2 inhibitor PD98059 (P<0.05). CONCLUSIONS Neferine remarkably alleviates Ang II-induced elevation of blood pressure, vascular dysfunction, and pathological changes in the abdominal aorta. This beneficial effect is mediated by the modulation of multiple pathways, including calcium and ERK1/2 pathways.
Animals ; Angiotensin II ; Male ; Benzylisoquinolines/therapeutic use* ; Network Pharmacology ; Blood Pressure/drug effects* ; Sequence Analysis, RNA ; Mice ; Hypertension/chemically induced* ; Mice, Inbred C57BL ; Calcium/metabolism*

Objective To explore the influencing factors of acute kidney injury in severe burn patients,and to construct a visual risk nomogram model.Methods A total of 390 patients with severe burn admitted to the Institute of Burn Frostbite and Tissue Function Reconstruction of Chinese People's Armed Police Force Specialty Medical Center from January 2018 to January 2022 were collected as an internal training data set,and 50 patients with severe burn admitted from February to December 2022 were collected as an external validation data set.The 390 patients of the internal training data set were divided into the acute kidney injury group and the non-acute kidney injury group according to the occurrence of acute kidney injury,and the baseline data of patients in the two groups were compared.Univariate and multivariate Logistic regression were used to analyze the risk factors of acute kidney injury in severe burn patients of the internal training data set,and a nomogram model was drawn.Subsequently,the model was verified both internally and externally.Kaplan-Meier analysis and Log-rank test were used to compare the 90-day survival rate of patients between the acute kidney injury group and the non-acute kidney injury group.Results The burn area(OR=1.18,95%CI:1.06 to 2.36,P=0.004),sequential organ failure assessment(SOFA)score(OR=1.81,95%CI:1.21 to 5.92,P<0.001),inhalation injury(OR=3.21,95%CI:1.23 to 6.35,P<0.001),neutrophil to lymphocyte ratio(NLR)(OR=1.22,95%CI:1.05 to 3.65,P<0.001)and albumin(ALB)(OR=0.78,95%CI:0.57 to 0.92,P=0.011)were the independent risk factors for the development of acute kidney injury in severe burn patients.The nomogram model was established by the above factors.The area under the receiver operating characteristic curve(AUC)of the internal training data set was 0.833(95%CI:0.752 to 0.935),the sensitivity was 81.2%,and the specificity was 83.2%.The AUC of the external validation data set was 0.842(95%CI:0.762 to 0.912),the sensitivity 87.2%,and the specificity was 78.7%.The 90-day survival rate of patients in the acute kidney injury group after burns was significantly lower than that in the non-acute kidney injury group(P<0.001).Conclusion Larger burn area,higher SOFA score,combined inhalation injury,increased NLR,and decreased ALB level are the risk factors for the occurrence of acute kidney injury in severe burn patients,which are related to the 90-day survival rate of patients after burns.The nomogram model based on the risk factors can provide certain reference for clinical individualized prevention and treatment of acute kidney injury in severe burn patients.

To investigate the transcriptionally regulatory mechanism of the senp8 promoter in yellow cat-fish(Pelteobagrus fulvidraco);this study used P.fulvidraco as the research subject.Dual-luciferase re-porter assay and electrophoretic mobility shift assay were employed to analyze the functional activity of the promoter;coupled with in vivo experiments.The results indicated that the 2 045 bp senp8 promoter se-quence contained key transcription factor binding sites such as SP1;TATA-Box;CCAAT-Box;SREBP1;PPARα;and PPARγ.The binding sites of SREBP1(-901/-910 bp);PPARα(-1 291/-1 308 bp);and PPARγ(-1 292/-1 306 bp)in the senp8 promoter positively regulate its activity;and oleic acid or palmitic acid promote this binding.Furthermore;high-fat feeding promoted the expression of the senp8 gene and its protein in the liver of P.fulvidraco;oleic acid or palmitic acid treatment significantly en-hanced the activity of the senp8 promoter;and this enhancement could be achieved through the regulatory effects of SREBP1;PPARα;and PPARγ response elements.Additionally;high-fat feeding influenced the mRNA and protein expression levels of genes related to deSUMOylation modification in the liver of P.fulvidraco.This study provides new insights into the relationship between deSUMOylation modification and the regulation of lipid metabolism in the vertebrates.

Objective:To evaluate the clinical predictive value of SPECT myocardial perfusion imaging (MPI) in the occurrence of cardiac death in patients with chronic kidney disease (CKD).Methods:A retrospective follow-up was performed for 160 patients (109 males, 51 females; age: 68.5(61.0, 74.0) years) who underwent MPI in Beijing Anzhen Hospital, Capital Medical University between June 2017 and March 2024. The 17-segment 5-point method was used for image analysis to obtain the left ventricular myocardial perfusion and functional parameters. The patients were followed up for cardiac death, and divided into death group and survival group. Clinical data of those 2 groups were compare by χ2 test, the independent-sample t test or Mann-Whitney U test. Cox proportional hazards regression analysis was used to analyze the predictors related to cardiac death. The ROC curve was used to analyze the performance of predictors. Survival curves were obtained by the Kaplan-Meier method, and log-rank test was performed to compare the difference between 2 groups. Results:The follow-up time of 160 patients with CKD was 26.0(10.0, 46.5) months. Of 160 patients, 17 died and 143 survived. There were statistically significant differences in body mass index (BMI), previous myocardial infarction, previous revascularization, hypersensitive C-reactive protein (hs-CRP), positive MPI, left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS) between the death group and the survival group ( χ2 values: 4.58-16.13, t values: -2.34, -3.97, Z values: from -2.81 to 5.02, all P<0.05). Multivariate Cox regression analysis showed that SSS (hazard ratio ( HR)=1.153, 95% CI: 1.062-1.252, P=0.001) and hs-CRP ( HR=1.031, 95% CI: 1.004-1.058, P=0.023) were independent risk factors for cardiac death in patients with CKD. The optimal cut-off value of SSS for predicting cardiac death in those patients was determined to be 8 with the AUC of 0.815, and the incidence of cardiac death in the SSS ≥8 group was significantly higher than that in the SSS<8 group (33.3%(12/36) vs 4.0%(5/124); χ2 = 25.44, P<0.001). Conclusion:MPI is an important imaging method for the evaluation of cardiac death in patients with CKD, SSS and hs-CRP are important risk factors in predicting cardiac death in those patients.

Purpose To evaluate the predictive value of multifunctional parameters of single photon emission computed tomography gated myocardial perfusion imaging(SPECT G-MPI)for major adverse cardiovascular events(MACE)in chronic kidney disease(CKD)with abnormal stress myocardial perfusion.Materials and Methods A total of 99 patients diagnosed with CKD from June 2017 to March 2024 who underwent stress and rest G-MPI indicating abnormal myocardial perfusion in Beijing Anzhen Hospital,Capital Medical University.The American Heart Association 17-segment 5-point method and PHASE software were used to obtain the left ventricular myocardial perfusion,functional and synchronization parameters.According to the occurrence of MACE,the patients were divided into MACE group and non-MACE group.Cox regression was used to analyze the predictors related to MACE.The receiver operator characteristic curve was used to analyze the performance of predictors,the survival curves were obtained by the Kaplan-Meier method,Log-rank test was used to compare the differences in different groups.Results Finally,we enrolled 99 CKD patients with abnormal stress myocardial perfusion.35 patients(35.35%)developed MACE during the follow-up period.Cox regression analysis showed that stress phase bandwidth(SPBW)(HR=1.015,95%CI 1.002-1.028)and sum difference score(SDS)(HR=1.105,95%CI 1.008-1.211)were independent risk factors for predicting MACE(both P<0.05).The optimal cut-off value of SPBW and SDS for predicting MACE were 69° and 6 points,the area under the curve was 0.801 and 0.778,respectively.The incidence of MACE in the SPBW≥69° group and SDS≥6 points group was higher than that in SPBW<69° group and SDS<6 points group(66.6%vs.13.2%,53.3%vs.20.4%,both P<0.05).Conclusion SPECT G-MPI multifunctional parameters can be used to predict the prognosis of CKD patients with abnormal stress myocardial perfusion.SPBW and SDS are independent risk factors for MACE in these patients.