Background: Visceral white adipose tissue (vWAT) inflammation is a critical pathology of obesity-caused heart damage and is closely associated with adipocyte endoplasmic reticulum (ER) dysfunction. Serine (or cysteine) peptidase inhibitor, clade A, member 3C (Serpina3c) has been identified as an adipokine with anti-vWAT inflammatory effects. However, it remains unclear whether Serpina3c deficiency promotion of vWAT inflammation involves adipocyte ER dysfunction and whether it further contributes to heart damage in obesity. Methods: Wild type and Serpina3c knockout (Serpina3c–/–) mice were fed a high-fat diet (HFD) for 12 weeks. An adeno-associated virus (AAV) was injected locally into epididymal white adipose tissue (eWAT) of Serpina3c–/– mice to induce eWAT-adipocyte- specific overexpression of Serpina3c (AAV-Serpina3c) or knockdown of hypoxia-inducible factor 1α (AAV-shHIF1α). In vitro experiments were performed in 3T3-L1 adipocytes. Results: Serpina3c–/– mice exhibited more severe eWAT, serum and heart inflammation after HFD feeding. Consistently, these adverse phenotypes were mitigated in AAV-Serpina3c and AAV-shHIF1α mice. Mechanistically, ER oxidoreductase 1α (Ero1α) and protein disulfide isomerase (PDI) family members PDIA3 and PDIA4 were found to be target genes of HIF1α. In the obese mice, Serpina3c deficiency caused adipocyte more hypertrophy, and activated HIF1α-Ero1α/PDI mediated ER overoxidation and ER stress in eWAT. Subsequently, this led to increased adipocyte apoptosis and chemokine production and decreased adiponectin expression, which promoted macrophage infiltration and M1 polarization in eWAT, thus exacerbating eWAT inflammation and ultimately facilitating serum and distal heart inflammation. Conclusion These findings indicate that Serpina3c is a significant regulator of adipocyte ER redox homeostasis, thus highlighting Serpina3c as a potential therapeutic target for obesity-related eWAT inflammation and heart damage.

Various chromatographic methods were comprehensively applied to study the chemical composition of the ethyl acetate extract from Aucklandiae Radix. The structures of all compounds were identified by analyzing their physicochemical properties and using spectroscopic methods. Two new sesquiterpenoids, named auclappsines A and B(1 and 2) were isolated and identified. Through in vitro high content screening and with the use of a guggulsterone-induced L02 cells, the effects of 1 and 2 on farnesoid X receptor(FXR) protein expression were investigated. The results showed that 1 had a significant FXR activation effect, providing a scientific basis for the development of drugs for the treatment of liver and gallbladder diseases.
Receptors, Cytoplasmic and Nuclear/genetics* ; Humans ; Sesquiterpenes/isolation & purification* ; Drugs, Chinese Herbal/isolation & purification* ; Cell Line ; Molecular Structure

Objective To observe the value of T1 mapping combining diffusion weighted imaging(DWI)for noninvasive preoperative predicting tumor-infiltrating lymphocyte(TIL)level in invasive breast cancer.Methods Totally 143 patients with invasive breast cancer were retrospectively collected and divided into high group(TIL≥10％,n=73)and low group(TIL＜10％,n=70)according to TIL level by postoperation pathology.Clinicopathological information were collected,MRI features of breast cancer lesions were documented,mean T1 values(T1mean)and mean ADC values(ADCmean)were measured,and then were compared between groups.Multivariate logistic regression analysis was used to identify independent predictive factors of TIL levels,and a nomogram was constructed based on regression model.The receiver operating characteristic(ROC)curve and the area under the curve(AUC)were used to evaluate the predictive value for TIL levels.Results Compared with low group,high group had higher proportion of human epidermal growth factor receptor 2(HER2)positivity(P＜0.05),and showed more circular/oval shapes and more smooth margins but less peritumoral edema(all P＜0.05).Significant differences of lesions enhancement pattern was found between groups(P＜0.05).T1mean and ADCmean were both higher in high group than those in low group(both P＜0.05).Lesions enhancement pattern,T1mean and ADCmean were all independent predictors of TIL levels in breast cancer.The AUC of nomogram combining the above 3 factors for predicting TIL level was 0.848,significantly higher than that of lesions enhancement pattern(AUC=0.569,Z=5.384,P＜0.05)and T1mean(AUC=0.662,Z=3.876,P＜0.05),but not statistically different with that of ADCmean(AUC=0.814,Z=1.578,P=0.115).Decision curve analysis showed that this nomogram had good clinical application value.Conclusion Combining T1 mapping and DWI could effectively predict level of TIL level in breast cancer before surgery.

BACKGROUND:Epidemiologic investigations and some experiments have shown that there is a close relationship between peripheral blood cells and osteoporosis,but the causal relationship between the two at the genetic level is still unclear. OBJECTIVE:To explore the causal relationship between peripheral blood cells and osteoporosis using Mendelian randomization methods. METHODS:Genome-wide association study data sets on peripheral blood cells,overall bone density at different ages,and calcaneal bone density were obtained from databases such as Blood Cell Consortium and MRC Integrative Epidemiology Unit. Blood cells were used as exposure data,with bone density at different ages and calcaneal bone density serving as outcome data. Mendelian randomization analyses were performed using methods such as inverse variance weighting,MR-Egger,weighted median method,and simple median. The results were assessed for heterogeneity,pleiotropy,and sensitivity using Cochran's Q,MR-Egger regression,and Leave-one-out method. The causal relationship between exposure and outcomes was evaluated using β values. RESULTS AND CONCLUSION:Due to the heterogeneity revealed by Cochran's Q test in the Mendelian randomization results,the results of the study were based on the inverse variance weighting method. The inverse variance weighting results showed that when age-specific bone density was used as an outcome,there was a negative causal relationship between white blood cell count and whole-body bone mineral density at the age of 45-60 years[β=-0.07,95％ confidence interval (CI):-0.13,-0.01,P=0.02],a positive causal relationship between monocyte count and whole-body bone mineral density at the age of 45-60 years (β=0.05,95％ CI:0.00,0.10,P=0.037),a negative causal relationship between white blood cell and basophil counts and whole-body bone mineral density over 60 years old (β=-0.04,95％ CI:-0.07,-0.01,P=0.005;β=-0.04,95％ CI:-0.07,-0.00,P=0.038),a positive causal relationship between hemoglobin concentration and hematocrit and whole-body bone mineral density over 60 years old (β=0.04,95％ CI:0.01,0.08,P=0.012;β=0.04,95％ CI:0.00,0.07,P=0.039),and a negative causal relationship between white cell count and whole-body bone mineral density at an undistinguished age (β=-0.10,95％ CI:-0.16,-0.03,P=0.002). When heel bone mineral density was used as an outcome,there was a negative causal relationship between white cell count and heel bone mineral density (β=-0.04,95％ CI:-0.07,-0.01,P=0.016),and a positive causal relationship between hemoglobin concentration and hematocrit and heel bone mineral density (β=0.05,95％ CI:0.01,0.08,P=0.007;β=0.05,95％ CI:0.01,0.08,P=0.004). To ensure the robustness of the results,meta-analyses of Mendelian randomization results of peripheral blood cells and whole-body bone mineral density as well as heel bone mineral density in different age groups were conducted. The results suggested that for every standard deviation decrease in log-transformed white blood cell count,there was a 5％ reduction in the risk of decreased bone mineral density (OR=0.95,95％ CI:0.94,0.97,P<0.001);whereas for every standard deviation increase in hemoglobin concentration and hematocrit,there was a 4％ reduction in the risk of decreased bone density (OR=1.04,95％ CI:1.03,1.06,P<0.001). In conclusion,increased white blood cell count in peripheral blood is a risk factor for bone mineral density;whereas increased hematocrit and hemoglobin concentration are protective factors for bone mineral density.

The chemical constituents in dried roots of Atractylodes macrocephala were investigated in this study. Through utilizing normal-phase silica gel and ODS column chromatography, TLC, and semi-preparative HPLC, 4 new sesquiterpenoids were purified from the ethyl acetate extract of A. macrocephala. By various spectroscopic techniques, such as 1D and 2D NMR, HR-ESI-MS, IR, UV, and CD, their structures were identified as atractylmacron A (1), 9β-hydroxyasterolide (2), atractylenolide H (3), atractylenolide J (4). Compound 1 possesses a rare 6/7 bicyclic skeleton.

OBJECTIVES: To investigate the genomic characteristics and prognostic factors of juvenile myelomonocytic leukemia (JMML) with RAS mutations. METHODS: A retrospective analysis was conducted on the clinical data of JMML children with RAS mutations treated at the Hematology Hospital of Chinese Academy of Medical Sciences, from January 2008 to November 2022. RESULTS: A total of 34 children were included, with 17 cases (50%) having isolated NRAS mutations, 9 cases (27%) having isolated KRAS mutations, and 8 cases (24%) having compound mutations. Compared to children with isolated NRAS mutations, those with NRAS compound mutations showed statistically significant differences in age at onset, platelet count, and fetal hemoglobin proportion (P<0.05). Cox proportional hazards regression model analysis revealed that hematopoietic stem cell transplantation (HSCT) and hepatomegaly (≥2 cm below the costal margin) were factors affecting the survival rate of JMML children with RAS mutations (P<0.05); hepatomegaly was a factor affecting survival in the non-HSCT group (P<0.05). CONCLUSIONS Children with NRAS compound mutations have a later onset age compared to those with isolated NRAS mutations. At initial diagnosis, children with NRAS compound mutations have poorer peripheral platelet and fetal hemoglobin levels than those with isolated NRAS mutations. Liver size at initial diagnosis is related to the prognosis of JMML children with RAS mutations. HSCT can improve the prognosis of JMML children with RAS mutations.
Humans ; Leukemia, Myelomonocytic, Juvenile/therapy* ; Mutation ; Male ; Female ; Child, Preschool ; Retrospective Studies ; Child ; Infant ; GTP Phosphohydrolases/genetics* ; Membrane Proteins/genetics* ; Adolescent ; Hematopoietic Stem Cell Transplantation ; Proportional Hazards Models ; Proto-Oncogene Proteins p21(ras)/genetics* ; Prognosis

OBJECTIVES: To explore the underlying pharmacological mechanisms and its potential effects of Chinese medicine herbal formula Sini Powder (SNP) on hepatocellular carcinoma (HCC). METHODS: The active components of SNP and their in vivo distribution were identified using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Construction of component-target-disease networks, protein-protein interaction network, Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and molecular docking were employed to analyze the active components and anti-HCC mechanisms of SNP. Cell viability assay and wound healing assay were utilized to confirm the effect of SNP-containing serum (2.5%, 5.0%, 10%, 20%, and 40%), isoprenaline or propranolol (both 10, 100, and 1,000 µ mol/L) on proliferation and migration of HepG 2 or Huh7 cells. Meanwhile, the effect of isoprenaline or propranolol on the β 2 adrenergic receptor (ADRB2) mRNA expression on HepG2 cells were measured by real-time quantitative reverse transcription (RT-qPCR). Mice with subcutaneous tumors were either subjected to chronic restraint stress (CRS) followed by SNP administration (364 mg/mL) or directly treated with SNP (364 mg/mL). These two parallel experiments were performed to validate the effects of SNP on stress responses. Stress-related proteins and hormones were quantified using RT-qPCR, enzyme-linked immunosorbent assay, and immunohistochemistry. Metagenomic sequencing was performed to confirm the influence of SNP on the gut microbiota in the tumor-bearing CRS mice. RESULTS: The distribution of the 12 active components of SNP was confirmed in various tissues and feces. Network pharmacology analysis confirmed the anti-HCC effects of the 5 active components. The potential anti-HCC mechanisms of SNP may involve the epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase Src (SRC) and signal transducer and activator of transcription 3 (STAT3) pathways. SNP-containing serum inhibited the proliferation of HepG2 and Huh7 cells at concentrations of 2.5% and 5.0%, respectively, after 24 h of treatment. Furthermore, SNP suppressed tumor progression in tumor-bearing mice exposed to CRS. SNP treatment also downregulated the expressions of stress-related proteins and pro-inflammatory cytokines, primarily by modulating the gut microbiota. Specifically, the abundance of Alistipes and Prevotella, which belong to the phylum Bacteroidetes, increased in the SNP-treated group, whereas Lachnospira, in the phylum Firmicutes, decreased. CONCLUSION SNP can combat HCC by alleviating stress responses through the regulation of gut microbiota.
Animals ; Gastrointestinal Microbiome/drug effects* ; Liver Neoplasms/microbiology* ; Carcinoma, Hepatocellular/microbiology* ; Humans ; Drugs, Chinese Herbal/therapeutic use* ; Powders ; Cell Proliferation/drug effects* ; Mice ; Molecular Docking Simulation ; Cell Line, Tumor ; Hep G2 Cells ; Receptors, Adrenergic, beta-2/genetics* ; Stress, Physiological/drug effects* ; Cell Movement/drug effects* ; Male ; Protein Interaction Maps/drug effects* ; Cell Survival/drug effects* ; Proto-Oncogene Mas

Cardiac arrest (CA) is a critical condition in the field of cardiovascular medicine. Despite successful resuscitation, patients continue to have a high mortality rate, largely due to post CA syndrome (PCAS). However, the injury and pathophysiological mechanisms underlying PCAS remain unclear. Experimental animal models are valuable tools for exploring the etiology, pathogenesis, and potential interventions for CA and PCAS. Current CA animal models include electrical induction of ventricular fibrillation (VF), myocardial infarction, high potassium, asphyxia, and hemorrhagic shock. Although these models do not fully replicate the complexity of clinical CA, the mechanistic insights they provide remain highly relevant, including post-CA brain injury (PCABI), post-CA myocardial dysfunction (PAMD), systemic ischaemia/reperfusion injury (IRI), and the persistent precipitating pathology. Summarizing the methods of establishing CA models, the challenges encountered in the modeling process, and the mechanisms of PCAS can provide a foundation for developing standardized CA modeling protocols.
Animals ; Disease Models, Animal ; Post-Cardiac Arrest Syndrome/physiopathology* ; Heart Arrest/physiopathology* ; Humans ; Ventricular Fibrillation/complications*

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

Objective To observe the value of T1 mapping combining diffusion weighted imaging(DWI)for noninvasive preoperative predicting tumor-infiltrating lymphocyte(TIL)level in invasive breast cancer.Methods Totally 143 patients with invasive breast cancer were retrospectively collected and divided into high group(TIL≥10％,n=73)and low group(TIL＜10％,n=70)according to TIL level by postoperation pathology.Clinicopathological information were collected,MRI features of breast cancer lesions were documented,mean T1 values(T1mean)and mean ADC values(ADCmean)were measured,and then were compared between groups.Multivariate logistic regression analysis was used to identify independent predictive factors of TIL levels,and a nomogram was constructed based on regression model.The receiver operating characteristic(ROC)curve and the area under the curve(AUC)were used to evaluate the predictive value for TIL levels.Results Compared with low group,high group had higher proportion of human epidermal growth factor receptor 2(HER2)positivity(P＜0.05),and showed more circular/oval shapes and more smooth margins but less peritumoral edema(all P＜0.05).Significant differences of lesions enhancement pattern was found between groups(P＜0.05).T1mean and ADCmean were both higher in high group than those in low group(both P＜0.05).Lesions enhancement pattern,T1mean and ADCmean were all independent predictors of TIL levels in breast cancer.The AUC of nomogram combining the above 3 factors for predicting TIL level was 0.848,significantly higher than that of lesions enhancement pattern(AUC=0.569,Z=5.384,P＜0.05)and T1mean(AUC=0.662,Z=3.876,P＜0.05),but not statistically different with that of ADCmean(AUC=0.814,Z=1.578,P=0.115).Decision curve analysis showed that this nomogram had good clinical application value.Conclusion Combining T1 mapping and DWI could effectively predict level of TIL level in breast cancer before surgery.