Inflammation plays a pivotal role in the etiology and progression of various diseases. In traditional Chinese medicine, the whole plants of Thesium chinense Turcz. and its preparations (e.g. Bairui Granules) have been employed to manage inflammatory conditions. While flavonoids were previously considered the primary anti-inflammatory components, other potentially active constituents have been largely overlooked and not thoroughly investigated. This study presents a novel finding that the total alkaloids of T. chinense (BC-Alk) are potent active substances underlying the traditional and clinical applications of T. chinense and Bairui Granules as anti-inflammatory agents. UPLC-MS/MS analysis identified the composition of BC-Alk as quinolizidine alkaloids. The anti-inflammatory efficacy of BC-Alk was evaluated using a lipopolysaccharide (LPS)-induced lung inflammation model in mice. Results demonstrated that BC-Alk significantly mitigated LPS-induced lung inflammation, attenuated the overproduction of IL-1β and the overproduction of inflammatory factors (TNF-α), and ameliorated lung tissue hyperplasia in mice in vivo. Mechanistic studies in vitro revealed that BC-Alk upregulated the expression of Nrf2 and its downstream proteins NQO1 and glutamate-cystine ligase and modifier subunit (GCLM), inhibited NF-κB phosphorylation, and suppressed NLRP3 activation. Collectively, these findings indicate that BC-Alk exerts potent inhibitory effects against lung inflammation by modulating Nrf2, NF-κB, and NLRP3 pathways. This study provides new insights into the anti-inflammatory constituents of T. chinense and Bairui Granules.
Animals ; Lipopolysaccharides/adverse effects* ; Alkaloids/pharmacology* ; NF-kappa B/metabolism* ; NF-E2-Related Factor 2/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Mice ; Signal Transduction/drug effects* ; Anti-Inflammatory Agents/pharmacology* ; Male ; Mice, Inbred C57BL ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Pneumonia/genetics*

Objective:To compare clinical characteristics,treatment patterns and physiological indicators in bipolar disorder(BD)patients with different age of onset.Methods:Totally 380 patients with DSM-5 BD were se-lected in this study.Psychiatrists diagnosed the patients using the Mini International Neuropsychiatric Interview.The clinical information questionnaire and the Global Assessment of Functioning scale were utilized to collected clinical characteristics,treatment status,and physiological indicators.The onset age of BD was divided into 21 and 35 years as cut-off points.Multivariate logistic regression and linear regression were used to analyze related factors.Results:Among the 380 patients with BD,199 cases were early-onset group(52.4％),121 cases were middle-onset group(31.8％),and 60 cases were late-onset group(15.8％).There were 26.6％of patients in the early-onset group in-itially diagnosed as depression,23.1％in the middle-onset group,and 11.7％in the late-onset group.Multivariate analysis revealed that compared to the early-onset group of BD,the middle-onset(OR=2.22)and late-onset(OR=4.99)groups had more risk to experience depressive episodes,and the late-onset group(OR=6.74)had 6.74 times of risk to suffer from bipolar Ⅱ disorder.Additionally,patients in the middle-onset(β=-1.52)and late-on-set(β=-4.29)groups had shorter durations of delayed treatment,and those in the middle-onset(β=-1.62)and late-onset(β=-3.14)groups had fewer hospitalizations.Uric acid levels were lower in both the middle-onset(β=-28.39)and late-onset(β=-31.47)groups,and total cholesterol level was lower in the middle-onset group(β=-0.23).Conclusion:Patients with BD in different age of onset show significant differences in clinical charac-teristics,treatment conditions and physiological indicators.

Objective:To describe the detail sampling design,weighting,instruments,filed procedures and quality control methods of the epidemiological survey on dementia among community residents in Tongliao City.Methods:A three-stage disproportionate probability sampling design was used to investigate the inhabitants aged 65 years and over in Tongliao City,Inner Mongolia Autonomous Region.The 10/66 Dementia Research Group(10/66 DRG)assessment instruments were used to diagnose dementia,using computer-assisted personal interview mode in the selected older people.Comprehensive quality control methods were implemented throughout the field-work.Results:A total of 166 villages or communities were sampled from nine counties or districts in Tongliao Cit-y.Totally 4 345 older people were interviewed with 96.2％response rate.By calculating sampling design weights,non-response adjustment weights and post-stratification adjustment weights,these weights were multiplied and per-formed trimming adjustment and standardization adjustment to generate final weights.The 171 interviewers were well-trained and qualified to carry out filed interview.Quality control methods included computer data check,audio record check,and telephone check in order to ensure the quality of the survey.Conclusion:This survey is imple-mented using a rigorous sampling design and timely quality control methods,and uses the 10/66 DRG assessment instruments with satisfactory international validity and reliability as survey instruments,which has international cross-cultural comparability.It provides a valid and feasible methodology of epidemiological survey on dementia for further studies in different regions in China.

Objective:To estimate the costs of dementia from a societal perspective in Tongliao City and ex-plore the influencing factors of these costs.Methods:Dementia was diagnosed using the 10/66 Dementia Research Group assessment instruments.Data on healthcare utilization,caregiver's care time or costs,and the distress due to caregiving were collected.The cost-proportion conversion method was used to estimate the per capita cost of health services based on data from the National Statistical Yearbook.The human capital approach was used to estimate the unit value of informal care time,and the willingness-to-pay method was used to measure the intangible costs of car-egivers.The total societal costs of dementia were calculated based on the reference year 2023,and a two-part model was employed to analyze the factors influencing the societal costs.Results:A total of 390 dementia patients were di-agnosed,with an average societal cost per capita of 117 877 Yuan.The largest cost component was informal care provided by unpaid family members,accounting for 73.1％of the total societal cost.The societal costs for female patients were 61 395 Yuan higher than those for male patients.Patients with comorbid stroke had a higher societal cost of 63 008 Yuan compared to patients without stroke,and each additional chronic disease added 5 868 Yuan to societal costs.Additionally,each non-memory dimension impairment in the Clinical Dementia Rating Scale in-creased the societal costs by 53 997 Yuan.Conclusion:Dementia poses a significant socio-economic burden,with informal care being the major component of this burden.

Recent studies have found that the pathological changes of Tau proteinopathy, such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), involve transmission or circulatory disturbance of synaptic vesicles. This article reviews the relations of AD/PSP with circulatory disturbance of synaptic vesicles and explore the pathogenesis of these diseases, aiming to provide a new perspective for new therapeutic drugs.

RNA modifications affect many biological processes and physiological diseases. The 5-methylcytosine (m⁵C) modification regulates the progression of multiple tumors. However, its characteristics and functions in hepatocellular carcinoma (HCC) remain largely unknown. Here, we found that HCC tissues had a higher m⁵C methylation level than the adjacent normal tissues. Transcriptome analysis revealed that the hypermethylated genes mainly participated in the phosphokinase signaling pathways, such as the Ras and PI3K-Akt pathways. The m⁵C methyltransferase NSUN2 was highly expressed in HCC tissues. Interestingly, the expression of many genes was positively correlated with the expression of NSUN2, including GRB2, RNF115, AATF, ADAM15, RTN3, and HDGF. Real-time PCR assays further revealed that the expression of the mRNAs of GRB2, RNF115, and AATF decreased significantly with the down-regulation of NSUN2 expression in HCC cells. Furthermore, NSUN2 could regulate the cellular sensitivity of HCC cells to sorafenib via modulating the Ras signaling pathway. Moreover, knocking down NSUN2 caused cell cycle arrest. Taken together, our study demonstrates the vital role of NSUN2 in the progression of HCC.
Humans ; ADAM Proteins ; Apoptosis Regulatory Proteins ; Carcinoma, Hepatocellular/metabolism* ; Liver Neoplasms/metabolism* ; Membrane Proteins ; Methyltransferases/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Repressor Proteins ; RNA, Messenger/metabolism* ; Sorafenib ; RNA Methylation/genetics*

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKIs remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations; however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures (PARIS) method is used to establish the higher-order RNA structure maps of EGFR-TKIs-resistant and -sensitive cells of NSCLC. Our results show that RNA structural regions are enriched in untranslated regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N⁶-threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKIs. RNA structure formation in YRDC 3' UTR suppresses embryonic lethal abnormal vision-like 1 (ELAVL1) binding, leading to EGFR-TKI sensitivity by impairing YRDC translation. A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; ErbB Receptors/metabolism* ; GTP-Binding Proteins/therapeutic use* ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; RNA ; RNA-Binding Proteins/genetics* ; Tyrosine Kinase Inhibitors/therapeutic use*

Objective To investigate the mechanism of HSP90 inhibitor AUY-922 reversing the resistance of human neuroblastoma cells to the second generation ALK inhibitor TAE684. Methods The effect of AUY-922 on the proliferation of human neuroblastoma cells SH-SY5Y and KELLY carrying ALK F1174L gene was detected by MTT method. The effect of AUY-922 on cell cycle of SH-SY5Y and KELLY cells was detected by flow cytometry. The effects of AUY-922 on cyclin Cdc2, ALK protein and downstream signal pathways p-Akt, p-Erk, p-stat3 in SH-SY5Y and KELLY cells were detected by Western blot. Results AUY-922 could significantly inhibit the proliferation of SH-SY5Y and KELLY cells, and the IC₅₀ were about 0.30 μmol/L and 0.12 μmol/L, respectively. AUY-922 could induce cell cycle arrest of SH-SY5Y and KELLY cells in G₂/M phase in a dose-dependent manner. AUY-922 could degrade Cdc2 and ALK proteins in SH-SY5Y and KELLY cells in a dose-dependent manner, and reduce the levels of p-Akt, p-Erk and p-stat3. Conclusion The reversal effect of HSP90 inhibitor AUY-922 on drug resistance of human neuroblastoma to ALK inhibitor may be related to its induction of G₂/M cell cycle arrest, the degradation of ALK protein and the inhibition of downstream signal pathway.

Non-small-cell lung cancer (NSCLC), the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) that carries the cancer-specific epigenetic patterns may represent the valuable biomarkers for discriminating tumor and healthy individuals, and thus could be potentially useful for NSCLC diagnosis. Here, we employed a sensitive and reliable method to map genome-wide 5hmC in the cfDNA of Chinese NSCLC patients and detected a significant 5hmC gain in both the gene bodies and promoter regions in the blood samples from tumor patients compared with healthy controls. Specifically, we identified six potential biomarkers from 66 patients and 67 healthy controls (mean decrease accuracy >3.2, P < 3.68E-19) using machine-learning-based tumor classifiers with high accuracy. Thus, the unique signature of 5hmC in tumor patient's cfDNA identified in our study may provide valuable information in facilitating the development of new diagnostic and therapeutic modalities for NSCLC.
5-Methylcytosine ; analogs & derivatives ; blood ; Biomarkers, Tumor ; blood ; genetics ; Carcinoma, Non-Small-Cell Lung ; blood ; diagnosis ; genetics ; Case-Control Studies ; Circulating Tumor DNA ; blood ; DNA Methylation ; Epigenomics ; Female ; Humans ; Lung Neoplasms ; blood ; diagnosis ; genetics ; Male ; Middle Aged

Objective To derive reference limits of cardiac functional parameters (CFP) determined by gated myocardial SPECT imaging, and to analyze the influence of gender, age and weight on CFP. Methods One hundred and seventy-five consecutive outpatients (89 males with age of (48.3±10.7) years and 86 females with age of (49.8±10.4) years) were defined as patients with low-likelihood coronary heart disease (LCHD). All patients underwent adenosine or exercise stress 99Tcm-MIBI G-MPI from February 2008 to April 2011. The EF, EDV and ESV of the left ventricle were measured by quantitative gated SPECT (QGS) software. The reference limits were derived by means of Gaussian distribution or percentiles. The influence of gender, age and weight on CFP was analyzed by multiple regressions for linear models. Two-sample t test was used to analyze data of 2 groups. Parameters between different age groups were compared by one-way analysis of variance. Results The lower reference limit of EF for males was 50%, the upper limit of EDV and ESV was 112 ml and 49 ml respectively. For females, the corresponding reference limits were 54%, 77 ml and 30 ml. Men had higher EDV, ESV (EDV: (75.8±18.3) ml vs (53.3±11.7) ml, t=9.35, P<001; ESV: (27.1±10.9) ml vs (14.3±7.9) ml, t=8.59, P<0.01) and lower EF than women ((65.1±76)% vs (74.7±10.0)%, t=-6.92, P<0.01). The incidence of small hearts in women was 76%(65/86). The gender and age was the primary and secondary predictors of both of EF and ESV, while the body weight was a significantly third predictor for cardiac volume. Patients were dived into different age (≤40 years, 41-49 years, ≥50 years) groups. For males, EDV, ESV and EF were not significantly different among the different age groups (F values: 1.106, 0.954, 1.029, all P>0.05). For females, EDV was not different (F=2408, P>005), while ESV and EF were significantly different among 3 groups (F values: 5.010, 6.229, both P<0.05). Conclusions The CFP determined by G-MPI in LCHD patients are significantly affected by gender and age. The age-related changes of CFP in males are different from those in females.