OBJECTIVE To explore the antidepressant mechanism of Wenyang jieyu granules （WYJYG） via the NOD-like receptor thermal protein domain associated protein 3 （NLRP3）/apoptosis-associated speck-like protein containing a CARD （ASC）/Caspase-1 pathway. METHODS A rat model of depression was established by chronic unpredictable mild stress combined with single-housing for 42 consecutive days.The experiment set up blank group， model group， MCC950 （NLRP3 inflammasome inhibitor） group （10 mg/kg）， fluoxetine group （positive control，2.08 mg/kg），low-dose WYJYG（3.78 g/kg） and high-dose WYJYG group （7.56 g/kg），with 10 rats in each group. From the 22nd day of the experiment， rats in the fluoxetine group， low-dose and high-dose WYJYG groups were intragastrically administered with the corresponding drugs and intraperitoneally injected with an equal volume of normal saline. Rats in the MCC950 group were intraperitoneally injected with MCC950 at the corresponding concentration and intragastrically administered with an equal volume of distilled water. Rats in the blank group and model group were given an equal volume of distilled water by gavage and an equal volume of normal saline by intraperitoneal injection. All interventions were performed once a day for 21 consecutive days. Behavioral tests were conducted once a week. After the last administration， the contents of ASC， ionized calcium binding adaptor molecule 1 （Iba1）， interleukin-1β （IL-1β）， and IL-18 in hippocampal tissues were detected. The protein expressions of NLRP3， cluster of differentiation 68 （CD68）， Caspase-1， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein were determined， and neuronal apoptosis was observed. RESULTS After the last administration， compared with the model group， the open-field activity time was significantly prolonged （ P ＜0.05）， and the latency to feed in a novel environment was significantly shortened （ P ＜0.05） in rats of the high-dose WYJYG group. In hippocampal tissue， the contents of ASC， Iba1， IL-1β， and IL-18， as well as the protein expression levels of NLRP3， Caspase-1， and CD68， and the positive rate of neuronal apoptosis were all significantly decreased/downregulated （ P ＜0.05）. Bcl-2 protein expression was significantly upregulated （ P ＜0.05）， and the density of neuronal apoptosis-positive cells was significantly reduced （ P ＜0.05）. CONCLUSIONS WYJYG play on antidepressant role by inhibiting the NLRP3/ASC/Caspase-1 pathway， reducing microglia-mediated neuroinflammation， and inhibiting hippocampal neurons apoptosis.

As the number of patients with compromised immune function increases and fungal resistance develops, so does the risk of contracting deadly fungi in humans. Both fungi and humans are eukaryotes, so identifying unique targets for antifungal drug development is difficult. In addition, the existing antifungal drugs are limited by toxicity, drug interaction and drug resistance in practical application, which leads to the increasing incidence and fatal rate of fungal infections. Therefore, it is urgent to develop new antifungal drugs. The semi-synthetic technology using microbial fermentation products from natural sources as lead compounds has become the most used method in structural modification of antifungal drugs due to its advantages of few reaction steps and easy operation. This paper will introduce the current status of natural antifungal drugs in clinical use, as well as the latest progress in the research and development of new semi-synthetic antifungal drugs, and summarize their mechanism of action, structural modifications, advantages and disadvantages, so as to provide reference for the subsequent development of new antifungal drugs.

Objective:To explore the influence of injection methods of different contrast agents on CMR image quality,and further optimize"one-stop"examination process under the premise of the analysis for high-pressure bolus pressure curve of contrast-enhanced(CE)cardiac magnetic resonance(CMR).Methods:The data of CMR examination of 70 patients with old myocardial infarction who admitted to the department of emergency of Xuanwu Hospital,Capital Medical University from December 2023 to December 2024 were selected as research objects.They were divided into an observation group and a control group by a simple randomization method,with 35 cases in each group.The observation group adopted gadolinium contrast agent injection with double-phase double-flow,with two bolus injections at 4 ml/s and 2 ml/s sequentially.The control group adopted the injection with single-phase double-flow,with only one bolus injection at 4 ml/s.The dynamic pressure time curve was drawn,and the total bolus dose and pressure peak of two kinds of injection methods were compared.The residual liquid samples of the observation group and the control group were collected after injection of contrast agent was conducted.After the residual liquids of 10 ml,20 ml and 30 ml were derived respectively,the T1 mapping sequence was used to collect signal intensity values,and to compared the difference of that between two groups.The signal-to-noise ratio(SNR)of left ventricular blood pool,infarcted myocardium and distal myocardium,and the contrast-to-noise ratios(CNR)between infarcted myocardium and blood pool,and between distal myocardium and blood pool were compared between the observation group and the control group.Results:There was no statistical difference in the total dose of bolus injection between the observation group and the control group(P>0.05).The peak value of the pressure of bolus injection in the observation group and control group were respectively(87.4±11.3)pound force per square inch(PSI)and(104.0±20.1)PSI,and the difference was statistically significant(t=5.81,P<0.05).T1 signal intensity values of 10 ml residual liquid and 20 mL residual liquid were respectively 1984.43±70.26 and 2190.56±195.96 in observation group,and they were respectively 1203.36±184.99 and 2884.64±349.39 in control group,and the differences were significant(t=-3.57,6.03,P<0.05).The T1 signal intensity value of 30mL residual fluid sample was 4371.75±75.16 in observation group,and that was 4261.86±110.68 in control group,and the difference was no significant(P>0.05).The SNR value of blood pool was(4.88±1.01)in observation group,which was lower than(8.25±1.36)in control group,and the difference of that between two groups was significant(t=6.11,P<0.05).The CNR values of infarcted myocardium and blood pool,of remote myocardium and blood pool between two groups were statistically significant(t=-4.79,-5.39,P<0.05).Conclusion:The contrast agent of high-pressure bolus injection with dual-phase dual-flow method can not only explore the time window of the extravasation of contrast agent,but also improve the SNR and the CNR of CMR images,and further optimize the CMR examination process.

Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.

Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

OBJECTIVE: Circadian rhythm disruption (CRD) is a risk factor that correlates with poor prognosis across multiple tumor types, including hepatocellular carcinoma (HCC). However, its mechanism remains unclear. This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity. METHODS: To quantify CRD, the HCC CRD score (HCCcrds) was developed. Using machine learning algorithms, we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort (n = 369), and the robustness of this method was validated. Furthermore, we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes. RESULTS: We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis. The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis, higher pathological grade, and advanced clinical stages, while the CRD-related subtype with low HCCcrds had better clinical outcomes. We also identified novel biomarkers for each subtype, such as nicotinamide n-methyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1. CONCLUSION We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers. Within these groups greater HCCcrds was associated with worse prognosis. This approach has the potential to improve prediction of an individual's prognosis, guide precision treatments, and assist clinical decision making for HCC patients. Please cite this article as: Li XJ, Chang L, Mi Y, Zhang G, Zhu SS, Zhang YX, et al. Integrated-omics analysis defines subtypes of hepatocellular carcinoma based on circadian rhythm. J Integr Med. 2025; 23(4): 445-456.
Humans ; Carcinoma, Hepatocellular/pathology* ; Liver Neoplasms/pathology* ; Circadian Rhythm/genetics* ; Prognosis ; Male ; Female ; Biomarkers, Tumor/genetics* ; Middle Aged ; Machine Learning ; Computational Biology

Objective Ticks serve as vectors for transmitting Babesia microti.However,the specific mechanism remains unclear.This study aimed to investigate the effect of tick autophagy molecules on the proliferation of Babesia microti.Methods An experimental model of infected and uninfected mice was used to collect tick materials for proteomic analysis to identify differentially expressed autophagy-related molecules in Haemaphysalis longicornis.The cloning of the HlATG8 gene,protein expression,and production of polyclonal antibodies were completed.The HlATG8 gene was then knocked down using RNAi interference technology.Results The tick autophagy molecule,HlATG8,was identified and found to be significantly upregulated in ticks infected with Babesia microti.The load of Babesia microti in ticks increased significantly following the knockdown of the HlATG8 gene.Conclusions The tick autophagy molecule in Hae.longicornis,HlATG8,inhibits the proliferation of Babesia.

OBJECTIVE: To investigate the association between ABO blood types and gestational diabetes mellitus (GDM) risk. METHODS: A prospective birth cohort study was conducted. ABO blood types were determined using the slide method. GDM diagnosis was based on a 75-g, 2-h oral glucose tolerance test (OGTT) according to the criteria of the International Association of Diabetes and Pregnancy Study Groups. Logistic regression was applied to calculate the odds ratios ( ORs) and 95% confidence intervals ( CIs) between ABO blood types and GDM risk. RESULTS: A total of 30,740 pregnant women with a mean age of 31.81 years were enrolled in this study. The ABO blood types distribution was: type O (30.99%), type A (26.58%), type B (32.20%), and type AB (10.23%). GDM was identified in 14.44% of participants. Using blood type O as a reference, GDM risk was not significantly higher for types A ( OR = 1.05) or B ( OR = 1.04). However, women with type AB had a 19% increased risk of GDM ( OR = 1.19, 95% CI = 1.05-1.34; P < 0.05), even after adjusting for various factors. This increased risk for type AB was consistent across subgroup and sensitivity analyses. CONCLUSION The ABO blood types may influence GDM risk, with type AB associated with a higher risk. Incorporating it-either as a single risk factor or in combination with other known factors-could help identify individuals at risk for GDM before or during early pregnancy.
Humans ; Female ; Pregnancy ; Diabetes, Gestational/etiology* ; ABO Blood-Group System ; Adult ; Prospective Studies ; Risk Factors ; Young Adult

OBJECTIVE Melatonin(MEL),a natural hormone with broad-spectrum anticancer effects,has been shown to potentiate the therapeutic outcomes of conventional chemotherapy.This study aims to investigate the combined effects of Doxorubicin(DOX)and MEL on head and neck squamous cell carcinoma(HNSCC)cell lines.METHODS The effects of MEL and DOX on cell proliferation in HNSCC cell lines TU686 and CAL-27 were assessed using the MTT assay.The effects of MEL and DOX on reactive oxygen species(ROS)expression levels in HNSCC cell lines were detected using DCFH-DA fluorescent probe.The effects of MEL and DOX on 8-hydroxy-2′-deoxyguanosine(8-oxodG)levels in HNSCC cell lines were measured by enzyme-linked immunosorbent assay(ELISA).The effects of MEL and DOX on γ-H2AX protein levels in HNSCC cell lines were analyzed via Western blot.The effects of MEL and DOX on antioxidant enzymes levels in HNSCC cell lines were evaluated based on spectrophotometry.The effects of MEL and DOX on cell apoptosis in HNSCC cell lines were detected using an ELISA cell death detection kit.RESULTS The MTT assay revealed that MEL significantly enhanced the cytotoxic effects of DOX in HNSCC cell lines(tTU686=13.51,tCAL-27=17.580,all P<0.05).The combination of MEL and DOX markedly increased intracellular ROS levels(FTU686=89.984,FCAL-27=102.853,all P<0.05),while the expression of antioxidant enzymes was significantly reduced(TU686:the F values of CAT,GPx,GR,GST and SOD are 176.035,34.662,20.260,120.105 and 184.254,all P<0.05;CAL-27:the F values are 96.801,177.398,97.849,102.750 and 186.608 respectively,all P<0.05).Furthermore,this combination treatment significantly elevated the expression levels of 8-oxodG(FTU686=200.078,FCAL-27=663.982,all P<0.05)and γ-H2AX(FTU686=192.500,FCAL-27=285.700,all P<0.01)in HNSCC cell lines.Additionally,compared to single-agent treatment,MEL significantly enhanced DOX-induced apoptosis in HNSCC cell lines(FTU686=2718.253,FCAL-27=5185.334,all P<0.01).CONCLUSION The combination of MEL and DOX can enhance cytotoxic effects on HNSCC cell lines,increase intracellular ROS levels,induce DNA oxidative damage,and impair cellular antioxidant defense capacity,thereby effectively promoting HNSCC cell apoptosis.This combination may represent a novel therapeutic approach to improve clinical outcomes in HNSCC.

Objective:To investigate the characteristics of cell subsets in rheumatoid arthritis patients complicated with interstitial lung disease (RA-ILD).Methods:The clinical data of 344 patients with RA admitted to the Affiliated Hospital of Nantong University from June 2022 to November 2023 were analyzed. The patients were categorized into two groups based on the diagnostic criteria of ILD: 120 cases in the RA associated with ILD group (RA-ILD group) were included and 224 cases in the RA without ILD group (RA group), the clinical characteristics were compared between the RA-ILD group and the RA group. The influence factors of RA-ILD were analyzed by univariate and multivariate logistic regression.Results:Compared with RA patients, RA-ILD patients were more common in males, with older age, longer course of disease, and higher smoking rate ( P<0.05). The high titer anti-cyclic citrullinated peptide (CCP) antibody, white blood cells, neutrophil, neutrophil to lymphocyte count ratio, aspartate aminotr-ansferase(AST), creatinine (Cr) and lactate dehydrogenase (LDH) levels in RA-ILD patients were higher than those in RA patients. The triglyceride level was lower than that of RA patients ( P<0.05). The percentage of total T cells in peripheral blood lymphocyte subsets in RA-ILD patients [68.65%(62.22%, 76.78%)] was lower than that in RA patients [71.88%(65.83%, 78.39%)] ( Z=-2.26, P=0.024). The percentage of CD4 +T cells [40.2% (32.10%, 45.23%)] was lower than that of RA patients [46.5% (39.74%, 53.19%)] ( Z=-6.29, P<0.001). CD4 +T cell count [486.50 (324.25, 636.75)cells/μl] was lower than that of RA patients [564.50 (438.25, 752.00)cells/μl] ( Z=-4.50, P<0.001). CD4 +/CD8 + levels [1.86 (1.26, 2.18)] were lower than those of RA patients [2.03 (1.40, 2.94)] ( Z=-2.79, P=0.005). B cell count [127.00 (78.00, 207.25)cells/μl] was lower than that of RA patients [163.50 (91.25, 231.50)cells/μl] ( Z=-2.11, P=0.035), The percentage of NK cells in peripheral blood lymphocyte subsets in RA-ILD patients [19.72%(13.14%, 25.83%)] was higher than that in RA patients [12.55% (8.23%, 17.80%)] ( Z=6.13, P<0.001). NK cell count [182.50 (109.00, 293.75)cells/μl] was higher than that of RA patients [156.00 (89.00, 194.75)cells/μl] ( Z=3.17, P=0.002). The percentage of CD8 +T cells [25.10 %(18.74%, 29.86%)] was higher than that of RA patients [22.27% (17.32%, 29.21%)] ( Z=2.00, P=0.046). Imaging types of RA-ILD patients showed that usual interstitial pneumonia (UIP) was more common, followed by non-specific interstitial pneumonia (NSIP). CD8 + T cell count and percentage expression level in UIP were higher than NSIP, and CD4 +/CD8 + expression level was lower than NSIP ( P<0.05). Multivariate logistic regression analysis of indicators with statistical differences were male gender [ OR(95% CI)=2.888 (1.556, 5.360), P=0.001], age [ OR(95% CI)=1.065 (1.033, 1.098), P<0.001], disease duration [ OR(95% CI)=1.004 (1.001, 1.007), P=0.013], high titer anti-CCP antibody [ OR(95% CI)=2.764 (1.214, 6.292), P=0.015], LDH [ OR(95% CI)=1.006 (1.002, 1.009), P=0.001], CD4 +T cell percentage [ OR(95% CI)=0.964 (0.929, 1.000), P=0.049], CD4 +T cell count [ OR(95% CI)=0.998 (0.996, 1.000), P=0.011] and NK cell count [ OR(95% CI)=1.004 (1.001, 1.007), P=0.003]. These indicators were correlated factors for RA-ILD. Conclusion:Male patients with older age, history of smoking and a long disease course are more likely to develop ILD. Male gender with older, long disease course, high titer anti-CCP antibody, increased LDH and NK cell count, CD4 +T cell percentage and decreased CD4 +T cell count are correlation factors for RA-ILD, which may help RA patients to recognize ILD early.