Background and aims The mechanism of cholestatic liver injury (CLI) is unclear, and effective therapies are lacking. While peroxisome proliferator-activated receptor alpha (PPARα) agonists show potential hepatoprotective effect and pyroptosis is implicated in hepatocellular damage, how PPARα activation mitigates lithocholic acid (LCA)-induced pyroptosis remains unknown. Methods The hepatoprotective effect of PPARα agonists was evaluated in a mouse model of intrahepatic cholestasis induced by LCA. Liver injury was assessed via serum biochemistry, hematoxylin and eosin and TUNEL staining, and electron microscopy. Pyroptosis pathways were analyzed using real-time quantitative polymerase chain reaction, Western blot, and co-immunoprecipitation. Results Combined morphological, histopathological, and biochemical analyses confirmed that PPARα activation protects against CLI. Compared with LCA treatment alone, PPARα activation significantly attenuated the elevation of serum lactate dehydrogenase (LDH), the increased TUNEL-positive cells, and the formation of hepatocyte membrane pores. Mechanistically, PPARα activation suppressed both NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis and apoptosis protease-activating factor-1 (APAF-1)/CASPASE-3/GSDME-mediated pyroptosis. Furthermore, PPARα agonist pretreatment inhibited activation of the nuclear factor-kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways. Conclusions PPARα protects against LCA-induced CLI by inhibiting both NLRP3 inflammasome-mediated pyroptosis associated with NF-κB and APAF-1/CASPASE-3/GSDME-mediated pyroptosis associated with the FOXO1 signaling pathway.

ObjectiveTo analyze the characteristic expression patterns of six neurotransmitters including 5-hydroxytryptamine （5-HT）， dopamine （DA）， acetylcholine （ACh）， norepinephrine （NE）， inhibitory neurotransmitter （INH）， and excitatory neurotransmitter （EXC） in the whole brain and different brain regions of depression patients by Search of Encephalo Telex （SET）， providing new ideas for the study of heterogeneous etiology of depression. Methods（1） A retrospective study was conducted on supra-slow signals of EEG fluctuations in 1 028 patients with depression. The SET system was used to obtain the expression information of six neurotransmitters in the whole brain and 12 brain regions： left frontal region （F3）， right frontal region （F4）， left central region （C3）， right central region （C4）， left parietal region （P3）， right parietal region （P4）， left occipital region （O1）， right occipital region （O2）， left anterior temporal region （F7）， right anterior temporal region （F8）， left posterior temporal region （T5）， and right posterior temporal region （T6）. The expression information of each neurotransmitter was compared with the normal model， and it was found that single neurotransmitter was in one of three states： increased， decreased， or normal expression. The simultaneous expression states of six neurotransmitters in the brain space were referred to as the expression pattern of multiple neurotransmitters. （2） A MySQL database was established to analyze the actual expression patterns of different neurotransmitters in the whole brain of patients with depression. （3） Factor analysis was conducted to further analyze the characteristic rules of 78 variables of neurotransmitters in the whole brain and 12 brain regions in depression patients. Results（1） The expression of single neurotransmitters in the whole brain and different brain regions of the total depression population showed one of three expression states （increased/decreased/normal）， being normal in the majority. The decreased and increased expression of 5-HT， ACh， DA， INH， EXC， and NE in the whole brain occurred in 6% and 25%， 31% and 17%， 36% and 9%， 15% and 31%， 32% and 14%， and 22% and 22%， respectively. （2） The antagonizing pairs of neurotransmitters （EXC/INH， DA/5-HT， and ACh/NE） showed significant antagonistic relationships in the whole brain and different brain regions， with a strong negative correlation between EXC and INH （P<0.01， |r| values ranging from 0.69 to 0.76）， a strong negative correlation between DA and 5-HT （P<0.01， |r| values ranging from 0.83 to 0.90）， and a moderate negative correlation between ACh and NE （P<0.01， with |r| values ranging from 0.56 to 0.66）. Meanwhile， non-antagonizing pairs of neurotransmitters in the whole brain and different brain regions also showed correlations， with DA/NE （P<0.01， |r| values ranging from 0.38 to 0.46） and NE/EXC （P<0.01， |r| values ranging from 0.56 to 0.61） showing weak and moderate negative correlations， respectively， and DA/EXC showing a weak positive correlation （P<0.01， |r| values ranging from 0.38 to 0.47）. （3） The six neurotransmitters in the 1 028 patients with depression presented a total of 170 expression patterns in the whole brain. The top 30 expression patterns were reported in this paper， with a cumulative rate of 60.60%， including patterns ① INH+/5-HT-/ACh+/DA+/NE-/EXC- （9.05%）， ② INH+/5-HT-/ACh↓/DA+/NE-/EXC- （4.57%）， and ③ INH+/5-HT-/ACh+/DA+/NE↓/EXC- （3.31%）. That is， the proportion of depression patients with normal levels of all the six neurotransmitters was 9.05%， and the patients with at least one neurotransmitter abnormality accounted for 91.95%. （4） The factor analysis extracted 22 common factors from 78 variables in the whole brain and different brain regions. These common factors showed the absolute values of loadings ranging from 0.32 to 0.86 and the eigenvalues （F） ranging from 1.03 to 13.43， with a cumulative contribution rate of 76.82%. The characteristic expression patterns included ① ACh_P3↓/ACh_W↓/ACh_C3↓/ACh_F3↓/ACh_O1↓/ACh_T5↓/ACh_F7↓/NE_P3↑/NE_W↑/NE_C3↑/NE_F3↑/NE_O1↑/NE_T5↑/NE_F7↑ （F=13.43， whole brain）， ② 5-HT_O2↑/DA_O2↓/5-HT_P4↑/DA_P4↓/5-HT_W↑/DA_W↓/5-HT_C4↑/DA_C4↓ （F=5.94）， and ③ EXC_F4↓/DA_F4↓/NE_F4↑/INH_F4↑/5-HT_F4↑/ACh_F4↓ （F=5.33）. ConclusionThe actual 170 expression patterns of 6 neurotransmitters in the whole brain of 1 028 depression patients indicate that depression is a heterogeneous disease with individualized characteristics. The 22 characteristic expression patterns in the whole brain and 12 brain regions verify the pathogenesis hypothesis of multi-neurotransmitters oscillation imbalance in brains of depression patients. In summary， this study provides new guidance for the etiology， diagnosis， and treatment of depression and establishes a methodological foundation for the effectiveness evaluation of individualized treatment of depression by traditional Chinese medicine based on the objective biological markers.

ObjectiveTo analyze the characteristic expression patterns of six neurotransmitters including 5-hydroxytryptamine （5-HT）， dopamine （DA）， acetylcholine （ACh）， norepinephrine （NE）， inhibitory neurotransmitter （INH）， and excitatory neurotransmitter （EXC） in the whole brain and different brain regions of depression patients by Search of Encephalo Telex （SET）， providing new ideas for the study of heterogeneous etiology of depression. Methods（1） A retrospective study was conducted on supra-slow signals of EEG fluctuations in 1 028 patients with depression. The SET system was used to obtain the expression information of six neurotransmitters in the whole brain and 12 brain regions： left frontal region （F3）， right frontal region （F4）， left central region （C3）， right central region （C4）， left parietal region （P3）， right parietal region （P4）， left occipital region （O1）， right occipital region （O2）， left anterior temporal region （F7）， right anterior temporal region （F8）， left posterior temporal region （T5）， and right posterior temporal region （T6）. The expression information of each neurotransmitter was compared with the normal model， and it was found that single neurotransmitter was in one of three states： increased， decreased， or normal expression. The simultaneous expression states of six neurotransmitters in the brain space were referred to as the expression pattern of multiple neurotransmitters. （2） A MySQL database was established to analyze the actual expression patterns of different neurotransmitters in the whole brain of patients with depression. （3） Factor analysis was conducted to further analyze the characteristic rules of 78 variables of neurotransmitters in the whole brain and 12 brain regions in depression patients. Results（1） The expression of single neurotransmitters in the whole brain and different brain regions of the total depression population showed one of three expression states （increased/decreased/normal）， being normal in the majority. The decreased and increased expression of 5-HT， ACh， DA， INH， EXC， and NE in the whole brain occurred in 6% and 25%， 31% and 17%， 36% and 9%， 15% and 31%， 32% and 14%， and 22% and 22%， respectively. （2） The antagonizing pairs of neurotransmitters （EXC/INH， DA/5-HT， and ACh/NE） showed significant antagonistic relationships in the whole brain and different brain regions， with a strong negative correlation between EXC and INH （P<0.01， |r| values ranging from 0.69 to 0.76）， a strong negative correlation between DA and 5-HT （P<0.01， |r| values ranging from 0.83 to 0.90）， and a moderate negative correlation between ACh and NE （P<0.01， with |r| values ranging from 0.56 to 0.66）. Meanwhile， non-antagonizing pairs of neurotransmitters in the whole brain and different brain regions also showed correlations， with DA/NE （P<0.01， |r| values ranging from 0.38 to 0.46） and NE/EXC （P<0.01， |r| values ranging from 0.56 to 0.61） showing weak and moderate negative correlations， respectively， and DA/EXC showing a weak positive correlation （P<0.01， |r| values ranging from 0.38 to 0.47）. （3） The six neurotransmitters in the 1 028 patients with depression presented a total of 170 expression patterns in the whole brain. The top 30 expression patterns were reported in this paper， with a cumulative rate of 60.60%， including patterns ① INH+/5-HT-/ACh+/DA+/NE-/EXC- （9.05%）， ② INH+/5-HT-/ACh↓/DA+/NE-/EXC- （4.57%）， and ③ INH+/5-HT-/ACh+/DA+/NE↓/EXC- （3.31%）. That is， the proportion of depression patients with normal levels of all the six neurotransmitters was 9.05%， and the patients with at least one neurotransmitter abnormality accounted for 91.95%. （4） The factor analysis extracted 22 common factors from 78 variables in the whole brain and different brain regions. These common factors showed the absolute values of loadings ranging from 0.32 to 0.86 and the eigenvalues （F） ranging from 1.03 to 13.43， with a cumulative contribution rate of 76.82%. The characteristic expression patterns included ① ACh_P3↓/ACh_W↓/ACh_C3↓/ACh_F3↓/ACh_O1↓/ACh_T5↓/ACh_F7↓/NE_P3↑/NE_W↑/NE_C3↑/NE_F3↑/NE_O1↑/NE_T5↑/NE_F7↑ （F=13.43， whole brain）， ② 5-HT_O2↑/DA_O2↓/5-HT_P4↑/DA_P4↓/5-HT_W↑/DA_W↓/5-HT_C4↑/DA_C4↓ （F=5.94）， and ③ EXC_F4↓/DA_F4↓/NE_F4↑/INH_F4↑/5-HT_F4↑/ACh_F4↓ （F=5.33）. ConclusionThe actual 170 expression patterns of 6 neurotransmitters in the whole brain of 1 028 depression patients indicate that depression is a heterogeneous disease with individualized characteristics. The 22 characteristic expression patterns in the whole brain and 12 brain regions verify the pathogenesis hypothesis of multi-neurotransmitters oscillation imbalance in brains of depression patients. In summary， this study provides new guidance for the etiology， diagnosis， and treatment of depression and establishes a methodological foundation for the effectiveness evaluation of individualized treatment of depression by traditional Chinese medicine based on the objective biological markers.

Purpose: This study assessed the performance of the ultrasound-guided attenuation parameter (UGAP) in diagnosing and grading hepatic steatosis in patients with metabolic dysfunctionassociated steatotic liver disease (MASLD). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) served as the reference standard. Methods: Patients with hepatic steatosis were enrolled in this prospective study and underwent UGAP measurements. MRI-PDFF values of ≥5%, ≥15%, and ≥25% were used as references for the diagnosis of steatosis grades ≥S1, ≥S2, and S3, respectively. Spearman correlation coefficients and area under the receiver operating characteristic curves (AUCs) were calculated. Results: Between July 2023 and June 2024, the study included 88 patients (median age, 40 years; interquartile range [IQR], 36 to 46 years), of whom 54.5% (48/88) were men and 45.5% (40/88) were women. Steatosis grades exhibited the following distribution: 22.7% (20/88) had S0, 50.0% (44/88) had S1, 21.6% (19/88) had S2, and 5.7% (5/88) had S3. The success rate for UGAP measurements was 100%. The median UGAP value was 0.74 dB/cm/MHz (IQR, 0.65 to 0.82 dB/ cm/MHz), and UGAP values were positively correlated with MRI-PDFF (r=0.77, P<0.001). The AUCs of UGAP for the diagnoses of ≥S1, ≥S2, and S3 steatosis were 0.91, 0.90, and 0.88, respectively. In the subgroup analysis, 98.4% (60/61) of patients had valid controlled attenuation parameter (CAP) values. UGAP measurements were positively correlated with CAP values (r=0.65, P<0.001). Conclusion Using MRI-PDFF as the reference standard, UGAP demonstrates good diagnostic performance in the detection and grading of hepatic steatosis in patients with MASLD.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated death globally. Liver transplantation (LT) has emerged as a key treatment for patients with HCC, and the Milan criteria have been adopted as the cornerstone of the selection policy. To allow more patients to benefit from LT, a number of expanded criteria have been proposed, many of which use radiologic morphological characteristics with larger and more tumors as surrogates to predict outcomes. Other groups developed indices incorporating biological variables and dynamic markers of response to locoregional treatment. These expanded selection criteria achieved satisfactory results with limited liver supplies. In addition, a number of prognostic models have been developed using clinicopathological characteristics, imaging radiomics features, genetic data, and advanced techniques such as artificial intelligence. These models could improve prognostic estimation, establish surveillance strategies, and bolster long-term outcomes in patients with HCC. In this study, we reviewed the latest findings and achievements regarding the selection criteria and post-transplant prognostic models for LT in patients with HCC.

Purpose: This study assessed the performance of the ultrasound-guided attenuation parameter (UGAP) in diagnosing and grading hepatic steatosis in patients with metabolic dysfunctionassociated steatotic liver disease (MASLD). Magnetic resonance imaging proton density fat fraction (MRI-PDFF) served as the reference standard. Methods: Patients with hepatic steatosis were enrolled in this prospective study and underwent UGAP measurements. MRI-PDFF values of ≥5%, ≥15%, and ≥25% were used as references for the diagnosis of steatosis grades ≥S1, ≥S2, and S3, respectively. Spearman correlation coefficients and area under the receiver operating characteristic curves (AUCs) were calculated. Results: Between July 2023 and June 2024, the study included 88 patients (median age, 40 years; interquartile range [IQR], 36 to 46 years), of whom 54.5% (48/88) were men and 45.5% (40/88) were women. Steatosis grades exhibited the following distribution: 22.7% (20/88) had S0, 50.0% (44/88) had S1, 21.6% (19/88) had S2, and 5.7% (5/88) had S3. The success rate for UGAP measurements was 100%. The median UGAP value was 0.74 dB/cm/MHz (IQR, 0.65 to 0.82 dB/ cm/MHz), and UGAP values were positively correlated with MRI-PDFF (r=0.77, P<0.001). The AUCs of UGAP for the diagnoses of ≥S1, ≥S2, and S3 steatosis were 0.91, 0.90, and 0.88, respectively. In the subgroup analysis, 98.4% (60/61) of patients had valid controlled attenuation parameter (CAP) values. UGAP measurements were positively correlated with CAP values (r=0.65, P<0.001). Conclusion Using MRI-PDFF as the reference standard, UGAP demonstrates good diagnostic performance in the detection and grading of hepatic steatosis in patients with MASLD.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated death globally. Liver transplantation (LT) has emerged as a key treatment for patients with HCC, and the Milan criteria have been adopted as the cornerstone of the selection policy. To allow more patients to benefit from LT, a number of expanded criteria have been proposed, many of which use radiologic morphological characteristics with larger and more tumors as surrogates to predict outcomes. Other groups developed indices incorporating biological variables and dynamic markers of response to locoregional treatment. These expanded selection criteria achieved satisfactory results with limited liver supplies. In addition, a number of prognostic models have been developed using clinicopathological characteristics, imaging radiomics features, genetic data, and advanced techniques such as artificial intelligence. These models could improve prognostic estimation, establish surveillance strategies, and bolster long-term outcomes in patients with HCC. In this study, we reviewed the latest findings and achievements regarding the selection criteria and post-transplant prognostic models for LT in patients with HCC.

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Objective To explore the application of plasma 7 microRNA (miR7) testing in the differential diagnosis of very early-stage hepatocellular carcinoma (HCC). Methods This study is a multicenter real-world study. Patients with single hepatic lesion (maximum diameter≤2 cm) who underwent plasma miR7 testing at Zhongshan Hospital, Fudan University, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Anhui Provincial Hospital, and Peking University People’s Hospital between January 2019 and December 2024 were retrospectively enrolled. Patients were divided into very early-stage HCC group and non-HCC group, and the clinical pathological characteristics of the two groups were compared. The value of plasma miR7 levels, alpha-fetoprotein (AFP), and des-gamma-carboxy prothrombin (DCP) in the differential diagnosis of very early-stage HCC was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC). In patients with both negative AFP and DCP (AFP＜20 ng/mL, DCP＜40 mAU/mL), the diagnostic value of plasma miR7 for very early-stage HCC was analyzed. Results A total of 64 528 patients from 4 hospitals underwent miR7 testing, and 1 682 were finally included, of which 1 073 were diagnosed with very early-stage HCC and 609 were diagnosed with non-HCC. The positive rate of miR7 in HCC patients was significantly higher than that in non-HCC patients (67.9% vs 24.3%, P＜0.001). ROC curves showed that the AUCs for miR7, AFP, and DCP in distinguishing HCC patients from the non-HCC individuals were 0.718, 0.682, and 0.642, respectively. The sensitivities were 67.85%, 43.71%, and 44.45%, and the specificities were 75.70%, 92.78%, and 83.91%, respectively. The pairwise comparison of AUCs showed that the diagnostic efficacy of plasma miR7 detection was significantly better than that of AFP or DCP (P＜0.05). Although its specificity was slightly lower than AFP and DCP, the sensitivity was significantly higher. Among patients negative for both AFP and DCP, miR7 maintained an AUC of 0.728 for diagnosing very early-stage HCC, with 67.82% sensitivity and 77.73% specificity. Conclusions Plasma miR7 testing is a potential molecular marker with high sensitivity and specificity for the differential diagnosis of small hepatic nodules. In patients with very early-stage HCC lacking effective molecular markers (negative for both AFP and DCP), miR7 can serve as a novel and effective molecular marker to assist diagnosis.

Objective To investigate the expression of the histone deacetylase SIRT7 in glioma cells and its impact on epithelial-mesenchymal transformation(EMT),as well as its effects on proliferative,migratory and invasive capabilities of glioma cells.Methods Bioinformatics analysis was conducted on data from glioma patients in the Cancer Genome Atlas(TCGA)and the Chinese glioma Genome Atlas(CGGA)databases to explore the expression of SIRT7 gene in gliomas and its correlation with tumor grading,molecular characteristics and patient clinical prognosis.Glioma cells were randomly divided into control,SIRT7 knockdown,SIRT7 overexpression,drug treatment(10 μmol/L hydrochlorothiazide)and drug(10 μmol/L hydrochlorothiazide)+SIRT7 overexpression groups.The CCK-8 assay,cell scratch assay and Transwell assay were used to observe the effects of upregulating and downregulating SIRT7 expression on glioma cell proliferation,migration and invasion.RT-qPCR and Western blotting were employed to detect the effects of SIRT7 on the expression of neural cadherin(N-cadherin),Vimentin,E-cadherin,transforming growth factor-β(TGF-β),Ki-67,and Smad3 protein in glioma cells.Nude mouse tumor-bearing experiments were conducted to observe the effect of SIRT7 knockdown on glioma growth.Results Higher expression levels of SIRT7 gene were associated with poorer clinical prognosis(P＜0.0001).SIRT7 expression levels were significantly correlated with tumor grading and 1p19q coding status(P＜0.01).Compared with normal HA cells,glioma cells showed significantly increased SIRT7 expression levels(P＜0.01).CCK-8 assay results indicated that,compared with control group,the proliferation activity of glioma cells in SIRT7 knockout group was significantly decreased(P＜0.01),while SIRT7 overexpression group showed significantly increased proliferation activity(P＜0.01).EdU assay results showed that,compared with control group,the proportion of glioma cells in the proliferative stage was significantly decreased in SIRT7 knockdown group(P＜0.01),and significantly increased in SIRT7 overexpression group(P＜0.01).Western blotting results revealed that,compared with control group,the protein expression levels of TGF-β,Smad3,N-cadherin and Vimentin were significantly decreased in SIRT7 knockdown group(P＜0.01),while the expression level of E-cadherin protein was significantly increased(P＜0.05).SIRT7 overexpression group showed significantly increased protein expression levels of TGF-β,Smad3,N-cadherin and Vimentin(P＜0.05),and a significantly decrease in E-cadherin protein expression level(P＜0.05).Scratch assay results indicated that,compared with control group,the migration ability of cells in SIRT7 knockdown group and drug group was significantly decreased(P＜0.01),and SIRT7 overexpression group showed significantly increased cell migration ability(P＜0.05).Compared with drug group,drug+SIRT7 overexpression group exhibited significantly increased cell migration ability(P＜0.01).Transwell assay results showed that,compared with control group,the migration and invasion abilities of cells in SIRT7 knockdown group and drug group were significantly decreased(P＜0.01),and SIRT7 overexpression group exhibited significantly increased migration and invasion abilities(P＜0.01).Compared with drug group,drug+SIRT7 overexpression group showed significantly increased migration and invasion abilities(P＜0.01).Nude mouse tumor-bearing assay results indicated that the volume and weight of glioma in SIRT7 knockdown group were significantly reduced compared with control group(P＜0.01).Conclusions Glioma patients with high SIRT7 expression have poorer clinical prognosis.SIRT7 can regulate the TGF-β/Smad3 pathway to mediate EMT,promoting the proliferation and migration of glioma cells.SIRT7 knockdown can inhibit the growth of transplanted gliomas in nude mice.