Background/Aims: Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell’s intrinsically fine-tuned regulatory framework is urgently needed. Methods: We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models. Results: ER lipid raft-associated 1 (ERLIN1), a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1–SCAP–SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired factor-inhibiting hypoxia-1-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11–ERLIN1 interaction and restoring cholesterol homeostasis. Conclusions ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11–ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.

Objective To develop an animal model that replicates the clinical phenotype of severe asthma.Methods Ovalbumin(OVA)combined with IL-33 or varying doses of lipopolysaccharides(LPS)was used to explore the construction of a severe asthma mouse model.Established model animals were assessed for lung function,number of inflammatory cells,and lung tissue pathology were assessed.Expression of key genes associated with severe asthma identified from the GEO database were validated in the new model.Results Compared with OVA alone,OVA combined with IL-33 or 5 μg LPS significantly increased airway resistance and the number of inflammatory cells in bronchoalveolar lavage fluid,and aggravated the pathological damage to lung tissues.The expression patterns of key genes in the newly constructed severe asthma models were consistent with those observed in clinical patients with severe asthma.Conclusions The modeling method of combining OVA with IL-33 or LPS(5 μg)can be used to construct experimentalanimal models of severe asthma.

Objective To develop an animal model that replicates the clinical phenotype of severe asthma.Methods Ovalbumin(OVA)combined with IL-33 or varying doses of lipopolysaccharides(LPS)was used to explore the construction of a severe asthma mouse model.Established model animals were assessed for lung function,number of inflammatory cells,and lung tissue pathology were assessed.Expression of key genes associated with severe asthma identified from the GEO database were validated in the new model.Results Compared with OVA alone,OVA combined with IL-33 or 5 μg LPS significantly increased airway resistance and the number of inflammatory cells in bronchoalveolar lavage fluid,and aggravated the pathological damage to lung tissues.The expression patterns of key genes in the newly constructed severe asthma models were consistent with those observed in clinical patients with severe asthma.Conclusions The modeling method of combining OVA with IL-33 or LPS(5 μg)can be used to construct experimentalanimal models of severe asthma.

Objective To explore the role of histone deacetylase 3(HDAC3)and the intestinal rhythm gene nuclear factor,inter-leukin 3 regulated(NFIL3)and visceral hypersensitivity in mice.Methods C57BL/6J mice were randomly divided into normal group(control group,CON group),sleep deprivation group(SD group),and HDAC3 inhibitor intervention group(SD+RGFP966group).The behaviors of mice were detected by open field test and elevated plus maze test,and visceral sensitivity was evaluated by colonic dila-tion test and pain threshold.The pathological changes of colon tissues in each group were evaluated by hematoxylin-eosin staining,and the expressions of inflammatory factors(IL-17,IL-6)and anti-inflammatory factors(IL-10)in serum were detected by enzyme-linked immunosorbent assay(ELISA).The mRNA expressions of junction proteins(ZO-1,Occludin),inflammatory factors(IL-1 β,IL-6)in colon tissues were determined by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR).The protein ex-pressions of NFIL3,HDAC3 and inflammatory factors(TNF-α,IL-1 β)in colon tissues were detected by Western blotting.Results Compared with the CON group,mice in the SD group exhibited anxiety and depression-like behaviors and increased visceral sensitivity(P＜0.05).The hematoxylin-eosin results showed no obvious damage to the structure of colon tissues.The results of Western blot and RT-qPCR showed that the expressions of inflammatory factors in colonic tissue increased(P＜0.05),while the expressions of junction proteins decreased(P＜0.05).The results of Western blot showed that the protein expressions of HDAC3 and NFIL3 increased.Com-pared with the SD group,the anxiety and depression-like behaviors and visceral sensitivity of mice in the SD+RGFP966group were im-proved(P＜0.05),and the expressions of inflammatory factors decreased(P＜0.05),while the expressions of junction proteins in-creased(P＜0.05).The expression of NFIL3decreased after HDAC3 inhibition(P＜0.05).Conclusion HDAC3 inhibitor RGFP966 can improve the visceral hypersensitivity of mice by regulating the intestinal rhythm gene NFIL3.

Objective To explore the role of histone deacetylase 3(HDAC3)and the intestinal rhythm gene nuclear factor,inter-leukin 3 regulated(NFIL3)and visceral hypersensitivity in mice.Methods C57BL/6J mice were randomly divided into normal group(control group,CON group),sleep deprivation group(SD group),and HDAC3 inhibitor intervention group(SD+RGFP966group).The behaviors of mice were detected by open field test and elevated plus maze test,and visceral sensitivity was evaluated by colonic dila-tion test and pain threshold.The pathological changes of colon tissues in each group were evaluated by hematoxylin-eosin staining,and the expressions of inflammatory factors(IL-17,IL-6)and anti-inflammatory factors(IL-10)in serum were detected by enzyme-linked immunosorbent assay(ELISA).The mRNA expressions of junction proteins(ZO-1,Occludin),inflammatory factors(IL-1 β,IL-6)in colon tissues were determined by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR).The protein ex-pressions of NFIL3,HDAC3 and inflammatory factors(TNF-α,IL-1 β)in colon tissues were detected by Western blotting.Results Compared with the CON group,mice in the SD group exhibited anxiety and depression-like behaviors and increased visceral sensitivity(P＜0.05).The hematoxylin-eosin results showed no obvious damage to the structure of colon tissues.The results of Western blot and RT-qPCR showed that the expressions of inflammatory factors in colonic tissue increased(P＜0.05),while the expressions of junction proteins decreased(P＜0.05).The results of Western blot showed that the protein expressions of HDAC3 and NFIL3 increased.Com-pared with the SD group,the anxiety and depression-like behaviors and visceral sensitivity of mice in the SD+RGFP966group were im-proved(P＜0.05),and the expressions of inflammatory factors decreased(P＜0.05),while the expressions of junction proteins in-creased(P＜0.05).The expression of NFIL3decreased after HDAC3 inhibition(P＜0.05).Conclusion HDAC3 inhibitor RGFP966 can improve the visceral hypersensitivity of mice by regulating the intestinal rhythm gene NFIL3.

Isatis indigotica Fort. (Ban-Lan-Gen) is an herbal medicine prescribed for influenza treatment. However, its active components and mode of action remain mostly unknown. In the present study, erucic acid was isolated from Isatis indigotica Fort., and subsequently its underlying mechanism against influenza A virus (IAV) infection was investigated in vitro and in vivo. Our results demonstrated that erucic acid exhibited broad-spectrum antiviral activity against IAV resulting from reduction of viral polymerase transcription activity. Erucic acid was found to exert inhibitory effects on IAV or viral (v) RNA-induced pro-inflam-matory mediators as well as interferons (IFNs). The molecular mechanism by which erucic acid with antiviral and anti-inflammatory properties was attributed to inactivation of NF-kB and p38 MAPK signaling. Furthermore, the NF-kB and p38 MAPK inhibitory effect of erucic acid led to diminishing the transcriptional activity of interferon-stimulated gene factor 3 (ISGF-3), and thereby reducing IAV-triggered pro-inflammatory response amplification in IFN-β-sensitized cells. Additionally, IAV- or vRNA-triggered apoptosis of alveolar epithelial A549 cells was prevented by erucic acid. In vivo, erucic acid administration consistently displayed decreased lung viral load and viral antigens expression. Meanwhile, erucic acid markedly reduced CD8+cytotoxic T lymphocyte (CTL) recruitment, pro-apoptotic signaling, hyperactivity of multiple signaling pathways, and exacerbated immune inflammation in the lung, which resulted in decreased lung injury and mortality in mice with a mouse-adapted A/FM/1/47-MA(H1N1) strain infection. Our findings provided a mechanistic basis for the action of erucic acid against IAV-mediated inflammation and injury, suggesting that erucic acid may have a therapeutic potential in the treatment of influenza.

Objective To investigate the value of flexi-rigid thoracoscopy in pleural effusion of unknown causes and the correlation with CEA, TK1 and ADA. Methods The clinical data and results of CEA, TK1 and ADA of 25 patients were retrospective analyzed in our department from 2015 January to November 2015. These patients accepted the examination of flexi-rigid thoracoscopy with pleural effusion of unknown causes. Results In the 25 patients with pleural effusion of unknown causes, definite diagnosis was made in 22 cases (88.00 %), of which 9 cases were malignant pleural effusion (36.00 %), 11 cases were tuberculous pleural effusion (44.00 %), 2 cases were inflammatory pleural effusion (8.00 %), 3 cases were undetermined (12.00 %). The positive rate of TK1 and CEA in malignant group was significantly higher than that in the tuberculosis group and inflammatory group, the positive rate of ADA in the tuberculosis group was significantly higher than that in the malignant group and inflammatory group. Conclusion Flexi-rigid medical thoracoscopy examination is an effective and safe method for diagnosis of unexplained pleural effusion with high exact diagnosis rate, less trauma and less complication. Combination with CEA, TK1 and ADA are helpful to improve diagnostic rate of pleural effusion of unknown causes.