Tenovin 3 induces apoptosis and ferroptosis in EGFR 19del non small cell lung cancer cells.

Epidermal growth factor receptor (EGFR) exon 19 deletion is a major driver for the drug resistance of non-small cell lung cancer (NSCLC). Identification small inhibitor capable of selectively inhibiting EGFR-19del NSCLC is a desirable strategy to overcome drug resistance in NSCLC. This study aims to screen an inhibitor for EGFR exon 19 deletion cells and explore its underlying mechanism. High through-put screen was conducted to identify an inhibitor for EGFR-19del NSCLC cells. And tenovin-3 was identified as a selective inhibitor of PC9 cells, an EGFR-19del NSCLC cells. Tenovin-3 showed particular inhibition effect on PC9 cells proliferation through inducing apoptosis and ferroptosis. Mechanistically, tenovin-3 might induce the apoptosis and ferroptosis of PC9 cells through mitochondrial pathway, as indicated by the change of VDAC1 and cytochrome c (cyt c). And bioinformatics analyses showed that the expression levels of SLC7A11 and CPX4 were correlated with NSCLC patient's survival. Our findings provide evidences for tenovin-3 to be developed into a novel candidate agent for NSCLC with EGFR exon 19 deletion. Our study also suggests that inducing ferroptosis may be a therapeutic strategy for NSCLC with EGFR exon 19 deletion.

A survey on the current status of Helicobacter pylori infection in households in Hainan Province, China.

OBJECTIVE: This study aims to assess the prevalence of Helicobacter pylori (Hp) infection at the household level in Hainan Province in China and identify the factors that contribute to its spread. The findings of this study have significant implications for public health prevention strategies in the Hainan region. METHODS: A total of 421 families, comprising 1355 individuals, were tested for Hp infection across five cities in Hainan Province between July 2021 and April 2022. The study utilized questionnaires that included questions about personal characteristics, household shared lifestyle and dietary habits, and potential pathways of Hp infection in children to identify potential factors linked to household Hp infection and transmission patterns. RESULTS: The prevalence of Hp infection on an individual basis was 46.72% (629/1355), with age ≥ 20 years, being married and having junior secondary education and above as risk factors for Hp infection. The prevalence of Hp infection in households was 80.29% (338/421), household size of 5, 6 and above were risk factors for Hp infection with Odds Ratios (ORs) of 4.09 (1.17-14.33) and 15.19 (2.01-114.73), respectively, household income ≥ 100,000 yuan and drinking boiled water from a tap source were protective factors for Hp infection with ORs of 0.52 (0.31-0.89) and 0.51 (0.28-0.95), respectively. The prevalence of Hp infection among minors in the household was 24.89% (58/233), with paternal infection and maternal infection as risk factors for child infection, with ORs of 2.93 (1.29-6.62) and 2.51 (1.07-5.89), respectively. CONCLUSION: Hp infection was prevalent among Hainan families, and interaction with infected family members may be the primary cause of transmission.

Emodin Protects Against Lipopolysaccharide-Induced Acute Lung Injury via the JNK/Nur77/c-Jun Signaling Pathway.

Background: Acute lung injury (ALI) is a serious inflammatory disease with clinical manifestations of hypoxemia and respiratory failure. Presently, there is no effective treatment of ALI. Although emodin from Rheum palmatum L. exerts anti-ALI properties, the underlying mechanisms have not been fully explored. Purpose: This study aimed to investigate the therapeutic effect and mechanism of emodin on LPS-induced ALI in mice. Methods: RAW264.7 cells and zebrafish larvae were stimulated by LPS to establish inflammatory models. The anti-inflammatory effect of emodin was assessed by ELISA, flow cytometric analysis, and survival analysis. In vitro mechanisms were explored by using Western blotting, luciferase assay, electrophoretic mobility shift assay (EMSA), and small interfering RNA (siRNA) approach. The acute lung injury model in mice was established by the intratracheal administration of LPS, and the underlying mechanisms were assessed by detecting changes in histopathological and inflammatory markers and Western blotting in lung tissues. Results: Emodin inhibited the inflammatory factor production and oxidative stress in RAW264.7 cells, and prolonged the survival of zebrafish larvae after LPS stimulation. Emodin suppressed the expression levels of phosphorylated JNK at Thr183/tyr182 and phosphorylated Nur77 at Ser351 and c-Jun, and increased the expression level of Nur77 in LPS-stimulated RAW264.7 cells, while these regulatory effects of emodin on Nur77/c-Jun were counteracted by JNK activators. The overexpression of JNK dampened the emodin-mediated increase in Nur77 luciferase activity and Nur77 expression. Moreover, the inhibitory effect of emodin on c-Jun can be attenuated by Nur77 siRNA. Furthermore, emodin alleviated LPS-induced ALI in mice through the regulation of the JNK/Nur77/c-Jun pathway. Conclusions: Emodin protects against LPS-induced ALI through regulation on JNK/Nur77/c-Jun signaling. Our results indicate the potential of emodin in the treatment of ALI.

Cyclin B2 overexpression promotes tumour growth by regulating jagged 1 in hepatocellular carcinoma.

BACKGROUND: Our previous study showed that Cyclin B2 (CCNB2) is closely related to the occurrence and progression of hepatocellular carcinoma (HCC). AIM OF THE STUDY: This study aimed to clarify the effect of CCNB2 gene silencing on tumorigenesis in nude mice and to detect the potential mechanism. METHODS: The effect of CCNB2 on HCC was tested in vivo. The downstream target genes of CCNB2 were predicted by proteomics and confirmed by western blot assay. The regulatory functions of CCNB2 in the proliferation and migration of HCC cells were determined through functional recovery experiments. The expression of the downstream target genes of CCNB2 was detected by immunohistochemistry. RESULTS: Knockdown of CCNB2 decreased tumour formation rate and tumour volume and weight and inhibited tumour proliferation. A total of 130 differentially expressed proteins were detected by proteomics, and Jagged 1 (JAG1) was predicted as the potential downstream target of CCNB2. Western blot assay revealed that CCNB2 and JAG1 expression was significantly correlated in HCC cells. The results of functional recovery experiments suggested that CCNB2 knockdown weakened the proliferation and migration ability of HCC cells, while JAG1 overexpression restored this ability of HCC cells that was weakened by CCNB2 knockdown. Immunohistochemistry showed that JAG1 expression was higher in HCC tissues than in paracancerous tissues and was related to tumour size and number and tumour thrombus formation. CONCLUSIONS: The proliferation of HCC cells in vivo was inhibited by CCNB2 knockdown. CCNB2 may accelerate the proliferation and metastasis of HCC cells by increasing JAG1 expression.

Upregulation of Nei-Like DNA Glycosylase 3 Predicts Poor Prognosis in Hepatocellular Carcinoma.

BACKGROUND: Accumulating evidence has suggested that Nei-like DNA glycosylase 3 (NEIL3) is associated with human tumors. However, there are few studies on the role of NEIL3 in hepatocellular carcinoma (HCC). The aim of this study was to investigate the expression profile of NEIL3 and its clinical relevance in HCC. MATERIALS AND METHODS: A total of 130 HCC and corresponding nontumor tissues were collected to perform immunohistochemistry (IHC). The clinical relevance and prognostic value of NEIL3 in HCC were analyzed by the chi-square test, Kaplan-Meier analysis, the Cox proportional hazard model, and nomogram. RESULTS: IHC showed that the NEIL3 protein level was remarkably upregulated in tumor tissues compared with nontumor tissues (fold change = 1.24; P < 0.001). High NEIL3 expression was significantly correlated with BCLC stage (P=0.004) and TNM stage (P=0.005). Overall survival (OS) and disease-free survival (DFS) rates in the high NEIL3 expression group were significantly worse than those in the low NEIL3 expression group (P=0.007 and P=0.004, respectively). Furthermore, subgroup analysis showed that high NEIL3 expression predicted worse OS and DFS for HCC patients with advanced TNM stage, poorly differentiated tumor, HBsAg positive, or cirrhosis. Multivariate analysis and the prognostic nomograms revealed that tumor NEIL3 level may serve as a promising prognostic indicator for OS and DFS in HCC patients. CONCLUSION: Our findings suggested that NEIL3 might be a potential prognosis assessment marker and therapeutic target for HCC patients.

Revealing the Intrinsic Nature of the Synergistic Effect Caused by the Formation of Heterojunctions in Cu-Cu2O/rGO-NH2 Nanomaterials in the Catalysis of Selective Aerobic Oxidation of Benzyl Alcohol.

Ternary nanomaterials Cu-Cu2O/rGO-NH2 (rGO = reduced graphene oxide) exhibited a synergistic effect in the quantitative catalysis of selective aerobic oxidation of benzyl alcohol. The synergistic effect is attributed to the heterojunctions among the three components and in intrinsic nature, the formation of the heterojunctions lowered the conduction band (CB) energy level and raised the valence band (VB) energy level of the main catalyst Cu2O, which eases electron transfer from the catalyst to O2 in its activation and from the substrate to the catalyst in the oxidation, respectively.

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumor worldwide, with high incidence and mortality. However, the exact mechanisms leading to HCC development remain unclear. The cores of the Hippo signaling pathway consist of a kinase cascade to transmit signals, which inhibits the transcriptional coactivator translocate into the nucleus and reduces the transcription of downstream proliferation-related genes. Hippo signaling pathway regulates liver development and regeneration after liver resection, and it is also related to the occurrence of HCC. The Hippo pathway regulates proliferation, apoptosis, metastasis, autophagy, metabolic reprogramming of HCC cells, affects the tumor immune microenvironment, and participates multiple-drug resistance. Further study on the role of Hippo signaling pathway in HCC is important to develop new therapeutic targets.

Upregulation of Excision Repair Cross-Complementation Group 6-Like (ERCC6L) Promotes Tumor Growth in Hepatocellular Carcinoma.

BACKGROUND: Excision repair cross-complementation group 6-like (ERCC6L) is overexpressed in some malignancies; however, its role in hepatocellular carcinoma (HCC) remains to be further investigated. AIMS: In the present study, we explored the expression and function of ERCC6L in HCC. METHODS AND RESULTS: We investigated the expression of ERCC6L by microarray analysis, using the Cancer Genome Atlas database, and by HCC tissue microarray. The results showed that ERCC6L expression was upregulated in tumor specimens and HCC cell lines. High ERCC6L expression in tumor tissues was significantly correlated with poor prognosis and could serve as an independent prognostic indicator for HCC patients. Results of in vitro and in vivo assays revealed that ERCC6L substantially promoted cell proliferation, and our flow cytometry analysis revealed that this was accomplished by acceleration of the G1/S transition. Finally, gene set enrichment analysis and western blotting results indicated that ERCC6L might regulate HCC proliferation by activating p53 signaling. CONCLUSIONS: Our study suggests that ERCC6L plays an important role in HCC proliferation and that it might serve as a promising therapeutic target in HCC.

Cyclin B2 Overexpression in Human Hepatocellular Carcinoma is Associated with Poor Prognosis.

BACKGROUND AND AIMS: Cyclin B2 (CCNB2) has been reported to be highly expressed in a few malignancies. However, the biological function of CCNB2 in hepatocellular carcinoma (HCC) is largely unknown. We aimed to investigate the effect of CCNB2 in HCC. METHODS: The expression of CCNB2 in HCC and normal liver tissues and connection of its expression with prognosis and clinical parameters were studied. The effect of knocking down CCNB2 on cell proliferation, migration, cell cycle distribution, and apoptosis were estimated in BEL-7404 cells. RESULTS: Compared to normal liver tissues, the level of CCNB2 was higher in HCC tissues from the Gene Expression Profiling Interactive Analysis (GEPIA). The 5 year overall survival and disease-free survival of HCC patients with high CCNB2 levels were shorter than that of those with low CCNB2 levels. Immunohistochemistry analysis also discovered the expression differences of CCNB2 in HCC and normal liver tissues and showed that CCNB2 expression was significantly associated with tumor number, tumor size, tumor thrombus, and alanine aminotransferase level. CCNB2 expression was higher in HCC cell lines (BEL-7404, Hep3B, BEL-7402, and SMMC-7721) than that in the normal hepatic cell line (HL-7702). Knockdown of CCNB2 inhibited cell proliferation and migration, promoted cell apoptosis, and caused S phase arrest in BEL-7404 cells. Finally, CCNB2 was associated with Polo Like Kinase 1 (PLK1) in the GEPIA database and BEL-7404 cells. CONCLUSIONS: CCNB2 may serve as a prognostic factor and participated in the development and progression and promote cell proliferation and migration through CCNB2/PLK1 pathway in HCC.

Thrombospondin-4 expression as a prognostic marker in hepatocellular carcinoma.

BACKGROUND AND AIMS: The extracellular calcium-binding protein family member thrombospondin-4 (THBS4) regulates cell migration, proliferation, attachment, adhesion, angiogenesis, neural development, tissue structure, organ development, pain signal transduction, and tumor growth. The aim of this study was to study THBS4 expression in hepatocellular carcinoma (HCC) and determine if it was a prognostic marker for this malignancy. METHODS: We used immunohistochemistry and tissue microarrays to evaluate THBS4 expression in 84 HCC and matched para-cancerous tissues. Then, we assessed relationships between THBS4 expression and clinicopathological parameters. RESULTS: THBS4 expression was higher in HCCs than in matched para-cancerous tissues (P < 0.001). There was a significant correlation between high THBS4 levels and preoperative serum alanine aminotransferase (P < 0.04). In HCC patients, high THBS4 expression was associated with shorter overall and disease-free survival compared with low THBS4 expression. Additionally, subgroup analysis showed that high THBS4 levels were only associated with poor overall survival for alpha-fetoprotein >40 ng/mL (P = 0.028) and cirrhosis (P = 0.002). Multivariate analysis showed that high THBS4 expression was an independent prognostic factor for both overall and disease-free survival. CONCLUSIONS: Our data suggest that THBS4 may play a role in HCC development, and thus may be an independent prognostic marker and/or potential therapeutic target for HCC patients.

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF-κB pathway and ROS signaling.

Casticin, a compound purified from the Chinese herb Viticis Fructus, has been proven effective in preventing tumor progression in previous studies. Ulcerative colitis (UC) is a common inflammatory bowel disease that affects millions of people worldwide, but no effective and safe drugs are available. In this study, we aimed to study how did casticin affect UC by evaluating its effects on dextran sulfate sodium (DSS)-induced colitis in mice. Our data suggested that casticin attenuated body weight loss, colon length shortening, and pathological damage in the colon of DSS-treated mice. Casticin decreased reactive oxygen species level and chemocytokines (IL-1ß, IL-6, TNF-α) productions in colon tissue. The decreased reactive oxygen species level and suppressed proinflammatory cytokines productions were also confirmed in casticin-treated LPS-stimulated RAW264.7 cells and hydrogen peroxide-treated CACO-2 cells in vitro. Mechanistically, casticin treatment prevented the profound activation of AKT signaling caused by DSS administration. And casticin inhibited the productions of proinflammatory chemocytokines through downregulating AKT/NF-κB pathway in macrophages. Meanwhile, data revealed that casticin increased expressions of endogenous antioxidants peroxiredoxin 3 and MnSOD were through activation in FOXO3α signaling by downregulating AKT signaling in colon epithelium cells. Our findings demonstrated that casticin alleviated DSS-induced UC by increasing the antioxidant enzyme peroxiredoxin 3 and MnSOD expressions, and decreasing the production of proinflammatory chemocytokines through inhibition of AKT signaling.

Liang-Ge-San, a classic traditional Chinese medicine formula, protects against lipopolysaccharide-induced inflammation through cholinergic anti-inflammatory pathway.

Liang-Ge-San (LGS) is a classic formula in traditional Chinese medicine, which is widely used to treat acute lung injury (ALI), pharyngitis and amygdalitis in clinic. However, the underlying mechanisms remain poorly defined. In this study, we discovered that LGS exerted potent anti-inflammatory effects in lipopolysaccharide (LPS)-induced inflammation. We found that LGS significantly depressed the production of IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophage cells. The degradation and phosphorylation of IκBα and the nuclear translocation of NF-κB p65 were also inhibited. Moreover, LGS activated α7 nicotinic cholinergic receptor (α7nAchR). The blockage of α7nAchR by selective inhibitor methyllycaconitine (MLA) or α7nAchR siRNA attenuated the inhibitory effects of LGS on IκBα, NF-κB p65, IL-6 and TNF-α. Critically, LGS significantly inhibited inflammation in LPS-induced ALI rats through the activation of NF-κB signaling pathway. However, these protective effects could be counteracted by the treatment of MLA. Taken together, we first demonstrated anti-inflammatory effects of LGS both in vitro and in vivo through cholinergic anti-inflammatory pathway. The study provides a rationale for the clinical application of LGS as an anti-inflammatory agent and supports the critical role of cholinergic anti-inflammatory pathway in inflammation.