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Previous studies have shown that selenium possessed chemotherapeutic effect against multiple malignant cancers, inducing diverse stress responses including apoptosis and autophagy. Selenite was previously shown to induce apoptosis and autophagy in colorectal cancer cells. However, the relationship between selenite-induced apoptosis and autophagy was not fully understood. Our results revealed a pro-survival role of selenite-induced autophagy against apoptosis in colorectal cancer cells. Real-time PCR array of autophagy-related genes showed that GABARAPL-1 was significantly upregulated in colorectal cancer cells, which was confirmed by western blot and immunofluorescence results. Knockdown of GABARAPL-1 significantly inhibited selenite-induced autophagy and enhanced apoptosis. Furthermore, we found that selenite-induced upregulation of GABARAPL-1 was caused by upregulated p-AMPK and FoxO3a level. Their interaction was correlated with involved in regulation of GABARAPL-1. We observed that activation and inhibition of AMPK influenced both autophagy and apoptosis level via FoxO3a/ GABARAPL-1 signaling, implying the pro-survival role of autophagy against apoptosis. Importantly, we corroborated these findings in a colorectal cancer xenograft animal model with immunohistochemistry and western blot results. Collectively, these results show that sodium selenite could induce ROS/AMPK/FoxO3a/GABARAPL-1-mediated autophagy and downregulate apoptosis in both colorectal cancer cells and colon xenograft model. These findings help to explore sodium selenite as a potential anti-cancer drug in clinical practices.

Background As a minimally invasive treatment for common bile duct (CBD) stones, ultrasound-guided percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) is gaining attention and recognition from the medical community. Methods A retrospective analysis was conducted on patients with CBD stones treated in our hospital from January 2016 to April 2022. Patients were divided into three groups: 77 treated with PTCSL, 93 with endoscopic retrograde cholangiopancreatography (ERCP), and 103 with laparoscopic common bile duct exploration (LCBDE). Their clinical data, perioperative indicators, and complications were analyzed comparatively. Then, risk factors for the post-PTCSL recurrence of CBD stones were analyzed by logistic regressions. Finally, the receiver operating characteristic curve was drawn. Results All perioperative indicators of the PTCSL group were better than the LCBDE group ( P  < 0.001). The incidences of cholangitis, hemobilia, and incisional infection after surgery were lower in the PTCSL group than in the LCBDE group ( P  < 0.05). Pancreatitis, reflux esophagitis, and papillary stenosis occurred less frequently in the PTCSL group than in the ERCP group ( P  < 0.05). Logistic regression analysis indicated that gallstones and family history were independent risk factors. The AUC for recurrent CBD stones predicted by multi-indicators was 0.895 (95% CI 0.792–0.999, P  < 0.001) with a sensitivity of 96.7% and specificity of 68.8%. Conclusions Ultrasound-guided PTCSL is a safe and effective treatment for CBD stones. Patients recovered quickly with fewer postoperative complications. It can be a first-line treatment for CBD stones. Gallstones and family history are independent risk factors for recurrent CBD stones, which provide a reference for clinicians in identifying the high-risk population needing close follow-up.

Sulfiredoxin 1 (SRXN1) is a pivotal regulator of the antioxidant response in eukaryotic cells. However, the role of SRXN1 in hepatocellular carcinoma (HCC) is far from clear. The present study aims to elucidate whether SRXN1 participates in tumorigenesis and metastasis of HCC and to determine the molecular mechanisms. We found that SRXN1 expression was up‐regulated in HCC tissue samples and correlated with poor prognosis in HCC patients. We also observed that SRXN1 knockdown by transient siRNA transfection inhibited HCC cell proliferation, migration and invasion. Overexpression of SRXN1 increased HCC cell migration and invasion. B‐cell translocation gene 2 (BTG2) was identified as a downstream target of SRXN1. Mechanistic studies revealed that SRXN1‐depleted reactive oxygen species (ROS) modulated migration and invasion of HCC cells. In addition, the ROS/p65/BTG2 signalling hub was found to regulate the epithelial‐mesenchymal transition (EMT), which mediates the pro‐metastasis role of SRXN1 in HCC cells. In vivo experiments showed SRXN1 promotes HCC tumour growth and metastasis in mouse subcutaneous xenograft and metastasis models. Collectively, our results revealed a novel pro‐tumorigenic and pro‐metastatic function of SRXN1 in HCC. These findings demonstrate a rationale to exploit SRXN1 as a therapeutic target effectively preventing metastasis of HCC.

BackgroundHepatectomy is a definitive treatment for hepatolithiasis because it simultaneously removes intrahepatic duct (IHD) stones and biliary tract strictures together with the involved liver region en bloc. Unlike cystic or solid liver tumors, hepatolithiasis is usually associated with alterations of anatomical structures and perihepatic adhesions because of chronic recurrent inflammation. This complicates identification of the target hepatic region and location of biliary strictures.MethodsTo determine the efficacy of near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG), we performed a comparative trial and developed a white-light and near-infrared dual-channel image-guided device (DPM-I) for both open and endoscopic surgery. Forty-four eligible patients were randomly assigned to Group A (NIRF imaging) or Group B (traditional hepatectomy). We injected ICG via peripheral veins for patients in Group A.ResultsThe NIRF imaging method was associated with less blood loss (OR 1.004, 95% CI 0.999–1.010; P = 0.016), briefer hospitalization (OR 1.336, 95% CI 1.016–1.756; P = 0.001), lower rates of margins with dilated bile ducts (OR 1.278, 95% CI 1.030–1.585; P = 0.023), lower postoperative white blood cell counts (OR 1.262, 95% CI 0.931–1.712; P = 0.038), lower procalcitonin levels (OR 1.316, 95% CI 1.020–1.513; P = 0.002), and lower alanine aminotransferase levels (OR 1.013, 95% CI 1.003–1.023; P = 0.002) compared with traditional hepatectomy.ConclusionsThese data demonstrate the efficacy of NIRF imaging with ICG using DPM-I for treating hepatolithiasis.

Liver cancer is one of the most common and lethal cancers in human digestive system, which kills more than half a million people every year worldwide. This study aimed to investigate the effects of kaempferol, a flavonoid compound isolated from vegetables and fruits, on hepatic cancer HepG2 cell proliferation, migration, invasion, and apoptosis, as well as microRNA-21 (miR-21) expression. Cell viability was detected using cell counting kit-8 (CCK-8) assay. Cell proliferation was measured using 5-bromo-2'-deoxyuridine (BrdU) incorporation assay. Cell apoptosis was assessed using Guava Nexin assay. Cell migration and invasion were determined using two-chamber migration (invasion) assay. Cell transfection was used to change the expression of miR-21. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to analyze the expressions of miR-21 and phosphatase and tensin homologue (PTEN). Expression of key proteins involved in proliferation, apoptosis, migration, invasion, and phosphatidylinositol 3-kinase/protein kinase 3/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway were evaluated using western blotting. Results showed that kaempferol significantly inhibited HepG2 cell proliferation, migration, and invasion, and induced cell apoptosis. Kaempferol remarkably reduce the expression of miR-21 in HepG2 cells. Overexpression of miR-21 obviously reversed the effects of kaempferol on HepG2 cell proliferation, migration, invasion, and apoptosis. Moreover, miR-21 negatively regulated the expression of PTEN in HepG2 cells. Kaempferol enhanced the expression of PTEN and inactivated PI3K/AKT/mTOR signaling pathway in HepG2 cells. In conclusion, kaempferol inhibited proliferation, migration, and invasion of HepG2 cells by down-regulating miR-21 and up-regulating PTEN, as well as inactivating PI3K/AKT/mTOR signaling pathway.

Background: Hepatocellular carcinoma (HCC) is a common malignancy around the world. The molecular mechanisms underlying HCC tumorigenesis and metastasis are far from clear. Numerous studies have pointed out that signal sequence receptor (SSR) is an endoplasmic reticulum-related protein involved in protein folding and processing of eukaryotic cells. SSR2 is a subunit of SSR protein, but the role of SSR2 in hepatocellular carcinoma is largely unknown and warrants further study. Materials and Methods: Several public databases were data mined to analyze the expression of four subunits of SSR between tumor and its peritumor counterparts. Also, the expression of SSR2 in our own collected tissues from HCC patients were analyzed by IHC and quantitative PCR. Survival analyses were conducted to delineate the prognostic value of SSR2. Clinical data were obtained followed by analysis based on SSR2 expression. Afterwards, cell proliferation, migration and invasion were detected by IncuCyte and trans-well assays, respectively. RNA interference was carried out by transfecting specific siRNA targeting SSR2 into cells using lipo2000. Western blot was applied to validate the knockdown effect and regulation on EMT-related proteins. Results: We examined the expression of SSR and its correlation with recurrence and survival of patients. We discovered that SSR2 overexpression was negatively associated with survival of HCC patients from TCGA databases and the mutation of SSR2 was most among the four subunits of SSR protein. Additionally, in this study, we collected tumor and adjacent tissues from 125 cases of HCC patients. Through constructing tissue microarray, we have identified that SSR2 was highly expressed in HCC tumor tissues compared with adjacent normal tissues of hepatocellular carcinoma patients by immunohistochemistry assays. Furthermore, Kaplan-Meier survival analysis from our collected tissues revealed that the overexpression of SSR2 was inversely correlated with disease free survival and overall survival of HCC patients. We elucidated that SSR2 promotes proliferation, migration and invasion of HCC cells. SSR2 knockdown suppressed epithelial mesenchymal transition (EMT) of HCC cells. Conclusions: These results collectively show that SSR2 is overexpressed in HCC tumor tissues, and it is an important factor in predicting survival of HCC patients. Additionally, it is involved in metastasis of HCC. These findings may help to exploit SSR2 as a novel factor in predicting prognosis and metastasis of HCC.

Background: Epirubicin (EADM) is a common chemotherapeutic agent in hepatocellular carcinoma (HCC). The accumulation of hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone or with other drugs. Some tanshinones mediate HIF-1[alpha] regulation via PI3K/AKT. However, the role of Tan I combined with EADM to reduce the resistance of HCC to EADM has not been investigated. Therefore, this study aimed to investigate the combined use of Tan I and EADM in HCC and the underlying mechanism of PI3K/AKT/HIF-1[alpha]. Methods: HCC cells were treated with Tan I, EADM, or the combined treatment for 48 hrs. Cell transfection was used to construct HIF-1[alpha] overexpression HCC stable cells. Cell viability, colony formation, and flow cytometric assays were used to detect the viability, proliferation, and apoptosis in HCC cells. Synergism between Tan I and EADM were tested by calculating the Bliss synergy score, positive excess over bliss additivism (EOBA), and the combination index (CI). Western blotting analyses were used to detect the levels of [beta]-actin, HIF-1[alpha], PI3K p1 10[alpha], p-Akt Thr308, Cleaved Caspase-3, and Cleaved Caspase-9. Toxicity parameters were used to evaluate the safety of the combination in mice. The xenograft model of mice was built by HCC stable cell lines, which was administrated with Tan I, EADM, or a combination of them for 8 weeks. Immunohistochemistry staining (IHC) was used to assess tumor apoptosis in mouse models. Results: Hypoxia could upregulate HIF-1[alpha] to induce drug resistance in HCC cancer cells. The combination of Tan I and EADM was synergistic. Although Tan I or EADM alone could inhibit HCC cancer cells, the combination of them could further enhance the cytotoxicity and growth inhibition by targeting the PI3K/AKT/HIF-1[alpha] signaling pathway. Furthermore, Tan I and EADM synergistically reversed HIF-1[alpha]-mediated drug resistance to inhibit HCC. The results of toxicity parameters showed that the combination was safe in mice. Meanwhile, animal models showed that Tan I not only improved the anti-tumor effect of EADM, but also reduced the drug reactions of EADM-induced weight loss. Conclusion: Our results suggested that Tan I could effectively improve the anti-tumor effect of EADM, and synergize EADM to reverse HIF-1[alpha] mediated resistance via targeting PI3K/AKT/HIF-1[alpha] signaling pathway. Keywords: hepatocellular carcinoma, epirubicin, Tanshinone I, HIF-1[alpha], resistance

Epirubicin (EADM) is a common chemotherapeutic agent in hepatocellular carcinoma (HCC). The accumulation of hypoxia-inducible factor-1α (HIF-1α) is an important cause of drug resistance to EADM in HCC. Tanshinone I (Tan I) is an agent with promising anti-cancer effects alone or with other drugs. Some tanshinones mediate HIF-1α regulation via PI3K/AKT. However, the role of Tan I combined with EADM to reduce the resistance of HCC to EADM has not been investigated. Therefore, this study aimed to investigate the combined use of Tan I and EADM in HCC and the underlying mechanism of PI3K/AKT/HIF-1α. HCC cells were treated with Tan I, EADM, or the combined treatment for 48 hrs. Cell transfection was used to construct HIF-1α overexpression HCC stable cells. Cell viability, colony formation, and flow cytometric assays were used to detect the viability, proliferation, and apoptosis in HCC cells. Synergism between Tan I and EADM were tested by calculating the Bliss synergy score, positive excess over bliss additivism (EOBA), and the combination index (CI). Western blotting analyses were used to detect the levels of β-actin, HIF-1α, PI3K p110α, p-Akt Thr308, Cleaved Caspase-3, and Cleaved Caspase-9. Toxicity parameters were used to evaluate the safety of the combination in mice. The xenograft model of mice was built by HCC stable cell lines, which was administrated with Tan I, EADM, or a combination of them for 8 weeks. Immunohistochemistry staining (IHC) was used to assess tumor apoptosis in mouse models. Hypoxia could upregulate HIF-1α to induce drug resistance in HCC cancer cells. The combination of Tan I and EADM was synergistic. Although Tan I or EADM alone could inhibit HCC cancer cells, the combination of them could further enhance the cytotoxicity and growth inhibition by targeting the PI3K/AKT/HIF-1α signaling pathway. Furthermore, Tan I and EADM synergistically reversed HIF-1α-mediated drug resistance to inhibit HCC. The results of toxicity parameters showed that the combination was safe in mice. Meanwhile, animal models showed that Tan I not only improved the anti-tumor effect of EADM, but also reduced the drug reactions of EADM-induced weight loss. Our results suggested that Tan I could effectively improve the anti-tumor effect of EADM, and synergize EADM to reverse HIF-1α mediated resistance via targeting PI3K/AKT/HIF-1α signaling pathway.

The spacecraft is becoming bigger and bigger. This development trend brings us a strict challenge for the leak detection of spacecrafts, especially for the total leakage rate leak detection. So it is important to study the total leakage rate leak detection technology of the large spacecraft. In this paper, an idea on large flexible accumulation chamber was provided to overcome this strict challenge. But at the same time it also brings two key problems to be solved. That is how to build the large flexible accumulation chamber for accommodating the large spacecraft and whether the mixed helium gas concentration on the height direction in this flexible accumulation chamber is uniform because helium is lighter than air. The feasibility on building the large flexible accumulation chamber for the total leakage rate leak detection of the large spacecraft was firstly analyzed. Secondly, the mixed helium gas distributing rules on the height direction in the large accumulation chamber was also given from the theoretic analysis. Finally, a large flexible accumulation chamber was built for the total leakage rate leak detection of the large spacecraft and the six times repeatability tests were also finished. The results here indicated that the six times repeatability tests owned a well consistency and the large flexible accumulation chamber was suitable for the total leakage rate leak detection of the large spacecraft.