ROS-mediated NRF2/p-ERK1/2 signaling-involved mitophagy contributes to macrophages activation induced by CdTe quantum dots.

Cadmium telluride (CdTe) quantum dots (QDs) have garnered significant attention for tumor imaging due to their exceptional properties. However, there remains a need for further investigation into their potential toxicity mechanisms and corresponding enhancements. Herein, CdTe QDs were observed to accumulate in mouse liver, leading to a remarkable overproduction of IL-1ß and IL-6. Additionally, there was evidence of macrophage infiltration and activation following exposure to 12.5 µmol/kg body weight of QDs. To elucidate the underlying mechanism of macrophage activation, CdTe QDs functionalized with 3-mercaptopropionic acid (MPA) were utilized. In vitro experiments revealed that 1.0 µM MPA-CdTe QDs activated PINK1-dependent mitophagy in RAW264.7 macrophages. Critically, the autophagic flux remained unimpeded, as demonstrated by the absence of p62 accumulation, LC3 turnover assay results, and successful fusion of autophagosomes with lysosomes. Mechanically, QDs increased reactive oxygen species (ROS) and mitoROS by damaging both mitochondria and lysosomes. ROS, in turn, inhibited NRF2, resulting in the phosphorylation of ERK1/2 and subsequent activation of mitophagy. Notably, 1.0 µM QDs disrupted lysosomes but autophagic flux was not impaired. Eventually, the involvement of the ROS-NRF2-ERK1/2 pathway-mediated mitophagy in the increase of IL-1ß and IL-6 in macrophages was confirmed using Trolox, MitoTEMPO, ML385, specific siRNAs, and lentivirus-based interventions. This study innovatively revealed the pro-inflammatory rather than anti-inflammatory role of mitophagy in nanotoxicology, shedding new light on the mechanisms of mitochondrial disorders induced by QDs and identifying several molecular targets to comprehend the toxicological mechanisms of CdTe QDs.

Low-dose cadmium telluride quantum dots trigger M1 polarization in macrophages through mTOR-mediated transcription factor EB activation.

The increasing application of quantum dots (QDs) increases interactions with organisms. The inflammatory imbalance is a significant manifestation of immunotoxicity. Macrophages maintain inflammatory homeostasis. Using macrophages differentiated by phorbol 12-myristate 13-acetate-induced THP-1 cells as models, the study found that low-dose (5 µM) cadmium telluride QDs (CdTe-QDs) hindered monocyte-macrophage differentiation. CD11b is a surface marker of macrophage, and the addition of CdTe-QDs during induction resulted in a decrease in CD11b expression. Moreover, exposure of differentiated THP-1 macrophage (dTHP-1) to 5 µM CdTe-QDs led to the initiation of M1 polarization. This was indicated by the increased surface marker CD86 expression, along with elevated level of NF-κB and IL-1ß proteins. The potential mechanisms are being explored. The transcription factor EB (TFEB) plays a significant role in immune regulation and serves as a crucial regulator of the autophagic lysosomal pathway. After exposed to CdTe-QDs, TFEB activation-mediated autophagy and M1 polarization were observed to occur simultaneously in dTHP-1. The mTOR signaling pathway contributed to TFEB activation induced by CdTe-QDs. However, mTOR-independent activation of TFEB failed to promote M1 polarization. These results suggest that mTOR-TFEB is an advantageous target to enhance the biocompatibility of CdTe-QDs.

Protein corona exacerbated inflammatory response in macrophages elicited by CdTe quantum dots.

Nano-bio interface is significant concern in nanomedicine. When nanoparticles (NPs) come into contact with cells, they form complexes with proteins known as protein corona (PC). Cadmium telluride quantum dots (CdTe QDs) have been applied as bioimaging probes and for macrophage theragnostic. However, the impact of protein corona on the behavior of CdTe QDs is not well understood. Macrophages play a crucial role in defending against NPs. In this study, RAW264.7 cells were used to investigated the inflammatory response in macrophages when exposed to CdTe QDs before and after PC formation in fetal bovine serum. The results indicated that protein corona polarized more macrophages towards M1 phenotype. Transcriptomics analysis revealed that PC-CdTe QDs altered a greater number of differentially expressed genes (DEGs) compared to CdTe QDs (177 and 398) at 1.0 µM in macrophages. The DEGs affected by PC-CdTe QDs contained several personalized inflammatory cytokines. The enriched pathways after PC formation included Cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and TNF signaling pathway, etc. Furthermore, PC specifically exacerbated the overexpression of CCL2 and IL-1ß proteins. Importantly, PC altered the mechanism of CdTe QD-induced pyroptosis, shifting it from activating NLRC4 to both NLRP1 and NLRP3 inflammasomes, and from cleaving GSDMD and GSDMB to GSDMB alone. Overall, protein corona exacerbated the inflammatory response induced by CdTe QDs in macrophages. This study provides valuable insight into the pro-inflammatory effect of protein corona on CdTe QDs, with implications for their use in bioimaging or macrophage theragnostic by either exploiting or eliminating this biological interface effect.

Global Burden of Digestive Diseases: A Systematic Analysis of the Global Burden of Diseases Study, 1990 to 2019.

BACKGROUND & AIMS: This study assessed the worldwide burden of digestive diseases between 1990 and 2019. METHODS: We analyzed data from the Global Burden of Diseases study, covering 18 digestive diseases across 204 countries and territories. Key disease burden indicators, including incidence, prevalence, mortality, and disability-adjusted life years (DALYs), were studied. Linear regression analysis was applied to the natural logarithm of age-standardized outcomes to determine the annual percent change. RESULTS: In 2019, there were 7.32 billion incidents and 2.86 billion prevalent cases of digestive diseases, resulting in 8 million deaths and 277 million DALYs lost. Little to no decrease in global age-standardized incidence and prevalence of digestive diseases was observed between 1990 and 2019, with 95,582 and 35,106 cases per 100,000 individuals in 2019, respectively. The age-standardized death rate was 102 per 100,000 individuals. Digestive diseases accounted for a significant portion of the overall disease burden, with more than one-third of prevalent cases having a digestive etiology. Enteric infections were the primary contributor to incidence, death, and DALYs lost, whereas cirrhosis and other chronic liver diseases had the highest prevalence rate. The burden of digestive diseases was inversely related to the sociodemographic index, with enteric infections being the predominant cause of death in low and low-middle quintiles and colorectal cancer in the high quintile. CONCLUSIONS: Despite significant reductions in deaths and DALYs due to digestive diseases from 1990 to 2019, they remain prevalent. A significant disparity in the burden of digestive diseases exists among countries with different development levels.

Global increase of colorectal cancer in young adults over the last 30 years: an analysis of the Global Burden of Disease Study 2019.

OBJECTIVES: The US Preventive Services Task Force lowered the recommended starting age for colorectal cancer (CRC) screening in average-risk adults from 50 to 45 years. We aimed to estimate the global burden and trends of colorectal cancer in adults aged 20-49 years (early-onset CRC). METHODS: This is an analysis of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). The GBD 2019 estimation methods were used to describe the incidence, mortality, and disability-adjusted life years (DALYs) of early CRC from 1990 to 2019. Data from 204 countries and geographic areas were available. RESULTS: The global incidence rate of early-onset CRC increased from 4.2/100 000 to 6.7/100 000 from 1990 to 2019. Mortality and DALYs of early-onset CRC also increased. The CRC incidence rate increased faster in younger adults (1.6%) than in adults aged 50-74 years (0.6%) as measured by the annual percentage change. The increase in early-onset CRC incidence was consistently observed in all five socio-demographic index (SDI) regions and 190 out of 204 countries and territories. Middle and high-middle SDI regions had faster annual increases in early-onset CRC, which warrants further attention. CONCLUSIONS: The global incidence, mortality, and DALYs of early-onset CRC increased from 1990 to 2019. The increase in early-onset CRC incidence was prevalent worldwide. Several countries were found to have higher incidence rates than the United States or fast increase in early-onset CRC, which warrants further attention.

Characteristics of myeloproliferative neoplasm-associated portal hypertension and endoscopic management of variceal bleeding.

Background: Myeloproliferative neoplasms (MPNs) are a rare yet important clinical cause of portal hypertension, which may cause recurrent gastroesophageal variceal bleeding (GVB). MPN-associated variceal bleeding lacks specific guidelines and clinical consensus and desiderates cohort studies. We performed a multicenter retrospective study to investigate the efficacy of endoscopic management of bleeding in MPNs. Methods: We included consecutive MPN patients with gastroesophageal varices in eight tertiary university hospitals between January 2007 and March 2020. The clinical characteristics of participants were summarized. MPN patients with a history of GVB were followed up for the rebleeding and death, compared with controls suffering from schistosomiasis-associated portal hypertension who received endoscopic treatment for variceal bleeding at the same period. Results: A total of 62 MPN patients with gastroesophageal varices were identified, and 37 had a history of GVB. Of these, 24 patients received endoscopic variceal ligation and endoscopic injection of cyanoacrylate for the prophylaxis of variceal rebleeding. Endoscopic treatment significantly reduced the rebleeding rate in MPN patients with a history of GVB (28.2% versus 68.3%, p = 0.0269). Multivariable Cox regression indicated that endoscopic treatment (HR = 0.10, 95% CI: 0.02-0.54, p = 0.008) was the independent protective factor for decreasing the 3-year rebleeding rate, while the use of non-selective beta-blockers (NSBB) (HR = 13.41, 95% CI: 2.15-83.42, p = 0.005) was the risk factor for increasing the 3-year rebleeding rate. As for the efficacy of endoscopic management, 3-year rebleeding rate was significantly lower in MPN patients in contrast to 46 controls with schistosomiasis-associated variceal bleeding (32.9% versus 59.0%, p = 0.0346). Conclusion: Endoscopic treatment might be a feasible and potent approach in the management of gastroesophageal variceal rebleeding in MPNs, while NSBB might be ineffective.

CdTe quantum dots trigger oxidative stress and endoplasmic reticulum stress-induced apoptosis and autophagy in rat Schwann cell line RSC96.

In the current study, the cytotoxicity and mechanisms of cadmium telluride quantum dots (CdTe QDs) on RSC96 cells were evaluated by exposing different doses of CdTe QDs for 24 h. Two types of cell death, including apoptosis and autophagy, as well as two important organelles, mitochondria and endoplasmic reticulum, were focused after CdTe QDs exposure. The results showed that CdTe QDs induced apoptosis in RSC96 cells in a concentration-dependent manner; promoted the accumulation of intracellular reactive oxygen species; decreased the mitochondrial membrane potential; caused the release of cytochrome c; and also increased the expression of Bcl-2 associated X protein, caspase-3, and cytochrome c proteins and decreased the expression of Bcl-2 protein. Further results also confirmed that CdTe QDs could be internalized by RSC96 cells, and the exposure and internalization of CdTe QDs could induce excessive endoplasmic reticulum stress in the cells, and the expression levels of binding immunoglobulin protein, C/EBP homologous protein, and caspase12 proteins were increased in a concentration-dependent manner. Moreover, autophagy-related proteins LC3II, Beclin1, and P62 all increased after CdTe QDs exposure, suggesting that CdTe QDs exposure both promoted autophagosome formation and inhibited autophagosome degradation, and that CdTe QDs affected the autophagic flow in RSC96 cells. In conclusion, CdTe QDs are able to cause apoptosis and autophagy in RSC96 cells through mitochondrial and endoplasmic reticulum stress pathways, and the possible neurotoxicity of CdTe QDs should be further investigated.

Protein corona mitigated the cytotoxicity of CdTe QDs to macrophages by targeting mitochondria.

Despite the potential of cadmium telluride quantum dots (CdTe QDs) in bioimaging and drug delivery, their toxic effects have been documented. It is known that the immunotoxicity of CdTe QDs targeting macrophages is one of their adverse effects, and the protein corona (PC) will affect the biological effects of QDs. In order to prove whether the PC-CdTe QDs complexes could alleviate the toxicity of CdTe QDs without weakening their luminescence, we investigated the impact of protein corona formed in fetal bovine serum (FBS) on the cytotoxicity of CdTe QDs to mitochondria. RAW264.7 cells were used as the model to compare the effects of CdTe QDs and PC-CdTe QDs complexes on the structure, function, quantity, morphology, and mitochondrial quality control of mitochondria. As result, the protein corona form in FBS alleviated the inhibition of CdTe QDs on mitochondrial activity, the damage to mitochondrial membrane, the increase of ROS, and the reduction of ATP content. Also, CdTe QDs increased the number of mitochondria in macrophages, while the complexes did not. In line with this, the morphology of mitochondrial network in macrophages which were exposed to CdTe QDs and PC-CdTe QDs complexes was different. CdTe QDs transformed the network into fragments, punctuations, and short rods, while PC-CdTe QDs complexes made the mitochondrial network highly branched, which was related to the imbalance of mitochondrial fission and fusion. Mechanically, CdTe QDs facilitated mitochondrial fission and inhibited mitochondrial fusion, while protein corona reversed the phenomenon caused by QDs. Besides mitochondrial dynamics, mitochondrial biogenesis and mitophagy were also affected. CdTe QDs increased the expression of mitochondrial biogenesis signaling molecules including PGC-1α, NRF-1 and TFAM, while PC-CdTe QDs complexes played the opposite role. With regard to mitophagy, they both showed promoting effect. In conclusion, the formation of protein corona alleviated the toxic effects of CdTe QDs on the mitochondria in macrophages and affected mitochondrial quality control. Under the premise of ensuring the fluorescence properties of CdTe QDs, these findings provided useful insight into reducing the toxicity of CdTe QDs from two perspectives: protein corona and mitochondria, and shared valuable information for the safe use of QDs.

The role of ferroptosis mediated by NRF2/ERK-regulated ferritinophagy in CdTe QDs-induced inflammation in macrophage.

Cadmium telluride quantum dots (CdTe QDs) exist in the environment due to the abandonment of products. There is a potential risk to organisms and toxic mechanism is worth exploring. In this study, 12.5 µmol/Kg body weight CdTe QDs triggered systemic and local inflammatory response in mice and activated macrophages, then the mechanism of activating macrophages to overexpress IL-1ß and IL-6 was explored. RAW264.7 macrophages were used, and after macrophages exposing to 1 µM CdTe QDs for 24 h, oxidative stress occurred. Further investigation found that CdTe QDs triggered ferroptosis in RAW264.7 cells. And deferoxamine mesylate alleviated the excessive lipid hydroperoxide caused by QDs. Mechanistically, CdTe QDs-provoked decrease of nuclear factor erythroid 2-related factor 2 (NRF2) elicited phosphorylation of extracellular regulated protein kinases1/2 (ERK1/2) and then activated ferritinophagy, which made ferritin heavy chain 1 (FTH1) degraded in lysosome and proteasome to release free iron ions to initiate ferroptosis in macrophages. This paper updates the mechanism of macrophage activation by CdTe QDs with regard to ferritinophagy, and more importantly, identifies the key role of NRF2 and ERK1/2. Our research extends the role of ferroptosis in inflammatory responses triggered by nanoparticles (NPs) in macrophages and provides insightful reference for toxicity assessment of NPs.

Urban fine particulate matter causes cardiac hypertrophy through calcium-mediated mitochondrial bioenergetics dysfunction in mice hearts and human cardiomyocytes.

In recent years, the cardiovascular toxicity of urban fine particulate matter (PM2.5) has sparked significant alarm. Mitochondria produce 90% of ATP and make up 30% of the volume of cardiomyocytes. Thus knowledge of myocardial mitochondrial dysfunction due to PM2.5 exposure is essential for further cardiotoxic effects. Here, the mechanism of PM2.5-induced cardiac hypertrophy through calcium overload and mitochondrial dysfunction was investigated in vivo and in vitro. Male and female BALB/c mice were given 1.28, 5.5, and 11 mg PM2.5/kg bodyweight weekly through oropharyngeal inhalation for four weeks and were assigned to low, medium, and high dose groups, respectively. PM2.5-induced myocardial edema and cardiac hypertrophy were detected in the high-dose group. Mitochondria were scattered and ruptured with abnormal ultrastructural morphology. In vitro experiments on human cardiomyocyte AC16 showed that exposure to PM2.5 for 24 h caused opened mitochondrial permeability transition pore --leading to excessive calcium production, decreased mitochondrial membrane potential, weakened mitochondrial respiratory metabolism capacity, and decreased ATP production. Nevertheless, the administration of calcium chelator ameliorated the mitochondrial damage in the PM2.5-treated group. Our in vivo and in vitro results confirmed that calcium overload under PM2.5 exposure triggered mTOR/AKT/GSK-3ß activation, leading to mitochondrial bioenergetics dysfunction and cardiac hypertrophy.

Gastrointestinal Endoscopy and the Risk of Prosthetic Joint Infection: A Nationwide Database Analysis.

BACKGROUND: Current guidelines suggest antibiotics prophylaxis is not necessary for patients with orthopedic prosthetics undergoing gastrointestinal endoscopy. Clinical evidence to support this recommendation is lacking. AIMS: To analyze the association between inpatient gastrointestinal endoscopy and prosthetic joint infection (PJI) in patients with a recent arthroplasty. METHODS: We included patients admitted from July to October of each calendar year (index admissions) who had an arthroplasty in the same calendar year prior to the index admission. We followed the occurrence of PJI for 60 days after the index admission. Only admissions from July to October were chosen as index admissions, and the follow-up period was limited to 60 days because the database structure prohibits the analysis of events in different calendar years. We compared the rate of 60-day PJI between those who had gastrointestinal endoscopy on index admissions to those who had not. We excluded patients aged less than 18 years, who died on index admission, or had any infection in the same calendar year before or during the index admission. RESULTS: Of 1,831,218 patients with arthroplasty, 88,345 met the inclusion criteria, out of which 5,855 had gastrointestinal endoscopy. The rate of 60-day PJI in those who had endoscopy was 0.23%, and in those who had not was 0.52% (P < 0.001). EGD without excision (adjusted odds ratio [95% confidence interval]: 0.20 [0.03-1.42], P = 0.107), EGD with excision (0.58 [0.21-1.60], P = 0.295), colonoscopy without excision (0.43 [0.11-1.72], P = 0.233), colonoscopy with excision (0.31 [0.04-2.21], P = 0.241), and PEG/PEJ (0.38 [0.05-2.71], P = 0.337) were not associated with risk of 60-day PJI. We found no PJI cases in patients underwent esophageal dilation, ERCP, and EUS with FNA. CONCLUSIONS: Gastrointestinal endoscopy in hospitalized patients with a recent previous arthroplasty is not associated with an increased risk of 60-day prosthetic joint infection.

SREBF2 triggers endoplasmic reticulum stress and Bax dysregulation to promote lipopolysaccharide-induced endothelial cell injury.

An increased lipopolysaccharide (LPS) level in patients with cirrhosis induced the dysregulation of sterol regulatory element-binding transcription factor 2 (SREBF2), which participated in the modulation of tumor inflammatory microenvironment. However, the role of SREBF2 in the LPS-induced injury of portal vein endothelium was scarcely reported. This study aimed to investigate the effects of SREBF2 on the LPS-induced injury to endothelial cells (ECs) in vitro and in vivo and explore the underlying mechanism. In this study, we found that LPS increased SREBF2 expression through activating the TLR4/JNK/c-Jun pathway and suppressed UBE2I-mediated SREBF2 sumoylation to enhance its transcriptional activity. The dysregulation of SREBF2 induced ER stress by increasing the intracellular cholesterol level and facilitated Bax expression to cause additional damage to LPS-induced ECs. As a potential intervention, miR590-3p negatively regulated SREBF2 expression and upregulated UBE2I expression by targeting TLR4, thus alleviating LPS-induced injury. These results suggest that LPS-induced SREBF2 triggered ER stress and promoted Bax expression to injure ECs, which was reversed by miR590-3p. The mechanisms of SREBF2 mediated LPS-induced endothelial injury of portal vein, which might be the therapeutic target for PVT development in cirrhosis patients. 1. LPS promoted SREBF2 expression by activating the TLR4/JNK/c-Jun pathway and suppressed UBE2I-mediated SREBF2 sumoylation to upregulate SREBF2 transcriptional activity 2. SREBF2-mediated ER stress and Bax expression involved in LPS-induced EC injury 3. miR590-3p decreased SREBF2 expression by targeting TLR4 and mitigated LPS-induced EC injury.

NADPH oxidases regulate endothelial inflammatory injury induced by PM2.5 via AKT/eNOS/NO axis.

Fine particulate matter (PM2.5 )-induced detrimental cardiovascular effects have been widely concerned, especially for endothelial cells, which is the first barrier of the cardiovascular system. Among potential mechanisms involved, reactive oxidative species take up a crucial part. However, source of oxidative stress and its relationship with inflammatory response have been rarely studied in PM2.5 -induced endothelial injury. Here, as a key oxidase that catalyzes redox reactions, NADPH oxidase (NOX) was investigated. Human umbilical vein endothelial cells (EA.hy926) were exposed to Standard Reference Material 1648a of urban PM2.5 for 24 h, which resulted in NOX-sourced oxidative stress, endothelial dysfunction, and inflammation induction. These are manifested by the up-regulation of NOX, increase of superoxide anion and hydrogen peroxide, elevated endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA) level, reduced nitric oxide (NO) production, and down-regulation of phosphorylation of endothelial NO synthase (eNOS) with increased levels of inducible NO synthase, as well as the imbalance between tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1), and changes in the levels of pro-inflammatory and anti-inflammatory factors. However, administration of NOX1/4 inhibitor GKT137831 alleviated PM2.5 -induced elevated endothelial dysfunction biomarkers (NO, ET-1, ADMA, iNOS, and tPA/PAI-1), inflammatory factors (IL-1ß, IL-10, and IL-18), and adhesion molecules (ICAM-1, VCAM-1, and P-selectin) and also passivated NOX-dependent AKT and eNOS phosphorylation that involved in endothelial activation. In summary, PM2.5 -induced NOX up-regulation is the source of ROS in EA.hy926, which activated AKT/eNOS/NO signal response leading to endothelial dysfunction and inflammatory damage in EA.hy926 cells.

Positive consequences of splenectomy for patients with schistosomiasis-induced variceal bleeding.

BACKGROUND: Patients with hepatic schistosomiasis are at high risk of gastroesophageal variceal bleeding, which is highly torrential and life threatening. This study aimed to assess the effects of splenectomy on patients with schistosomiasis-induced variceal bleeding, especially those influences related to overall survival (OS) rate. METHODS: From January 2005 to December 2018, 112 patients with schistosomiasis-induced varices were enrolled. In that period, all the patients with hepatic schistosomiasis who received endoscopic treatment for primary and secondary prophylaxis of gastroesophageal variceal bleeding were found eligible. The patients were divided into splenectomized group (n = 44, 39.3%) and control group (n = 68, 60.7%). RESULTS: Multivariate regression analysis of OS showed that splenectomy, hepatic carcinoma, and times of endoscopic treatment were independent prognostic factors for OS. Kaplan-Meier analysis revealed that the 5-year OS rate was 82.7% in splenectomized group versus 53.2% in control group (P = 0.037). The rate of no recurrence of variceal bleeding during 5-year (56.8% vs. 47.7%, P = 0.449) indicated that there was no significant difference between the two groups. Patients who received splenectomy had increased risk of portal vein thrombosis (52.3% vs. 29.4%, P = 0.012) and decreased proportion of severe ascites (20.5% vs 50.0%, P = 0.002). CONCLUSION: Splenectomy prior to endoscopic treatment provides a superior long-term survival for patients with schistosomiasis-induced variceal bleeding.

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer.

Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood. Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration, and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings. Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates, and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with ß-cyclodextrin (ß-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo, knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of ß-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs. Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

Endoscopic treatment of gastroesophageal variceal bleeding after oxaliplatin-based chemotherapy in patients with colorectal cancer.

BACKGROUND : Oxaliplatin, used as first-choice treatment for colorectal cancer (CRC), induces sinusoidal endothelial injury and portal hypertension. This study investigated the characteristics of oxaliplatin-induced portal hypertension and evaluated the efficacy of endoscopic management of gastroesophageal variceal bleeding. METHODS : We performed a retrospective, multicenter, case-control study between January 2010 and December 2018. Patients who received oxaliplatin-based chemotherapy after CRC surgery and presented with portal hypertension and gastroesophageal varices were compared with consecutive patients with hepatitis B-related cirrhotic portal hypertension receiving endoscopic treatment for variceal bleeding. RESULTS : 39 patients with oxaliplatin-induced portal hypertension were identified, 35 of whom had a history of variceal bleeding. The median period between start of oxaliplatin-based chemotherapy and the occurrence of varices was 50.4 months (n = 39). A total of 26 patients with oxaliplatin-related portal hypertension and 230 patients with hepatitis B-related portal hypertension underwent endoscopic treatment. Kaplan-Meier analysis revealed that the 1-year rebleeding rate was significantly higher in the oxaliplatin group than in the hepatitis B group (43.3 % vs. 19.0 %, P = 0.001). Multivariable Cox regression analysis showed that oxaliplatin-based chemotherapy was an independent factor for 3-year rebleeding (hazard ratio [HR] 2.46, 95 % confidence interval [CI] 1.24-4.87; P = 0.01) and 3-year overall mortality (HR 9.43, 95 %CI 2.32-38.31; P = 0.002). CONCLUSIONS : Oxaliplatin-related portal hypertension was characterized by massive ascites, splenomegaly, gastric varices, concomitant arterioportal fistula, and relatively normal liver function. Endoscopic treatment to prevent variceal rebleeding in these patients was unsatisfactory compared with endoscopic treatment for hepatitis B-related portal hypertension.

Systemic inflammation and portal vein thrombosis in cirrhotic patients with gastroesophageal varices.

BACKGROUND AND AIM: Cirrhotic patients with gastroesophageal varices and non-tumoral portal vein thrombosis have a higher risk of re-bleeding and poor prognosis. This study aimed to analyze inflammatory biomarkers and thromboelastography in cirrhotic patients with portal vein thrombosis. METHODS: A total of 385 consecutive cirrhotic patients with gastroesophageal varices were prospectively enrolled between 1 December 2016, and 31 August 2017. Of these, 231 were eligible for analysis and were divided into portal vein thrombosis (n = 103) and non-portal vein thrombosis (n = 128) groups based on computerized tomography angiography findings. RESULTS: Patients with portal vein thrombosis generally had higher Child-Pugh scores than those without portal vein thrombosis (6.38 ± 0.12 vs. 5.81 ± 0.09, P < 0.001). The serum albumin levels were significantly lower in patients with portal vein thrombosis (35.90 ± 0.52 vs. 38.52 ± 0.43, P < 0.001). The portal vein thrombosis group had significant higher serum levels of interleukin 6 [4.85 (3.15-6.99) vs. 3.09 (2.06-5.20) pg/ml, P < 0.001] and tumor necrosis factor alpha [10.70 (7.60-15.20) vs. 9.07 (7.03-11.60) pg/ml, P = 0.020]. The interleukin 6 level was 2.5-fold higher in patients with portal vein thrombosis (adjusted odds ratio: 2.574; 95% confidential interval: 1.248-5.310). Thromboelastography showed that TEG-R, the reaction time, was significantly lower in the portal vein thrombosis group [5.20 (4.80-6.30) vs. 6.00 (5.20-6.95), P = 0.009], indicating enhanced coagulation activity. CONCLUSION: This study confirmed the important role of systemic inflammation in portal vein thrombosis. Interleukin 6, an important inflammatory cytokine, is independently associated with portal vein thrombosis. The correlation between the interleukin 6 level and portal vein thrombosis requires further investigation.

Portal vein thrombosis prevalence and mortality among alcoholic cirrhosis in a nationwide inpatient cohort.

OBJECTIVES: Portal vein thrombosis is commonly associated with cirrhosis. The effect of alcoholic cirrhosis on portal vein thrombosis prevalence and mortality has not been well studied. METHODS: We conducted a retrospective cohort study utilizing the 2000-2014 National Inpatient Sample Database. We included patients older than 18 years with decompensated cirrhosis without a history of liver transplantation or hepatocellular carcinoma. We further identified patients with alcoholic cirrhosis vs. non-alcoholic cirrhosis. Primary outcomes included the risk and mortality of portal vein thrombosis in alcoholic cirrhosis. Secondary outcomes included trends of portal vein thrombosis prevalence and mortality in alcoholic cirrhosis, implications of portal vein thrombosis on complications in alcoholic cirrhosis vs. non-alcoholic cirrhosis, and risk of venous thromboembolism in alcoholic cirrhosis. RESULTS: Among 1 892 271 patients with decompensated alcoholic cirrhosis, portal vein thrombosis prevalence was 1.3%. Alcoholic cirrhosis was associated with lower risk of portal vein thrombosis (odds ratio 0.76, P < 0.001) and venous thromboembolism (odds ratio 0.69, P < 0.001) compared to non-alcoholic cirrhosis. Portal vein thrombosis contributed to increased mortality (odds ratio 1.19, P < 0.001) in alcoholic cirrhosis. Portal vein thrombosis prevalence among alcoholic cirrhosis increased while mortality declined during the study period. CONCLUSION: Thrombotic events including portal vein thrombosis and venous thromboembolism were found in less frequent association with alcoholic cirrhosis compared with non-alcoholic cirrhosis. Despite this, the higher in-hospital mortality found among portal vein thrombosis with alcoholic cirrhosis should prompt careful consideration of management.

Candidate lncRNA-miRNA-mRNA network in predicting hepatocarcinogenesis with cirrhosis: an integrated bioinformatics analysis.

PURPOSE: This study aimed to explore the potential competing endogenous RNA (ceRNA) network in forecasting HCC development in patients with cirrhosis through a comprehensive bioinformatic analysis. METHODS: Data mining from GEO and TCGA databases was employed to dig a spectrum of differentially expressed mRNA, lncRNA and miRNA profiles. Their expression was confirmed by RT-PCR in matched HCC cohorts (n = 6/group). The ceRNA network was constructed by co-expression analysis. Their reciprocal regulations and their roles in epithelial-to-mesenchymal transition (EMT) process were validated by gain- and loss-of-function experiments at the cellular level. Kaplan-Meier method was applied to reveal prognostic values. RESULTS: By intersecting differentially expressed genes (DEGs) in GEO and TCGA data sets and Pearson correlation analysis, 20 mRNAs, 24 miRNAs and 41 lncRNAs were identified. Of these, FOXD2-AS1, BLVRA and CYTH2 were markedly upregulated in HCC tissues and HCC cells with high metastatic potential (MHCC97H) compared with their adjacent normal/cirrhotic tissues and L02 and MHCC97L cells. However, dysregulated miR-139-5p exhibited the opposite expression pattern. Using miRanda algorithms, FOXD2-AS1, BLVRA and CYTH2 showed potential binding sites for miR-139-5p. FOXD2-AS1 knockdown induced a marked increase in miR-139-5p and EMT inhibition. The loss of miR-139-5p led to an increase in BLVRA and CYTH2 expression and EMT process. Conversely, miR-139-5p overexpression suppressed BLVRA and CYTH expression and EMT process. FOXD2-AS1, miR-139-5p, BLVRA and CYTH2 highly correlated with prognosis in patients with HCC. CONCLUSION: FOXD2-AS1/miR-139-5p/BLVRA or CYTH2 axis might be the underlying molecular mechanism that dissects HCC development caused by cirrhosis.

Improved survival with radiotherapy in hepatocellular carcinoma with major vascular invasion: A propensity-matched analysis of Surveillance, Epidemiology, and End Results database.

OBJECTIVES: Hepatocellular carcinoma (HCC) associated with major vascular invasion is an advanced stage disease with an extremely poor prognosis and low survival rate. Our study evaluated the survival benefit of radiotherapy (RT) in HCC patients with major vascular invasion through Surveillance, Epidemiology, and End Results database. METHODS: We analyzed 3181 HCC patients with major vascular invasion cases diagnosed from 2004 to 2013. Patients (N = 308) who underwent RT and patients (N = 2873) who did not receive RT were compared. We successfully analyzed patients using propensity score matching (PSM). Kaplan-Meier and Cox-regression analyses were applied to assess prognosis. RESULTS: The median survival time in radiation-treated group was longer compared to the control group (7 months vs 3 months; P < 0.001) in the overall sample and 3 months longer compared to the control group (7 months vs 4 months; P < 0.001) in a PSM cohort. Cox-regression analyses showed that radiation-treated patients in propensity-matched sample had a significantly lower risk of mortality (HR: 0.625, 95% CI: 0.522-0.749, P < 0.001) compared with untreated patients. The radiation-treated groups had better survival rate than untreated group. Subgroup analysis revealed that the survival time of patients in radiation-treated group was significantly longer than that in the untreated group (P < 0.001 and P = 0.026, respectively). The subgroup analysis also revealed that RT provides a survival benefit regardless of race, marital status, and tumor size after PSM. CONCLUSIONS: Radiotherapy provides improves survival in HCC patients with major vascular invasion, especially for tumor(s) confined to one lobe and not on surface of liver.