The independent prognostic value of perioperative hepatic venous pressure gradient measurements in patients with portal hypertension who underwent laparoscopic splenectomy plus esophagogastric devascularization.

BACKGROUND: Hepatic venous pressure gradient (HVPG) is considered the gold standard for diagnosing portal hypertension (PHT). Laparoscopic splenectomy plus esophagogastric devascularization (LSED) is an important surgery for treating PHT. However, the variation trend of HVPG after surgery is not clear. Moreover, whether HVPG can provide precise prognostic information for patients undergoing surgery remains to be further studied. This study aimed to investigate the independent prognostic value of HVPG in LSED. METHODS: From January 2016 to March 2023, 135 patients with PHT underwent LSED at our hospital were retrospectively evaluated. We analyzed the correlations between clinical indicators and history of upper gastrointestinal bleeding (UGIB). Among them, 57 patients remeasured postoperative HVPG. We further investigated the postoperative alterations of HVPG and correlative factors, as well as the relationship between the HVPG and postoperative UGIB. RESULTS: In this study, we found that 94 patients with preoperative UGIB (16.27 ± 5.73 mmHg) had a higher baseline HVPG than the other 41 patients without (14.02 ± 5.90 mmHg) (p = 0.04). The mean postoperative HVPG significantly decreased (-3.57 ± 8.09 mmHg, p = 0.001) compared to the baseline, and 66% of patients (38/57) experienced a decreased HVPG-response after surgery. The baseline HVPG and preoperative CTP class B were associated with the decreased HVPG-response (p<0.05). Additionally, patients with postoperative HVPG decreased>20% from baseline exhibited better recurrent hemorrhage-free survival rates than those without (log-rank, p = 0.013). CONCLUSION: We found that LSED led to a significantly decreased HVPG, and patients with postoperative HVPG decreased >20% obtained better UGIB-free survival benefits than those without.

The learning curve of laparoscopic splenectomy and esophagogastric devascularization for portal hypertension with 10-year follow-up.

INTRODUCTION AND OBJECTIVES: Laparoscopic splenectomy and esophagogastric devascularization (LSED) are minimally invasive, effective, and safe in treating esophageal-fundic variceal bleeding with portal hypertension (PHT). The study aimed to assess the learning curve of LSED by cumulative summation (CUSUM) analysis. The 10-year follow-up data for LSED and open surgery were also examined. PATIENTS AND METHODS: Five hundred and ninety-four patients were retrospectively analyzed. Operation time, intraoperative blood loss, open operation conversion, and postoperative complications were selected as the evaluation indicators of surgical ability. The learning curve of LESD was assessed by the CUSUM approach. Patient features, perioperative indices, and 10-year follow-up data were examined. RESULTS: Totally 236 patients underwent open surgery, and 358 underwent LSED. Patient characteristics were similar between groups. The LSED patients experienced less intraoperative blood loss, fewer complications, and faster recovery compared to the open surgery cohort. The learning curve of LESD was maximal for a case number of 50. Preoperative general characteristics were comparable for both stages. But the skilled stage had decreased operation time, reduced blood loss, less postoperative complications, and better recovery compared to the learning stage. The LSED group had higher recurrent hemorrhage-free survival rate and increased overall survival in comparison with cases administered open surgery in the 10-year follow-up. Free-liver cancer rates were similar between two groups. CONCLUSIONS: About 50 cases are needed to master the LSED procedure. Compared to open surgery, LSED is a safer, feasible, and safe procedure for PHT patients, correlating with decreased rebleeding rate and better overall survival.

Downregulation of miR-20b-5p Contributes to the Progression of Liver Fibrosis via the STAT3 Signaling Pathway In Vivo and In Vitro.

BACKGROUND: Activated hepatic stellate cells (HSCs) are primarily involved in liver fibrosis and portal hypertension (PHT). We aimed to investigate the effect of miR-20b-5p on HSCs, liver fibrosis, and PHT. METHODS: MiR-20b-5p expression in HSCs and in mouse liver fibrosis was determined by qPCR. Further, the effects of miR-20b-5p mimic on HSCs migration, proliferation, and apoptosis were investigated in vitro. A dual-luciferase reporter assay was performed to confirm the direct interaction between miR-20b-5p and STAT3. In vivo, mouse liver fibrosis was established by common bile duct ligation and intervened by agomiR-20b-5p. Sirius red staining and hydroxyproline content were used to evaluate collagen deposition. The α-SMA expression in the liver was detected by IHC and Western blotting. The STAT3 signaling pathway and its downregulated cytokines as well as portal pressure and angiogenesis were explored. RESULTS: MiR-20b-5p was significantly downregulated during HSCs activation and in mouse liver fibrosis. The functional analyses demonstrated that miR-20b-5p inhibited cell proliferation, activation, and promoted apoptosis in HSCs in vitro. Moreover, miR-20b-5p regulated STAT3 expression by binding to the 3'UTR of its miRNA directly. Overexpression of miR-20b-5p facilitated HSC activation and proliferation by inhibiting the STAT3 signaling pathway. MiR-20b-5p overexpression suppressed the STAT3 and its downstream cytokines and ameliorated liver fibrosis in mice. The intra- and inter-hepatic angiogenesis were also effectively inhibited. The inhibition of liver fibrosis and neoangiogenesis contributed to the decrease of portal pressure. CONCLUSIONS: MiR-20b-5p plays an important role in the fibrosis and angiogenesis of liver fibrosis by targeting the STAT3 signaling pathway.

Erratum: PDLSCs Regulate Angiogenesis of Periodontal Ligaments via VEGF Transferred by Exosomes in Periodontitis: Erratum.

[This corrects the article DOI: 10.7150/ijms.40918.].

The severity of portal hypertension by a non-invasive assessment: acoustic structure quantification analysis of liver parenchyma.

BACKGROUND: Acoustic structure quantification (ASQ) has been applied to evaluate liver histologic changes by analyzing the speckle pattern seen on B-mode ultrasound. We aimed to assess the severity of portal hypertension (PHT) through hepatic ultrasonography. METHODS: Sixty patients diagnosed with PHT and underwent surgical treatment with portosystemic shunts were enrolled. Portal pressure (PP) was measured intraoperatively. Patients were divided into subgroups according to the severity of gastroesophageal varices and Child-Pugh class. Three difference ratio (Cm2) values on ASQ histogram mode were analyzed for their relationships with PP, degree of gastroesophageal varices and Child-Pugh liver function. Thirty healthy volunteers matched with the patients for gender and age were enrolled as controls. Comparisons among groups and correlation of the parameters with PP were analyzed. Area under the receive operating characteristic curve was used to evaluate the predicting value of ASQ parameters. RESULTS: In the patients, the ASQ parameters peak Cm2 (Cm2max), mean Cm2 (Cm2mean) and the highest occurred Cm2 value of the obtained red curve (RmaxCm2) were all greatly increased (P < 0.0001, P < 0.0001, P = 0.027). Multiple comparisons indicated that, regardless of Child-Pugh class and degree of gastroesophageal varices, the patients had significantly increased Cm2max and Cm2mean compared with the controls (all P < 0.0001). No differences among subgroups were observed. Cm2max was significantly statistically correlated with PP (r = 0.3505, P < 0.01), degree of varices (r = 0.4998, P < 0.0001). Youden's index for Cm2max with a cut-off value of 140.3 for predicting the presence of PHT, gastroesophageal varices and liver function equal to or worse than Child-Pugh class B were 0.8, 0.91 and 0.84, respectively. CONCLUSIONS: ASQ analysis of ultrasonographic images may have a role in the evaluation of the severity of PHT by detecting liver histologic changes in the speckle pattern caused by cirrhosis.

PDLSCs Regulate Angiogenesis of Periodontal Ligaments via VEGF Transferred by Exosomes in Periodontitis.

Abnormal angiogenesis is one of the significant features in periodontitis leading to progressive inflammation, but angiogenic changes of periodontal ligaments under inflammatory condition were rarely reported. Periodontal ligament stem cells (PDLSCs) were a kind of dental stem cells associated with vascularization. Here we investigated the alteration of angiogenesis of periodontal ligament in periodontitis, and revealed an exosome-mediated pathway to support the effect of PDLSCs on angiogenic improvement. Vascular specific marker CD31 and VEGFA were found to be highly expressed in periodontal ligaments of periodontitis. The VEGFA expression was up-regulated in inflamed PDLSCs compared to control, meanwhile the tube formation of HUVECs was improved when co-cultured with inflamed PDLSCs. Exosomes secretion of PDSLCs was augmented by inflammation, and promoted angiogenesis of HUVECs, whereas blocking secretion of exosomes led to degenerated angiogenesis of HUVECs. Exosome-trasferred VEGFA was proven to be the crucial communicator between PDLSCs and HUVECs. Inflammation inhibited miR-17-5p expression of PDLSCs and relieved its target VEGFA. However, overexpression of miR-17-5p blocked the pro-angiogenic ability of inflamed PDLSCs. In conclusion, the findings indicated that vascularization of periodontal ligaments was enhanced, and inflammatory micro-environment of periodontitis facilitated pro-angiogenesis of PDLSCs through regulating exosome-mediated transfer of VEGFA, which was targeted by miR-17-5p.

Combined administration of propranolol + AG490 offers better effects on portal hypertensive rats with cirrhosis.

BACKGROUND AND AIMS: AG490, the specific inhibitor of JAK2/STAT3 signaling, has been shown to decrease portal pressure, splanchnic hyperdynamic circulation and liver fibrosis in cirrhotic rats. Nonselective betablockers such as propranolol are the only drugs recommended in the treatment of portal hypertension. The aim of this study was to explore the combinative effect of treatment with propranolol and AG490 on portal hypertension. METHODS: Rats induced by common bile duct ligation were treated with vehicle, AG490, propranolol, or AG490 + propranolol for 2 weeks. Hemodynamics parameters were assessed. Expressions of phospho-STAT3 protein and its down-regulated cytokines in splanchnic organs were detected by ELISA or western blot. Lipopolysaccharide binding protein (LBP) and IL-6 were assessed by ELISA or western blot. Characterization of liver and mesentery was performed by histological analyses. RESULTS: Highly expressed phospho-STAT3 protein in cirrhotic rats could successfully be inhibited by AG490 or AG490 + propranolol treatments but not by propranolol alone. Both AG490 and propranolol significantly reduced portal pressure and hyperdynamic splanchnic circulation, and combination of AG490 and propranolol achieved an additive effect than with either drug alone. AG490, alone or in combination with propranolol, inhibited liver fibrosis, splenomegaly and splanchnic angiogenesis. Increased markers of bacterial translocation (LBP and IL6) were greatly reduced by propranolol but not by AG490. CONCLUSIONS: The combination of propranolol and AG490 caused a greater improvement of portal hypertension and might therefore offer a potentially promising therapy in the portal hypertension treatment.

Evaluation of carotid artery elasticity changes in patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes is one of the most common causes of cardiovascular disease as it causes arterial stiffness changes. The purpose of this study is to characterize, in vivo, carotid arterial structural and functional changes by applying radio frequency and X-strain ultrasound techniques. METHODS: Ninety-one subjects were assigned into two groups; a diabetes group and a control group. Structural and functional changes in the common carotid arterial wall were investigated by quality intima-media thickness (QIMT), quality arterial stiffness (QAS), and X-strain analysis with a Mylab Twice ultrasound instrument. The relationships among variables between the two groups were analyzed in this study. RESULTS: There was no significant difference in carotid IMT (626.5 ± 169.1 µm vs. 568.5 ± 122.6 µm, P = 0.1506) between two groups. Pulse wave velocity (PWV) and stiffness index (ß) were remarkably greater (8.388 ± 3.254 m/s vs. 7.269 ± 1.332 m/s; 12.51 ± 14.16 vs.9.279 ± 2.871), while compliance coefficient (CC) decreased significantly in the diabetes group (0.802 ± 0.3094 mm2/Kpa vs. 0.968 ± 0.3992 mm2/Kpa) (P < 0.05). The displacement difference of radial (RD-D), longitudinal (LD-D) and rotation (ROT-D) directions were significantly different between two groups' comparison (P = 0.0212, P = 0.0235 and P = 0.0072, respectively). The time of circumferential peak strain difference (CS-DT) and the time of radial peak strain rate (RSR-T) were found to be significantly different between the two groups (341.9 ± 77.56 ms vs. 369.0 ± 78.26 ms, P = 0.0494; 142.7 ± 22.43 ms vs. 136.2 ± 30.70 ms, P = 0.0474). CS-TD and RSR-T were also found to be positively correlated with CC value (r = 0.3908, P < 0.005 and r = 0.3027, P = 0.0326, respectively). Finally, PWV was negatively correlated with CC with (r = -0.6177, P < 0.001). CONCLUSIONS: In type 2 diabetes, the functional changes in CCA can be identified using the methods presented in this article earlier than the structural changes. Arterial stiffness values provided by QAS and X-strain analysis can be used as indicators of CCA functional lesions in patients with type 2 diabetes.

A PROTAC Augmenter for Photo-Driven Pyroptosis in Breast Cancer.

Proteolysis targeting chimera (PROTAC) has recently emerged as a promising strategy for inducing post-translational knockdown of target proteins in disease treatment. The degradation of bromodomain-containing protein 4 (BRD4), an essential nuclear protein for gene transcription, induced by PROTAC is proposed as an epigenetic approach to treat breast cancer. However, the poor membrane permeability and indiscriminate distribution of PROTAC in vivo results in low bioavailability, limiting its development and application. Herein, a nano "targeting chimera" (abbreviated as L@NBMZ) consisting of BRD4-PROTAC combined with a photosensitizer, to serve as the first augmenter for photo-driven pyroptosis in breast cancer, is developed. With excellent BRD4 degradation ability, high biosafety, and biocompatibility, L@NBMZ blocks gene transcription by degrading BRD4 through proteasomes in vivo, and surprisingly, induces the cleavage of caspase-3. This type of caspase-3 cleavage is synergistically amplified by light irradiation in the presence of photosensitizers, leading to efficient photo-driven pyroptosis. Both in vitro and in vivo outcomes demonstrate the remarkable anti-cancer efficacy of this augmenter, which significantly inhibits the lung metastasis of breast cancer in vivo. Thus, the photo-PROTAC "targeting chimera" augmenter construction strategy may pave a new way for expanding PROTAC applications within anti-cancer paradigms.

The Early Initiation of Perioperative Anticoagulation Therapy in Cirrhotic Patients with Portal Hypertension After Laparoscopic Splenectomy Plus Esophagogastric Devascularization: A 10-Year Single-Center Experience.

Background: Portal veinous system thrombosis (PVST) is a common complication after laparoscopic splenectomy plus esophagogastric devascularization (LSED). Anticoagulation therapy was still in debate in LSED perioperation. This study aimed to determine the postoperative risk factors of PVST, the efficacy and safety of the anticoagulation therapy after LSED procedure, and the potential impact of anticoagulation on patients' liver function and overall survival (OS). Methods: Three hundred patients who underwent LSED were retrospectively enrolled and analyzed in the study. The characteristics of patients, perioperative parameters, risk of PVST, and long-term follow-up data were recorded and analyzed. Results: One hundred eighty six of 300 patients received perioperative anticoagulation therapy (p-AT) postoperation, while 114 patients did not receive p-AT (non-p-AT). The non-p-AT group had more intraoperative blood loss, PVST, longer abdominal drain days, and postoperative hospital stays separately compared with the p-AT group. No significant difference of postoperative complications was found between the two groups. In the 1-year follow-up postoperation, both groups had great improvement in hypersplenism and the portal vein hemodynamics. During the 10-year follow-up period, the incidence of PVST was significantly higher in the non-p-AT group than in the p-AT group. Anticoagulation therapy, sex, variceal hemorrhage history, portal vein diameter, and portal vein velocity were the independent prognostic factors determined by the Cox regression analysis for PVST. The thrombosis-free survival rate (P = .002), recurrent hemorrhage-free survival rate (P < .01), and the OS rate (P < .01) were significantly lower in the non-p-AT group than in the p-AT group. Conclusions: The initiate use of anticoagulation therapy in postoperation of LSED is effective and safe in cirrhotic patients. The anticoagulation therapy after LSED will help decrease portal vein thrombosis, the rebleeding rate, and extend the OS of the patients, especially among women, with variceal hemorrhage history, high portal vein diameter, and low portal vein velocity.

Effects of hypersplenism on the outcome of hepatectomy in hepatocellular carcinoma with hepatitis B virus related portal hypertension.

Background: Although hepatectomy plus splenectomy is not regularly recommended for hepatocellular carcinoma (HCC) with portal hypertension related hypersplenism due to the high risk accompanied with surgical procedures for now. Many researchers still believe that hypersplenism is a controversial adverse prognostic factor for HCC patients. Thus, the primary objective of the study was to determine the effects of hypersplenism on the prognosis of these patients during and after hepatectomy. Methods: A total of 335 patients with HBV-related HCC who underwent surgical resection as primary intervention were included in this study and categorized into three groups. Group A consisted of 226 patients without hypersplenism, Group B included 77 patients with mild hypersplenism, and Group C contained 32 patients with severe hypersplenism. The influence of hypersplenism on the outcome during the perioperative and long-term follow-up periods was analyzed. The independent factors were identified using the Cox proportional hazards regression model. Results: The presence of hypersplenism is associated with longer hospital stays, more postoperative blood transfusions, and higher complication rates. The overall survival (OS, P = 0.020) and disease-free survival (DFS, P = 0.005) were significantly decreased in Group B compared to those in Group A. Additionally, the OS (P = 0.014) and DFS (P = 0.005) were reduced in Group C compared to those in Group B. Severe hypersplenism was a significant independent prognostic variable for both OS and DFS. Conclusion: Severe hypersplenism prolonged the hospital stay, increased the rate of postoperative blood transfusion, and elevated the incidence of complications. Furthermore, hypersplenism predicted lower overall and disease-free survivals.

A functional polymorphism in PER3 gene is associated with prognosis in hepatocellular carcinoma.

BACKGROUND: Previous studies have revealed that circadian genes play important roles in cell proliferation, apoptosis, cell cycle control, DNA damage response and treatment response of chemotherapy agents in cancers. AIMS: We hypothesized that the polymorphisms in circadian genes may be associated with prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE). METHODS: Twelve functional single nucleotide polymorphisms (SNPs) in circadian negative feedback regulation genes (including CRY1, CRY2, PER1, PER2 and PER3) were genotyped using Sequenom iPLEX genotyping method in 337 HCC patients treated with TACE and analysed for associations with overall survival. RESULTS: Our data showed that one SNP rs2640908 in PER3 gene was significantly associated with overall survival of HCC patients (P = 0.027). Patients carrying at least one variant allele of rs2640908 (WV + VV) had a significantly decreased risk of death (hazard ratio, 0.71; 95% confidence interval, 0.53-0.90), when compared with those carrying homozygous wild-type alleles (WW). Kaplan-Meier analyses showed a significantly longer median survival time in patients with WV + VV genotypes of SNP rs2640908 than those with WW genotype (11.6 months vs. 8.1 months; log rank P = 0.030). In addition, we also observed a significant difference on the genotype distribution of SNP rs2640908 in patients with and without portal vein thrombus (P = 0.041). CONCLUSIONS: Our study provides the first evidence that a single functional polymorphism of PER3 gene is significantly associated with overall survival in HCC patients treated with TACE.

Laparoscopic splenectomy and esophagogastric devascularization combined with fast-track principles offers greater benefit for patients with portal hypertension.

Introduction: Laparoscopic splenectomy and esophagogastric devascularization (LSED) is becoming increasingly popular in the treatment of esophageal-fundic variceal bleeding with portal hypertension (PHT) in China, and its high safety and minimal trauma have been proven. Fast-track (FT) surgery improves patient recovery and decreases postoperative complications. Aim: To determine whether LSED with fast-track principles can provide better outcomes than traditional treatment for patients with PHT. Material and methods: A total of 140 patients who underwent LSED with either traditional treatment or fast-track principles in our department were retrospectively analyzed. The postoperative outcomes, complications, inflammatory mediators, portal vein thrombosis (PVT) and recurrent esophagogastric variceal bleeding rate were recorded. Results: No significant differences were found in the patients' preoperative characteristics. The FT group had better outcomes than the non-FT group with respect to gastrointestinal function recovery, resumption of oral intake, and postoperative hospitalization. The incidence of postoperative complications, including pneumonia, severe ascites, and urinary tract infection, were significantly lower in the FT than the non-FT group. The C-reactive protein and interleukin 6 concentrations and the incidence of PVT were significantly lower in the FT than the non-FT group. The overall recurrent bleeding rate is 11.5% and no significant difference was found between the two groups in the follow-up period. Conclusions: LSED with fast-track principles was superior to LSED with traditional treatment in terms of postoperative outcomes, complications, postoperative inflammatory reactions, and the incidence of PVT. This strategy is safe and effective for the treatment of PHT.

Laparoscopic splenectomy and devascularization for massive splenomegaly in portal hypertensive patients: a retrospective study of a single surgical team's experience with 6-year follow-up data.

Background: In China, laparoscopic splenectomy and esophagogastric devascularization (LSED) are effective and safe tools that are used to treat esophageal-fundic variceal bleeding with portal hypertension (PHT) with minimal trauma; however, due to the increased difficulty of operation, their application in massive splenomegaly (MS) remains limited. This study sought to determine the efficacy and safety of LSED in treating MS patients with PHT. Methods: The data of 124 patients who underwent LSED by a single surgical team at our department from January 2015 to December 2020 were retrospectively analyzed. The characteristics of the patients, perioperative parameters, and long-term follow-up data were examined. Results: A total of 61 MS and 63 mild-to-moderate splenomegaly (MMS) patients underwent LSED. Much larger spleen and significant lower of white blood cells and platelets was found in MS group compared the MMS group preoperation (P<0.05). The MS group had a significantly longer operation time (P=0.009), more blood loss (P=0.003), and more abdominal drainage days (P=0.017) than the MMS group. Four patients in the MS group and 0 patients in the MMS group were converted to open surgery. No significant difference was found between the 2 groups in terms of postoperative complications. Nine patients in the MMS group and 10 in the MMS group experienced recurrent bleeding in the follow-up period, but no significant differences were observed in terms of recurrent bleeding and overall survival (OS) between the 2 groups. Conclusions: LSED can be used to treat MS patients with PHT under careful perioperative management. For experienced surgeons, LSED is a safe, feasible, and minimally invasive procedure with satisfactory long-term outcomes that can be used to treat MS patients with PHT. Keywords: Laparoscopic splenectomy (LS); massive splenomegaly (MS); devascularization; portal hypertension (PHT).

Common genetic variants in cell cycle pathway are associated with survival in stage III-IV non-small-cell lung cancer.

Cell cycle progression contributes to the cellular response to DNA-damaging factors, such as chemotherapy and radiation. We hypothesized that the genetic variations in cell cycle pathway genes may modulate treatment responses and affect survival in patients with advanced non-small-cell lung cancer (NSCLC). We genotyped 374 single-nucleotide polymorphisms (SNPs) from 49 cell cycle-related genes in 598 patients with stages III-IV NSCLC treated with first-line platinum-based chemotherapy with/without radiation. We analyzed the individual and combined associations of these SNPs with survival and evaluated their gene-gene interactions using survival tree analysis. In the analysis of survival in all the patients, 39 SNPs reached nominal significance (P < 0.05) and 4 SNPs were significant at P <0.01. However, none of these SNPs remained significant after correction for multiple comparisons at a false discovery rate of 10%. In stratified analysis by treatment modality, after adjusting for multiple comparisons, nine SNPs in chemotherapy alone and one SNP in chemoradiation remained significant. The most significant SNP in chemotherapy group was CCNB2:rs1486878 [hazard ratio (HR) = 1.69, 95% confidence interval (CI), 1.25-2.30, P = 0.001]. TP73: rs3765701 was the only significant SNP in chemoradiation group (HR = 1.87; 95% CI = 1.35-2.59, P = 1.8 × 10(-4)). In cumulative analysis, we found a significant gene-dosage effect in patients receiving chemotherapy alone. Survival tree analysis demonstrated potential higher order gene-gene and gene-treatment interactions, which could be used to predict survival status based on distinct genetic signatures. These results suggest that genetic variations in cell cycle pathway genes may affect the survival of patients with stages III-IV NSCLC individually and jointly.

Assessment of intrahepatic blood flow by Doppler ultrasonography: relationship between the hepatic vein, portal vein, hepatic artery and portal pressure measured intraoperatively in patients with portal hypertension.

BACKGROUND: Abnormality of hepatic vein (HV) waveforms evaluated by Doppler ultrasonography has been widely studied in patients with chronic liver disease. We investigated the correlation between changes in HV waveforms and portal vein velocity (PVVel), the hepatic artery pulsatility index (HAPI), and also the extent of abnormal Doppler HV waveforms expressed as damping index (DI), severity of portal hypertension expressed as Child-Pugh scores and portal pressure (PP) measured directly from patients with portal hypertension (PHT) to evaluate the indicative value of abnormal HV waveforms and discuss the cause of abnormal HV waveform. METHODS: Sixty patients who had been diagnosed with PHT and accepted surgical therapy of portosystemic shunts were investigated. PP was measured intraoperatively. Thirty healthy volunteers with no history of chronic liver disease were enrolled as the control group. HV waveforms were categorized as triphasic, biphasic or monophasic. DI was compared as the quantitative indicator of abnormal HV waveforms. Another two Doppler parameters, PVVel and HAPI were also measured. These Doppler features were compared with PP, Child-Pugh scores and histological changes assessed by liver biopsy. RESULTS: In the patient group, the Doppler flow waveforms in the middle HV were triphasic in 31.6%, biphasic in 46.7%, and monophasic in 21.6% of subjects. These figures were 86.7%, 10.0%, and 3.3%, respectively, in healthy subjects. With the flattening of HV waveforms, the HAPI increased significantly (r = 00.438, p < 0.0001), whereas PVVel decreased significantly (r = -0.44, p <0.0001). Blood flow parameters, HAPI, PVVel and HV-waveform changes showed no significant correlations with Child-Pugh scores. The latter showed a significant correlation with PP (r = 0.589, p = 0.044). Changes of HV waveform and DI significantly correlated with PP (r = 0.579, r = 0.473, p <0.0001), and significant correlation between DI and Child-Pugh scores was observed (r = 0.411, p = 0.001). PP was significantly different with respect to nodule size (p < 0.05), but HV-waveform changes were not significantly correlated with pathological changes. CONCLUSION: In patients with PHT, a monophasic HV waveform indicates higher portal pressure. Furthermore, quantitative indicator DI can reflect both higher portal pressure and more severe liver dysfunction. Flattening of HV waveforms accompanied by an increase in the HAPI and decrease in PVVel support the hypothesis that histological changes reducing HV compliance be the cause of abnormality of Doppler HV waveforms from the hemodynamic angle.

Sulforaphane exerts anticancer effects on human liver cancer cells via induction of apoptosis and inhibition of migration and invasion by targeting MAPK7 signalling pathway.

Retraction of: 'Sulforaphane exerts anticancer effects on human liver cancer cells via induction of apoptosis and inhibition of migration and invasion by targeting MAPK7 signalling pathway', by Bo Huang, Shixiong Lei, Dong Wang, Yibo Sun, Jikai Yin JBUON 2019;25(2):959-964; PMID:32521892. Following the publication of the above article, readers drew to our attention that part of the data was unreliable. The authors were requested to provide the raw data to prove the originality, but were unable to do so. After an investigation, the Editors of JBUON decided to retract this article. We thank the readers for bringing this matter to our attention. We apologize for any inconvenience it may cause.

Splenectomy improves liver fibrosis via tumor necrosis factor superfamily 14 (LIGHT) through the JNK/TGF-ß1 signaling pathway.

Splenectomy has been reported to improve liver fibrosis in patients with cirrhosis and hypersplenism. However, the mechanisms remain unclear. Tumor necrosis factor superfamily 14 (TNFSF14; also known as LIGHT) is highly expressed in the context of fibrosis and promotes disease progression in patients with fibrotic diseases such as pulmonary and skin fibrosis. Here, we determined whether splenectomy controls the production of LIGHT to improve liver fibrosis. Splenectomy reduced serum LIGHT levels in cirrhotic patients with hypersplenism and a ConA-induced liver fibrosis mouse model. Blocking LIGHT resulted in the downregulation of TGF-ß1 in RAW264.7 cells. LIGHT treatment of RAW264.7 and JS1 cells in coculture regulated transforming growth factor-ß1 (TGF-ß1) expression through the activation of JNK signaling. Small interfering RNA-mediated silencing of lymphotoxin ß receptor (LTßR) in macrophages resulted in pronounced decreases in the levels of fibrosis and αSMA in JS1 cells. These results indicated that LIGHT bound to LTßR and drove liver fibrosis in vitro. Blocking TGF-ß1 abolished the effect of LIGHT in vitro. Furthermore, the administration of recombinant murine LIGHT protein-induced liver fibrosis with splenectomy, while blocking LIGHT without splenectomy improved liver fibrosis in vivo, revealing that the decrease in fibrosis following splenectomy was directly related to reduced levels of LIGHT. Thus, high levels of LIGHT derived from the spleen and hepatic macrophages activate JNK signaling and lead to increased TGF-ß1 production in hepatic macrophages. Splenectomy attenuates liver fibrosis by decreasing the expression of LIGHT.

Sulforaphane exerts anticancer effects on human liver cancer cells via induction of apoptosis and inhibition of migration and invasion by targeting MAPK7 signalling pathway.

PURPOSE: This study was undertaken to investigate the anticancer effects of Sulforaphane against liver cancer and to elucidate the underlying molecular mechanisms. METHODS: WST-1 assay was used to monitor the proliferation rate. DAPI and annexin V/propidium iodide (PI) staining was used for apoptosis. Flow cytometry was used for cell cycle analysis. Wound heal and transwell assays were used to monitor cell migration and invasion. The protein expression was determined by western blot analysis. RESULTS: It was found that Sulforaphane decreased the viability of the liver cancer HepG2 cells and exhibited an IC50 of 9 µM. Nonetheless, Sulforaphane (µM) exerted very low toxic effects on the normal AML12 hepatocytes and exhibited an IC50 of 100 µM. Flow cytometery analysis showed that Sulforaphane triggered G2/M arrest of the liver HepG2 cancer cells. DAPI staining revealed that Sulforaphane triggered the apoptotic cell death of HepG2 cells which was accompanied with activation of caspases 3 and 9, upregulation of Bax and downregulation of Bcl-2. Transwell assays showed that Sulforaphane inhibited the migration and invasion of the HepG2 liver cancer cells in a dose dependent manner. The effects of Sulforaphane were also investigated on the MAPK7 signalling pathway and it was found that Sulforaphane could block this pathway in HepG2 cells. CONCLUSION: Taken together, Sulforaphane may prove essential in the development of chemotherapy for liver cancers.

Glypican-3 Enhances Reprogramming of Glucose Metabolism in Liver Cancer Cells.

Glypican-3(GPC3) is a transmembrane protein which has been found to be frequently overexpressed on the surfaces of liver cancer (LC) cells, which contributes to both the growth and metastasis of LC cells. Recently, the expression of GPC3 has been reported to be inversely associated with glucose metabolism activity in LC patients, suggesting that GPC3 may play a role in the regulation of glucose metabolism in LC. However, the role of GPC3 in glucose metabolism reprogramming, as well as in LC cell growth and metastasis, is unknown. Here, we found that GPC3 significantly contributed to the reprogramming of glucose metabolism in LC cells. On the one hand, GPC3 enhanced the glycolysis of LC cells through upregulation of the glycolytic genes of Glut1, HK2, and LDH-A. On the other hand, GPC3 repressed mitochondrial respiration through downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), which has been well known as a crucial regulator in mitochondrial biogenesis. Mechanistic investigations revealed that HIF-1α was involved in both GPC3-regulated upregulation of glycolytic genes of HK2, PKM2, and Glut1 and downregulation of mitochondrial biogenesis regulator PGC-1α in LC cells. Additionally, GPC3-regulated reprogramming of glucose metabolism played a critical role in the growth and metastasis of LC cells. Conclusion. Our findings demonstrate that GPC3 is a critical regulator of glucose metabolism reprogramming in LC cells, which provides a strong line of evidence for GPC3 as an important therapeutic target to normalize glucose metabolic aberrations responsible for LC progression.