Long-term intermittent oral administration of selective COX-2 inhibitor improved the clinical outcomes of COVID-19 in patients with cirrhosis.

OBJECTIVES: Patients with cirrhosis are more susceptible to coronavirus disease 2019 (COVID-19) due to immune dysfunction. In this retrospective study we aimed to investigate whether suppression of mild systemic inflammation with selective cyclooxygenase-2 inhibitor (COX-2-I) during chronic care of cirrhotic patients would reduce the occurrence of acute decompensated events and improve patient prognosis of COVID-19. METHODS: Medical records of cirrhotic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were sequentially reviewed. The patients were divided into the COX-2-I and control groups depending on whether they took oral selective COX-2-I for over 3 months or not. The primary outcomes included the occurrence of severe/critical COVID-19, acute decompensated events, and acute-on-chronic liver failure (ACLF). RESULTS: After propensity score matching analysis, there were 314 cases in the control group and 118 cases in the COX-2-I group. Compared with the control group, the risk of severe/critical COVID-19 in the COX-2-I group was significantly decreased by 83.1% (p = 0.004). Acute decompensated events and ACLF occurred in 23 (7.32%) and nine (2.87%) cases in the control group, but none in the COX-2-I group (p = 0.003 and 0.122). The rate of hospitalization in the COX-2-I group was significantly lower than that of the control group (3.39% vs 13.06%, p = 0.003). No patient in the COX-2-I group required intensive care unit admission. CONCLUSIONS: Long-term intermittent oral administration of selective COX-2-I in cirrhotic patients significantly reduces the occurrence of severe/critical COVID-19, acute decompensated events, and ACLF. It may also be used for systemic inflammation caused by other pathogens.

Remission of organ failure in patients with predicted severe acute pancreatitis treated by somatostation, octreotide and cyclooxygenase-2 inhibitors.

BACKGROUND: /Objectives: Persistent organ failure (OF) in severe acute pancreatitis (SAP) is caused by activation of cytokine cascades, resulting in inflammatory injury. Anti-inflammation may be helpful in OF remission in early SAP. To assess the efficacy of anti-inflammatory regimens for OF prevention and remission in patients with predicted SAP and display clinical doctors' acceptance of these strategies, we conducted this retrospective study in the real world. METHODS: Clinical data of patients with predicted SAP from 2010 to 2017 were retrospectively reviewed. Cases were divided into conventional support (C), C+ somatostatin/octreotide (C + S/O), and C + S/O + Cyclooxygenase-2-inhibitors (C + S/O + COX-2-I). The occurrence of SAP, OF, changes of proportion for three strategies, length of hospital stay, meperidine injection, and cytokine levels were compared. The constituent ratios of the three schemes over eight years were evaluated. RESULTS: A total of 580 cases (C = 124, C + S/O = 290, C + S/O + COX-2-I = 166) were included. The occurrences of SAP in the C + S/O (28.3 %) and C + S/O + COX-2-I (18.1 %) groups were significantly lower than that in C group (60.5 %, P < 0.001), mainly by reducing persistent respiratory failure (P < 0.001) and renal failure (P = 0.002). C + S/O and C + S/O + COX-2-I regimens significantly decreased new onset OF and enhanced OF amelioration within 48 h when compared with C treatment (P < 0.001) in patients with OF score <2 and ≥ 2 on admission, respectively. C + S/O and C + S/O + COX-2-I as compared with C group significantly decrease OF occurrences in a multivariate logistic regression analysis (P < 0.05). CONCLUSIONS: Somatostatin or its analogs and cyclooxygenase-2 inhibitors are promising for OF prevention and remission in patients with predicted SAP. The acceptance of combined strategies in the real world has increased, and the occurrence of SAP has decreased annually.

Incidence, prevalence, and comorbidities of chronic pancreatitis: A 7-year population-based study.

BACKGROUND: Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to reduced quality of life and shortened life expectancy. Population-based estimates of the incidence, prevalence, and comorbidities of CP in China are scarce. AIM: To characterize the incidence, prevalence, and comorbidities of CP in Sichuan Province, China, with population-based data. METHODS: Data on CP from 2015 to 2021 were obtained from the Health Information Center of Sichuan Province. During the study period, a total of 38090 individuals were diagnosed with CP in Sichuan Province. The yearly incidence rate and point prevalence rate (December 31, 2021) of CP were calculated. The prevalence of comorbid conditions in CP patients was estimated. The annual number of CP-related hospitalizations, hospital length of stay, and hospitalization costs for CP were evaluated. Yearly incidence rates were standardized for age by the direct method using the permanent population of Sichuan Province in the 2020 census as the standard population. An analysis of variance test for the linearity of scaled variables and the Cochran-Armitage trend test for categorical data were performed to investigate the yearly trends, and a two-sided test with P < 0.05 was considered statistically significant. RESULTS: The 38090 CP patients comprised 23280 males and 14810 females. The mean age of patients at CP diagnosis was 57.83 years, with male patients (55.87 years) being younger than female patients (60.11 years) (P < 0.001). The mean incidence rate of CP during the study period was 6.81 per 100000 person-years, and the incidence of CP increased each year, from 4.03 per 100000 person-years in 2015 to 8.27 per 100000 person-years in 2021 (P < 0.001). The point prevalence rate of CP in 2021 was 45.52 per 100000 individuals for the total population, with rates of 55.04 per 100000 individuals for men and 35.78 per 100000 individuals for women (P < 0.001). Individuals aged 65 years or older had the highest prevalence of CP (113.38 per 100000 individuals) (P < 0.001). Diabetes (26.32%) was the most common comorbidity in CP patients. The number of CP-related hospitalizations increased from 3739 in 2015 to 11009 in 2021. The total costs for CP-related hospitalizations for CP patients over the study period were 667.96 million yuan, with an average of 17538 yuan per patient. CONCLUSION: The yearly incidence of CP is increasing, and the overall CP hospitalization cost has increased by 1.4 times during the last 7 years, indicating that CP remains a heavy health burden.

Application of Bone Marrow Mesenchymal Stem Cells Effectively Eliminates Endotoxemia to Protect Rat from Acute Liver Failure Induced by Thioacetamide.

BACKGROUND: Endotoxemia is related to worse clinical outcomes in acute liver failure (ALF), but its management remains unsatisfactory. In this study, we aimed to assess whether the application of bone marrow mesenchymal stem cells (BMSCs) could eliminate endotoxemia and protect rats against ALF induced by thioacetamide (TAA). METHODS: BMSCs were isolated from rats and identified by the specific morphology, differentiation potential, and surface markers. The optimal dose of TAA for this study was explored and TAA-induced ALF rats were randomized to three groups: the normal control group (Saline), ALF group (TAA + Saline), and BMSCs-treated group (TAA + BMSCs). The intestinal migration and differentiation of BMSCs was tracked in vivo, and intestinal permeability, endotoxin and inflammatory cytokines, histology, and mortality were analyzed. Moreover, we added the inhibitor of the PI3K/AKT/mTOR signaling pathway into the co-culture system of BMSCs with enterocytes and then performed CK and Villin expression experiments to assess the role of PI3K/AKT/mTOR signal pathway in the intestinal differentiation of BMSCs. RESULTS: BMSCs migrated to the intestinal injury sites and differentiated into enterocytes, intestinal permeability was decreased compared with the ALF group. The higher expression of endotoxin and inflammatory cytokines were reversed after BMSCs transplantation in rats with ALF. Mortality and intestinal lesion were significantly decreased. Blocking the PI3K/AKT/mTOR signal pathway inhibited BMSCs' intestinal differentiation in vitro. CONCLUSION: BMSCs can eliminate endotoxemia and reduce mortality in rats with ALF, and the PI3K/AKT/mTOR signal pathway is involved in intestinal differentiation. BMSCs transplantation could be a potential candidate for the treatment of endotoxemia in ALF.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Management and outcomes of surgical patients with intestinal Behçet's disease and Crohn's disease in southwest China.

BACKGROUND: Gastrointestinal involvement in Behçet's disease (GIBD) and Crohn's disease (CD) are inflammatory diseases sharing a considerable number of similarities. However, different from CD, the operative and postoperative management of GIBD remains largely empirical because of the lack of comprehensive treatment guidelines. AIM: To compare surgical patients with GIBD and those with CD in a medical center and identify notable clinical features and effective postoperative treatment for surgical patients with GIBD. METHODS: We searched patients diagnosed with CD and GIBD who underwent operations for gastrointestinal complications from 2009 to 2015 at West China Hospital of Sichuan University. A total of 10 surgical patients with GIBD and 106 surgical patients with CD were recruited. Information including demographic data, medication, and operative and postoperative parameters were collected and analyzed. As the incidence of surgical GIBD is low, their detailed medical records were reviewed and compared to previous studies. Moreover, the prognoses of CD and GIBD were evaluated respectively between groups treated with biological and non-biological agents. RESULTS: Indication for first surgery was often acute intestinal perforation for GIBD patients (7/10 vs 0/106, P < 0.001), whereas intestinal fistulae (0/10 vs 44/106, P = 0.013) and ileus (0/10 vs 40/106, P = 0.015) were the indications for surgical CD patients. Approximately 40% of patients with GIBD and 23.6% of patients with CD developed postoperative complications, 50% of patients with GIBD and 38.7% of patients with CD had recurrence postoperatively, and 40% (4/10) of patients with GIBD and 26.4% (28/106) of patients with CD underwent reoperations. The average period of postoperative recurrence was 7.87 mo in patients with Behçet's disease (BD) and 10.43 mo in patients with CD, whereas the mean duration from first surgery to reoperation was 5.75 mo in BD patients and 18.04 mo in CD patients. Surgical patients with GIBD more often used corticosteroids (6/10 vs 7/106, P < 0.001) and thalidomide (7/10 vs 9/106, P < 0.001) postoperatively, whereas surgical patients with CD often used infliximab (27/106), azathioprine, or 6-mercaptopurine (74/106) for maintenance therapy. CONCLUSION: Patients suffering GIBD require surgery mostly under emergency situations, which may be more susceptible to recurrence and reoperation and need more aggressive postoperative treatment than patients with CD.

5-Aza-2-deoxycytidine alleviates the progression of primary biliary cholangitis by suppressing the FoxP3 methylation and promoting the Treg/Th17 balance.

Primary biliary cholangitis (PBC) is a common autoimmune liver disease manifested by the infiltration of CD4+ T cells, and the subsequent targeted injury of biliary epithelial cells (BECs). As important components of CD4 subsets, the Treg/Th17 axis maintains an immunological balance between self-tolerance and inflammation in the liver microenvironment. However, the role and regulatory mechanism of the Treg/Th17 axis in PBC remain unclear. In this study, we examined the Treg/Th17 axis in PBC patients and found that the Treg/Th17 axis was imbalanced in PBC at both the transcriptional and cellular levels, with Treg being a weak candidate, which correlates with the PBC progression. This imbalanced Treg/Th17 axis was likely to be affected by the FoxP3 hypermethylation, which was related to the increase of DNA methyltransferase. Furthermore, the effect of 5-Aza-2-deoxycytidine (DAC)-mediated FoxP3 demethylation on PBC mice was investigated. We verified that DAC significantly suppressed the FoxP3 methylation and rebuilt the Treg/Th17 balance, resulting in the alleviation of liver lesions and inflammation. Taken together, our data indicate that DAC plays a positive role in alleviating the progression of PBC through the inhibition of DNA methylation of FoxP3 to rebuild the balanced Treg/Th17 axis. DAC could be considered as a potential candidate for the development of new anti-inflammation strategies in the treatment of PBC.

Risk factors for overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt creation in patients with liver cirrhosis.

OBJECTIVE: This study aimed to determine the risk factors and establish a risk score for post-transjugular intrahepatic portosystemic shunt (TIPS) overt hepatic encephalopathy (OHE). METHODS: Altogether 299 and 62 cirrhotic patients receiving TIPS from January 2015 to March 2018 were divided into the derivation and validation cohorts, respectively. The data of the derivation cohort were analyzed for risk factors of post-TIPS OHE. A risk score was established from the derivation cohort and verified by the validation cohort. RESULTS: During a median follow-up of 112.6 weeks, 52 (17.4%) patients in the derivation cohort experienced post-TIPS OHE. Logistic regression showed that alcoholic cirrhosis (odds ratio [OR] 3.068, 95% confidence interval [CI] 1.423-6.613, P = 0.004), stent diameter of 10 mm (OR 12.046 [95% CI 2.308-62.862], P = 0.003), portal pressure gradient (PPG) decrement ≥60% (OR 3.548 [95% CI 1.741-7.230], P < 0.001), model for end-stage liver disease (MELD) score ≥10 (OR 2.695 [95% CI 1.203-6.035], P = 0.016), blood ammonia (OR 1.009 [95% CI 1.000-1.018], P = 0.043) and notable hydrothorax (OR 4.393 [95% CI 1.554-12.415], P = 0.005) were associated with an increased risk of post-TIPS OHE. The risk score reached a promising risk evaluation of post-TIPS OHE when verified by the validation cohort (sensitivity 71.4%, specificity 70.7%, accuracy 71.0%). CONCLUSIONS: Alcoholic cirrhosis and notable hydrothorax are independent risk factors for post-TIPS OHE in liver cirrhosis, together with the stent diameter of 10 mm, PPG decrement ≥60%, MELD score ≥10 and blood ammonia. The established risk score is reliable to identify high-risk individuals of developing post-TIPS OHE.

Artificial intelligence technique in detection of early esophageal cancer.

Due to the rapid progression and poor prognosis of esophageal cancer (EC), the early detection and diagnosis of early EC are of great value for the prognosis improvement of patients. However, the endoscopic detection of early EC, especially Barrett's dysplasia or squamous epithelial dysplasia, is difficult. Therefore, the requirement for more efficient methods of detection and characterization of early EC has led to intensive research in the field of artificial intelligence (AI). Deep learning (DL) has brought about breakthroughs in processing images, videos, and other aspects, whereas convolutional neural networks (CNNs) have shone lights on detection of endoscopic images and videos. Many studies on CNNs in endoscopic analysis of early EC demonstrate excellent performance including sensitivity and specificity and progress gradually from in vitro image analysis for classification to real-time detection of early esophageal neoplasia. When AI technique comes to the pathological diagnosis, borderline lesions that are difficult to determine may become easier than before. In gene diagnosis, due to the lack of tissue specificity of gene diagnostic markers, they can only be used as supplementary measures at present. In predicting the risk of cancer, there is still a lack of prospective clinical research to confirm the accuracy of the risk stratification model.

Dysregulated Kras/YY1/ZNF322A/Shh transcriptional axis enhances neo-angiogenesis to promote lung cancer progression.

Angiogenesis enhances cancer metastasis and progression, however, the roles of transcription regulation in angiogenesis are not fully defined. ZNF322A is an oncogenic zinc-finger transcription factor. Here, we demonstrate a new mechanism of Kras mutation-driven ZNF322A transcriptional activation and elucidate the interplay between ZNF322A and its upstream transcriptional regulators and downstream transcriptional targets in promoting neo-angiogenesis. Methods: Luciferase activity, RT-qPCR and ChIP-qPCR assays were used to examine transcription regulation in cell models. In vitro and in vivo angiogenesis assays were conducted. Immunohistochemistry, Kaplan-Meier method and multivariate Cox regression assays were performed to examine the clinical correlation in tumor specimens from lung cancer patients. Results: We validated that Yin Yang 1 (YY1) upregulated ZNF322A expression through targeting its promoter in the context of Kras mutation. Reconstitution experiments by knocking down YY1 under KrasG13V activation decreased KrasG13V-promoted cancer cell migration, proliferation and ZNF322A promoter activity. Knockdown of YY1 or ZNF322A attenuated angiogenesis in vitro and in vivo. Notably, we validated that ZNF322A upregulated the expression of sonic hedgehog (Shh) gene which encodes a secreted factor that activates pro-angiogenic responses in endothelial cells. Clinically, ZNF322A protein expression positively correlated with Shh and CD31, an endothelial cell marker, in 133 lung cancer patient samples determined using immunohistochemistry analysis. Notably, patients with concordantly high expression of ZNF322A, Shh and CD31 correlated with poor prognosis. Conclusions: These findings highlight the mechanism by which dysregulation of Kras/YY1/ZNF322/Shh transcriptional axis enhances neo-angiogenesis and cancer progression in lung cancer. Therapeutic strategies that target Kras/YY1/ZNF322A/Shh signaling axis may provide new insight on targeted therapy for lung cancer patients.

Celecoxib attenuates hepatocyte apoptosis by inhibiting endoplasmic reticulum stress in thioacetamide-induced cirrhotic rats.

BACKGROUND: Endoplasmic reticulum (ER) stress is an important mechanism in the progression of chronic and acute liver diseases, especially in the progression and recovery of liver fibrosis. Excessive and long-term ER stress induces apoptosis. ER stress-induced apoptosis is considered to be an important pathway in the development of liver fibrosis. Cyclooxygenase-2 (COX-2) induction is also closely related to ER stress. In our previous studies, we showed that celecoxib, a COX-2 inhibitor, improves liver fibrosis and portal hypertension. However, the role and mechanism of celecoxib in alleviating liver fibrosis remain unclear. AIM: To investigate whether celecoxib alleviates liver fibrosis by inhibiting hepatocyte apoptosis via the ER stress response. METHODS: Cirrhosis was induced by intraperitoneal injections of thioacetamide (TAA) for 16 wk (injection dose is 200 mg/kg per 3 d for the first 8 wk and 100 mg /kg per 3 d after 8 wk). Thirty-six male Sprague-Dawley rats were randomly divided into three groups, namely, control group, TAA group, and TAA + celecoxib group. In the last 8 wk, TAA-induced cirrhotic rats received celecoxib (20 mg/kg/day) or the vehicle by gastric gavage. After 16 wk, the rats were sacrificed, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) were detected. The hepatic fibrosis areas were evaluated by Sirius red staining and the degree of fibrosis was assessed by measuring the level of hydroxyproline. ER stress levels were evaluated by detecting the marker proteins glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP), PKR-like ER protein kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 alpha (IRE1α). Apoptosis levels were evaluated by detecting caspase-12 and caspase-3. RESULTS: The serum ALT and AST levels in the liver were significantly reduced by celecoxib; however, the serum ALB had no significant changes. Celecoxib significantly reduced the degree of liver fibrosis and the levels of hydroxyproline (-38% and -25.7%, respectively, P < 0.01). Celecoxib ameliorated ER stress by reducing the level of GRP78 compared to the TAA group (P < 0.05). Consistently, after celecoxib administration, the upregulation of TAA-induced hepatic apoptosis markers (caspase-12 and caspase-3) and CHOP were significantly inhibited. In addition, after celecoxib treatment, the expression of key molecules associated with ER stress (PERK, ATF6, and IRE1) was decreased (P < 0.05). CONCLUSION: Therapeutic administration of celecoxib effectively reduces hepatic apoptosis in TAA-induced cirrhotic rats. The mechanism of action may be attributed to the suppression of CHOP expression, which subsequently inhibits ER stress.

Multiomics Reveals Ectopic ATP Synthase Blockade Induces Cancer Cell Death via a lncRNA-mediated Phospho-signaling Network.

The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation of DNA topoisomerase IIα (topo IIα) at serine 1106 and subsequently increases the expression of long noncoding RNA, GAS5. Additionally, we also determine that downstream of GAS5, p53 pathway, is activated by ecto-ATP synthase inhibitor for regulation of programed cell death. Interestingly, GAS5-proteins interactomic profiling elucidates that GAS5 associates with topo IIα and subsequently enhancing the phosphorylation level of topo IIα. Taken together, our findings suggest that ecto-ATP synthase blockade is an effective therapeutic strategy via regulation of CK2/phospho-topo IIα/GAS5 network in gefitinib-resistant lung cancer cells.

Suppressing growth and invasion of human hepatocellular carcinoma cells by celecoxib through inhibition of cyclooxygenase-2.

Purpose: Biomarkers are lacking in hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) and its metabolites play crucial roles in the process of inflammation-tumor transformation. This study was aimed to detect COX-2 expression in HCC tissues and evaluate the effects of a COX-2 inhibitor, celecoxib, on biological behaviors of HCC cell lines in vitro. Methods: COX-2 expression was detected by immunohistochemistry on a human HCC tissue microarray. The correlations of COX-2 expression with tumor clinicopathological variables and overall survival were analyzed. The proliferation, apoptosis, cell cycle distribution, invasion capacity, and related signaling molecules of HCC cells after incubated with COX-2 inhibitor celecoxib were evaluated in vitro. Results: Expression levels of COX-2 in HCC tissues were significantly higher than those in paracancerous tissues. The TNM stage III-IV, tumor size >5 cm, lymphovascular invasion and distant metastasis was higher in high COX-2 expression group compared with that in low COX-2 expression group. Patients with low COX-2 expression achieved better 5-year overall survival than those with high COX-2 expression. Treatment with celecoxib was sufficient to inhibit cell proliferation, promote apoptosis, and induce G0/G1 cell cycle arrest in HCC cells with concentration- and time-dependent manners. Celecoxib up-regulated E-cadherin protein through inhibiting COX-2-prostaglandin E2 (PGE2)-PGE2 receptor 2 (EP2)-p-Akt/p-ERK signaling pathway to suppress HCC cells migration and invasion. Conclusion: High COX-2 expression was associated with advanced TNM stage, larger tumor size, increased lymphovascular invasion and short survival. Targeting inhibition of COX-2 by celecoxib exhibited anti-tumor activities by suppressing proliferation, promoting apoptosis, and inhibiting the aggressive properties of HCC cells.

Cyclooxygenase-2 up-regulates hepatic somatostatin receptor 2 expression.

Somatostatin and its analogues, which function by binding to somatostatin receptors (SSTRs) 1-5, play a protective role in liver cirrhosis. Hepatic SSTR-2 expression is up-regulated in subjects with liver cirrhosis. However, little is known about the mechanisms underlying this process. In the present study, we observed the up-regulation of hepatic SSTR-2 expression in thioacetamide (TAA)-induced cirrhotic rats and further showed that cyclooxygenase-2 (COX-2) might play a role in this process via the protein kinase C (PKC)-cAMP response element binding protein (CREB) signaling pathway. In vivo, the up-regulated SSTR-2 in liver cirrhosis was inhibited by the addition of a selective COX-2 inhibitor, such as celecoxib. In vitro, the up-regulation of COX-2 by either transfection with COX-2 plasmids or treatment with TAA increased levels of SSTR-2 and phosphorylated CREB (p-CREB) in the human hepatocyte cell line L02. Furthermore, the increase in SSTR-2 expression was inhibited by the addition of celecoxib and a PKC inhibitor. Moreover, for comparable DNA methylation levels in the region upstream of the hepatic SSTR-2 gene in normal and cirrhotic livers, DNA methylation may not contribute to the up-regulation of SSTR-2 expression in cirrhotic livers. In conclusion, the up-regulation of hepatic SSTR-2 might be induced by COX-2 via the PKC-CREB signaling pathway but is probably not induced by DNA methylation.

SK-Hep1: not hepatocellular carcinoma cells but a cell model for liver sinusoidal endothelial cells.

SK-Hep1 cells serve as a cell model of hepatocellular carcinoma and hepatocyte biology. However, SK-Hep1 cells are markedly different from normal hepatocytes and other hepatocellular carcinoma cells in their gene expression and protein levels. Furthermore, endothelial-specific makers and morphological characteristics are found in SK-Hep1 cells, indicating an endothelial origin. To confirm their cell phenotype, we investigated and compared the surface ultrastructure, endothelial function, and molecular markers of SK-Hep1 cells in vitro and in vivo. The results revealed that SK-Hep1 cells expressed endothelial-specific makers and exhibited the endothelial function of endocytosis and tubular formation. Capillary-like structures with CD31 expression were also observed in SK-Hep1 allografts in nude mice. Moreover, SK-Hep1 cells possessed fenestrae without diaphragms, consistent with liver sinusoidal endothelial cells, as seen by electron microscopy. In conclusion, SK-Hep1 cells would be better considered a cell model for liver sinusoidal endothelial cells instead of hepatocellular carcinoma cells.

Effect of octreotide on pancreatic fibrosis in rats with high-fat diet-induced obesity.

BACKGROUND/AIMS: To explore the effect of octreotide on pancreatic fibrosis induced by high-fat diet (HFD) and its mechanism of action. METHODS: Sprague-Dawley (SD) rats were assigned to control, HFD, or octreotide treatment groups. Glucose and insulin tolerance tests (GTT and ITT), fasting plasma glucose (FPG), and fasting insulin (FINS), serum and pancreatic lipid levels, were measured, and the Lee's index and the homeostatic model assessment (HOMA) index were calculated. The expression levels of alpha-smooth muscle actin (α-SMA), desmin, connective tissue growth factor (CTGF), transforming growth factor beta1 (TGF-ß1), Smad3, and Smad7 in the pancreas were quantified. The LTC-14 cell line, which has features of primary rat pancreatic stellate cells (PSCs), was used for in vitro studies. RESULTS: The AUC of ipGTT and ipITT, and FPG, FINS, lipid levels, were elevated after HFD feeding; however, they decreased after octreotide administration. The expression of α-SMA, CTGF, TGF-ß1, and Smad3 in the HFD group were increased relative to the control group, but Smad7 expression was decreased. After treatment with octreotide, α-SMA, CTGF, TGF-ß1, and Smad3 expression decreased, whereas the expression of Smad7 increased. In vitro studies showed that the expression of CTGF, TGF-ß1, and Smad3 increased with palmitate treatment (PA), which mimics HFD treatment; and octreotide treatment decreased the expression of these proteins. The α-SMA and Smad7 expression levels remained unchanged among the three groups. CONCLUSIONS: Octreotide can ameliorate pancreatic fibrosis and improve pancreatic beta-cell function induced in HFD treated rats, possibly by inhibiting PSC activation and by decreasing pancreatic extracellular matrix (ECM) through the TGF-ß1/Smad signaling pathway.