Subacute liver and respiratory failure after segmental hepatectomy for complicated hepatolithiasis with secondary biliary cirrhosis: A case report.

BACKGROUND: Despite being a benign disease, hepatolithiasis has a poor prognosis because of its intractable nature and frequent recurrence. Nonsurgical treatment is associated with high incidences of residual and recurrent stones. Consequently, surgery via hepatic lobectomy or segmental hepatectomy has become the main treatment modality. Clinical management and resolution of complicated hepatolithiasis with bilateral or diffuse intrahepatic stones remain very difficult and challenging. Repeated cholangitis and calculous obstruction may result in secondary biliary cirrhosis, a limiting factor in the treatment of hepatolithiasis. CASE SUMMARY: A 53-year-old woman with a 5-year history of intermittent abdominal pain and fever was admitted to the hepatopancreatobiliary surgery department following worsening symptoms over a 3-d period. Blood tests revealed elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and total bilirubin, as well as anemia. Magnetic resonance cholangiopancreatography showed dilatation of the intrahepatic, left and right hepatic, common hepatic, and common bile ducts, and multiple short T2 signals in the intrahepatic and common bile ducts. Abdominal computed tomography showed splenomegaly and splenic varices. The diagnosis was bilateral hepatolithiasis and choledocholithiasis with cholangitis. Surgical treatment included hepatectomy of segments II and III, cholangioplasty, left hepaticolithotomy, second biliary duct exploration, choledocholithotomy, T-tube drainage, and accretion lysis. Surgical and pathological findings confirmed secondary biliary cirrhosis. Liver-protective therapy and anti-infectives were administered. The patient developed liver and respiratory failure, severe abdominal infection, and septicemia. Eventually, her family elected to discontinue treatment. CONCLUSION: Liver transplantation, rather than hepatectomy, might be a treatment option for complicated bilateral hepatolithiasis with secondary liver cirrhosis.

CiRS-7 promotes growth and metastasis of esophageal squamous cell carcinoma via regulation of miR-7/HOXB13.

The circular RNA ciRS-7 has been reported to be involved in the pathogenesis of various tumors, including gastric and colorectal cancer. However, the role of ciRS-7 in esophageal squamous cell carcinoma (ESCC) remains unsolved. In this study, we found that the ciRS-7 expression was significantly upregulated in ESCC cancer tissues compared with matched normal tissues and associated with poor patient survival. Overexpression of ciRS-7 abrogated the tumor-suppressive roles of miR-7 including cell proliferation, migration and invasion in vitro as well as tumor growth and lung metastasis in vivo. Mechanistically, ciRS-7 functioned as the sponge of miR-7 and reactivated its downstream HOXB13-mediated NF-κB/p65 pathway. Conclusively, our findings demonstrate how ciRS-7 induces malignant progression of ESCC and that ciRS-7 may act as a novel prognostic marker and therapeutic target for this lethal disease.

Hepatitis B virus upregulates host expression of α-1,2-mannosidases via the PPARα pathway.

AIM: To assess the effects of hepatitis B virus (HBV) on the expression of host α-1,2-mannosidases and determine the underlying mechanisms. METHODS: We measured the expression levels of MAN1A1, MAN1A2, MAN1B1, and MAN1C1 in cell lines HepG2.2.15, HepN10, HepAD38 and HepG2 by Western blot. Viral antigens (HBsAg and HBeAg) in the culture medium were measured using the chemiluminescence method. HBV DNA quantification assays were performed using a commercial real-time PCR kit. Protein levels of human liver tissue α-1,2-mannosidases were also evaluated by Western blot. Plasmids containing seven individual viral genes of HBV (PTT22-HBx, PTT22-HBs, PTT22-preS2, PTT22-preS1, PTT22-HBc, PTT22-HBe, and PTT22-HBp) or control plasmids (PTT22-vector) were transfected into HepG2 cells. MK886 (PPARα) and GW9662 (PPARγ) inhibitors were used to explore the effects of HBV on α-1,2-mannosidase expression after the PPARα and PPARγ pathways were blocked. RESULTS: We showed that the expression of α-1,2-mannosidases was higher in stably transfected HBV cells than in controls. The expression levels of α-1,2-mannosidase were higher in AD38 cells than those in ND10 cells, which were in turn greater than those in G2.2.15 cells, and positively correlated with the expression of HBsAg in all the cell lines. Levels of α-1,2-mannosidase in non-tumorous liver tissues of HBV-related HCC patients were also higher than in the tissues from non-HBV-related HCC patients. Moreover, transfecting HepG2 cells with a component of the HBV viral envelope also increased the expression of α-1,2-mannosidases. However, this envelope protein component could not induce MAN1C1 expression in the presence of a PPARα inhibitor, MK886. We also found that MK886 did not affect the expression of MAN1C1 in AD38 cells without tetracycline in the culture medium. This phenomenon was not observed in the case of GW9662. CONCLUSION: Our results indicate that HBV increases the expression of α-mannosidases both in vitro and in vivo via activation of the PPARα pathway by its envelope protein.

Sodium tanshinone IIA sulfonate attenuates the transforming growth factor-ß1-induced differentiation of atrial fibroblasts into myofibroblasts in vitro.

The differentiation of atrial fibroblasts into myofibroblasts is a critical event in atrial fibrosis. One of the most important factors in atrial fibroblast differentiation is transforming growth factor-ß1 (TGF-ß1). Accumulating evidence indicates that sodium tanshinone IIA sulfonate (STS) possesses antifibrotic properties. In this study, we therefore investigated whether STS attenuates the TGF-ß1­induced differentiation of atrial fibroblasts. TGF-ß1 enhanced collagen production, collagen synthesis and the expression of collagen type I and III, as shown by hydroxyproline assay, collagen synthesis assay and western blot analysis, respectively. In addition, as shown by immunohistochemistry and western blot analysis, TGF-ß1 enhanced the expression of α-smooth muscle actin (α-SMA), which is the hallmark of myofibroblast differentiation. These responses were attenuated by treatment with STS. In addition, STS suppressed the TGF-ß1­induced expression of phosphorylated (p)Smad/pSmad3 expression and nuclear translocation. Furthermore, STS suppressed extracellular signal-regulated kinase (ERK) phosphorylation. In conclusion, the current study demonstrates that STS exerts antifibrotic effects by modulating atrial fibroblast differentiation through ERK phosphorylation and the Smad pathway.

[Effect of sodium tanshinone II (A) sulfonate on Ang II -induced atrial fibroblast collagen synthesis and TGF-beta1 activation].

OBJECTIVE: To observe the effect of sodium tanshinone II (A) sulfonate (STS) on Ang II -induced atrial fibroblast collagen synthesis and TGF-beta1 activation. METHOD: Atrial fibroblasts of neonatal rats were cultured to determine the content of collagen protein. The original synthesis rate determined by the [3H]-proline incorporation method was taken as the index for myocardial fibrosis. The content of active TGF-beta1 and total TGF-beta1 in cell culture supernatants were tested and cultured by ELISA. The expression of thrombospondin-1 (TSP-1) was assessed by using Western blot. RESULT: Ang II could significantly increase the content of atrial fibroblast collagen and the collagen synthesis rate, the TSP-1 expression and the concentration of active TGF-beta1, without any obvious change in total TGF-beta1. After the STS treatment, all of the indexes, apart from total TGF-beta1, were obviously down-regulated. CONCLUSION: STS could decrease the secretion of Ang II -induced atrial fibroblast collagen and the synthesis rate. Its mechanism is related to the inhibition of TSP-1/TGF-beta1 pathway.

Endoplasmic reticulum stress and C/EBP homologous protein-induced Bax translocation are involved in angiotensin II-induced apoptosis in cultured neonatal rat cardiomyocytes.

The aim of this study was to identify the roles and potential mechanisms of endoplasmic reticulum stress (ER stress), proapoptotic transcription factor C/EBP homologous protein (CHOP) and Bax in angiotensin II (Ang II)-induced cardiomyocyte apoptosis. Cultured neonatal rat cardiomyocytes were incubated with Ang II or antisense CHOP oligonucleotide which was used to inhibit CHOP expression. Expressions of ER chaperone immunoglobulin heavy chain-binding protein (BiP), CHOP and cytochrome c were examined by Western blotting. Mitochondrial membrane potential (MMP) was detected by a spectrofluorimeter. Apoptosis was analyzed with flow cytometry. Bax translocation was determined by double-labeling of immunofluorescence and Western blotting. Our results showed that Ang II-induced cardiomyocyte apoptosis was associated with the upregulations of BiP and CHOP, Bax translocation, MMP deplorization and cytochrome c release. These above effects were suppressed by antisense CHOP oligonucleotide. Furthermore, BiP and CHOP expressions, reactive oxygen species (ROS) production and cardiomyocyte apoptosis, which were upregulated by Ang II, were depressed by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. From our results, ROS, ER stress and CHOP-mediated Bax translocation may be involved in Ang II-induced cardiomyocyte apoptosis.

Sodium tanshinone IIA sulfonate attenuates angiotensin II-induced collagen type I expression in cardiac fibroblasts in vitro.

Cardiac fibrosis occurs after pathological stimuli to the cardiovascular system. One of the most important factors that contribute to cardiac fibrosis is angiotensin II (AngII). Accumulating studies have suggested that reactive oxygen species (ROS) plays an important role in cardiac fibrosis and sodium tanshinone IIA sulfonate (STS) possesses antioxidant action. We therefore examined whether STS depresses Ang II-induced collagen type I expression in cardiac fibroblasts. In this study, Ang II significantly enhanced collagen type I expression and collagen synthesis. Meanwhile, Ang II depressed matrix metalloproteinase-1 (MMP-1) expression and activity. These responses were attenuated by STS. Furthermore, STS depressed the intracellular generation of ROS, NADPH oxidase activity and subunit p47(phox) expression. In addition, N-acetylcysteine the ROS scavenger, depressed effects of Ang II in a manner similar to STS. In conclusion, the current studies demonstrate that anti-fibrotic effects of STS are mediated by interfering with the modulation of ROS.

Propofol depresses angiotensin II-induced cardiomyocyte hypertrophy in vitro.

Cardiomyocyte hypertrophy is formed in response to pressure or volume overload, injury, or neurohormonal activation. The most important vascular hormone that contributes to the development of hypertrophy is angiotensin II (Ang II). Accumulating studies have suggested that reactive oxygen species (ROS) may play an important role in cardiac hypertrophy. Propofol is a general anesthetic that possesses antioxidant action. We therefore examined whether propofol inhibited Ang II-induced cardiomyocyte hypertrophy. Our results showed that both ROS formation and hypertrophic responses induced by Ang II in cardiomyocytes were partially blocked by propofol. Further studies showed that propofol inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase/ERK kinase 1/2 (MEK1/2) induced by Ang II via a decrease in ROS production. In addition, propofol also markedly attenuated Ang II-stimulated nuclear factor-kappaB (NF-kappaB) activation via a decrease in ROS production. In conclusion, propofol prevents cardiomyocyte hypertrophy by interfering with the generation of ROS and involves the inhibition of the MEK/ERK signaling transduction pathway and NF-kappaB activation.

Inhibition of ethanol-induced toxicity by tanshinone IIA in PC12 cells.

AIM: To observe the effects of tanshinone IIA (Tan IIA) on the neurotoxicity induced by ethanol in PC12 cells and to explore its protective role. METHODS: PC12 cell survival was measured by MTT assay. The formation of reactive oxygen species (ROS) and lactate dehydrogenase (LDH) release were detected by 2',7'-dichlorofluorescin (DCF) fluorescence and calorimetric method, respectively. The percentage of cell apoptosis was monitored by flow cytometry. The expression of p53 was detected by immuno-fluorescence and flow cytometry. RESULTS: Ethanol significantly impaired the survival of PC12 cells as demonstrated by MTT assay. Ethanol also induced significant ROS formation and increased LDH release. Pre-incubation with Tan IIA in the culture medium significantly reversed these changes. Ethanol caused cell apoptosis and the upregulation of p53 protein. The anti-apoptosis effects of Tan IIA on ethanol-induced toxicity were accompanied by the downregulation of pro-apoptotic p53 protein expression. CONCLUSION: Tan IIA can protect neurons from apoptosis and might serve as a potential therapeutic drug for neurological disorders induced by ethanol.