Intrahepatic Cholangiocarcinoma in Wilson's Disease: A Case Report.

BACKGROUND Wilson's disease is a rare autosomal recessive disorder characterized by excessive accumulation of copper in the liver, brain, and kidneys. Although it affects only approximately 1 in 30 000 individuals, it leads to progressive liver damage and neurological issue. Wilson's disease presents a wide spectrum of clinical manifestations related to hepatic disease, ranging from asymptomatic cases to acute liver failure. The occurrence of hepatobiliary malignancies, including intrahepatic cholangiocarcinoma, is relatively uncommon in Wilson's disease, even among patients with cirrhosis. Only 14 cases have been published so far, including the present report, and its etiology remains unclear. CASE REPORT We report the successful treatment of intrahepatic cholangiocarcinoma in a 39-year-old woman with Wilson's disease. Twenty-two years after being diagnosed with Wilson's disease, intrahepatic cholangiocarcinoma was diagnosed. She had an intrahepatic mass that was found to be a 4.3-cm ill-defined hypodense lesion in liver segment 3/4, with features suggesting infiltrative intrahepatic cholangiocarcinoma rather than hepatocellular carcinoma. Laboratory results showed slightly elevated liver enzymes and tumor markers. There was no evidence of metastasis on chest computed tomography or positron emission tomography, and the tumor was resectable, so surgery was the first-choice treatment option. Left hepatectomy was performed successfully, and the final pathology confirmed adenocarcinoma with clear resection margins. The patient received adjuvant chemotherapy with capecitabine. To date, the patient has been doing well without evidence of recurrence or metastasis. CONCLUSIONS Despite limited knowledge regarding hepatic malignancy in Wilson's disease, it is crucial to prioritize careful monitoring and develop suitable treatment strategies upon diagnosis to achieve favorable outcomes, considering the potential occurrence of intrahepatic cholangiocarcinoma in Wilson's disease.

α-Iso-cubebene attenuates neointima formation by inhibiting HMGB1-induced monocyte to macrophage differentiation via suppressing ROS production.

α-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis, a medicinal herb used to improve cardiovascular symptoms. To investigate the mechanisms involved, the effects of ICB on cellular production of reactive oxygen species (ROS) was determined using cultured human THP-1 cells. When THP-1 cells were stimulated with HMGB1, cellular concentration of ROS was increased in dose- and time-dependent manners. These increases were significantly attenuated in cells pretreated with NADPH oxidase inhibitors, diphenyleneiodonium chloride and apocynin, but not by other inhibitors related to ROS generation in monocytes. The expression of constitutively expressed NADPH oxidase (NOX) subunits including NOX1, NOX2, NOX4 and NOX5 was not affected by HMGB1, but HMGB1-induced ROS production was exclusively attenuated in NOX2-deficient cells using siRNA, suggesting an enhanced NOX2 complex assembly. When cells were stimulated with HMGB1, p47phox phosphorylation at ser345, ser359 and ser370 was increased in dose- and time-dependent manners, which were significantly attenuated in ICB (3-10 µg/mL)-pretreated cells. In addition, HMGB1-induced monocyte-macrophage differentiation (MMD) in bone marrow-derived cells isolated from mice were significantly attenuated in cells treated with apocynin and ICB. Also, macrophage infiltration and intimal hyperplasia in the wire-injured femoral artery were significantly attenuated in ICB-treated mice compared to wild-type control mice. The results of this study show that ICB inhibits HMGB1-induced MMD by suppressing ROS production in monocytes, thus suggest that ICB has therapeutic potential for vascular inflammation with subsequent intimal hyperplasia related to vascular injury.

Liquiritigenin inhibits hepatic fibrogenesis and TGF-ß1/Smad with Hippo/YAP signal.

BACKGROUND: Recent reports highlighted the possibility that Yes-associated protein (YAP) and transforming growth factor-ß1 (TGF-ß1) can act as critical regulators of hepatic stellate cells (HSCs) activation; therefore, it is natural for compounds targeting Hippo/YAP and TGF-ß1/Smad signaling pathways to be identified as potential anti-fibrotic candidates. PURPOSE: Liquiritigenin (LQ) is an aglycone of liquiritin and has been reported to protect the liver from injury. However, its effects on the Hippo/YAP and TGF-ß1/Smad pathways have not been identified to date. METHODS: We conducted a series of experiments using CCl4-induced fibrotic mice and cultured LX-2 cells. RESULT: LQ significantly inhibited liver fibrosis, as indicated by decreases in regions of hepatic degeneration, inflammatory cell infiltration, and the intensity of α-smooth muscle actin (α-SMA) staining in mice. Moreover, LQ blocked the TGF-ß1-induced phosphorylation of Smad 3, and the transcript levels of plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase-2 (MMP-2) in LX-2 cells, which is similar with resveratrol and oxyresveratrol (positive controls). Furthermore, LQ increased activation of large tumor suppressor kinase 1 (LATS1) with the induction of YAP phosphorylation, thereby preventing YAP transcriptional activity and suppressing the expression of exacerbated TGF-ß1/Smad signaling molecules. CONCLUSION: These results clearly show that LQ ameliorated experimental liver fibrosis by acting on the TGF-ß1/Smad and Hippo/YAP pathways, indicating that LQ has the potential for effective treatment of liver fibrosis.

Oxyresveratrol ameliorates nonalcoholic fatty liver disease by regulating hepatic lipogenesis and fatty acid oxidation through liver kinase B1 and AMP-activated protein kinase.

Oxyresveratrol (OXY) is a naturally occurring polyhydroxylated stilbene that is abundant in mulberry wood (Morus alba L.), which has frequently been supplied as a herbal medicine. It has been shown that OXY has regulatory effects on inflammation and oxidative stress, and may have potential in preventing or curing nonalcoholic fatty liver disease (NAFLD). This study examined the effects of OXY on in vitro model of NAFLD in hepatocyte by the liver X receptor α (LXRα)-mediated induction of lipogenic genes and in vivo model in mice along with its molecular mechanism. OXY inhibited the LXRα agonists-mediated sterol regulatory element binding protein-1c (SREBP-1c) induction and expression of the lipogenic genes and upregulated the mRNA of fatty acid ß-oxidation-related genes in hepatocytes, which is more potent than genistein and daidzein. OXY also induced AMP-activated protein kinase (AMPK) activation in a time-dependent manner. Moreover, AMPK activation by the OXY treatment helped inhibit SREBP-1c using compound C as an AMPK antagonist. Oral administration of OXY decreased the Oil Red O stained-positive areas significantly, indicating lipid droplets and hepatic steatosis regions, as well as the serum parameters, such as fasting glucose, total cholesterol, and low density lipoprotein-cholesterol in high fat diet fed-mice, as similar with orally treatment of atorvastatin. Overall, this result suggests that OXY has the potency to inhibit hepatic lipogenesis through the AMPK/SREBP-1c pathway and can be used in the development of pharmaceuticals to prevent a fatty liver.

Fucoxanthin, the constituent of Laminaria japonica, triggers AMPK-mediated cytoprotection and autophagy in hepatocytes under oxidative stress.

BACKGROUND: Laminaria japonica has frequently been used as a food supplement and drug in traditional oriental medicine. Among the major active constituents responsible for the bioactivities of L. japonica, fucoxanthin (FX) has been considered as a potential antioxidant. This study was conducted to examine the effects of L. japonica extract (LJE) or FX against oxidative stress on hepatocytes and to elucidate the overall their cellular mechanisms of the effects. METHODS: We constructed an in vitro model with the treatment of arachidonic acid (AA) + iron in HepG2 cells to stimulate the oxidative damage. The cells were pre-treated with LJE or FX for 1 h, and incubated with AA + iron. The effect on oxidative damage and cellular mechanisms of LJE or FX were assessed by cytological examination and several biochemical assays under conditions with or without kinase inhibitiors. RESULTS: LJE or FX pretreatment effectively blocked the pathological changes caused by AA + iron treatment, such as cell death, altered expression of apoptosis-related proteins such as procaspase-3 and poly (ADP-ribose) polymerase, and mitochondria dysfunction. Moreover, FX induced AMPK activation and AMPK inhibitor, compound C, partially reduced the protective effect of FX on mitochondria dysfunction. Consistent with AMPK activation, FX increased the protein levels of autophagic markers (LC3II and beclin-1) and the number of acridine orange stained cells, and decreased the phosphorylation of mTOR and simultaneously increased the phosphorylation of ULK1. And the inhibition of autophagy by 3-methylanine or bafilomycin A1 partially inhibited the protective effect of FX on mitochondria dysfunction. CONCLUSION: These findings suggest that FX have the function of being a hepatic protectant against oxidative damages through the AMPK pathway for the control of autophagy.

Sauchinone exerts anticancer effects by targeting AMPK signaling in hepatocellular carcinoma cells.

Sauchinone is a pharmacologically active compound isolated from Saururus chinensis, which has been used as a traditional Oriental medicine to treat fever, jaundice, and various inflammatory diseases. In this study, we investigated the effect of sauchinone against hepatocellular carcinoma (HCC) and sought to elucidate the mechanism involved. Cell viability was measured by an MTT assay. Cell cycle distributions and the mitochondrial membrane potential were analyzed using flow cytometry. Cell death was analyzed by annexin V assay, 4',6-diamidino-2-phenylindole staining, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Protein and mRNA levels were assessed by western blot and real-time PCR, respectively. Malignant properties were investigated by a wound healing migration assay and invasion assay. Sauchinone suppressed the proliferation of human HCC cells in a dose-dependent manner. Moreover, it induced the G0/G1 phase cell cycle arrest and mitochondrial dysfunction and then triggered the apoptosis by activating the JNK/p38 pathway in Huh-7 cells. In addition, sauchinone induced the activation of the AMP-activated protein kinase (AMPK) pathway, and compound C (an AMPK inhibitor) blocked the sauchinone-induced mitochondrial dysfunction. The AMPK activation by sauchinone inhibited the phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream targets, such as ribosomal protein S6 kinase 1 and eIF4E-binding protein 1. Furthermore, sauchinone attenuated key proangiogenic factors, including hypoxia-inducible factor-1α, vascular endothelial growth factor, and plasminogen activator inhibitor-1, resulting in decreased migration and invasion of HCC cells. These results provide evidence for sauchinone to be considered as a potent anticancer agent by targeting of the AMPK-mTOR pathway in HCC.

Cordyceps militaris Enhances Cell-Mediated Immunity in Healthy Korean Men.

Cordyceps militaris is a mushroom traditionally used for diverse pharmaceutical purposes in East Asia, including China, and has been found to be effective for enhancing immunity through various types of animal testing. The aim of this study is to determine the efficacy of C. militaris for enhancing cell-mediated immunity and its safety in healthy male adults. Healthy male adults were divided into the experimental group (n = 39), given 1.5 g/day of ethanol treated C. militaris in capsules, and the control group (n = 40), given the same number of identical placebo capsules filled with microcrystalline cellulose and lactose for 4 weeks from February 13 to March 14, 2012; the natural killer (NK) cell activity, lymphocyte proliferation index (PI), and T-helper cell 1 (Th1) cytokine cluster (interferon [IFN]-γ, interleukin [IL]-12, IL-2, and tumor necrosis factor [TNF]-α) were measured, along with stability test, at weeks 0, 2, and 4. The C. militaris group showed a statistically significant greater increase in NK200 (P = .0010), lymphocyte PI (P ≤ .0001), IL-2 (P = .0096), and IFN-γ (P = .0126), compared with the basal level, than the placebo group. There was no statistically significant adverse reaction. C. militaris enhanced the NK cell activity and lymphocyte proliferation and partially increased Th1 cytokine secretion. Therefore, C. militaris is safe and effective for enhancing cell-mediated immunity of healthy male adults.

Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway.

BACKGROUND: Korean ginseng (Panax ginseng C.A. Meyer) has been used as a botanical medicine throughout the history of Asian traditional Oriental medicine. Formulated red ginseng (one form of Korean ginseng) has been shown to have antioxidant and chemopreventive effects. METHODS: This study investigated the cytoprotective effects and mechanism of action of Korean red ginseng extract (RGE) against severe ROS production and mitochondrial impairment in a cytotoxic cell model induced by AA + iron. RESULTS: RGE protected HepG2 cells from AA + iron-induced cytotoxicity by preventing the induction of mitochondrial dysfunction and apoptosis. Moreover, AA + iron-induced production of ROS and reduction of cellular GSH content (an important cellular defense mechanism) were remarkably attenuated by treatment with RGE. At the molecular level, treatment with RGE activated LKB1-dependent AMP-activated protein kinase (AMPK), which in turn led to increased cell survival. The AMPK pathway was confirmed to play an essential role as the effects of RGE on mitochondrial membrane potential were reversed upon treatment with compound C, an AMPK inhibitor. CONCLUSIONS: Our results demonstrate that RGE has the ability to protect cells from AA + iron-induced ROS production and mitochondrial impairment through AMPK activation.

Stanford type A aortic dissection secondary to infectious aortitis: a case report.

Nowadays, infectious aortitis has become a rare disease thanks to antibiotics, but remains life-threatening. We present a case of a patient with acupuncture-induced infectious aortitis leading to aortic dissection. Chest computed-tomogram scan revealed Stanford type A dissection with pericardial effusion. Under the impression of an impending rupture, emergent surgery was performed. During surgery, infectious aortitis was identified incidentally, so she underwent resection of the infected aorta including surrounding tissues. Then the ascending aorta and hemi-arch were replaced with a prosthetic graft as an in situ fashion. The resected tissue and blood cultures revealed Staphylococcus aureus, so prolonged antibiotherapy was prescribed.