Exploring the feasibility of robotic liver resection in a limited resource setting.

The transition from open hepatectomy to minimally invasive techniques has reduced morbidity and mortality. However, laparoscopic liver resection (LLR) requires substantial expertise. Robotic liver resection (RLR) combines minimal invasiveness with open surgical precision. It may facilitate complex procedures without the learning required for LLR. We evaluated RLR outcomes in a limited resource setting and assessed its efficacy and practicality. This retrospective study analyzed 67 robotic hepatectomies conducted from 2020 to 2023. Demographic, perioperative factors, and surgical outcomes were analyzed. Major hepatectomies were required in 46/67 (68.7%) patients who underwent RLR. No open conversions, 30-day mortalities, or readmissions occurred. Complications occurred in 7.4% of patients; major complications occurred in 5.9%. Learning curve analysis showed a negative correlation between operation sequence and operative time. Effective use of robotic technology combined with the expertise of well-trained surgeons facilitates successful execution of RLR with feasible surgical outcomes, even at smaller centers.

Comparative analysis of robotic single-site cholecystectomy outcomes between novice and expert surgeons.

Single-incision laparoscopic cholecystectomy (SILC) has declined in popularity, posing a challenge for novice surgeons. However, robotic single-site cholecystectomy (RSSC) has gained popularity in hepatopancreatic surgery, suggesting a paradigm shift in minimally invasive procedures due to the advantages of robotic platforms. The purpose of this study was to compare the surgical outcomes and learning curves between experts and novices without SILC experience, and discuss the utility and potential of RSSC for novice surgeons. A total of 235 patients underwent RSSC between April 2019 and June 2023 at the OOO University Hospital. Among them, 31 cases from novice and expert surgeons were selected to compare their initial experience. Comprehensive demographic and perioperative factors were analyzed and statistical comparisons were made, including cumulative sum analysis (CUSUM) for learning curves. The demographic factors showed no statistically significant differences between the two groups. Although the docking time (P < 0.001) and hospital stay (P = 0.014) were statistically significant, the total operative time and other perioperative factors were comparable. Novice surgeons demonstrated a shorter absolute total operative time, primarily attributed to differences in docking time. The CUSUM analysis indicated a shorter learning curve for novice surgeons. This study shows that the inherent benefits of the robotic platform make it an accessible and reproducible technique for novices. The benefits of integrating observational learning into robotic surgery training programs and the intrinsic advantages of the robotic platform in minimizing the learning curve for RSSC were also highlighted.

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.

Propensity Score Matched Comparison of Robotic Single-Site and Laparoscopic Cholecystectomy.

Background and Objectives: To demonstrate the feasibility and potential of robotic single-site cholecystectomy, the study aimed to compare it with conventional laparoscopic cholecystectomy. Methods: In total, 791 consecutive patients underwent conventional laparoscopic cholecystectomy or robotic single-site cholecystectomy at our center between 2019 and 2022. After 1:1 propensity score matching, 117 patients for each group were selected. Results: After propensity score matching, the only statistically significant difference between conventional laparoscopic cholecystectomy and robotic single-site cholecystectomy was operative time, which was 29.15 ±11.45 min in the conventional laparoscopic cholecystectomy group versus 38.57 ± 12.59 min in the robotic single-site cholecystectomy group (P < 0.001). Because the difference in surgical time between the two groups was minimal, it has little clinical relevance. Using cumulative sum analysis, the maturation phase of the total operation and docking times occurred after the 53rd case. To reduce bias, a comparison of results with conventional laparoscopic cholecystectomy and cases of robotic single-site cholecystectomy was performed in the maturation phase, which revealed only total operative time as statistically significant (P < 0.001). Conclusion: Robotic single-site cholecystectomy is a technically feasible and safe method for treating benign gallbladder diseases, with a relatively short learning curve and reasonable operative time.

Construction of a risk scoring system using clinical factors and RYR2 polymorphisms for bleeding complications in patients on direct oral anticoagulants.

Introduction: Bleeding is one of the most undesirable complications of direct oral anticoagulants (DOACs). While the ryanodine receptor (RYR2) has been related to cardiac diseases, research on bleeding complications is lacking. This study aimed to elucidate the association between RYR2 and bleeding risk to develop the risk scoring system in patients treated with DOACs. Methods: This study was a retrospective analysis of prospectively collected samples. We selected ten SNPs within the RYR2 gene, and two models were constructed (Model I: demographic factors only, Model II: demographic and genetic factors) in multivariable analysis. Independent risk factors for bleeding were used to develop a risk scoring system. Results: A total of 447 patients were included, and 49 experienced either major bleeding or clinically relevant non-major bleeding. In Model I, patients using rivaroxaban and experiencing anemia exhibited an increased bleeding risk after adjusting for covariates. Upon incorporating genetic factors into Model I, a significant association with bleeding was also observed in cases of overdosing on DOACs and in patients with a creatinine clearance (CrCl) < 30 mL/min, in addition to rivaroxaban and anemia (Model II). Among genetic factors, RYR2 rs12594 GG, rs17682073 AA, rs3766871 GG, and rs6678625 T alleles were associated with bleeding complications. The area under the receiver operating characteristic curve (AUROC) of Model I was 0.670, whereas that of Model II increased to 0.803, demonstrating better performance with the inclusion of genetic factors. Using the significant variables in Model II, a risk scoring system was constructed. The predicted bleeding risks for scores of 0, 1-2, 3-4, 5-6, 7-8, and 9-10 points were 0%, 1.2%, 4.6%, 15.7%, 41.7%, and 73.3%, respectively. Conclusion: This study revealed an association between RYR2 and bleeding complications among patients taking DOACs and established a risk scoring system to support individualized DOAC treatment for these patients.

Association between SLCO1B1 genetic polymorphisms and bleeding risk in patients treated with edoxaban.

Since SLCO1B1 encodes the uptake transporter OATP1B1, which can influence the pharmacokinetic and pharmacodynamic profiles of edoxaban, polymorphisms in SLCO1B1 may affect the edoxaban response. This study aimed to investigate the association between SLCO1B1 gene polymorphisms and the bleeding risk in patients receiving edoxaban. We genotyped 10 single-nucleotide polymorphisms (SNPs) from the SLCO1B1 gene in patients receiving edoxaban. We also analyzed rs3842 of ABCB1 as a confounder. The odds ratio (OR) and adjusted OR (AOR) were calculated from univariate and multivariable analysis, respectively. The area under the receiver operating characteristic curve (AUROC) was constructed for the discrimination of the model. A total of 159 patients receiving edoxaban were analyzed. Overdose and rs4149056 showed significant association with bleeding complications by around 11- and 5.5-fold, respectively. Additionally, patients with the rs4149057 variant allele (C) had a 3.9-fold increased bleeding risk compared with wild-type homozygote carriers (TT), whereas rs2306283 variant homozygote (GG) carriers had a 0.27-fold reduced bleeding risk compared with wild-type allele (A) carriers. Patients with the variant-type homozygote (CC) of ABCB1 rs3842 had a higher bleeding risk than T allele carriers (AOR = 5.3 and 5.9). The final models for multivariable analyses were acceptable based on the AUROC values (> 0.70). These findings may help predict bleeding risk in patients taking edoxaban and help personalize treatment.

Effectiveness and Safety of Recombinant Human Follicle-Stimulating Hormone (Follitrope™) in Inducing Controlled Ovarian Stimulation in Infertile Women in Real-World Practice: a Prospective Cohort Study.

To evaluate the safety and effectiveness of recombinant human follicle-stimulating hormone (rhFSH [Follitrope™]) in infertile women undergoing in vitro fertilization (IVF). To identify predictors of ovarian response that induce optimal clinical outcomes. This multicenter prospective study enrolled infertile women who were scheduled to undergo IVF after ovarian stimulation with rhFSH (Follitrope™) following the gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist protocol. Predictive factors for ovarian response were identified in the GnRH antagonist group based on the number of oocytes retrieved. A total of 516 infertile women were enrolled, among whom 136 (except one who withdrew before administration) received rhFSH using the GnRH agonist protocol and 379 using the antagonist protocol. The mean number of oocytes retrieved was 13.4 in the GnRH agonist group and 13.6 in the GnRH antagonist group. The clinical pregnancy rates were 32.3% (30/93) and 39.9% (115/288) in the GnRH agonist and antagonist groups, respectively. The incidence of ovarian hyperstimulation syndrome was 1.8% and 3.4% in the GnRH agonist and antagonist groups, respectively. No other significant safety risks associated with rhFSH administration were identified. Body mass index, basal serum FSH and anti-Müllerian hormone levels, and antral follicle count were identified as predictors of ovarian response by multiple regression with backward elimination, and the final regression model accounted for 26.5% of the response variability. In real-world practice, rhFSH (Follitrope™) is safe and effective in inducing ovarian stimulation in infertile women. Patient characteristics identified as predictors can be considered to be highly related to optimal clinical outcomes.

Six-Transmembrane Epithelial Antigen of Prostate 4: An Indicator of Prognosis and Tumor Immunity in Hepatocellular Carcinoma.

Purpose: The six-transmembrane epithelial antigen of prostate 4 (STEAP4) has been linked to tumor progression via its involvement in inflammatory responses, oxidative stress, and metabolism. However, STEAP4 has rarely been studied in hepatocellular carcinoma (HCC). We explored STEAP4 expression associated with tumor prognosis to understand its role in tumor biology in HCC. Patients and Methods: STEAP4 mRNA and protein expressions were primarily analyzed using bioinformatics tools based on The Cancer Genome Atlas database to understand the expression pattern, molecular mechanism, prognostic impact, and association with immune cell infiltration. We further investigated the association between STEAP4 protein expression and clinicopathological parameters and their predictive value in HCC patients using immunohistochemical staining of tissue microarrays. Results: The expression of STEAP4 mRNA and protein in HCC tissues was significantly lower than in normal liver tissues. Reduced expression of STEAP4 was linked to advanced HCC stages, poor recurrence-free survival (RFS), and overall survival. Furthermore, reduced STEAP4 expression was a significant predictor of worse RFS in univariate and multivariate analyses in the immunohistochemical cohort. GO, KEGG, and GSEA analyses revealed that STEAP4 is related to numerous biological processes and pathways, including drug metabolism, DNA replication, RNA metabolism, and immune response. In terms of the immune system, the decreased level of STEAP4 was correlated with the immunosuppressive microenvironment. Conclusion: Our data indicated that reduced STEAP4 expression was significantly associated with tumor aggressiveness and poor prognosis, possibly because of its link to various biological processes and induction of HCC immune evasion. Therefore, STEAP4 expression may serve as a potential prognostic biomarker for cancer progression and immunity, as well as a therapeutic target in HCC.

Early Experience of Pure Robotic Right Hepatectomy for Liver Donors in a Small-Volume Center.

Background and Objectives: Living donor right hepatectomy has become the most common method of liver transplantation. With minimally invasive surgery, laparoscopic donor hepatectomy became possible, but with some limitations. Advancements in robotic technology made it possible to overcome these shortcomings and maximize the advantages of minimally invasive surgery in transplantation. For this reason, some centers have started robotic donor hepatectomy. Our study aimed to introduce our early experience of robotic donor right hepatectomy and investigate the feasibility of this surgery. Methods: This study included 10 (30%) living donors who underwent pure robotic donor right hepatectomy at Dong-A University Hospital from January 1, 2020 to December 31, 2021. The medical records were analyzed to determine the short-term outcomes of these patients. Results: The total operation time and warm ischemic time were 396.6 min ± 62.7 min and 19.7 min± 5.6 min, respectively. Moreover, there was no transfusion during the operation and no other port use and open conversion. The average real graft volume was 590 mL ± 73.5 mL, and the mean hospital stay was 8.7 d ± 2.6 d. There have been no specific complications noted in the donor group. Conclusions: Based on our positive experience with pure robotic right hepatectomy for a liver donor, the robotic technique may be a new option for achieving minimally invasive surgery for a liver donor.

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.

Effect of ITPA Polymorphism on Adverse Drug Reactions of 6-Mercaptopurine in Pediatric Patients with Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

6-Mercaptopurine (6-MP) is a cornerstone of the maintenance regimen for pediatric acute lymphoblastic leukemia (ALL). Inosine triphosphate pyrophosphatase (ITPA) is considered a candidate pharmacogenetic marker that may affect metabolism and 6-MP-induced toxicities; however, the findings are inconsistent. Therefore, we attempted to evaluate the effect of ITPA 94C>A polymorphism on 6-MP-induced hematological toxicity and hepatotoxicity through a systematic review and meta-analysis. A literature search for qualifying studies was conducted using the PubMed, Web of Science, and Embase databases until October 2021. Overall, 10 eligible studies with 1072 pediatric ALL patients were included in this meta-analysis. The results indicated that ITPA 94C>A was significantly associated with 6-MP-induced neutropenia (OR 2.38, 95% CI: 1.56−3.62; p = 0.005) and hepatotoxicity (OR 1.98, 95% CI: 1.32−2.95; p = 0.0009); however, no significant association was found between the ITPA 94C>A variant and 6-MP-induced leukopenia (OR 1.75, 95% CI: 0.74−4.12; p = 0.20). This meta-analysis demonstrated that ITPA 94C>A polymorphism could affect 6-MP-induced toxicities. Our findings suggested that ITPA genotyping might help predict 6-MP-induced myelosuppression and hepatotoxicity.

Inflammatory myofibroblastic tumors arising from pancreas head and peri-splenic area mimicking a malignancy.

Inflammatory myofibroblastic tumors (IMTs) are a rare chronic inflammatory disease with unclear pathogenesis and pathological features that are not those of a malignant tumor. It is difficult to differentially diagnose them without surgical excision because of their unpredictable clinical behavior, which ranges from benign to locally invasive aggressiveness. We report two cases of IMTs that were diagnosed after surgery. In one case, the IMT originated in peri-splenic area in a 63-year-old female patient. The other case involved a 48-year-old female patient who suffered from an IMT of the head of the pancreas. Both of these cases did not require further treatment based on histological findings, and there has been no evidence of recurrence or metastasis so far. These cases show that the primary choice for the exact diagnosis and proper treatment of IMTs is complete surgical resection.

Continuous quality improvement program and its results of Korean Society for Cytopathology.

BACKGROUND: Since 1995, the Korean Society for Cytopathology has overseen the Continuous Quality Improvement program for cytopathology laboratories. The Committee of Quality Improvement has carried out an annual survey of cytology data for each laboratory and set standards for proficiency tests. METHODS: Evaluations were conducted four times per year from 2008 to 2018 and comprised statistics regarding cytology diagnoses of previous years, proficiency tests using cytology slides provided by the committee, assessment of adequacy of gynecology (GYN) cytology slides, and submission of cytology slides for proficiency tests. RESULTS: A total of 206 institutes participated in 2017, and the results were as follows. The number of cytology tests increased from year to year. The ratio of liquid-based cytology in GYN gradually decreased, as most of the GYN cytology had been performed at commercial laboratories. The distribution of GYN diagnoses demonstrated nearly 3.0% as atypical squamous cells. The rate for squamous cell carcinoma was less than 0.02%. The atypical squamous cell/squamous intraepithelial lesion ratio was about 3:1 and showed an upward trend. The major discordant rate of cytology-histology in GYN cytology was less than 1%. The proficiency test maintained a major discordant rate less than 2%. The rate of inappropriate specimens for GYN cytology slides gradually decreased. CONCLUSIONS: The Continuous Quality Improvement program should be included in quality assurance programs. Moreover, these data can contribute to development of national cancer examination guidelines and facilitate cancer prevention and treatment.

Single-Port Laparoscopic and Robotic Cholecystectomy in Obesity (>25 kg/m2).

BACKGROUND AND OBJECTIVES: Single-port cholecystectomy has emerged as an alternative technique to reduce the number of ports and improve cosmesis. Few previous studies have assessed obesity-related surgical outcomes following single-port cholecystectomy. In this study, technical feasibility and surgical outcomes of single-port laparoscopic cholecystectomy (SPLC) and robotic single-site cholecystectomy (RSSC) in obese patients were investigated. METHODS: We conducted a two-center collaborative study and retrospectively reviewed initial experiences of RSSC and SPLC in patients whose body mass index was over 25 kg/m2. Medical records of patients were reviewed. Clinical characteristics and short-term oncologic outcomes were considered and compared between SPLC and RSSC groups. RESULTS: RSSC and SPLC were performed in 39 and 78 patients, respectively. In comparative analysis, the total operative time was longer in the RSSC group (109.92 minutes vs. 60.99 minutes; P < .001).However, requiring additional port for completion of surgical procedure was less frequent in the RSSC group (0% vs. 12.8%; P = .029). Immediate postoperative pain score was not significantly different between the two groups (4.95 vs. 5.00; P = .882). However, pain score was significantly lower in the RSSC group at the time of discharge (1.79 vs. 2.38; P = .010). Conversion to conventional multiport cholecystectomy, intraoperative bile spillage, or complication rate was not significantly different between the two groups (P > .05). CONCLUSIONS: SPLC and RSSC could be safely performed in selected patients with high body mass index, showing no significant clinical differences.

Early experience of laparoscopic liver resection: A single institution experience with 37 consecutive cases.

BACKGROUNDS/AIMS: Laparoscopic liver resection (LLR) has evolved and broadened in scope. While open liver resections are currently being performed safely in our hospital, LLRs are being implemented in fewer cases. The aim of this study was to review our initial experience in LLR to assess early outcomes of the procedure. METHODS: A retrospective chart review was conducted for 37 patients who underwent laparoscopic liver resections for various indications between January 2014 and July 2017 by a single surgeon who had performed 161 open liver resections and 50 live donor hepatectomies during the same period. RESULTS: Of 37 laparoscopic liver resections performed, male to female ratio was 23 to 4. Their mean age was 61.4 years. There were 13 cases of wedge resections, 7 cases of left lateral sectionectomy, 9 cases of left hepatectomy, and 8 cases of right hepatectomy. Pathology included hepatocellular carcinoma (n=20), cholangiocarcinoma (n=3), intrahepatic duct stones (n=6), metastatic liver carcinoma (n=6), primary neuroendocrine tumor of liver (n=1), and huge hemangioma (n=1). The mean operation time was 174.7 minutes (range, 40-410 minutes). Mean blood loss was 200.5 ml (range, 10-2200 ml). There were no open-conversion cases. There were no intraoperative or postoperative complications except that a case of severe portal vein stenosis in the laparoscopic right hepatectomy occurred postoperatively. The patient underwent reoperation (portal vein resection and anastomosis, stenting). The mean hospital stay was 8.7 days (range, 2-44 days). CONCLUSIONS: Even though our experience in laparoscopic liver resection is still developing, our results are comparable to those of other studies. Therefore, an experienced surgeon in performing open liver resection should be able to perform the laparoscopic liver resection safely.

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.

Single Port Laparoscopic Cholecystectomy in a Patient with Situs Inversus Totalis: A Case Report.

The use and application of a laparoscopic cholecystectomy has been regarded as a first-choice treatment option for benign gallbladder disease, even if patients have situs inversus totalis. Furthermore, surgical procedures in general are becoming less invasive, because of both patient and surgeon preferences for reduced trauma and improved cosmetic outcomes attributable to minimized incisions. A 37 years old man was aware of situs inversus totalis with chronic cholecystitis. The operation was successfully performed without any specific complications. Single port laparoscopic cholecystectomy, in an experienced operator, is possible even in patients with situs inversus totalis.

Salinomycin ameliorates oxidative hepatic damage through AMP-activated protein kinase, facilitating autophagy.

Salinomycin, a monocarboxylic ionophore in Streptomyces albus, has been studied as an anti-cancer agent. However, we wondered whether salinomycin has another effect such as an anti-oxidant and hepatic protectant, because some chemical drugs treating human diseases were sometimes related with their toxic effects. Therefore, this study was conducted to examine the effects of salinomycin against oxidative stress and mitochondrial impairment in vivo and in vitro as well as the cellular mechanisms of action. In hepatocyte, salinomycin inhibited arachidonic acid (AA) + iron-induced apoptosis, mitochondrial dysfunction and ROS production. As a molecular mechanism, salinomycin induced autophagy through AMP-activated protein kinase (AMPK) activation, as assessed by the accumulation of acidic vesicle organelles, p62 and LC3-II. Moreover, these protective effects were blocked by AMPK inhibition, which indicates the importance of AMPK in the process of salinomycin's effects. In mice, oral administration of salinomycin protected against carbon tetrachloride (CCl4)-induced oxidative stress and liver injury, and also activated AMPK as well as autophagy-related proteins in the liver. Collectively, salinomycin had the ability to protect hepatocytes against AA+iron-induced reactive oxygen species production and mitochondrial dysfunction, as well as CCl4-induced liver injury. Although this beneficial effect was demonstrated under severe oxidative stress, this study showed that salinomycin protected the liver against the oxidative stress and liver damage through AMPK and autophagy, and suggest that salinomycin has a possibility to treat a broad range of diseases.

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.