Pharmacological Prevention of Ectopic Erythrophagocytosis by Cilostazol Mitigates Ferroptosis in NASH.

Hepatic iron overload (HIO) is a hallmark of nonalcoholic fatty liver disease (NAFLD) with a poor prognosis. Recently, the role of hepatic erythrophagocytosis in NAFLD is emerging as a cause of HIO. We undertook various assays using human NAFLD patient pathology samples and an in vivo nonalcoholic steatohepatitis (NASH) mouse model named STAMTM. To make the in vitro conditions comparable to those of the in vivo NASH model, red blood cells (RBCs) and platelets were suspended and subjected to metabolic and inflammatory stresses. An insert-coculture system, in which activated THP-1 cells and RBCs are separated from HepG2 cells by a porous membrane, was also employed. Through various analyses in this study, the effect of cilostazol was examined. The NAFLD activity score, including steatosis, ballooning degeneration, inflammation, and fibrosis, was increased in STAMTM mice. Importantly, hemolysis occurred in the serum of STAMTM mice. Although cilostazol did not improve lipid or glucose profiles, it ameliorated hepatic steatosis and inflammation in STAMTM mice. Platelets (PLTs) played an important role in increasing erythrophagocytosis in the NASH liver. Upregulated erythrophagocytosis drives cells into ferroptosis, resulting in liver cell death. Cilostazol inhibited the augmentation of PLT and RBC accumulation. Cilostazol prevented the PLT-induced increase in ectopic erythrophagocytosis in in vivo and in vitro NASH models. Cilostazol attenuated ferroptosis of hepatocytes and phagocytosis of RBCs by THP-1 cells. Augmentation of hepatic erythrophagocytosis by activated platelets in NASH exacerbates HIO. Cilostazol prevents ectopic erythrophagocytosis, mitigating HIO-mediated ferroptosis in NASH models.

Hepatic STAMP2 alleviates polychlorinated biphenyl-induced steatosis and hepatic iron overload in NAFLD models.

Polychlorinated biphenyls (PCBs) have been associated with neurotoxicity, hepatoxicity, oncogenicity, and endocrine-disrupting effects. Although the recent studies have demonstrated that PCB exposure leads to nonalcoholic fatty liver disease (NAFLD), the underlying mechanism has remained unsolved. In this study, we examined the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, and PCB 126 in C57BL/6 mice. Male C57Bl/6 mice were fed a standard diet or a 60% high-fat diet and exposed to Aroclor 1260 (10 mg/kg or 20 mg/kg) or PCB 126 (1 mg/kg or 5 mg/kg) by intraperitoneal injection for a total of four injections (2, 3, 4, and 5 weeks) for 6 weeks. In mice, both Aroclor 1260 and PCB 126-induced liver damage, hepatic steatosis and inflammation. We also observed that PCB exposure-induced hepatic iron overload (HIO). We previously demonstrated that hepatic six transmembrane protein of prostate 2 (STAMP2) may represent a suitable therapeutic target for NAFLD patients. Thus, we further examined whether hepatic STAMP2 is involved in PCB-induced NAFLD. We observed that hepatic STAMP2 was significantly decreased in PCB-induced NAFLD models in vivo and in vitro. Furthermore, overexpression of hepatic STAMP2 using an adenoviral delivery system resulted in improvement of PCB-induced steatosis and HIO in vivo and in vitro. Our findings indicate that enhancing hepatic STAMP2 expression represents a potential therapeutic avenue for the treatment of PCB exposure-induced NAFLD.

Hepatic STAMP2 mediates recombinant FGF21-induced improvement of hepatic iron overload in nonalcoholic fatty liver disease.

Although previous studies have shown that the administration of fibroblast growth factor 21 (FGF21) reverses hepatic steatosis, the mechanism by which FGF21 exerts a therapeutic effect on nonalcoholic fatty liver disease (NAFLD) is not yet entirely understood. We previously demonstrated that hepatic six transmembrane protein of prostate 2 (STAMP2) may represent a suitable target for NAFLD. We investigated the mechanism underlying the therapeutic effect of recombinant FGF21 on NAFLD, focusing on the involvement of hepatic STAMP2. In this study, we used human nonalcoholic steatosis patient pathology samples, C57BL/6 mice for a high-fat diet (HFD)-induced in vivo NAFLD model, and used human primary hepatocytes and HepG2 cells for oleic acid (OA)-induced in vitro NAFLD model. We observed that recombinant FGF21 treatment ameliorated hepatic steatosis and insulin resistance through the upregulation of STAMP2 expression. We further observed hepatic iron overload (HIO) and reduced iron exporter, ferroportin expression in the liver samples obtained from human NAFLD patients, and HFD-induced NAFLD mice and in OA-treated HepG2 cells. Importantly, recombinant FGF21 improved HIO through the hepatic STAMP2-mediated upregulation of ferroportin expression. Our data suggest that hepatic STAMP2 may represent a suitable therapeutic intervention target for FGF21-induced improvement of NAFLD accompanying HIO.

Palmitate induces lipoapoptosis in Schwann cells through ROS generation-mediated STAMP2 downregulation.

Free fatty acids (FFAs) are considered the principal inducers of lipotoxicity, leading to cell dysfunction and/or cell death. Lipotoxicity in Schwann cells (SCs) damages neurons, which may be associated with peripheral neuropathies and axon degeneration. However, the molecular mechanism by which FFAs exert lipotoxicity in SCs remains to be established. In the present study, we demonstrate that palmitate exerts lipotoxicity in SCs through apoptosis and that palmitate-induced lipotoxicity in SCs is mediated through reactive oxygen species (ROS) generation. We observed that the six-transmembrane protein of prostate 2 (STAMP2), which plays a pivotal role in lipid homeostasis, is expressed in SCs. We further demonstrate that palmitate induces lipoapoptosis in SCs through ROS generation-mediated STAMP2 downregulation and that STAMP2 depletion accelerates the palmitate-exerted lipoapoptosis in SCs, indicating that STAMP2 confers on SCs the ability to resist palmitate-induced lipotoxicity. In conclusion, palmitate induces lipoapoptosis in SCs through ROS generation-mediated STAMP2 downregulation. Our findings indicate that ROS and STAMP2 may represent suitable targets for pharmacological interventions targeting lipotoxicity-associated peripheral neuropathies and axon degeneration.

Clinical prognostic index for recurrence of papillary thyroid carcinoma including intraoperative findings.

This study created a new staging system using a risk model that employed clinical factors that were associated with recurrence, verified by preoperative clinical information and intraoperative finding and was compared with other staging systems. A review was conducted of patients who have undergone thyroidectomy and followed-up between January 1, 1983 and September 31, 2007 at Yonsei University Wonju Christian Hospital. The final prognostic staging system was defined as University of Yonsei clinical staging system (Prognostic score = 0.03 × Age + 0.8 × (if male gender) + 0.5 × (if extrathyroidal tumor extension present) + 0.7 × (if clinically apparent lymph node metastasis present), Stage I, less than 1.50; Stage II, 1.50 to 2.29; Stage III, 2.30 to 3.29; Stage IV 4, 3.3 or more). Compared with the other staging systems, the proportion of variation explained (PVE %) was calculated for each. The University of Yonsei clinical staging system appeared to be first as an accurate prognosis predictor with 11.9%. New staging system can predict recurrence and has advantage can use preoperative clinical information and intraoperative finding. Those who are diagnosed as high risk patients using the new staging system should be treated with aggressive surgical treatment and close follow-up.

The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review.

YKL-40, a chitinase-3-like protein 1 (CHI3L1) or human cartilage glycoprotein 39 (HC gp-39), is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells and vascular smooth muscle cells. Its biological function is not well elucidated, but it is speculated to have some connection with inflammatory reactions and autoimmune diseases. Although having important biological roles in autoimmunity, there were only attempts to elucidate relationships of YKL-40 with a single or couple of diseases in the literature. Therefore, in order to analyze the relationship between YKL-40 and the overall diseases, we reviewed 51 articles that discussed the association of YKL-40 with rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Behçet disease and inflammatory bowel disease. Several studies showed that YKL-40 could be assumed as a marker for disease diagnosis, prognosis, disease activity and severity. It is also shown to be involved in response to disease treatment. However, other studies showed controversial results particularly in the case of Behçet disease activity. Therefore, further studies are needed to elucidate the exact role of YKL-40 in autoimmunity and to investigate its potential in therapeutics.

Persistent Organic Pollutant-Mediated Insulin Resistance.

Persistent organic pollutants (POPs) such as organochlorine (OC) pesticides, polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) have become wide-spread environmental contaminants as a consequence of their extensive use, long-range transport, and persistence. Because POPs are highly resistant to metabolic degradation, humans bioaccumulate these lipophilic and hydrophobic pollutants in fatty tissues for many years. Previous studies have demonstrated that POPs including PCBs are involved in the development of diabetes mellitus (DM) type 2 and insulin resistance. Numerous epidemiological studies suggest an association between POP burden and DM type 2/metabolic syndrome. In addition, several experimental studies have provided additional evidence supporting the association between POP exposure and DM type 2 or insulin resistance. Epidemiological and experimental studies have provided compelling evidence indicating that exposure to POPs increases the risk of developing insulin resistance and metabolic disorders. However, the detailed molecular mechanism underlying POP-induced insulin resistance is yet to be elucidated. In this article, we review literature that has reported on the association between POP burden and insulin resistance and the mechanism underlying POP-induced insulin resistance, and discuss implications for public health.

Dietary Exposure to Transgenic Rice Expressing the Spider Silk Protein Fibroin Reduces Blood Glucose Levels in Diabetic Mice: The Potential Role of Insulin Receptor Substrate-1 Phosphorylation in Adipocytes.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR). T2DM is correlated with obesity and most T2DM medications have been developed for enhancing insulin sensitivity. Silk protein fibroin (SPF) from spiders has been suggested as an attractive biomaterial for medical purposes. We generated transgenic rice (TR) expressing SPF and fed it to diabetic BKS.Cg-m+/+Leprdb mice to monitor the changes in blood glucose levels and adipose tissue proteins associated with energy metabolism and insulin signaling. In the present study, the adipocyte size in abdominal fat in TR-SPF-fed mice was remarkably smaller than that of the control. Whereas the adenosine monophosphate-activated protein kinase (AMPK)-activated protein kinase and insulin receptor substrate 1 (IRS1) protein levels were increased in abdominal adipose tissues after TR-SPF feeding, levels of six-transmembrane protein of prostate 2 (STAMP2) proteins decreased. Phosphorylation of AMPK at threonine 172 and IRS1 at serine 307 and tyrosine 632 were both increased in adipose tissues from TR-SPF-fed mice. Increased expression and phosphorylation of IRS1 at both serine 307 and tyrosine 632 in adipose tissues indicated that adipocytes obtained from abdominal fat in TR-SPF-fed mice were more susceptible to insulin signaling than that of the control. STAMP2 protein levels decreased in adipose tissues from TR-SPF-fed mice, indicating that STAMP2 proteins were reducing adipocytes that were undergoing lipolysis. Taken together, this study showed that TR-SPF was effective in reducing blood glucose levels in diabetic mice and that concurrent lipolysis in abdominal adipocytes was associated with alterations of AMPK, IRS1, and STAMP2. Increased IRS1 expression and its phosphorylation by TR-SFP were considered to be particularly important in the induction of lipolysis in adipocytes, as well as in reducing blood glucose levels in this animal model.

Ultrasonographic guideline for thyroid nodules cytology: single institute experience.

PURPOSE: The main issue with the current ultrasonography (US) guidelines is the overestimation of malignant and indeterminate nodules as they do not aid in making decisions to treat patients. To overcome this, new US guidelines for thyroid nodules that have been shown to be better correlated with cytologic results have been proposed. We also suggested specific indications for US-guided fine needle aspiration (FNA) using the new US guidelines. METHODS: Clinical and pathologic data from 925 patients and 1,419 thyroid nodules were retrospectively collected. All subjects underwent US- and US-guided FNA at Department of Surgery, Wonju Christian Hospital, between March 2010 and July 2011. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated for both the current guidelines and the new guidelines. RESULTS: The accuracy, sensitivity, specificity, PPV, and NPV for the current guidelines in predicting malignancy were 24.1%, 99.3%, 62.2%, 25.0%, and 99.8%, respectively. The accuracy, sensitivity, specificity, PPV, and NPV for the new guidelines in predicting malignancy were 66.0%, 96.0%, 86.7%, 47.7%, and 99.4%, respectively. CONCLUSION: The use of the new US guidelines allow for a more accurate and specific diagnosis and a better treatment plan than the current guidelines. Additionally, the use of the new FNA guidelines may help prevent unnecessary FNAs and promote cost-effective follow-up for patients.

Analysis of prognostic factors in patients with multiple recurrences of papillary thyroid carcinoma.

PURPOSE: Numerous studies in the past have mentioned various factors that influence the recurrence of papillary thyroid carcinoma, including age, tumor size, advanced stage, extrathyroidal extension, and distant metastasis, and attempts have been made to classify the disease into low-risk and high-risk group based on these clinicopathological factors. However, there has been relatively scarce study on patients with multiple recurrent papillary thyroid carcinoma. This study analyzed the risk factors associated with such cases. MATERIALS AND METHODS: This study investigated various clinicopathological factors of 416 patients who were diagnosed with papillary thyroid carcinoma and received primary surgery at Yonsei University Wonju College of Medicine, Department of Surgery, from January 1983 to December 2006 and were followed up until October 2010. An investigation of factors associated with patients showing multiple recurrences was made. RESULTS: Patients were divided into 3 groups: group 1 (no recurrence, n=380), group 2 (1 recurrence only, n=21), and group 3 (multiple recurrences, n=15). The univariate analysis on risk factors revealed tumor size greater than 2 cm, multifocality, clinical apparent lymph node metastasis to be risk factors associated with multiple recurrences of papillary thyroid carcinoma. A multivariate analysis performed on variables selected from univariate analysis demonstrated no significant risk factor. The 10-year disease-specific survival for 3 different patient groups (group 1, 2, and 3) was 100%, 100%, and 83.1%, respectively, and patients in more clinically advanced group demonstrated poorer prognosis (p<0.001). The 10-year overall survival rate for the 3 patient groups was 93.9%, 100%, and 92%, respectively, and clinically advanced groups tended to show poorer overall survival rate as well (p=0.046). DISCUSSION: A more aggressive and extensive surgery, as well as closer follow up, is to be required when operating on patients with tumor size greater than 2 cm, multifocality, clinical apparent lymph node metastasis. The use of imaging modalities, such as ultrasonography and PET-CT scan, may be desirable when monitoring such patients.

Hungry bone syndrome after parathyroidectomy of a minimally invasive parathyroid carcinoma.

The prognosis of parathyroid carcinoma varies significantly between numerous studies. Therefore, many attempts have been made to grade the degree of parathyroid carcinoma, and recently, classifying parathyroid carcinomas into either minimally invasive or widely invasive carcinoma- similar to follicular carcinoma of the thyroid- has led to a more reliable prediction of the prognosis. Hungry bone syndrome can occur if parathyroidectomy is performed due to primary hyperparathyroidism regardless of the cause of the disease. Hungry bone syndrome is characterized by postoperative a hypocalcemic state due to remineralization of various minerals, including calcium, of the bone; this syndrome requires a long-term supplementation of calcium. The authors aim to report, along with a review of related literatures, 1 case of a 29-year-old female patient diagnosed with minimally invasive parathyroid carcinoma who fell into hungry bone syndrome after parathyroidectomy.

Neuron-like differentiation of bone marrow-derived mesenchymal stem cells.

PURPOSE: Mesenchymal stem cells (MSCs) are multipotent and give rise to distinctly differentiated cells from all three germ layers. Neuronal differentiation of MSC has great potential for cellular therapy. We examined whether the cluster of mechanically made, not neurosphere, could be differentiated into neuron-like cells by growth factors, such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: BMSCs grown confluent were mechanically separated with cell scrapers and masses of separated cells were cultured to form cluster BMSCs. As described here cluster of BMSCs were differentiated into neuron-like cells by EGF, HGF, and VEGF. Differentiated cells were analyzed by means of phase-contrast inverted microscopy, reverse transcriptase-polymerase chain reaction (RT-PCR), immunofluorescence, and immunocytochemistry to identify the expression of neural specific markers. RESULTS: For the group with growth factors, the shapes of neuron-like cells was observable a week later, and two weeks later, most cells were similar in shape to neuron-like cells. Particularly, in the group with chemical addition, various shapes of filament structures were seen among the cells. These culture conditions induced MSCs to exhibit a neural cell phenotype, expressing several neuro-glial specific markers. CONCLUSION: bone marrow-derived mesenchymal stem cells (BMSCs) could be easily induced to form clusters using mechanical scraping, not neurospheres, which in turn could differentiate further into neuron-like cells and might open an attractive possibility for clinical cell therapy for neurodegenerative diseases. In the future, we consider that neuron-like cells differentiated from clusters of BMSCs are needed to be compared and analyzed on a physiological and molecular biological level with preexisting neuronal cells, and studies on the possibility of their transplantation and differentiation capability in animal models are further required.