Temporal Changes in 18F-FDG PET/CT in Familial Neuronal Intranuclear Inclusion Disease, Based on the Clinical Course.

ABSTRACT: We report temporal changes in 18F-FDG PET/CT in neuronal intranuclear inclusion disease (NIID). In a patient with encephalitis-like episodes, PET showed hypermetabolism correlating with EEG alterations. Affected sites later became hypometabolic and showed diffusion changes on MRI. In another patient, hypermetabolic regions correlated well with the EEG, whereas MRI showed changes after only 1 month. One chronic patient had diffuse hypometabolism, which correlated with atrophy on MRI and cerebral dysfunction on EEG. This is the first report of temporal changes in PET in NIID and suggests that it reflects the disease activity of NIID while correlating well with EEG.

7-Ketocholesterol plays a key role in cholesterol-induced hepatitis via macrophage and neutrophil infiltration.

This study sought to explore the role of 7-ketocholesterol (7-KC) in liver damage caused by high cholesterol intake and its potential pathological mechanism in mice. Our in vivo findings indicated that mice fed a high-cholesterol diet had elevated serum levels of 7-KC, accompanied by liver injury and inflammation, similar to human nonalcoholic steatohepatitis. Furthermore, the high-cholesterol diet induced neutrophil infiltration, which played a critical role in liver damage through myeloperoxidase (MPO) activity. Upon stimulation with 7-KC, macrophages exhibited increased expression of C-X-C motif chemokine ligand 1 (CXCL1) and CXCL2, as well as ATP-binding cassette transporter A1 (ABCA1) and ABCG1. Hepatocytes, on the other hand, exhibited increased expression of CXCL2 and ABCG1. The infiltration of neutrophils in the liver was primarily caused by CXCL1 and CXCL2, resulting in hepatocyte cell death due to elevated MPO activity. Our data also revealed that the activation of macrophages by 7-KC via ABCA1 or ABCG1 was not associated with lipid accumulation. Collectively, these findings suggest that high cholesterol-induced hepatitis in mice involves, at least partially, the recruitment of neutrophils to the liver by 7-KC-activated macrophages. This is mediated by increased expression of CXCL1 and CXCL2 through ABCA1 or ABCG1, which act as 7-KC efflux transporters. Additionally, hepatocytes contribute to this process by increased expression of CXCL2 through ABCG1. Therefore, our findings suggest that 7-KC may play a role in high cholesterol-induced hepatitis in mice by activating macrophages and hepatocytes, ultimately leading to neutrophil infiltration.

High Cholesterol-Induced Bone Loss Is Attenuated by Arctiin via an Action in Osteoclasts.

High cholesterol-induced bone loss is highly associated with oxidative stress, which leads to the generation of oxysterols, such as 7-ketocholesterol (7-KC). Here, we conducted in vivo and in vitro experiments to determine whether arctiin prevents high cholesterol diet-induced bone loss by decreasing oxidative stress. First, arctiin was orally administered to atherogenic diet (AD)-fed C57BL/6J male mice at a dose of 10 mg/kg for 6 weeks. Micro-computerized tomography (µCT) analysis showed that arctiin attenuated AD-induced boss loss. For our in vitro experiments, the anti-oxidant effects of arctiin were evaluated in 7-KC-stimulated osteoclasts (OCs). Arctiin decreased the number and activity of OCs and inhibited autophagy by disrupting the nuclear localization of transcription factor EB (TFEB) and downregulating the oxidized TFEB signaling pathway in OCs upon 7-KC stimulation. Furthermore, arctiin decreased the levels of reactive oxygen species (ROS) by enhancing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), catalase, and heme oxygenase 1 (HO-1), all of which affected OC differentiation. Conversely, silencing of Nrf2 or HO-1/catalase attenuated the effects of arctiin on OCs. Collectively, our findings suggested that arctiin attenuates 7-KC-induced osteoclastogenesis by increasing the expression of ROS scavenging genes in the Nrf2/HO-1/catalase signaling pathway, thereby decreasing OC autophagy. Moreover, arctiin inhibits the oxidation and nuclear localization of TFEB, thus protecting mice from AD-induced bone loss. Our findings thus demonstrate the therapeutic potential of arctiin for the prevention of cholesterol-induced bone loss.

Doxorubicin Induces Bone Loss by Increasing Autophagy through a Mitochondrial ROS/TRPML1/TFEB Axis in Osteoclasts.

Doxorubicin (DOX), a widely used chemotherapeutic agent, has been linked to an increased risk of bone damage in human patients and induces bone loss in mice. DOX induces autophagy, which contributes to bone homeostasis and excess autophagy in osteoclasts (OCs), resulting in bone loss. We hypothesized that DOX-induced bone loss is caused by the induction of autophagy in OCs. In vitro, DOX significantly increased the area of OCs and bone resorption activity, whereas it decreased OC number through apoptosis. DOX enhanced the level of LC3II and acidic vesicular organelles-containing cells in OCs, whereas an autophagy inhibitor, 3-methyladenine (3-MA), reversed these, indicating that enhanced autophagy was responsible for the effects of DOX. Increased mitochondrial reactive oxygen species (mROS) by DOX oxidized transient receptor potential mucolipin 1 (TRPML1) on the lysosomal membrane, which led to nuclear localization of transcription factor EB (TFEB), an autophagy-inducing transcription factor. In vivo, micro-computerized tomography analysis revealed that the injection of 3-MA reversed DOX-induced bone loss, and tartrate-resistant acid phosphatase staining showed that 3-MA reduced the area of OCs on the bone surface, which was enhanced upon DOX administration. Collectively, DOX-induced bone loss is at least partly attributable to autophagy upregulation in OCs via an mROS/TRPML1/TFEB axis.

Morin Disrupts Cytoskeleton Reorganization in Osteoclasts through an ROS/SHP1/c-Src Axis and Grants Protection from LPS-Induced Bone Loss.

Morin is a naturally occurring flavonoid with anti-inflammatory and antioxidative properties. Therefore, we hypothesized that morin may prevent inflammatory bone loss by reducing oxidative stress. To investigate the effect of morin on inflammatory bone loss, mice were injected with lipopolysaccharide (LPS). Osteoclasts (OCs) were analyzed by tartrate-resistant acid phosphatase (TRAP) staining and actin ring formation. Micro-computerized tomography analysis indicated that morin prevented LPS-induced bone loss in mice. In vivo TRAP staining indicated that morin decreased the number and surface of the OCs that were increased in LPS-treated mice. Furthermore, in vitro experiments indicated that morin decreased the number and activity of OCs upon LPS stimulation. Morin decreased actin ring-containing OCs with decreased activation of c-Src (Y416)/vav guanine nucleotide exchange factor 3/Ras-related C3 botulinum toxin substrate 1 compared with LPS alone. Morin decreased cytosolic reactive oxygen species (ROS), thus preventing the oxidation of Src homology region 2 domain-containing phosphatase 1 (SHP-1), followed by the inactivation of c-Src via direct interaction with SHP1. Conversely, SHP1 knockdown abolished the inhibitory effect of morin on OCs. Therefore, our findings suggest that morin disrupted cytoskeletal reorganization via an ROS/SHP1/c-Src axis in OCs, thereby granting protection from LPS-induced bone loss, which demonstrates its therapeutic potential against inflammatory bone loss.

Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice.

Loss of ovarian function is closely related to estrogen (E2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E2/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p-Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E2/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E2-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.

Estrogen enhances browning in adipose tissue by M2 macrophage polarization via heme oxygenase-1.

Loss of ovarian function results in increased fat mass, leading to the accumulation of adipose tissue macrophages that participate in chronic inflammation. We hypothesized that ovariectomy (OVX)-induced increases in body weight and fat mass are associated with decreased adipose tissue (AT) browning due to estrogen (E2 ) deficiency. In mice, OVX decreased AT browning along with increased body weight, fat mass, and size of lipid droplets 12 weeks after surgery. Exogenous E2 recovered the OVX-induced changes. AT browning was enhanced by M2 macrophages induced by exogenous E2. E2 -induced M2 polarization occurred due to the increased expression of heme oxygenase-1 (HO-1) in macrophages, leading to decreased reactive oxygen species levels. Collectively, we demonstrated that E2 enhances AT browning via M2 polarization mediated by HO-1.

Pretreatment with 6-Gingerol Ameliorates Sepsis-Induced Immune Dysfunction by Regulating the Cytokine Balance and Reducing Lymphocyte Apoptosis.

Sepsis is characterized by an initial net hyperinflammatory response, followed by a period of immunosuppression, termed immunoparalysis. During this immunosuppressive phase, patients may have difficulty eradicating invading pathogens and are susceptible to life-threatening secondary hospital-acquired infections. Due to progress in antimicrobial treatment and supportive care, most patients survive early sepsis. Mortality is more frequently attributed to subsequent secondary nosocomial infections and multiorgan system failure. 6-Gingerol is the major pharmacologically active component of ginger. Although it is known to exhibit a variety of biological activities, including anti-inflammation and antioxidation, the role of 6-gingerol in sepsis-induced immune dysfunction remains elusive. Thus, we investigated whether 6-gingerol improves septic host response to infections during sepsis. 6-Gingerol-treated mice showed significantly lower mortality in polymicrobial sepsis induced by cecal ligation and puncture LPS via enhanced bacterial clearance in the peritoneum, blood, and organs (liver, spleen, and kidney) and inhibited the production of TNF-α and IL-6 in TLR2 and/or TLR4-stimulated macrophages. In addition, we demonstrated that survival improvement of secondary infection following septic insult was associated with an initial response of enhanced neutrophil numbers and function at the infection site, reduced apoptosis of immune cells, and a shift from a T helper cell type 2 (Th2) to a T helper cell type 1 (Th1) cytokine balance in the hypoinflammation phase. Our overall findings suggest that 6-gingerol potentially restores sepsis-induced immune dysfunction by shifting the balance of Th1/Th2 and by regulating apoptosis of immune cells.

Tonicity-responsive enhancer-binding protein promotes stemness of liver cancer and cisplatin resistance.

BACKGROUND: High recurrence and chemoresistance drive the high mortality in hepatocellular carcinoma (HCC). Although cancer stem cells are considered to be the source of recurrent and chemoresistant tumors, they remain poorly defined in HCC. Tonicity-responsive enhancer binding protein (TonEBP) is elevated in almost all HCC tumors and associated with recurrence and death. We aimed to identify function of TonEBP in stemness and chemoresistance of liver cancer. METHODS: Tumors obtained from 280 HCC patients were analyzed by immunohistochemical analyses. Stemness and chemoresistance of liver CSCs (LCSCs) were investigated using cell culture. Tumor-initiating activity was measured by implanting LCSCs into BALB/c nude mice. FINDINGS: Expression of TonEBP is higher in LCSCs in HCC cell lines and correlated with markers of LCSCs whose expression is significantly associated with poor prognosis of HCC patients. TonEBP mediates ATM-mediated activation of NF-κB, which stimulates the promoter of a key stem cell transcription factor SOX2. As expected, TonEBP is required for the tumorigenesis and self-renewal of LSCSs. Cisplatin induces the recruitment of the ERCC1/XPF dimer to the chromatin in a TonEBP-dependent manner leading to DNA repair and cisplatin resistance. The cisplatin-induced inflammation in LSCSs is also dependent on the TonEBP-ERCC1/XPF complex, and leads to enhanced stemness via the ATM-NF-κB-SOX2 pathway. In HCC patients, tumor expression of ERCC1/XPF predicts recurrence and death in a TonEBP-dependent manner. INTERPRETATION: TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence.

Primary hepatic extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), is one of the specific type of low-grade B-cell lymphoma not infrequently found worldwide. It typically involves mucosal sites such as stomach and conjunctiva; however, primary hepatic MALT lymphoma has been extremely rarely reported. We describe a case of hepatic MALT lymphoma in a 70-year-old male patient who underwent left hepatectomy due to the incidentally detected liver masses at a medical checkup. The resected specimen revealed multinodular masses consisting of small-to-intermediate-sized lymphoid cells with serpentine pattern and focal lymphoepithelial lesions. The tumor cells were diffusely positive for CD20 and Bcl-2 but negative for CD3, CD10, CD5, CD23, CD43, and cyclinD1. The Ki-67 labeling index was 10% and immunoglobulin heavy chain gene rearrangement study confirmed monoclonal proliferation. In this paper, we discuss several unique clinicopathologic characteristics which will be helpful to the differential diagnosis of hepatic MALT lymphoma.

Dauricine Protects from LPS-Induced Bone Loss via the ROS/PP2A/NF-κB Axis in Osteoclasts.

Dauricine (DAC), an isoquinoline alkaloid, exhibits anti-inflammatory activity. We hypothesized that DAC may prevent the inflammatory bone loss induced by lipopolysaccharide (LPS). LPS-induced bone loss was decreased by DAC in female C57BL/6J mice as evaluated by micro-computerized tomography (µCT) analysis. In vivo tartrate-resistant acid phosphatase (TRAP) staining showed that the increased number of osteoclasts (OCs) in LPS-treated mice was attenuated by DAC, indicating that DAC exhibited bone sparing effects through acting on OCs. DAC also decreased the differentiation and activity of OCs after LPS stimulation in vitro. LPS-induced cytosolic reactive oxygen species (cROS) oxidized PP2A, a serine/threonine phosphatase, leading to the activation of IKKα/ß, followed by the nuclear localization of p65. DAC decreased LPS-induced ROS, resulting in the recovery of the activity of PP2A by reducing its oxidized form. Consequently, DAC reduced the phosphorylation of IKKα/ß to block the nuclear localization of p65, which decreased NF-κB activation. Taken together, DAC reduced the differentiation and activity of OCs by decreasing ROS via the ROS/PP2A/NF-κB axis, resulting in protection from LPS-induced bone loss. We have demonstrated that LPS-induced bone loss was inhibited by DAC via its action on OCs, implying the therapeutic potential of DAC against inflammatory bone loss.

Programmed death-ligand 1 expression and its correlation with clinicopathological parameters in gallbladder cancer.

BACKGROUND: Immunomodulatory therapies targeting the interaction between programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) have become increasingly important in anticancer treatment. Previous research on the subject of this immune response has established an association with tumor aggressiveness and a poor prognosis in certain cancers. Currently, scant information is available on the relationship between PD-L1 expression and gallbladder cancer (GBC). METHODS: We investigated the expression of PD-L1 in 101 primary GBC cases to determine the potential association with prognostic impact. PD-L1 expression was immunohistochemically assessed using a single PD-L1 antibody (clone SP263). Correlations with clinicopathological parameters, overall survival (OS), or progression- free survival (PFS) were analyzed. RESULTS: PD-L1 expression in tumor cells at cutoff levels of 1%, 10%, and 50% was present in 18.8%, 13.8%, and 7.9% of cases. Our study showed that positive PD-L1 expression at any cutoff was significantly correlated with poorly differentiated histologic grade and the presence of lymphovascular invasion (p < .05). PD-L1 expression at cutoff levels of 10% and 50% was significantly positive in patients with perineural invasion, higher T categories, and higher pathologic stages (p < .05). Additionally, there was a significant association noted between PD-L1 expression at a cutoff level of 50% and worse OS or PFS (p = .049 for OS, p = .028 for PFS). Other poor prognostic factors included histologic grade, T category, N category, pathologic stage, lymphovascular invasion, perineural invasion, growth pattern, and margin of resection (p < .05). CONCLUSIONS: The expression of PD-L1 in GBC varies according to cutoff level but is valuably associated with poor prognostic parameters and survival. Our study indicates that the overexpression of PD-L1 in GBC had a negative prognostic impact.

Atherogenic diet-induced bone loss is primarily due to increased osteoclastogenesis in mice.

Atherogenic diet (AD) decreased bone density and increased serum cholesterol level in male mice, implying that cholesterol participates in bone loss. The aim of the present study was to identify the cells responsible for bone loss and evaluate the involved mechanism. AD resulted in increased number and surface of osteoclasts (OCs) with in vivo tartrate-resistant acid phosphatase (TRAP) staining, suggesting a critical role of OCs in cholesterol-induced bone loss. In vitro, cholesterol loading by oxidized low-density lipoprotein (oxLDL) increased the size and number of OCs as well as bone resorption activity, suggesting that cholesterol loading affects the number and activity of OCs. In contrast, cholesterol depletion by simvastatin decreased osteoclastogenesis and bone resorption. oxLDL stimulated osteoblasts (OBs) to increase expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), resulting in increased OC formation when OBs were co-cultured with bone marrow derived macrophages. oxLDL increased expression of CD36 and liver X receptors (LXRα) in OCs as well as low density lipoprotein receptor (LDLR) and LXRα in OBs. These results suggest that CD36 and LXRα mediate the effect of oxLDL in OCs, whereas LDLR and LXRα mediate the effect of oxLDL in OBs. These findings demonstrate cholesterol-induced bone loss with increasing number and activity of OCs in mice, suggesting another harmful effect of cholesterol, a major cause of atherosclerosis.

Lycorine Attenuates Autophagy in Osteoclasts via an Axis of mROS/TRPML1/TFEB to Reduce LPS-Induced Bone Loss.

Lycorine, a plant alkaloid, exhibits anti-inflammatory activity by acting in macrophages that share precursor cells with osteoclasts (OCs). We hypothesized that lycorine might decrease bone loss by acting in OCs after lipopolysaccharide (LPS) stimulation, since OCs play a main role in LPS-induced bone loss. Microcomputerized tomography (µCT) analysis revealed that lycorine attenuated LPS-induced bone loss in mice. In vivo tartrate-resistant acid phosphatase (TRAP) staining showed that increased surface area and number of OCs in LPS-treated mice were also decreased by lycorine treatment, suggesting that OCs are responsible for the bone-sparing effect of lycorine. In vitro, the increased number and activity of OCs induced by LPS were reduced by lycorine. Lycorine also decreased LPS-induced autophagy in OCs by evaluation of decreased lipidated form of microtubule-associated proteins 1A/1B light chain 3B (LC3) (LC3II) and increased sequestosome 1 (p62). Lycorine attenuated oxidized transient receptor potential cation channel, mucolipin subfamily (TRPML1) by reducing mitochondrial reactive oxygen species (mROS) and decreased transcription factor EB (TFEB) nuclear translocation. Lycorine reduced the number and activity of OCs by decreasing autophagy in OCs via an axis of mROS/TRPML1/TFEB. Collectively, lycorine protected against LPS-induced bone loss by acting in OCs. Our data highlight the therapeutic potential of lycorine for protection against inflammatory bone loss.

MicroRNA-29b Enhances Osteoclast Survival by Targeting BCL-2-Modifying Factor after Lipopolysaccharide Stimulation.

Recent findings suggest that microRNAs (miRs) play a critical role in osteoclastogenesis, which regulates bone loss. We hypothesized that inflammation induces miR-29b, which increases the survival rate in osteoclasts (OCs), leading to bone loss. The expression level of miR-29b increased in OC stimulated by lipopolysaccharide (LPS) in an in vitro system which correlated with its increase in tibiae from mice that received LPS injections compared with those that received vehicle treatment. An miR-29b mimic increased OC survival rate without any change in OC differentiation, and furthermore, the inhibition of endogenous miR-29b induced by LPS decreased OC survival rate. Increased OC survival rate after overexpression of miR-29b was associated with antiapoptotic activity, as shown by staining annexin V-positive cells. We found that a target gene of miR-29b is BCL-2-modifying factor (Bmf), which acts as a proapoptotic factor, and that miR-29b binds to the 3'-UTR of Bmf. Our data demonstrate that LPS-induced miR-29b increases the number of OC by enhancing OC survival through decreased BMF.

MCP-1 deficiency enhances browning of adipose tissue via increased M2 polarization.

Obesity is strongly associated with chronic inflammation for which adipose tissue macrophages play a critical role. The objective of this study is to identify monocyte chemoattractant protein-1 (MCP-1, CCL2) as a key player governing M1-M2 macrophage polarization and energy balance. We evaluated body weight, fat mass, adipocyte size and energy expenditure as well as core body temperature of Ccl2 knockout mice compared with wild-type mice. Adipose tissues, differentiated adipocyte and bone marrow-derived macrophages were assessed by qPCR, Western blot analysis and histochemistry. MCP-1 deficiency augmented energy expenditure by promoting browning in white adipose tissue and brown adipose tissue activity via increasing the expressions of Ucp1, Prdm16, Tnfrsf9, Ppargc1a, Nrf1 and Th and mitochondrial DNA copy number. MCP-1 abrogation promoted M2 polarization which is characterized by increased expression of Arg1, Chil3, Il10 and Klf4 whereas it decreased M1 polarization by decreased p65 nuclear translocation and attenuated expression of Itgax, Tnf and Nos2, leading to increased browning of adipocytes. Enhanced M2 polarization and attenuated M1 polarization in the absence of MCP-1 are independent. Collectively, our results suggest that the action of MCP-1 in macrophages modulates energy expenditure by impairing browning in adipose tissue.

Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse aetiological agents and wide heterogeneity in individual tumours impede effective and personalised treatment. Tonicity-responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of proinflammatory genes. Although inflammation is intimately associated with the pathogenesis of HCC, the role of TonEBP is unknown. We aimed to identify function of TonEBP in HCC. DESIGN: Tumours with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analysed by quantitative reverse transcription-quantitative real-time PCR (RT-PCR) and immunohfistochemical analyses of tissue microarrays. Mice with TonEBP haplodeficiency, and hepatocyte-specific and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines. RESULTS: TonEBP expression is higher in tumours than in adjacent non-tumour tissues in 92.6% of patients with HCC regardless of aetiology associated. The TonEBP expression in tumours and adjacent non-tumour tissues predicts recurrence, metastasis and death in multivariate analyses. TonEBP drives the expression of cyclo-oxygenase-2 (COX-2) by stimulating the promoter. In mouse models of HCC, three common sites of TonEBP action in response to diverse aetiological agents leading to tumourigenesis and tumour growth were found: cell injury and inflammation, induction by oxidative stress and stimulation of the COX-2 promoter. CONCLUSIONS: TonEBP is a key component of the common pathway in tumourigenesis and tumour progression of HCC in response to diverse aetiological insults. TonEBP is involved in multiple steps along the pathway, rendering it an attractive therapeutic target as well as a prognostic biomarker.

4-Phenylbutyric acid protects against lipopolysaccharide-induced bone loss by modulating autophagy in osteoclasts.

4-Phenylbutyric acid (4-PBA) has been used clinically to treat urea cycle disorders and is known to be an inhibitor of endoplasmic reticulum (ER) stress. We hypothesized that 4-PBA attenuates inflammatory bone loss by inducing autophagy, a process that is frequently accompanied by ER stress. Micro computerized tomography analysis showed that 4-PBA attenuated LPS-induced bone loss in mice. The increased area of TRAP-positive osteoclasts (OCs) and serum level of collagen type I fragments in lipopolysaccharide (LPS)-treated mice were also decreased when 4-PBA was administered, suggesting a protective role of 4-PBA in OCs. In vitro, 4-PBA significantly reduced OC area without affecting the number of OCs induced by LPS and decreased bone resorption upon LPS stimulation. LPS-induced autophagy was attenuated by 4-PBA in OCs, as demonstrated by reduced LC3II accumulation, increased p62 level, and reduction in AVO-containing cells. Silencing of autophagy-related protein 7 attenuated the effects of 4-PBA on OC size and fusion. Moreover, 4-PBA reduced nuclear factor-κB (NF-κB) DNA binding upon LPS stimulation of OCs. Inhibition of NF-κB activation diminished the inhibitory effect of 4-PBA on LPS-stimulated changes in LC3II level, OC area, and OC fusion, implying that the effects of 4-PBA on OCs are due at least in part to inhibition of NF-κB. These data demonstrate that 4-PBA attenuates LPS-induced bone loss by reducing autophagy in OCs. Our data highlight the therapeutic potential of 4-PBA for ameliorating inflammatory bone loss.

Ultrasonographic Features of Eccrine Spiradenoma.

The purpose of this series was to evaluate the features of eccrine spiradenoma on ultrasonography (US). We reviewed the clinical data of 8 patients with eccrine spiradenoma who underwent preoperative US at 4 different medical institutions from 2004 to 2016 and analyzed the US features in terms of the tumor location, size, shape, margin, echo texture, echogenicity, posterior acoustic enhancement, calcification, septum, and color Doppler flow. There were 7 female patients and 1 male patient. The mean patient age was 45.6 years (range, 28-60 years). Most of the tumors were located primarily in the subcutaneous fat layer. The mean size of the tumors was 14.3 mm. The masses had a lobular appearance in 7 patients and had a tractlike structure in 3 patients. In 6 patients, the masses had a heterogeneous echo texture. Six cases showed hypoechogenicity with more hypoechoic foci in the masses, and 2 cases showed hypoechogenicity only. Color Doppler flow was evaluated in 7 patients; the blood flow was central and peripheral in 4 patients and only peripheral in 3 patients. All cases showed posterior acoustic enhancement and had well-defined margins. Calcification and septa were not seen in any cases. Eccrine spiradenoma is usually located in the subcutaneous fat layer, has a well-defined margin, a lobulated appearance, occasionally with a tractlike structure, a heterogeneous echo texture, a hypoechoic appearance with internal hypoechoic foci and posterior acoustic enhancement, and shows blood flow in the peripheral portion, with or without blood flow in the central portion.