Metabolic Syndrome Is not an Independent Risk Factor for Hearing Impairment.

OBJECTIVE: We aimed to investigate the association between metabolic syndrome (MS) and hearing impairment (HI) using nationally representative data from Korean adults. DESIGN, SETTING AND PARTICIPANTS: A total of 16,799 subjects (≥19 years old; 7,170 men and 9,629 women) who underwent pure tone audiometry testing were included in the analysis. Data were obtained from the fifth Korea National Health and Nutrition Examination Survey (2010-2012). Subjects were divided into two groups according to the presence of MS. RESULTS: Among the subjects with MS, 47% had HI. Logistic regression analysis revealed that MS was not an independent risk factor for HI, although increased fasting plasma glucose (OR 1·4, 95% CI: 1·1-1·8) was independently associated with HI. In addition, older age, male sex, very low body mass index (≤17·5 kg/m2), lower education level, smoking history, and occupational noise exposure were independently associated with HI. For low-frequency HI, independent risk factors included older age, lower educational level, lower economic status, and very low BMI (≤17·5 kg/m2). For high-frequency HI, independent risk factors included older age, male sex, lower educational level, lower economic status, increased blood pressure, lower high-density lipoprotein cholesterol, and smoking history. CONCLUSIONS: MS itself was not an independent risk factor for HI, and, among the individual metabolic components, only increased fasting plasma glucose was independently associated with HI.

Targeted inhibition of galectin 1 by thiodigalactoside dramatically reduces body weight gain in diet-induced obese rats.

BACKGROUND: Galectin 1 (GAL1), an animal lectin is well characterized in the context of cancer, tumor environment, but its physiological roles in obesity remain to be demonstrated. In this study, we investigated whether targeted inhibition of GAL1 prevents obesity based on the previous observations that GAL1 is highly expressed in adipose tissues of high-fat diet (HFD)-induced obese rats. METHODS: Lipogenic capacity of Lgals1 knocked down adipocytes was evaluated by determining the expression levels of major lipogenic markers using real-time PCR and immunoblot analysis. GAL1 partner proteins were identified using co-immunoprecipitation followed by protein mass fingerprinting. Finally, inhibitory effect of GAL1 by thiodigalactoside (TDG) was assessed in adipocytes and HFD-induced obese rats. RESULTS: Knockdown of GAL1-encoding gene (Lgals1) attenuated adipogenesis and lipogenesis in both 3T3-L1 and HIB1B adipocytes. Further, direct treatment with TDG, a potent inhibitor of GAL1, to cultured adipocytes in vitro significantly reduced fat accumulation. Our animal experiment revealed that intraperitoneal injection of TDG (5 mg kg(-1)) once per week for 5 weeks in Sprague-Dawley (SD) rats resulted in dramatic inhibition of HFD-induced body weight gain (27.3% reduction compared with HFD-fed controls) by inhibiting adipogenesis and lipogensis as well as by increasing expression of the proteins associated with thermogenesis and energy expenditure. CONCLUSION: GAL1 has an essential role in HFD-induced obesity development. From a clinical viewpoint, pharmaceutical targeting of GAL1 using TDG and other inhibitor compounds would be a novel therapeutic approach for the treatment of obesity.

Influence of hepatitis B virus reactivation on the recurrence of HBV-related hepatocellular carcinoma after curative resection in patients with low viral load.

It is unclear whether the reactivation of hepatitis B virus (HBV) influences the prognosis of hepatocellular carcinoma (HCC) after resection in patients with chronic hepatitis B. The aim of this study was to identify the influence of HBV reactivation on the recurrence of hepatitis B-related HCC after curative resection in patients with low viral load (HBV DNA <2000 IU/mL). We retrospectively analysed a total of 130 patients who underwent curative resection for HBV-related early stage HCC (single nodule; <5 cm/two or three nodules; <3 cm) with pre-operative HBV DNA levels <2000 IU/mL with serial HBV DNA tests. The predictive factors including HBV reactivation for the recurrence of HBV-related HCC after curative resection were investigated. Fifty-three patients (41%) had HBV reactivation after resection among 130 patients. HBV reactivation was observed in 22 of 53 patients with undetectable baseline HBV DNA and in 31 of 77 patients with detectable baseline HBV DNA. Cumulative recurrence rates after resection at 1, 2 and 3 years were 17.0%, 23.3% and 31.4%, respectively. The multivariable analysis demonstrated that the risk factors for the recurrence were the presence of microvascular invasion (hazard ratio (HR) 2.62, P = 0.003), multinodularity (HR 4.61, P = 0.005), HBV reactivation after resection (HR 2.03, P = 0.032) and HBeAg positivity (HR 2.06, P = 0.044). HBV reactivation after curative resection is associated with the recurrence of HBV-related HCC in patients with low viral load.

Bone marrow-derived clonal mesenchymal stem cells inhibit ovalbumin-induced atopic dermatitis.

Mesenchymal stem cells (MSCs) possess immunomodulatory activities, including suppression of T- and B-cell activation. However, their effects on atopic dermatitis (AD) have not yet been studied. Using an ovalbumin-induced AD mouse model, we investigated whether MSCs can be used as therapeutics in AD. We isolated both allogeneic and syngeneic clonal MSCs (cMSCs) from mouse bone marrow according to the subfractionation culturing method. Our cMSCs suppressed both T- and B-cell activation. T-cell proliferation and cytokine production, including interferon (IFN)-γ and interleukin (IL)-4, were suppressed by inhibition of transcription factors, such as T-bet, GATA-3, and c-Maf. Those transcription factors were nitric oxide dependent. Immunoglobulin E (IgE) suppression occurred through downregulation of AID and BLIMP-1, important regulators for isotype class switch and B-cell differentiation. The cMSCs were injected intravenously into ovalbumin-induced AD mouse model, and the therapeutic effects were analyzed. Injection of both allogeneic and syngeneic cMSCs in an AD mouse model inhibited cell infiltration in skin lesions and decreased the serum level of IgE. IL-4 expression was also suppressed by cMSCs in both the lymph node and skin. The cMSCs migrated to skin lesions and draining lymph nodes. Taken together, these data demonstrated that cMSCs, which suppressed T- and B-cell functions, can be used for the treatment of AD in mice.

Levels of 4-1BB transcripts and soluble 4-1BB protein are elevated in the adipose tissue of human obese subjects and are associated with inflammatory and metabolic parameters.

BACKGROUND: 4-1BB, a member of the TNF receptor superfamily, has a role in various inflammatory pathologies through its interaction with 4-1BB ligand. We previously demonstrated that it participates in initiating and promoting obesity-induced adipose inflammation in a rodent model. OBJECTIVE: In this study, we examined whether 4-1BB is related to obesity-induced adipose inflammation and metabolic parameters in humans. METHODS: A total of 50 subjects, 25 obese (body mass index (BMI)≥25 kg m(-2)) and 25 lean (BMI<23 kg m(-2)) participated in the study. The levels of 4-1BB transcripts and soluble 4-1BB protein (s4-1BB) in subcutaneous adipose tissue were measured by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. Inflammatory and metabolic parameters were measured by enzymatic analysis and immunoassay. RESULTS: Obese subjects had higher levels of both 4-1BB transcripts and s4-1BB protein in subcutaneous adipose tissue than lean controls, and the levels were correlated with BMI and the expression of inflammatory markers, as well as with serum metabolic parameters. Moreover, s4-1BB was released from human adipocytes, and elicited chemotactic responses from human monocytes/T cells as well as enhancing their inflammatory activity, indicating that it may promote human adipose inflammation. DISCUSSION: Our data demonstrate that elevated levels of 4-1BB transcripts and s4-1BB in adipose tissue are closely associated with obesity-induced inflammation and metabolic dysregulation. They suggest that both 4-1BB transcripts and s4-1BB could serve as novel biomarkers and/or therapeutic targets for obesity-induced inflammation and metabolic syndrome in humans.

Effectiveness of locoregional therapy before living donor liver transplantation in patients with hepatocellular carcinoma who meet the Milan criteria.

BACKGROUND: Many patients are diagnosed with hepatocellular carcinoma (HCC) within the Milan criteria. In Korea, these patients are preferentially treated with locoregional therapy (LRT) instead of living donor liver transplantation. We investigated the effectiveness of LRT in liver transplant recipients who met the Milan criteria at the time of HCC diagnosis and investigated risk factors for HCC recurrence. METHODS: We retrospectively reviewed the medical records of patients diagnosed with HCC who met the Milan criteria between 2002 and 2008. RESULTS: We performed 101 liver transplants for HCC during the study period. Seventy-one patients (70%) underwent pretransplant LRT. The disease-free survival rates at 1, 3, and 5 years in patients who received LRT were 96.6%, 93.1%, and 93.1%, and in those who did not receive LRT, 94.2%, 83.4%, and 83.4%, respectively. There were no differences between the 2 groups. Multivariate analysis showed that a low Model for End-Stage Liver Disease (MELD) score and microvascular invasion were independent predictors of HCC recurrence after transplantation. The MELD scores and rate of microvascular invasion were not statistically different in patients with or without previous LRT. CONCLUSION: Pretransplant LRT for patients with HCC who met the Milan criteria at the time of diagnosis did not provide a clear benefit with respect to HCC recurrence after transplantation. If patients have suitable living donors, those who meet the Milan criteria should undergo a liver transplantation as soon as possible.

microRNAs in the regulation of adipogenesis and obesity.

Worldwide obesity is a growing health problem, associated with increased risk of chronic disease. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation, insulin action and fat metabolism. Recent studies show miRNAs are dysregulated in obese adipose tissue. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In addition miRNAs may regulate adipogenic lineage commitment in multipotent stem cells and hence govern fat cell numbers. Recent findings suggest miR-519d may be associated with human obesity, but larger case-control studies are needed. Few miRNA targets have been experimentally validated in adipocytes but interestingly both miR-27 and miR-519d target PPAR family members, which are well established regulators of fat cell development. In this review recent advances in our understanding of the role of miRNAs in fat cell development and obesity are discussed. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.

Prophylactic use of lamivudine for hepatitis B exacerbation in post-operative breast cancer patients receiving anthracycline-based adjuvant chemotherapy.

BACKGROUND: With the increasing incidence of breast cancer worldwide, in particular in southeast Asia (including Korea), and the common use of anthracyclines in the adjuvant and metastatic settings, the occurrence of Hepatitis B virus (HBV) reactivation may develop in this patient population. The use of prophylactic antiviral agents in cancer patients may result in a reduced HBV exacerbation. The purpose of the current study was to assess the efficacy of prophylactic lamivudine in reducing the incidence and severity of HBV reactivation in post-operative breast cancer patients undergoing adjuvant doxorubicin-containing chemotherapy. METHODS: The medical records of patients undergoing anthracycline-based adjuvant chemotherapy at Samsung Medical Center between January 2001 and September 2008 were reviewed. RESULTS: From the database, 1912 breast cancer patients who had received anthracycline-based adjuvant chemotherapy were identified. Of 131 patients who were HBV surface antigen positive, 55 and 76 did and did not receive prophylactic lamivudine, respectively. In all, 30 patients (23%) developed hepatitis during doxorubicin-containing adjuvant chemotherapy. Of the 30 patients, 5 (9%) were in the prophylactic lamivudine group and 25 (33%) in the control group (P=0.001). In the prophylactic lamivudine group, there was significantly less HBV reactivation (1 patient (2%) vs 20 patients (16%); P=0.002), less disruption of chemotherapy (7 vs 14%; P=0.04), and less severe hepatitis (0 vs 17%; P=0.002). CONCLUSION: Prophylactic lamivudine significantly reduced the incidence and severity of HBV reactivation in breast cancer patients undergoing anthracycline-based adjuvant chemotherapy.

Variations of clonal marrow stem cell lines established from human bone marrow in surface epitopes, differentiation potential, gene expression, and cytokine secretion.

Bone marrow has been considered to contain many different types of progenitor or stem cells. This study aims to establish a new strategy that provides for the rapid establishment of human clonal marrow stem cell (hcMSC) lines with a relatively small amount of bone marrow aspirate and to characterize newly generated hcMSC lines for their cell phenotype, differentiation potential, lineage-specific gene expression, and cytokine secretion. Human cMSC lines were generated with human bone marrow aspirates using a new protocol, called the subfractionation culturing method. The newly established hcMSC lines were analyzed for their cell surface epitopes by fluorescence-activated cell sorting (FACS), differentiation potential by in vitro differentiation assays, lineage-specific gene expression by RT-PCR, and cytokine secretion by enzyme-linked immunoassay (ELISA). The overall profile of the cell-surface epitopes of the newly established hcMSC lines was similar to those of the known MSCs. These hcMSC lines were capable of differentiating into multilineages with some differences in differentiation capability. In addition, these hcMSC lines secrete high levels of transforming growth factor-beta1 (TGF-beta1), leukemia inhibitory factor (LIF), TGF-alpha, and interleukein-10 (IL-10), again with some variation in each cell line. The newly designed protocol may be an efficient method to establish hcMSC lines rapidly with a relatively small amount of bone marrow sample, and these newly established hcMSC lines possess stem cell characteristics and exhibit some differences in cell-surface epitopes, differentiation potential, lineage-specific gene expression, and cytokine secretion.

Compositional study on rice bran oil after lipase-catalyzed glycerolysis and solvent fractionations.

Rice bran oil (RBO) was modified through lipase-catalyzed glycerolysis. After 48 h reaction, the reactant (RBO-G, solved in hexane) containing 0.14 mg/mL of MAG, 0.19 mg/mL of DAG, and 0.93 mg/mL of TAG was obtained. Extending the reaction to 72 h resulted in 0.37 mg/mL of DAG with concomitant reduction in TAG (0.68 mg/mL). Two solvent fractionation methods, independent and sequential fractionation, were performed with acetone and hexane at 0, -8, -14, or -35 degrees C. The fraction with most unsaturated fatty acids (Sigma UFA) was liquid fraction from independent fractionation at -35 degrees C (-35 In) from hexane, showing 88.3%Sigma UFA content. Nevertheless, when yield (wt%) was considered, the highest amount of UFA was obtained from 0 In (liquid fraction from independent fractionation at 0 degrees C) with hexane, resulting in 82.3%Sigma UFA with 97.9 wt% recovery. Normal-phase HPLC was conducted for the compositional study of RBO-G. Overall, solid fractions from sequential fractionation at 0 degrees C (0 SeSo) and independent fractionation at -35 degrees C (-35 InSo) with hexane contained the high concentration of total MAG and DAG, ranging from 0.94 to 1.35 (mg/mL).

Clinical significance of pre-S mutations in patients with genotype C hepatitis B virus infection.

We investigated the overall and site-specific prevalence of pre-S mutations and its clinical significance in patients with genotype C hepatitis B virus (HBV) infection. Three hundred subjects were included: 50 asymptomatic carriers (AC), 87 chronic hepatitis (CH), 91 liver cirrhosis (LC) and 72 hepatocellular carcinoma (HCC). Pre-S mutations were determined by nucleotide sequence analysis. Possible correlations between pre-S mutations and clinical/virological parameters were examined. Pre-S mutations were detected in 82 cases (27.3%); it was more frequently found in HCC (43.1%) and LC (35.2%) group than in the CH (20.7%) and AC (2.0%) group. Pre-S2 deletion was the most commonly found mutation (10.7%), followed by pre-S2 start codon mutation (9.7%), pre-S1-S2 deletion (3.0%) and both pre-S2 deletion and start codon mutation (2.7%). Pre-S2 deletion and pre-S2 start codon mutation were more frequently detected in advanced diseases (LC and HCC). Pre-S mutations were associated with older age and higher rates of positive HBV DNA (>/=0.5 pg/mL). Advanced disease and positive HBV DNA were shown to be independent predictors of pre-S mutations by logistic regression analysis. These findings suggest that pre-S mutations, especially pre-S2 deletions and pre-S2 start codon mutations, are common in patients with genotype C HBV infection and are associated with advanced liver disease and active viral replication.

Polyoma virus-associated nephropathy and concurrent cytomegalovirus infection in the kidney transplant recipients.

INTRODUCTION: Cytomegalovirus (CMV) and polyoma virus BK (BKV) may both establish latency following primary infection. Frequent reactivation of these viruses can occur in the kidney transplant recipients. BKV may induce CMV gene expression by stimulating cellular regulator proteins or by its own gene regulator proteins. A high rate of concurrent CMV infections has been noted in kidney transplant recipients with polyoma virus-associated nephropathy (PVAN). METHODS: PVAN was identified in 10 of 191 patients who received kidney transplants between October 1998 and September 2003. PVAN was confirmed by allograft kidney biopsy. Four of the 10 patients were complicated by concurrent CMV infection. RESULTS: Two patients had only serological evidence of CMV infection and one patient had CMV gastritis. These three patients were treated with intravenous ganciclovir with good results. Disseminated ganciclovir-resistant CMV disease was demonstrated in the remaining patient. This 34-year-old kidney transplant recipient with PVAN died of multiorgan failure despite antiviral therapy with both ganciclovir and foscarnet. CONCLUSION: PVAN with concurrent CMV infection in kidney transplant recipients showed variable clinical courses including mortality. Further studies are needed to elucidate the influence of PVAN on the pathogenesis of CMV infection.

Polyphenol (-)-epigallocatechin gallate protection from ischemia/reperfusion-induced renal injury in normotensive and hypertensive rats.

INTRODUCTION: The effect of epigallocatechin gallate (EGCG) in an in vivo renal model of ischemia with reperfusion (I/R) was compared between normotensive (WKR) and hypertensive (SHR) rats. METHODS: WKR (groups I, II, III) and SHR groups (groups IV, V, VI) were divided into three types. Groups I and IV were sham-operated animals; groups II and V were subjected to 45 minutes of renal I/R; and groups III and VI received 10 mg/kg EGCG intravenously at the time of reperfusion. Three days after renal I/R, we compared renal function markers, malondialdehyde (MDA), and histologic changes. RESULTS: Following renal I/R, levels of blood urea nitrogen (BUN) and serum creatinine (sCr) were increased and serum creatinine clearance (CrCl) decreased in group V compared to group II (P < .001). Those receiving EGCG treatment (groups III and VI) had decreased BUN and sCr compared to non-EGCG I/R groups (P < .001), but not surprisingly, higher than sham groups. CrCl was lowest in the SHR groups. The MDA was significantly decreased after EGCG treatment (P = .028 in group III, P = .002 in group VI). Following renal I/R, tissue necrosis was more severe among SHR (P < .001). However, the ratio of regeneration to damage significantly increased in SHR after EGCG treatment. CONCLUSIONS: The reperfusion injury was greater among SHR compared with WKR in terms of renal function, lipid peroxidation, and tissue damage. EGCG treatment significantly ameliorated renal impairment and promoted tissue regeneration following renal I/R.

Outcomes in patients with hepatopulmonary syndrome undergoing liver transplantation.

Hepatopulmonary syndrome (HPS) is a condition of significant hypoxia due to intrapulmonary shunting (IPS) in patients with advanced liver disease. Reversibility of HPS after liver transplantation (LT) has been suggested, but the results of LT for HPS remain poorly defined. We studied 78 patients with decompensated liver disease who underwent LT after a preoperative evaluation including contrast echocardiography. We compared the baseline characteristics and outcomes after LT in patients with HPS (n = 13) with those of patients without HPS (n = 65, controls). Before LT, prolongation of prothrombin time was more severe and an advanced Child-Pugh class were more frequent among HPS, patients compared with controls (INR 2.5 +/- 0.8 vs 1.9 +/- 0.7, P = .01; Child-Pugh class A:B:C = 0%:31%:69% vs 14%:65%:21%, P < .01). After LT, no significant differences were observed between the two groups in: clinical outcomes, duration of endotracheal intubation (4.5 +/- 7.7 vs 4.4 +/- 15.0 days), duration of intensive care unit stay (12.0 +/- 8.7 vs 14.4 +/- 19.4 days), duration of total hospital stay (40.0 +/- 33.5 vs 39.8 +/- 23.0), rate of pulmonary complications (7.7% vs 9.2%), or 3-month survival rates (92.3% vs 86.1%). These findings suggest that the presence of HPS does not significantly affect LT outcomes in patients with decompensated liver disease.

Can we expand the Milan criteria for hepatocellular carcinoma in living donor liver transplantation?

INTRODUCTION: The Milan criteria, namely, tumors 5 cm or less in diameter in patients with single hepatocellular carcinoma (HCC), no more than 3 tumor nodules, and each 3 cm or less in diameter in patients with multiple tumors, are accepted for cadaveric liver allocation. However, in living donor liver transplantation (LDLT), graft donation may only depend on the donor's intention. The aim of this study was to elucidate the feasibility of Milan criteria in LDLT. MATERIALS AND METHODS: From January 2001 to December 2002, 46 cases of liver transplantation (LT) for HCC included 5 hospital mortalities and 3 cadaveric transplantations, all of which were excluded. We classified the patients into Group I cases that met the Milan criteria and Group II cases that did not meet the Milan criteria. The analyses examined tumor-related risk factors affecting recurrence and survival, such as tumor size, number of tumor nodules, and presence of microvascular and macrovascular invasion. RESULTS: Twenty-one cases belonged to Group I and 17 to Group II. There was no significant difference in the recurrence or survival rates between Groups I and II. The risk factors affecting recurrence were macrovascular invasion and tumor size (5 cm). The number of tumor nodules and microvascular invasion did not appear to affect recurrence. The risk factor affecting survival was macrovascular invasion. CONCLUSION: We suggest that in selected cases the Milan criteria could be extended to increase the number of tumor nodules as long as the HCC were small and did not macrovascular invasion.

Clinicopathological features of incidental hepatocellular carcinoma in liver transplantation.

The incidence of detecting hepatocellular carcinoma (HCC) in a removed recipient liver after a liver transplant is not rare. The clinical features are expected to be different from the preoperatively diagnosed HCC. The aim of this study was to evaluate the clinicopathological features of incidental HCC. This study retrospectively analyzed five cases of incidental HCC among 51 liver transplant cases of HCC operated from September 1996 to February 2002. The proportion of an incidental HCC was 9.8%. The mean age was 46.2 years with a higher prevalence in may (80%, four cases). The alpha-fetoprotein level was normal or mildly elevated. HBsAg was positive in all cases. Imaging studies revealed regenerative or dysplastic nodules, or no specific lesion. The pathological findings demonstrated a mean size of 1.16 cm, multiplicity in three cases (60%), no microvascular invasion, and Edmonson grade I (60%) and II (40%). There was no recurrence of the HCC. However, two patients died due to an intracranial hemorrhage and a graft failure, respectively. In conclusion, incidentally found HCC showed less invasive pathological features and a better prognosis.

Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects.

BACKGROUND AND AIMS: Preliminary studies have shown that naringin has a potent lipid-lowering effect and antioxidant capacity in high-cholesterol diet fed animals. Accordingly, the present study was conducted to investigate the effect of naringin on hypercholesterolemic subjects. METHODS: A hypercholesterolemic group (n=30) and healthy control group (n=30) were established based on the plasma cholesterol levels in the subjects, then all subjects received naringin (400mg/capsule/day) with regular meals for a period of 8 weeks. RESULTS: In the hypercholesterolemic subjects, naringin supplementation was found to lower the plasma total cholesterol by 14% and low-density lipoprotein cholesterol concentrations by 17%, while the plasma triglyceride and high-density lipoprotein cholesterol concentrations remained unaffected. The apolipoprotein B levels in the hypercholesterolemic subjects were significantly lowered after naringin treatment, yet no change was observed in the apolipoprotein A-1 levels. The erythrocyte superoxide dismutase and catalase activities in the hypercholesterolemic group were significantly increased, whereas the glutathione peroxidase activity and plasma TBARS levels were not different from the baseline measurements. Meanwhile, naringin supplementation had no affect on plasma lipids, apolipoproteins, and TBARS levels or antioxidant enzyme activities in the control group. CONCLUSIONS: Therefore, these data suggest that naringin may play an important role in lowering plasma cholesterol and regulating the antioxidant capacity in hypercholesterolemic subjects.

Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin.

The potassium ionophore nigericin induces cell death and promotes the maturation and release of IL-1beta in lipopolysaccharide (LPS)-primed monocytes and macrophages, the latter depending on caspase-1 activation by an unknown mechanism. Here, we investigate the pathway that triggers cell death and activates caspase-1. We show that without LPS priming, nigericin alone triggered caspase-1 activation and IL-18 generation in THP-1 monocytic cells. Simultaneously, nigericin induced caspase-1-independent necrotic cell death, which was blocked by the cathepsin B inhibitor CA-074-Me and other cathepsin inhibitors. Cathepsin B activation after nigericin treatment was determined biochemically and corroborated by rapid lysosomal leakage and translocation of cathepsin B to the cytoplasm. IL-18 maturation was prevented by both caspase-1 and cathepsin B inhibitors in THP-1 cells, primary mouse macrophages and human blood monocytes. Moreover, IL-18 generation was reduced in THP-1 cells stably transformed either with cystatin A (an endogenous cathepsin inhibitor) or antisense cathepsin B cDNA. Collectively, our study establishes a critical role for cathepsin B in nigericin-induced caspase-1-dependent IL-18 maturation and caspase-1-independent necrosis.

Effects of rutin and harmaline on rat reflux oesophagitis.

1. This study was aimed at evaluating the effect of rutin and harmaline (1-methyl-7-methoxy-3,4-dihydro-beta-carboline) on the development of the surgically induced reflux oesophagitis, on gastric secretion, lipid peroxidation, polymorphonucleocytes (PMNs) accumulation, superoxide and hydroxyl radical production in PMNs, cytokine [interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha)] production in blood and [Ca2+]i mobilization in PMNs. 2. Rutin and harmaline significantly prevented the development of reflux oesophagitis and gastric secretion. Treatments of oesophagitis rats with rutin and harmaline inhibited lipid peroxidation, and myeloperoxidase (MPO) in the oesophagus in comparison with untreated rats. 3. Superoxide anion and hydrogen peroxide production in 1 microm formylmethionylleucylphenylalanine (fMLP)- or 0.1 microg ml-1N-phorbol 12-myristate 13-acetate (PMA)-activated PMNs was inhibited by rutin and harmaline in a dose-dependent fashion. Rutin and harmaline effectively scavenged the hydroxyl radical and hydrogen peroxide. Treatments of oesophagitis rats with rutin and harmaline inhibited IL-1beta production in the oesophagus in comparison with untreated rats, but TNF-alpha production was not affected by rutin and harmaline. The fMLP-induced elevation of [Ca2+]i was inhibited by rutin. 4. The results of this study suggest that rutin and harmaline may have beneficial protective effects against reflux oesophagitis by the inhibition of gastric acid secretion, oxidative stress, inflammatory cytokine production (i.e. IL-1beta), and intracellular calcium mobilization in PMNs in rats.

Lipid-lowering and antioxidative activities of 3,4-di(OH)-cinnamate and 3,4-di(OH)-hydrocinnamate in cholesterol-fed rats.

BACKGROUND: Polyphenols appear to have antioxidant activities and may mediate lipid lowering. METHODS: Four groups of rats, a high-cholesterol control (HC), HC+lovastatin, HC+3,4-di(OH)-cinnamate, and HC+3,4-di(OH)-hydrocinnamate, were given a semi-synthetic diet. The cinnamate derivative or lovastatin (0.1 g/100 g) supplements were given for 6 weeks. RESULTS: The plasma total cholesterol concentration was significantly lowered by the 3,4-di(OH)-cinnamate supplement compared to the control or lovastatin group. The 3,4-di(OH)-cinnamate and 3,4-di(OH)-hydrocinnamate supplements significantly lowered both the hepatic cholesterol and triglyceride levels, while lovastatin only lowered the hepatic cholesterol. The hepatic HMG-CoA reductase activities were significantly lower in the 3,4-di(OH)-cinnamate and 3,4-di(OH)-hydrocinnamate groups than in the control or lovastatin group. The ACAT activity was only significantly lower in the lovastatin group compared to the other groups. With regards the hepatic antioxidant enzyme system, the CAT activity was significantly higher in the 3,4-di(OH)-cinnamate and 3,4-di(OH)-hydrocinnamate groups compared to the control or lovastatin group. The two cinnamate derivatives resulted in an increased hepatic GSH-Px activity. Meanwhile, all the supplements significantly lowered the hepatic thiobarbituric acid reactive substances (TBARS) content. However, the 3,4-di(OH)-cinnamate and 3,4-di(OH)-hydrocinnamate supplements did not alter the neutral sterol and total fecal sterol. CONCLUSIONS: Both cinnamate derivatives were potent in lipid-lowering and altering the antioxidative enzyme. Furthermore, these results also suggest that 3,4-di(OH)-cinnamate is more effective than 3,4-di(OH)-hydrocinnamate in its lipid-lowering action.