Reversibility of some oxidative stress markers in chronic hepatitis C patients after receiving direct-acting antiviral agents.

Introduction: Hepatitis C (HCV) is associated with extra-hepatic involvment, morbidity as well as metabolic changes. Whether these might be reversible if sustained virologic response (SVR) is achieved by direct-acting antiviral (DAA) therapy remains unknown. Methods: Chronic hepatitis C (CHC) individuals receiving DAA treatment with SVR were compared to those who underwent spontaneous clearance (SC) of HCV infection at the 2-year follow-up. Plasma oxidative stress markers (oxidized low-density lipoprotein (oxLDL), 8-hydroxy-2'-deoxyguanosine (8-OHdG), malondialdehyde (MDA) and ischemia-modified albumin (IMA)) as well as progression of liver fibrosis were evaluated. Results: Compared to SC individuals, those in the CHC group exhibited at baseline higher levels of oxLDL, 8-OHdG and IMA but not of MDA. In the SC group, 8-OHdG levels were elevated at 2-year post-SVR (p = 0.0409), while the DAA-treated CHC group showed decrease in oxLDL (p < 0.0001) and 8-OHdG (p = 0.0255) levels, approaching those of the SC group, but increased MDA (p = 0.0055) levels. Additionally, oxLDL levels were positively correlated with liver stiffness measurements at SVR (p = 0.017) and at 1 year post- SVR (p = 0.002). Conclusions: Plasma oxLDL showed post-SVR normalization after clearance of HCV viremia with DAAs and was associated with levels of hepatic fibrosis.

Antagonizing apolipoprotein J chaperone promotes proteasomal degradation of mTOR and relieves hepatic lipid deposition.

BACKGROUND AND AIMS: Overnutrition-induced activation of mammalian target of rapamycin (mTOR) dysregulates intracellular lipid metabolism and contributes to hepatic lipid deposition. Apolipoprotein J (ApoJ) is a molecular chaperone and participates in pathogen-induced and nutrient-induced lipid accumulation. This study investigates the mechanism of ApoJ-regulated ubiquitin-proteasomal degradation of mTOR, and a proof-of-concept ApoJ antagonist peptide is proposed to relieve hepatic steatosis. APPROACH AND RESULTS: By using omics approaches, upregulation of ApoJ was found in high-fat medium-fed hepatocytes and livers of patients with NAFLD. Hepatic ApoJ level associated with the levels of mTOR and protein markers of autophagy and correlated positively with lipid contents in the liver of mice. Functionally, nonsecreted intracellular ApoJ bound to mTOR kinase domain and prevented mTOR ubiquitination by interfering FBW7 ubiquitin ligase interaction through its R324 residue. In vitro and in vivo gain-of-function or loss-of-function analysis further demonstrated that targeting ApoJ promotes proteasomal degradation of mTOR, restores lipophagy and lysosomal activity, thus prevents hepatic lipid deposition. Moreover, an antagonist peptide with a dissociation constant (Kd) of 2.54 µM interacted with stress-induced ApoJ and improved hepatic pathology, serum lipid and glucose homeostasis, and insulin sensitivity in mice with NAFLD or type II diabetes mellitus. CONCLUSIONS: ApoJ antagonist peptide might be a potential therapeutic against lipid-associated metabolic disorders through restoring mTOR and FBW7 interaction and facilitating ubiquitin-proteasomal degradation of mTOR.

Interdependence of glycemic and lipid modulation in cured chronic hepatitis C patients by direct-acting antiviral agents.

BACKGROUND: Chronic hepatitis C virus (HCV) infection causes various liver diseases and metabolic disorders. With direct-acting antiviral agents (DAAs), which effectively eradicate pan-genotypic HCV, hepatic and concomitant metabolic restorations are achieved. The study aims to evaluate the posttherapeutic benefits of lipid and glycemic homeostasis. METHODS: Nighty-five chronic hepatitis C patients who achieved sustained virological response (SVR) by using DAAs were enrolled to collect plasma samples and fractionated lipoproteins at baseline, SVR, and during the post-SVR follow-ups for 6 months (pS6m) and 1 year (pS1yr). The lipid and glycemic parameters were analyzed to establish muturally modulatory relationships. RESULTS: Plasma cholesterol (Chol) and glucose were elevated at SVR from baseline, whereas plasma Chol remained increased until pS1yr; however, glucose returned to the basal level. The post-SVR responses included a peak elevation of glycated hemoglobin at pS6m, a sustained elevation of triglyceride (Tg), and sustained declines in insulin, homeostasis model assessment (HOMA)-insulin resistance, and HOMA-beta levels until pS1yr. The changes in plasma Chol and high-density-lipoprotein Chol showed positive correlations, as did the plasma Tg with low-density-lipoprotein Tg and very-low-density-lipoprotein Tg per particle load. Very-low-density-lipoprotein was found to be loaded with increased Tg and Chol and underwent efficient Tg catabolism in the form of conversion into low-density-lipoprotein. Additionally, the posttherapeutic dynamics exhibited correlations of high-density-lipoprotein Chol with plasma glucose and HOMA-beta. CONCLUSION: Irrespective of the baseline metabolic status, the posttherapeutic interdependent modulation of blood glycemic and lipid metabolic parameters were revealed in chronic hepatitis C patients following clearance of HCV viremia by DAA treatment.

Assessment of ELISA-based method for the routine examination of serum indoxyl sulfate in patients with chronic kidney disease.

Introduction: Indoxyl sulfate (IS), a protein-bound uremic toxin, is associated with kidney function and chronic kidney disease (CKD)-related complications. Currently, serum IS levels are primarily quantified using mass spectrometry-based methods, which are not feasible for routine clinical examinations. Methods: The efficiencies of three commercial ELISA kits in determination of serum IS were validated by comparing with ultra-performance liquid chromatography (UPLC)-MS/MS-based method using Bland-Altman analysis. The associations between kidney parameters and serum IS levels determined by ELISA kit from Leadgene and UPLC-MS/MS were evaluated by Spearman correlation coefficient in a CKD validation cohort. Results: ELISA kit from Leadgene showed clinical agreement with UPLC-MS/MS in the determination of serum IS levels (p = 0.084). In patients with CKD, Spearman's correlation analysis revealed a perfect correlation between the IS levels determined using the Leadgene ELISA kit and UPLC-MS/MS (r = 0.964, p < 0.0001). IS levels determined using the Leadgene ELISA kit were associated with the estimated glomerular filtration rate (r = -0.772, p < 0.0001) and serum creatinine concentration (r = 0.824, p < 0.0001) in patients with CKD, and on dialysis (r = 0.557, p = 0.006). Conclusions: The Leadgene ELISA kit exhibits comparable efficacy to UPLC-MS/MS in quantifying serum IS levels, supporting that ELISA would be a personalized method for monitoring the dynamic changes in serum IS levels in dialysis patients to prevent the progression of CKD.

The Relationship between Metabolic Syndrome and Plasma Metals Modified by EGFR and TNF-α Gene Polymorphisms.

With the escalating global prevalence of metabolic syndrome (MetS), it is crucial to detect the high-risk population early and to prevent chronic diseases. Exposure to various metals has been indicated to promote MetS, but the findings were controversial, and the effect of genetic modification was not considered. Epidermal growth factor receptor (EGFR) was proposed to be involved in the pathway of metabolic disorders, and tumor necrotic factor-α (TNF-α) was regarded as an early inflammatory biomarker for MetS. This research aimed to analyze the impact of EGFR and TNF-α gene polymorphisms on the prevalence of MetS under environmental or occupational exposure to metals. We gathered data from 376 metal industrial workers and 639 non-metal workers, including physical parameters, biochemical data, and plasma concentrations of six metals. According to the genomic database of Taiwan Biobank, 23 single nucleotide polymorphisms (SNPs) on EGFR gene and 6 SNPs on TNF-α gene were incorporated in our research. We applied multivariable logistic regression to analyze the probability of MetS with various SNPs and metals. Our study revealed some susceptible and protective EGFR and TNF-α genotypes under excessive exposure to cobalt, zinc, selenium, and lead. Thus, we remind the high-risk population of taking measures to prevent MetS.

Sterol O-acyltransferase 2 chaperoned by apolipoprotein J facilitates hepatic lipid accumulation following viral and nutrient stresses.

The risks of non-alcoholic fatty liver disease (NAFLD) include obese and non-obese stresses such as chronic hepatitis C virus (HCV) infection, but the regulatory determinants remain obscure. Apolipoprotein J (ApoJ) served as an ER-Golgi contact-site chaperone near lipid droplet (LD), facilitating HCV virion production. We hypothesized an interplay between hepatic ApoJ, cholesterol esterification and lipid deposit in response to NAFLD inducers. Exposures of HCV or free-fatty acids exhibited excess LDs along with increased ApoJ expression, whereas ApoJ silencing alleviated hepatic lipid accumulation. Both stresses could concomitantly disperse Golgi, induce closer ApoJ and sterol O-acyltransferase 2 (SOAT2) contacts via the N-terminal intrinsically disordered regions, and increase cholesteryl-ester. Furthermore, serum ApoJ correlated positively with cholesterol and low-density lipoprotein levels in normal glycaemic HCV patients, NAFLD patients and in mice with steatosis. Taken together, hepatic ApoJ might activate SOAT2 to supply cholesteryl-ester for lipid loads, thus providing a therapeutic target of stress-induced steatosis.

Rapid SARS-CoV-2 Spike Protein Detection by Carbon Nanotube-Based Near-Infrared Nanosensors.

To effectively track and eliminate COVID-19, it is critical to develop tools for rapid and accessible diagnosis of actively infected individuals. Here, we introduce a single-walled carbon nanotube (SWCNT)-based optical sensing approach toward this end. We construct a nanosensor based on SWCNTs noncovalently functionalized with ACE2, a host protein with high binding affinity for the SARS-CoV-2 spike protein. The presence of the SARS-CoV-2 spike protein elicits a robust, 2-fold nanosensor fluorescence increase within 90 min of spike protein exposure. We characterize the nanosensor stability and sensing mechanism and passivate the nanosensor to preserve sensing response in saliva and viral transport medium. We further demonstrate that these ACE2-SWCNT nanosensors retain sensing capacity in a surface-immobilized format, exhibiting a 73% fluorescence turn-on response within 5 s of exposure to 35 mg/L SARS-CoV-2 virus-like particles. Our data demonstrate that ACE2-SWCNT nanosensors can be developed into an optical tool for rapid SARS-CoV-2 detection.

Click chemistry-based biopolymeric hydrogels for regenerative medicine.

Click chemistry is not a single specific reaction, but describes ways of generating products which emulate examples in nature. Click reactions occur in one pot, are not disturbed by water, generate minimal and inoffensive byproducts, and are characterized by a high thermodynamic driving force, driving the reaction quickly and irreversibly towards a high yield of a single reaction product. As a result, over the past 15 years it has become a very useful bio-orthogonal method for the preparation of chemical cross-linked biopolymer-based hydrogel, in the presence of e.g. growth factors and live cells, or in-vivo. Biopolymers are renewable and non-toxic, providing a myriad of potential backbone toolboxes for hydrogel design. The goal of this review is to summarize recent advances in the development of click chemistry-based biopolymeric hydrogels, and their applications in regenerative medicine. In particular, various click chemistry approaches, including copper-catalyzed azide-alkyne cycloaddition reactions, copper-free click reactions (e.g. the Diels-Alder reactions, the strain-promoted azide-alkyne cycloaddition reactions, the radical mediated thiol-ene reactions, and the oxime-forming reactions), and pseudo-click reactions (e.g. the thiol-Michael addition reactions and the Schiff base reactions) are highlighted in the first section. In addition, numerous biopolymers, including proteins (e.g. collagen, gelatin, silk, and mucin), polysaccharides (e.g. hyaluronic acid, alginate, dextran, and chitosan) and polynucleotides (e.g. deoxyribonucleic acid), are discussed. Finally, we discuss biopolymeric hydrogels, cross-linked by click chemistry, intended for the regeneration of skin, bone, spinal cord, cartilage, and cornea. This article provides new insights for readers in terms of the design of regenerative medicine, and the use of biopolymeric hydrogels based on click chemistry reactions.

Rapid SARS-CoV-2 Detection by Carbon Nanotube-Based Near-Infrared Nanosensors.

To effectively track and eliminate COVID-19, it is critical to develop tools for rapid and accessible diagnosis of actively infected individuals. Here, we introduce a single-walled carbon nanotube (SWCNT)-based optical sensing approach towards these ends. We construct a nanosensor based on SWCNTs noncovalently functionalized with ACE2, a host protein with high binding affinity for the SARS-CoV-2 spike protein. Presence of the SARS-CoV-2 spike protein elicits a robust, two-fold nanosensor fluorescence increase within 90 min of spike protein exposure. We characterize the nanosensor stability and sensing mechanism, and passivate the nanosensor to preserve sensing response in saliva and viral transport medium. We further demonstrate that these ACE2-SWCNT nanosensors retain sensing capacity in a surface-immobilized format, exhibiting a 73% fluorescence turn-on response within 5 s of exposure to 35 mg/L SARS-CoV-2 virus-like particles. Our data demonstrate that ACE2-SWCNT nanosensors can be developed into an optical tool for rapid SARS-CoV-2 detection.

Differential dynamics of hepatic protein expressions with long-term cultivated hepatitis C virus infection.

BACKGROUND: The liver maintains blood chemical homeostasis by active uptake and secretion through endocytosis, exocytosis, and intracellular trafficking between the plasma and intracellular membranes. Hepatitis C virus (HCV) infection affects the host membrane architecture and might thus impair the regulation of the cellular transportation machinery. Additionally, the hepatic expressions of differential protein dynamics with long-term HCV infection remain fully recover. METHODS: In this study, comparative proteomic analysis was performed in HCV-infected and mock-control Huh7 cells according to the viral dynamics of exponential, plateau, declined, and silencing phases at the acute stage, and the chronic stage. The proteins with <0.8-fold and ≥1.25-fold changes in expression were analyzed using functional pathway clustering prediction. RESULTS: The combined experimental repetitions identified full-spectrum cellular proteins in each of 5 sample sets from acute exponential, plateau, declined, and silencing phases, and the chronic stage. The clustering results revealed that HCV infection might differentiate regulatory pathways involving extracellular exosome, cadherin, melanosome, and RNA binding. Overall host proteins in HCV-infected cells exhibited kinetic pattern 1, in which cellular expression was downregulated from the acute exponential to plateau phases, reached a nadir, and was then elevated at the chronic stage. The proteins involved in the membrane-budding pathway exhibited kinetic pattern 2, in which their expressions were distinctly downregulated at the chronic stage. CONCLUSION: The current comparative proteomics revealed the differential regulatory effects of HCV infection on host intracellular transport functional pathways, which might contribute to the pathogenic mechanisms of HCV in hepatocytes that sustain long-term infection.

The Association of Serum TNF-α Levels and Blood Multi-Elements Modified by TNF-α Gene Polymorphisms in Metal Industrial Workers.

Health of the metal industrial workers should be a noteworthy issue due to the hazard ofchronic exposure to metals or toxic elements. The interactions among multiple elements aresophisticated and may differ from person to person. Tumor necrosis factor-α (TNF-α) genepolymorphisms were supposed to be involved with the interactions because TNF-α plays animportant role in inflammation, a mechanism by which toxic elements cause threats to humanhealth. This research aimed to analyze the influence of TNF-αgene polymorphisms and multielementson serum TNF-α level. Blood multi-elements concentrations (lead, cadmium, arsenic,selenium, cobalt, copper, and zinc), serum TNF-α level, and TNF-α single nucleotidepolymorphisms (SNPs), including -238G > A (rs361525), -308G > A (rs1800629), -857C > T(rs1799724), -863C > A (rs1800630), and -1031T > C (rs1799964), were measured in 462 metalindustrial workers. We applied mixed-effect models to analyze the interactions among multielementsand TNF-α SNPs. Blood concentration of all elements were positively associated withserum TNF-α level, and the effects may be modified by TNF-α gene polymorphisms. Our studyrevealed that TNF-α -308A/A and -1031C/C may be susceptible genotypes, and thus we suggestthat those workers should take preventive measures against metal toxicity.

Etifoxine, a TSPO Ligand, Worsens Hepatitis C-Related Insulin Resistance but Relieves Lipid Accumulation.

Etifoxine, an 18 kDa translocator protein (TSPO) agonist for the treatment of anxiety disorders in clinic, may be able to cause acute liver injury or cytolytic hepatitis. TSPO has been demonstrated to participate in inflammatory responses in infective diseases as well as to modulate glucose and lipid homeostasis. Hepatitis C virus (HCV) infection disrupts glucose and lipid homoeostasis, leading to insulin resistance (IR). Whether TSPO affects the HCV-induced IR remains unclear. Here, we found that the administration of etifoxine increased the TSPO protein expression and recovered the HCV-mediated lower mitochondrial membrane potential (MMP) without affecting HCV infection. Moreover, etifoxine reversed the HCV-induced lipid accumulation by modulating the expressions of sterol regulatory element-binding protein-1 and apolipoprotein J. On the other hand, in infected cells pretreated with etifoxine, the insulin-mediated insulin receptor substrate-1/Akt signals, forkhead box protein O1 translocation, and glucose uptake were blocked. Taken together, our results pointed out that etifoxine relieved the HCV-retarded MMP and reduced the lipid accumulation but deteriorated the HCV-induced IR by interfering with insulin signal molecules.

TARBP2-Enhanced Resistance during Tamoxifen Treatment in Breast Cancer.

Tamoxifen is the most widely used hormone therapy in estrogen receptor-positive (ER+) breast cancer, which accounts for approximately 70% of all breast cancers. Although patients who receive tamoxifen therapy benefit with respect to an improved overall prognosis, resistance and cancer recurrence still occur and remain important clinical challenges. A recent study identified TAR (HIV-1) RNA binding protein 2 (TARBP2) as an oncogene that promotes breast cancer metastasis. In this study, we showed that TARBP2 is overexpressed in hormone therapy-resistant cells and breast cancer tissues, where it enhances tamoxifen resistance. Tamoxifen-induced TARBP2 expression results in the desensitization of ER+ breast cancer cells. Mechanistically, tamoxifen post-transcriptionally stabilizes TARBP2 protein through the downregulation of Merlin, a TARBP2-interacting protein known to enhance its proteasomal degradation. Tamoxifen-induced TARBP2 further stabilizes SOX2 protein to enhance desensitization of breast cancer cells to tamoxifen, while similar to TARBP2, its induction in cancer cells was also observed in metastatic tumor cells. Our results indicate that the TARBP2-SOX2 pathway is upregulated by tamoxifen-mediated Merlin downregulation, which subsequently induces tamoxifen resistance in ER+ breast cancer.

TARBP2-mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a lethal human malignancy and a leading cause of cancer-related death worldwide. Patients with HCC are often diagnosed at an advanced stage, and the prognosis is usually poor. The multikinase inhibitor sorafenib is the first-line treatment for patients with advanced HCC. However, cases of primary or acquired resistance to sorafenib have gradually increased, leading to a predicament in HCC therapy. Thus, it is critical to investigate the mechanism underlying sorafenib resistance. Transactivation response element RNA-binding protein 2 (TARBP2) is a multifaceted miRNA biogenesis factor that regulates cancer stem cell (CSC) properties. The tumorigenicity and drug resistance of cancer cells are often enhanced due to the acquisition of CSC features. However, the role of TARBP2 in sorafenib resistance in HCC remains unknown. Our results demonstrate that TARBP2 is significantly downregulated in sorafenib-resistant HCC cells. The TARBP2 protein was destabilized through autophagic-lysosomal proteolysis, thereby stabilizing the expression of the CSC marker protein Nanog, which facilitates sorafenib resistance in HCC cells. In summary, here we reveal a novel miRNA-independent role of TARBP2 in regulating sorafenib resistance in HCC cells.

Calcitriol Inhibits HCV Infection via Blockade of Activation of PPAR and Interference with Endoplasmic Reticulum-Associated Degradation.

Vitamin D has been identified as an innate anti-hepatitis C virus (HCV) agent but the possible mechanisms for this issue remain unclear. Here, we clarified the mechanisms of calcitriol-mediated inhibition of HCV infection. Calcitriol partially inhibited HCV infection, nitric oxide (NO) release and lipid accumulation in Huh7.5 human hepatoma cells via the activation of vitamin D receptor (VDR). When cells were pretreated with the activators of peroxisome proliferator-activated receptor (PPAR)-α (Wy14643) and -γ (Ly171883), the calcitriol-mediated HCV suppression was reversed. Otherwise, three individual stimulators of PPAR-α/ß/γ blocked the activation of VDR. PPAR-ß (linoleic acid) reversed the inhibition of NO release, whereas PPAR-γ (Ly171883) reversed the inhibitions of NO release and lipid accumulation in the presence of calcitriol. The calcitriol-mediated viral suppression, inhibition of NO release and activation of VDR were partially blocked by an inhibitor of endoplasmic reticulum-associated degradation (ERAD), kifunensine. Furthermore, calcitriol blocked the HCV-induced expressions of apolipoprotein J and 78 kDa glucose-regulated protein, which was restored by pretreatment of kifunensine. These results indicated that the calcitriol-mediated HCV suppression was associated with the activation of VDR, interference with ERAD process, as well as blockades of PPAR, lipid accumulation and nitrative stress.

Favouring modulation of circulating lipoproteins and lipid loading capacity by direct antiviral agents grazoprevir/elbasvir or ledipasvir/sofosbuvir treatment against chronic HCV infection.

OBJECTIVE: Lipid homoeostasis is disturbed in patients with HCV infection. Direct-acting antiviral agent (DAA) treatment eradicates chronic HCV viraemia, but the dynamics of lipid components remain elusive. This study investigates the clinical manifestation and mechanistic relevance of plasma triglyceride (TG), cholesterol (Chol), lipoproteins and apolipoproteins (apos) after DAA treatment. DESIGN: Twenty-four patients with chronic genotype 1 (GT1) HCV treated with elbasvir/grazoprevir or ledipasvir/sofosbuvir for 12 weeks, and followed-up thereafter, were recruited. Their TG, Chol, apoAI and apoB levels were quantified in plasma samples and individually fractionated lipoprotein of various classes. Liver fibrosis was evaluated using the FIB-4 Score. The TG and Chol loading capacities were calculated with normalisation to apoB, which represents per very low density lipoprotein (VLDL) and LDL particle unit RESULTS: DAA treatment achieved a sustained virological response rate of 91.7% and reduced the FIB-4 Score. Relative to the baseline, the plasma TG level was reduced but the Chol level increased gradually. Plasma apoB levels and apoB/apoAI ratio were transiently downregulated as early as the first 4 weeks of treatment. The TG and Chol loading capacities in VLDL were elevated by ~20% during the period of DAA treatment and had steadily increased by 100% at follow-up. Furthermore, the TG-to-Chol ratio in VLDL was increased, while the ratio in LDL was reduced, indicating an efficient catabolism. CONCLUSION: The DAA treatment of patients with chronic hepatitis C might lead to efficient HCV eradication and hepatic improvement concomitantly evolving with favouring lipoprotein/apo metabolisms.

Viral dynamics of persistent hepatitis C virus infection in high-sensitive reporter cells resemble patient's viremia.

BACKGROUND: Hepatitis C virus (HCV) infection has a high persistence rate in patients. Although immune cells play a central role in determining the outcomes of HCV infection, the liver is crucial in controlling HCV activity from acute to chronic stages. This investigation grew HCV from a long-term cell culture, and provided an experimental model for studies on HCV persistence in hepatocytes. METHODS: Huh7.5 cells implanted with the NS3/4 protease-based secreted alkaline phosphatase (SEAP) reporter were infected with JFH-1 HCV (moiety of infection = 0.01) and incubated for over 130 days. RESULTS: The viral activity was obtained by sampling supernatant continuously for SEAP activity measurement. Combined with extracellular and intracellular HCV-RNAs and viral infectivity assays, the experimental results exhibited in vitro viral dynamics resembling the patients' viremia pattern from acute to chronic infections. The HCV in acute infection comprised exponential accumulation (week 1), plateau (week 2), declining production (weeks 3-4) and silencing (weeks 5-14) phases, and were then reactivated at the onset of chronic infection (after week 15). The HCV-infected cells grew more slowly than the mock controls, and exhibited a prominent decrease of cell growth rate and increase of early apoptosis in the declining-to-silencing phase transition, suggesting that fitness selection might occur as the infected cells moved across the boundary of active to occult viral activity. CONCLUSION: Cultivated HCV in the highly sensitive NS3/4-based SEAP reporter cells could establish persistence, which might mimic the viral dynamics from acute to chronic infections in hepatitis C patients.

The association of nephrolithiasis with metabolic syndrome and its components: a cross-sectional analysis.

BACKGROUND: Metabolic syndrome is a worldwide disorder and also the major risk factor of several systemic diseases. Evidence identifying the association between metabolic syndrome and nephrolithiasis is lacking, especially in Taiwan. AIM: The aim of this study was to investigate the association between nephrolithiasis and metabolic syndrome and its components. DESIGN AND SETTING: This was a cross-sectional study conducted in the Health Examination Department of a medical center in Changhua, Taiwan, from January 2010 to December 2010. METHODS: We reviewed the medical records of patients who had visited the Health Examination Center of Changhua Christian Hospital in 2010. A total of 3,886 individuals were enrolled. According to the exclusion criteria, those with an age <20 years and an abnormal renal function were excluded. A total of 3,793 subjects were included. All P-values are two tailed, and P<0.05 was defined as statistically significant. RESULTS: The results showed a correlation between nephrolithiasis and metabolic syndrome and its components. The multivariate-adjusted odds ratio (OR) (95% confidence interval [CI]) of metabolic syndrome for nephrolithiasis was 1.318 (1.083-1.604), with a P-value of 0.006. Larger waist circumference (multivariable-adjusted OR 1.338; 95% CI 1.098-1.631; P=0.004), higher blood pressure (multivariable-adjusted OR 1.333; 95% CI 1.106-1.607; P=0.003), and increased fasting glucose (multivariable-adjusted OR 1.276; 95% CI 1.054-1.546; P=0.01) were associated with nephrolithiasis. CONCLUSION: This is the first study in Taiwan to investigate the relationship between metabolic syndrome and nephrolithiasis. The mechanism is controversial, and several hypotheses are offered. Adequate lifestyle modification and proper treatment in metabolic syndrome management may both contribute to nephrolithiasis prevention.

Lipoprotein lipase liberates free fatty acids to inhibit HCV infection and prevent hepatic lipid accumulation.

Lipoprotein lipase (LPL) has been identified as an anti-hepatitis C virus (HCV) host factor, but the cellular mechanism remains elusive. Here, we investigated the cellular mechanism of LPL involving in anti-HCV. The functional activation of peroxisome proliferator-activated receptor (PPAR) α signal by LPL transducing into hepatocytes was investigated in HCV-infected cells, primary human hepatocytes, and in HCV-core transgenic mice. The result showed that the levels of transcriptional transactivity and nuclear translocation of PPARα in Huh7 cells and primary human hepatocytes were elevated by physiologically ranged LPL treatment of either very-low density lipoprotein or HCV particles. The LPL-induced hepatic PPARα activation was weakened by blocking the LPL enzymatic activity, and by preventing the cellular uptake of free unsaturated fatty acids with either albumin chelator or silencing of CD36 translocase. The knockdowns of PPARα and CD36 reversed the LPL-mediated suppression of HCV infection. Furthermore, treatment with LPL, like the direct activation of PPARα, not only reduced the levels of apolipoproteins B, E, and J, which are involved in assembly and release of HCV virions, but also alleviated hepatic lipid accumulation induced by core protein. HCV-core transgenic mice exhibited more hepatic miR-27b, which negatively regulates PPARα expression, than did the wild-type controls. The induction of LPL activity by fasting in the core transgenic mice activated PPARα downstream target genes that are involved in fatty acid ß-oxidation. Taken together, our study reveals dual beneficial outcomes of LPL in anti-HCV and anti-steatosis and shed light on the control of chronic hepatitis C in relation to LPL modulators.

Fluoxetine regulates cell growth inhibition of interferon-α.

Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.