ATG10S promotes IFNL1 expression and autophagic degradation of multiple viral proteins mediated by IFNL1.

ATG10S is a newly discovered subtype of the autophagy protein ATG10. It promotes complete macroautophagy/autophagy, degrades multiple viral proteins, and increases the expression of type III interferons. Here, we aimed to investigate the mechanism of ATG10S cooperation with IFNL1 to degrade viral proteins from different viruses. Using western blot, immunoprecipitation (IP), tandem sensor RFP-GFP-LC3B and in situ proximity ligation assays, we showed that exogenous recombinant ATG10S protein (rHsATG10S) could enter into cells through clathrin, and ATG10S combined with ATG7 with IFNL1 assistance to facilitate ATG12-ATG5 conjugation, thereby contributing to the autophagosome formation in multiple cell lines containing different virions or viral proteins. The results of DNA IP and luciferase assays also showed that ATG10S was able to directly bind to a core motif (CAAGGG) within a binding site of transcription factor ZNF460 on the IFNL1 promoter, by which IFNL1 transcription was activated. These results clarified that ATG10S promoted autophagosome formation with the assistance of IFNL1 to ensure autophagy flux and autophagic degradation of multiple viral proteins and that ATG10S could also act as a novel transcription factor to promote IFNL1 gene expression. Importantly, this study further explored the antiviral mechanism of ATG10S interaction with type III interferon and provided a theoretical basis for the development of ATG10S into a new broad-spectrum antiviral protein drug.Abbreviation: ATG: autophagy related; ATG10S: the shorter isoform of autophagy-related 10; CC50: half cytotoxicity concentration; CCV: clathrin-coated transport vesicle; CLTC: clathrin heavy chain; CM: core motif; co-IP: co-immunoprecipitation; CPZ: chlorpromazine; ER: endoplasmic reticulum; HCV: hepatitis C virus; HBV: hepatitis B virus; HsCoV-OC43: Human coronavirus OC43; IFN: interferon; PLA: proximity ligation assay; rHsATG10S: recombinant human ATG10S protein; RLU: relative light unit; SQSTM1: sequestosome 1; ZNF: zinc finger protein.

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

Bacteroides thetaiotaomicron ameliorates mouse hepatic steatosis through regulating gut microbial composition, gut-liver folate and unsaturated fatty acids metabolism.

Gut microbiota plays an essential role in the progression of nonalcoholic fatty liver disease (NAFLD), making the gut-liver axis a potential therapeutic strategy. Bacteroides genus, the enriched gut symbionts, has shown promise in treating fatty liver. However, further investigation is needed to identify specific beneficial Bacteroides strains for metabolic disorders in NAFLD and elucidate their underlying mechanisms. In this study, we observed a positive correlation between the abundance of Bacteroides thetaiotaomicron (B. theta) and the alleviation of metabolic syndrome in the early and end stages of NAFLD. Administration of B. theta to HFD-fed mice for 12 weeks reduced body weight and fat accumulation, decreased hyperlipidemia and insulin resistance, and prevented hepatic steatohepatitis and liver injury. Notably, B. theta did not affect these indicators in low-fat diet (LFD)-fed mice and exhibited good safety. Mechanistically, B. theta regulated gut microbial composition, characterized by a decreased Firmicutes/Bacteroidetes ratio in HFD-Fed mice. It also increased gut-liver folate levels and hepatic metabolites, alleviating metabolic dysfunction. Additionally, treatment with B. theta increased the proportion of polyunsaturated fatty acid in the mouse liver, offering a widely reported benefit for NAFLD improvement. In conclusion, this study provides evidence that B. theta ameliorates NAFLD by regulating gut microbial composition, enhancing gut-liver folate and unsaturated fatty acid metabolism, highlighting the therapeutic role of B. theta as a potential probiotic for NAFLD.

Establishment and application of a high-throughput screening model for cell adhesion inhibitors.

The cell adhesion between leukocytes and endothelial cells plays an important balanced role in the pathophysiological function, while excessive adhesion caused by etiological agents is associated with the occurrence and development of many acute and chronic diseases. Cell adhesion inhibitors have been shown to have a potential therapeutic effect on these diseases, therefore, efficient and specific inhibitors against cell adhesion are highly desirable. Here, using lipopolysaccharide-induced human umbilical vein endothelial cells (HUVECs) and calcein-AM-labeled human monocytic cell THP-1, we established a high-throughput screening model for cell adhesion inhibitors with excellent model evaluation parameters. Using the drug repurposing strategy, we screened out lifitegrast, a potent cell adhesion inhibitor, which inhibited cell adhesion between HUVEC and THP-1 cells by directly interrupting the adhesion interaction between HUVEC and THP-1 cells and showed a strong therapeutic effect on the mouse acute liver injury induced by poly (I:C)/D-GalN. Therefore, the screening model is suitable for screening and validating cell adhesion inhibitors, which will promote the research and development of inhibitors for the treatment of diseases caused by excessive cell adhesion.

Bicyclol ameliorates advanced liver diseases in murine models via inhibiting the IL-6/STAT3 signaling pathway.

Bicyclol, a synthetic hepatoprotective and anti-inflammatory agent approved in China, was widely used to treat various hepatitis accompanied by elevated serum aminotransferases. However, the pharmacological effects and mechanisms of bicyclol on advanced liver diseases, such as fibrosis/cirrhosis and hepatocellular carcinoma (HCC), remain to be explored. Here, we revealed that bicyclol prevents from formatting severe fibrosis, slows the progression of moderate liver fibrosis, accelerates the regression of moderate liver fibrosis, decreases the malignancy of HCC in rat models induced by diethylnitrosamine (DEN), and also blocks steatohepatitis to HCC in mice induced by western diet plus carbon tetrachloride and DEN. The detailed pharmacological mechanism showed that bicyclol alleviates chronic progressive liver diseases by inhibiting the levels of IL-6 and subsequent phosphorylated STAT3. Conclusion: Bicyclol plays significant protective roles in multiply stages of fibrosis/cirrhosis-HCC and nonalcoholic fatty liver disease-related HCC via inhibiting IL-6/STAT3 signaling pathway. Therefore, bicyclol might be a promising therapeutic strategy for treating advanced liver diseases.

Combined Use of Bicyclol and Berberine Alleviates Mouse Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is a liver disease worldwide without approved therapeutic drugs. Anti-inflammatory and hepatoprotective drug bicyclol and multi-pharmacological active drug berberine, respectively, have shown beneficial effects on NAFLD in murine nutritional models and patients, though the therapeutic mechanisms remain to be illustrated. Here, we investigated the combined effects of bicyclol and berberine on mouse steatosis induced by Western diet (WD), and NASH induced by WD/CCl4. The combined use of these was rather safe and better reduced the levels of transaminase in serum and triglycerides and cholesterol in the liver than their respective monotherapy, accompanied with more significantly attenuating hepatic inflammation, steatosis, and ballooning in mice with steatosis and NASH. The combined therapy also significantly inhibited fibrogenesis, characterized by the decreased hepatic collagen deposition and fibrotic surface. As per mechanism, bicyclol enhanced lipolysis and ß-oxidation through restoring the p62-Nrf2-CES2 signaling axis and p62-Nrf2-PPARα signaling axis, respectively, while berberine suppressed de novo lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase, along with enrichment of lipid metabolism-related Bacteroidaceae (family) and Bacteroides (genus). Of note, the combined use of bicyclol and berberine did not influence each other but enhanced the overall therapeutic role in the amelioration of NAFLD. Conclusion: Combined use of bicyclol and berberine might be a new available strategy to treat NAFLD.

TGF-ß isoforms inhibit hepatitis C virus propagation in transforming growth factor beta/SMAD protein signalling pathway dependent and independent manners.

Transforming growth factor beta (TGF-ß) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation-associated responses. However, the antiviral activities and mechanisms of TGF-ß isoforms, including TGF-ß1, TGF-ß2 and TGF-ß3, remain unclear. Here, we demonstrated that all of the three TGF-ß isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF-ß isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF-ß isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF-ß/SMAD signalling pathway-dependent and TGF-ß/SMAD signalling pathway-independent manners. TGF-ß isoforms showed additional anti-HCV activities when combined with each other. However, the elevated TGF-ß1 and TGF-ß2, not TGF-ß3, could also induce liver fibrosis with a high expression of type I collagen alpha-1 and α-smooth muscle actin in LX-2 cells. Our results showed a new insight into TGF-ß isoforms in the HCV-related liver disease progression.

Aloperine inhibits hepatitis C virus entry into cells by disturbing internalisation from endocytosis to the membrane fusion process.

Aloperine, a natural alkaloid isolated from the Chinese traditional herb Sophora alopecuroides, is a broad-spectrum antiviral agent with anti-inflammatory activity. Here, we found that aloperine effectively inhibited hepatitis C virus (HCV) propagation in Huh7.5 cells and primary human hepatocytes without cytotoxicity, and it blocked HCV cell-to-cell viral transmission. The antiviral mechanism evidence demonstrated that aloperine inhibits HCV internalisation from endocytosis to the membrane fusion process, and the target may be associated with host factors. Aloperine additively inhibited HCV propagation with direct-acting antivirals (DAAs) and was effective against HCV variants resistant to known DAAs. Therefore, aloperine might be a natural lead compound for the development of innovative antivirals, and the combined use of aloperine with DAAs might contribute to eliminating liver diseases caused by HCV infection.

IL28A protein homotetramer structure is required for autolysosomal degradation of HCV-NS5A in vitro.

Interferon lambda-2 (IL28A) has a wide antiviral effect with fewer side-effects. Autophagy is a host mechanism to maintain intracellular homeostasis and defends invasion of pathogenic microorganisms. HCV NS5A can disable host defense systems to support HCV replication. Thus, molecular mechanism of interaction among interferon lambda, autophagy, and HCV was concerned and explored in this study. We report that HCV NS5A activated an incomplete autophagy by promoting the autophagic ubiquitylation-like enzymes ATG3, ATG5, ATG7, ATG10, and autophagosome maker LC3B, but blocked autophagy flux; IL28A bound to NS5A at NS5A-ISDR region, and degraded HCV-NS5A by promoting autolysosome formations in HepG2 cells. A software prediction of IL28A protein conformation indicated a potential structure of IL28A homotetramer; the first α-helix of IL28A locates in the interfaces among the four IL28A chains to maintain IL28A homotetrameric conformation. Co-IP and cell immunofluorescence experiments with sequential deletion mutants demonstrate that IL28A preferred a homotetramer conformation to a monomer in the cells; the IL28A homotetramer is positively correlated with autolysosomal degradation of HCV NS5A and the other HCV proteins. Summarily, the first α-helix of IL28A protein is the key domain for maintaining IL28A homotetramer which is required for promoting formation of autolysosomes and degradation of HCV proteins in vitro.

A proof-of-concept study in HCV-infected Huh7.5 cells for shortening the duration of DAA-based triple treatment regimens.

With the development of more effective direct-acting antivirals (DAAs), dual- or triple-therapy regimens represent the major strategy used to cure chronic hepatitis C virus (HCV) infection. Thus, shorter treatment duration regimens with low burden, few adverse effects and good patient adherence are urgently needed. This study theoretically demonstrates a proof-of-concept approach for shortening therapy duration by examining HCV-infected Huh7.5 cells after treatment with a high or low fixed dose of three DAAs (simeprevir + daclatasvir + sofosbuvir) for 6-15 days. The results demonstrated that HCV-infected Huh7.5 cells achieved an ultrarapid virologic response with undetectable HCV RNA and protein and were cured after treatment with the triple-therapy regimen for 15 days. When the treatment duration was shortened, virologic relapse might occur after treatment with a low fixed dose of the three DAAs for 9 days and did occur after treatment with a low fixed dose for 6 days, although HCV was below detectable levels at the end of treatment. However, virologic relapse could be avoided with treatment of a high fixed dose of the three DAAs for 9 or 6 days. Although a virologic breakthrough occurred after an intermittent treatment regimen at the low fixed dose, the high fixed dose cured HCV-positive Huh7.5 cells with intermittent treatment. In conclusion, HCV is persistently present below detectable levels in HCV-infected Huh7.5 cells for a long time after treatment, and a shortened therapy duration is associated with an increased risk of virologic relapse, but virologic relapse or breakthrough might be avoided by treatment with a combination of more highly effective DAAs.

Farnesoid X receptor agonist GW4064 indirectly inhibits HCV entry into cells via down-regulating scavenger receptor class B type I.

Farnesoid X receptor (FXR) agonists play important regulatory roles in bile acid, lipid and glucose metabolism in vitro and in vivo. Thus, FXR agonists exhibit potential therapeutic effects on metabolism-related diseases that are associated with extrahepatic manifestations induced by hepatitis C virus (HCV) infection. This study investigated the effect and mechanism of FXR agonist GW4064 against HCV in vitro to explore the potential application of FXR agonists. Results showed that GW4064 and other FXR agonists have potent antiviral activity against HCV in Huh7.5 cells. GW4064 down-regulated the expression of scavenger receptor class B type I protein via FXR and thereby indirectly inhibited HCV entry into cells, leading to interruption of HCV life cycle. GW4064 also exhibited synergistic anti-HCV effect with known direct-acting antiviral agents (DAAs) used in the clinic and remained sensitive to DAA-resistant HCV mutations. Therefore, FXR agonists are also a kind of antiviral agent, and might be helpful in treatment of HCV-induced hepatic and extrahepatic manifestations.

Differential Effects of Autophagy-Related 10 Protein on HCV Replication and Autophagy Flux Are Mediated by Its Cysteine44 and Cysteine135.

Autophagy-related 10 (ATG10) is essential for autophagy since it promotes ATG5-ATG12 complex formation. Our previous study found that there are two isoforms of the ATG10 protein, ATG10 (a longer one) and ATG10S, which have identical sequences except an absence of a 36-amino acid fragment (peptide B) in ATG10S, yet exhibit distinct effects on HCV genome replication. Here, we report the existence of two amino acids, cysteine at residue 44 and 135 (Cys44 and Cys135, respectively), in ATG10 being related to differential effects of ATG10 on HCV replication and autophagy flux. Through a series of ATG10 mutation experiments and protein modeling prediction, we found that Cys44 was involved in the dual role of the two isoforms of ATG10 protein on HCV replication and autophagy flux, and that Cys135 plays similar roles as Cys44, but the disulfide bond of Cys44-Cys135 was not verified in the ATG10 protein. Further analyses by full HCV virion infection confirmed the roles of -SH of Cys44 and Cys135 on HCV replication. ATG10 with deleted or mutated Cys44 and/or Cys135 could activate expression of innate immunity-related genes, including il28a, irf-3, irf-7, and promote complete autophagy by driving autophagosomes to interact with lysosomes via IL28A-mediation. Subcellular localization assay and chromatin immunoprecipitation assay showed that ATG10 with the sulfydryl deletion or substitution of Cys44 and Cys135 could translocate into the nucleus and bind to promoter of IL28A gene; the results indicated that ATG10 with Cys44 and/or Cys135 absence might act as transcriptional factors to trigger the expression of anti-HCV immunological genes, too. In conclusion, our findings provide important information for understanding the differential roles on HCV replication and autophagy flux between ATG10 and ATG10S, and how the structure-function relationship of ATG10 transformed by a single -SH group loss on Cys44 and Cys135 in ATG10 protein, which may be a new target against HCV replication.

Retraction: Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases.

[This retracts the article DOI: 10.21037/sci.2017.08.01.].

Bicyclol Attenuates Liver Inflammation Induced by Infection of Hepatitis C Virus via Repressing ROS-Mediated Activation of MAPK/NF-κB Signaling Pathway.

Treatment with direct-acting antivirals (DAAs) cures most patients infected with hepatitis C virus (HCV) in the real world. However, some patients, especially those with the underlying advanced liver disease, have a limited reduction of liver injury after achieving a sustained viral response (SVR). Bicyclol was widely used in clinics for the treatment of a variety of liver injuries but with an unknown mechanism for the treatment of hepatitis C. We investigated the anti-inflammatory effects and mechanisms of bicyclol in HCV-infected hepatocytes and further confirmed the putative results in a mouse hepatitis model induced by the coinjection of polyinosinic-polycytidylic acid [poly (I:C)] and D-galactosamine (D-GalN). The results showed that the activation of nuclear factor kappa B (NF-κB) and the subsequent increase of inflammatory factors were directly induced by HCV infection and were persistent after clearance of the virus in Huh7.5 cells. Bicyclol decreased the activation of NF-κB and the levels of inflammatory factors in HCV-infected hepatocytes by inhibiting the activation of the ROS-MAPK-NF-κB pathway, and the effect was synergistic with DAAs in HCV-infected hepatocytes. Bicyclol attenuated the ROS-MAPK-NF-κB axis via recovering mitochondrial function without a dependence on dihydronicotinamide adenine dinucleotide phosphate oxidase and superoxide dismutases. The anti-inflammatory effects and mechanism of bicyclol were verified in mouse hepatitis induced by the coinjection of poly(I:C)/D-GalN. Bicyclol directly ameliorates the chronic inflammation caused by HCV infection and might be used with DAAs or after DAA therapy for ultimately curing chronic hepatitis C.

Internal driving factors leading to extrahepatic manifestation of the hepatitis C virus infection.

The hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, which are correlated with poor outcomes, and thus increase the morbidity and mortality of chronic hepatitis C (CHC). Therefore, understanding the internal linkages between systemic manifestations and HCV infection is helpful for treatment of CHC. Yet, the mechanism by which the virus evokes the systemic diseases remains to be elucidated. In the present study, using gene set enrichment analysis (GSEA) and signaling pathway impact analysis (SPIA), a comprehensive analysis of microarray data of mRNAs was conducted in HCV-infected and -uninfected Huh7.5 cells, and signaling pathways (which are significantly activated or inhibited) and certain molecules (which are commonly important in those signaling pathways) were selected. Forty signaling pathways were selected using GSEA, and eight signaling pathways were selected with SPIA. These pathways are associated with cancer, metabolism, environmental information processing and organismal systems, which provide important information for further clarifying the intrinsic associations between syndromes of HCV infection, of which seven pathways were not previously reported, including basal transcription factors, pathogenic Escherichia coli infection, shigellosis, gastric acid secretion, dorso-ventral axis formation, amoebiasis and cholinergic synapse. Ten genes, SOS1, RAF1, IFNA2, IFNG, MTHFR, IGF1, CALM3, UBE2B, TP53 and BMP7 whose expression may be the key internal driving molecules, were selected using the online tool Anni 2.1. Furthermore, the present study demonstrated the internal linkages between systemic manifestations and HCV infection, and presented the potential molecules that are key to those linkages.

Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases.

Applications of bone marrow-derived mesenchymal stem cells (BM-MSCs) have been documented for diseases occur in the sports system, the central nervous system, the cardiovascular system etc. However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency. Although the autophagy theory has been reported, the underlying mechanisms are still poorly understood. Isolation and culture methods of mesenchymal stem cells are currently concentrate on four ways. Overall, BM-MSCs have both important research significance and clinical application value in cell replacement therapy, gene therapy and reconstruction of tissues as well as organs especially for myocardial infarction (MI). In this article, we review the biological characteristics of BM-MSCs and its research progress especially in MI.

A Simple but Accurate Method for Evaluating Drug-Resistance in Infectious HCVcc System.

Use of direct-acting antivirals sometimes causes viral drug resistance, resulting in inefficiency in treated patients in real-world practice. Therefore, how to rapidly and accurately evaluate drug resistance is an urgent problem to be solved for rational use and development of antivirals in the future. Here, we aim to develop a new method by which we can evaluate easily but effectively whether a drug will still be efficient in the future treatment in infectious hepatitis C virus cell culture system. HCV-infected Huh7.5 cells were treated with drugs and the culture supernatants were replaced with fresh culture media containing the same drugs at 24 hours. The supernatants were harvested at 48 hours and incubated with naïve Huh7.5 cells. Intracellular HCV RNAs or proteins in the newly infected cells were extracted and analyzed at 48 hours or longer. Results showed that after being treated with telaprevir mutant viruses were easily detected which were resistant to telaprevir, while after being treated with sofosbuvir drug-resistant viruses did not emerge. In conclusion, the new method is simple and quick but accurate to evaluate whether a drug will be still efficient in the forthcoming therapeutic regimen and whether drug resistance will occur after long-term treatment with drugs.

Dual Roles of Two Isoforms of Autophagy-related Gene ATG10 in HCV-Subgenomic replicon Mediated Autophagy Flux and Innate Immunity.

Autophagy and immune response are two defense systems that human-body uses against viral infection. Previous studies documented that some viral mechanisms circumvented host immunity mechanisms and hijacked autophagy for its replication and survival. Here, we focus on interactions between autophagy mechanism and innate-immune-response in HCV-subgenomic replicon cells to find a mechanism linking the two pathways. We report distinct effects of two autophagy-related protein ATG10s on HCV-subgenomic replication. ATG10, a canonical long isoform in autophagy process, can facilitate HCV-subgenomic replicon amplification by promoting autophagosome formation and by combining with and detaining autophagosomes in cellular periphery, causing impaired autophagy flux. ATG10S, a non-canonical short isoform of ATG10 proteins, can activate expression of IL28A/B and immunity genes related to viral ds-RNA including ddx-58, tlr-3, tlr-7, irf-3 and irf-7, and promote autophagolysosome formation by directly combining and driving autophagosomes to perinuclear region where lysosomes gather, leading to lysosomal degradation of HCV-subgenomic replicon in HepG2 cells. ATG10S also can suppress infectious HCV virion replication in Huh7.5 cells. Another finding is that IL28A protein directly conjugates ATG10S and helps autophagosome docking to lysosomes. ATG10S might be a new host factor against HCV replication, and as a target for screening chemicals with new anti-virus mechanisms.

CD36 is a co-receptor for hepatitis C virus E1 protein attachment.

The cluster of differentiation 36 (CD36) is a membrane protein related to lipid metabolism. We show that HCV infection in vitro increased CD36 expression in either surface or soluble form. HCV attachment was facilitated through a direct interaction between CD36 and HCV E1 protein, causing enhanced entry and replication. The HCV co-receptor effect of CD36 was independent of that of SR-BI. CD36 monoclonal antibodies neutralized the effect of CD36 and reduced HCV replication. CD36 inhibitor sulfo-N-succinimidyl oleate (SSO), which directly bound CD36 but not SR-BI, significantly interrupted HCV entry, and therefore inhibited HCV replication. SSO's antiviral effect was seen only in HCV but not in other viruses. SSO in combination with known anti-HCV drugs showed additional inhibition against HCV. SSO was considerably safe in mice. Conclusively, CD36 interacts with HCV E1 and might be a co-receptor specific for HCV entry; thus, CD36 could be a potential drug target against HCV.

Whole-brain CT perfusion combined with CT angiography for ischemic complications following microsurgical clipping and endovascular coiling of ruptured intracranial aneurysms.

Ischemic complications associated with microsurgical clipping and endovascular coiling affects the outcome of patients with intracranial aneurysms. We prospectively evaluated 58 intracranial aneurysm patients who had neurological deterioration or presented with poor grade (Hunt-Hess grades III and IV), aneurysm size >13 mm and multiple aneurysms after clipping or coiling. Thirty patients had ischemic complications (52%) as demonstrated by whole-brain CT perfusion (WB-CTP) combined with CT angiography (CTA). Half of these 30 patients had treatment-associated reduction in the diameter of the parent vessels (n=6), ligation of the parent vessels or perforating arteries (n=2), and unexplained or indistinguishable vascular injury (n=7); seven of these 15 (73%) patients suffered infarction. The remaining 15 patients had disease-associated cerebral ischemia caused by generalized vasospasm (n=6) and focal vessel vasospasm (n=9); six of these 15 (40%) patients developed infarction. Three hemodynamic patterns of ischemic complications were found on WB-CTP, of which increased time to peak, time to delay and mean transit time associated with decreased cerebral blood flow and cerebral blood volume were the main predictors of irreversible ischemic lesions. In conclusion, WB-CTP combined with CTA can accurately determine the cause of neurological deterioration and classify ischemic complications. This combined approach may be helpful in assessing hemodynamic patterns and monitoring operative outcomes.