Although the cytokine transforming growth factor beta (TGF-β) has been shown to be a key regulator of this process, a variety of other cytokines and their downstream signaling pathways also have been identified as crucial actors in the context of fibrotic liver disease.1 find protocol MicroRNAs (miRNAs) are small, noncoding, 21-nucleotide-long to 23-nucleotide-long RNAs that negatively regulate gene expression by base pairing with the 3-untranslated region of

their target messenger RNAs (mRNAs).2 If pairing is perfect or nearly perfect, target mRNAs are degraded (predominantly seen in plants). However, their pairing with most mammalian mRNAs is imperfect, resulting in translational repression.3 In the last years, the number of known miRNAs has grown exponentially, and currently more than 1000 miRNAs are known to be encoded by the human genome.4 Recently, an involvement of miRNAs was

demonstrated in highly regulated processes such as hepatocyte apoptosis and hepatocarcinogenesis.5, 6 Furthermore, expression of miR-122 correlates with response to interferon treatment of patients infected with hepatitis C virus.7 However, the involvement of miRNAs in the development of liver fibrosis remains to be determined. Here, we demonstrate that several miRNAs are specifically regulated in mouse models of liver fibrosis. Among those, the miR-29 family members showed a significant down-regulation in livers of mice developing liver fibrosis as well as in livers from patients with advanced hepatic fibrosis. We show that murine miR-29b inhibits

the expression of collagen in HSCs and is down-regulated during the activation Enzalutamide price of HSCs in a TGF-β and lipopolysaccharide (LPS)/nuclear factor kappa B (NF-κB)–dependent manner. Finally, we confirm that the specific regulation of miR-29 family members in livers of fibrosis patients correlates with down-regulation of miR-29a in the serum of fibrosis patients, suggesting MCE that miR-29 might not only be a candidate for novel treatment strategies but also might have potential as a biomarker to monitor liver fibrosis in humans. CCl4, carbon tetrachloride; GRX-HSC, immortalized murine hepatic stellate cells; HSC, hepatic stellate cells; LPS, lipopolysaccharide; miRNA, microRNA; mRNA, messenger RNA; NF-κB, nuclear factor-κB; qPCR, quantitative polymerase chain reaction; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor. Total RNA (3 μg) was labeled and hybridized to the array-system miCHIP as previously described.8 MiCHIP is based on Tm- normalized capture probes (miRCURY; Exiqon, Copenhagen, Denmark). The miRCURY probes spotted on these arrays were designed to target approximately 500 (miRBase v9.2) unique mouse miRNAs. Array images were generated by using the Genepix 4200AL laser scanner (Molecular Devices, Sunnyvale, CA), miCHIP arrays were scanned in batches using the Genepix auto Photo Multiplayer algorithm, with pixel saturation tolerance set to 0.2%.

Two hundred mg/kg bodyweight

(b.w.) TAA was injected intraperitoneally into DPPIV− F344 rats (1.5 to 2 months of age) twice weekly for up to 3 months prior to cell transplantation, followed by 100 or 200 mg/kg b.w. TAA FDA-approved Drug Library supplier twice weekly after cell infusion. All animal studies were conducted under protocols approved by the Institutional Animal Care and Use Committees of AECOM and University of Pittsburgh in accordance with National Institutes of Health (NIH) guidelines. Unfractionated fetal liver cells were isolated from ED14/15 fetal livers of pregnant DPPIV+ or DPPIV+/EGFP+ F344 rats, as described.[18, 19] Hepatocytes were isolated from livers of adult DPPIV+ F344 rats. Detailed information concerning the cell isolation procedures can be found in the Supplemental Materials and Methods of Ref. [21]. Fetal liver cells (viability >95%) or adult hepatocytes (viability >80%) were transplanted through the portal vein into DPPIV− F344 rats[22] treated with TAA or untreated recipients with or without 2/3 PH (hepatectomized liver lobes were used to assess liver fibrosis and for other studies). After rats were sacrificed at different

times following cell transplantation, liver repopulation was determined by enzyme histochemistry for DPPIV, as described.[18, learn more 19] For engraftment studies, transplanted fetal liver cells were detected by immunohistochemistry for EGFP. Total RNA was extracted from snap-frozen liver tissue derived from TAA-treated DPPIV− F344 rats and untreated age-matched control rats. Qualitative RT-PCR analyses were performed at least twice. Quantitative real-time RT-PCR was performed in doublet/triplicate, as described in the Supplemental Materials and Methods of Ref. [21]. A list of the primers is shown in Supporting

Table 1. Information concerning histochemical and immunohistochemical analyses can be found in the Supporting Materials and Methods. Using two different fragments per liver, the HYP content was determined biochemically, as described.[23] Tissue slides were examined under an AxioObserver Z1 microscope. Images were obtained with an AxioCam ICc3, ICm1, or HRc camera and processed with AxioVision 4.8 or ZEN imaging software (Carl Zeiss MicroImaging). Data were analyzed using SigmaStat 2.01 MCE (SPSS Scientific), GraphPad Prism5 (GraphPad), and NIS-Elements D (Nikon) software and are reported as mean ± SEM. After chronic TAA administration (200 mg/kg b.w., twice weekly), liver fibrosis was assessed (Fig. 1) using the Laennec classification system.[24] At 6 weeks, the progressive liver injury produces moderate fibrosis and mild cirrhosis, i.e., predominant nodularity caused by narrow fibrous septa bridging portal areas. By 3 months, more advanced fibrosis occurs, leading to moderate to severe cirrhosis in different parts of the liver.

Two hundred mg/kg bodyweight

(b.w.) TAA was injected intraperitoneally into DPPIV− F344 rats (1.5 to 2 months of age) twice weekly for up to 3 months prior to cell transplantation, followed by 100 or 200 mg/kg b.w. TAA Lumacaftor twice weekly after cell infusion. All animal studies were conducted under protocols approved by the Institutional Animal Care and Use Committees of AECOM and University of Pittsburgh in accordance with National Institutes of Health (NIH) guidelines. Unfractionated fetal liver cells were isolated from ED14/15 fetal livers of pregnant DPPIV+ or DPPIV+/EGFP+ F344 rats, as described.[18, 19] Hepatocytes were isolated from livers of adult DPPIV+ F344 rats. Detailed information concerning the cell isolation procedures can be found in the Supplemental Materials and Methods of Ref. [21]. Fetal liver cells (viability >95%) or adult hepatocytes (viability >80%) were transplanted through the portal vein into DPPIV− F344 rats[22] treated with TAA or untreated recipients with or without 2/3 PH (hepatectomized liver lobes were used to assess liver fibrosis and for other studies). After rats were sacrificed at different

times following cell transplantation, liver repopulation was determined by enzyme histochemistry for DPPIV, as described.[18, Navitoclax ic50 19] For engraftment studies, transplanted fetal liver cells were detected by immunohistochemistry for EGFP. Total RNA was extracted from snap-frozen liver tissue derived from TAA-treated DPPIV− F344 rats and untreated age-matched control rats. Qualitative RT-PCR analyses were performed at least twice. Quantitative real-time RT-PCR was performed in doublet/triplicate, as described in the Supplemental Materials and Methods of Ref. [21]. A list of the primers is shown in Supporting

Table 1. Information concerning histochemical and immunohistochemical analyses can be found in the Supporting Materials and Methods. Using two different fragments per liver, the HYP content was determined biochemically, as described.[23] Tissue slides were examined under an AxioObserver Z1 microscope. Images were obtained with an AxioCam ICc3, ICm1, or HRc camera and processed with AxioVision 4.8 or ZEN imaging software (Carl Zeiss MicroImaging). Data were analyzed using SigmaStat 2.01 medchemexpress (SPSS Scientific), GraphPad Prism5 (GraphPad), and NIS-Elements D (Nikon) software and are reported as mean ± SEM. After chronic TAA administration (200 mg/kg b.w., twice weekly), liver fibrosis was assessed (Fig. 1) using the Laennec classification system.[24] At 6 weeks, the progressive liver injury produces moderate fibrosis and mild cirrhosis, i.e., predominant nodularity caused by narrow fibrous septa bridging portal areas. By 3 months, more advanced fibrosis occurs, leading to moderate to severe cirrhosis in different parts of the liver.

Reassuring results of a low rate of de novo inhibitors in PTPs who switched from pd-FVIII to rFVIII were shown in prospective premarketing studies carried out with these new products [45-50]. Subsequently, Buparlisib molecular weight national product switches have provided important pieces of evidence. Two surveillance studies were carried out in Canada during the population switch from pd-FVIII to rFVIII and then from first to second generation rFVIII and neither of these studies showed an increase in inhibitor incidence [51, 52]. A retrospective

study performed in Ireland after a national tender with consequent en masse switch to a third generation full-length rFVIII did not detect changes in the rate of de novo inhibitor formation [53]. In the UK a national tender was floated in 2009–2010 and it required half of patients using rFVIII to change

rFVIII brands [54]. Inhibitor testing was performed in all patients prior to the switching date and 6-monthly thereafter. Overall 1217 patients with severe haemophilia A and no inhibitor history were analysed (535 switched and 682 did not). Almost all patients who switched changed to B-domainless rFVIII. The inhibitor incidence was not significantly different from that observed during the previous two decades [54]. All these studies indicate that switching is not associated with an increased risk of de novo inhibitor formation. However, due to the very low inhibitor incidence in PTPs, all studies were selleck chemical underpowered. Meta-analyses of PTPs studies were also performed to gain further insight into the available evidence. This methodology was applied to compare the inhibitor risk in PTPs receiving full-length rFVIII with that of patients given B-domainless rFVIII [55]. Unexpectedly, a sevenfold to 10-fold higher inhibitor incidence was found MCE公司 in recipients of B-domainless FVIII [55]. These results were not confirmed in a subsequent systematic review

and meta-analysis adopting strict criteria for study selection [56]. In conclusion, prospective, controlled surveillance programmes on switching and not switching patients are still required to provide robust evidence concerning the inhibitor risk related to product switching. In this respect, inhibitor testing before and after the switch as well as testing of not switching patients is a crucial element to establish the correlation with the new treatment. The availability over time of newer therapeutic molecules and the variable market accessibility of different products often entail switching; in this light, patient information on evidences concerning potential risks and benefits associated with product switching is mandatory and should be part of our routine practice. Furthermore, physicians should discuss with patients and their caregivers the different therapeutic approaches and the available product options before the possible need for considering product switch.

Five micrograms of MeOH-solubilized flu antigen–p7 protein was dried by evaporation, then resolubilized overnight at room temperature in 20 mM sodium phosphate buffer (pH 7.0) containing 100 mM lyso-myristoylphosphatidylglycerol (LMPG) (monomeric) or 100 mM 1,2-diheptanoyl-sn-glycero-3-phosphocholine (DHPC) (oligomeric),31 incorporating 4 mM rimantadine-HCl (Sigma) or 4 mM N-nonyl deoxynojirimycin (NN-DNJ) (Toronto Biochemicals); 2× native polyacrylamide gel electrophoresis (PAGE) loading dye (150 mM Tris-Cl (pH 7.0), 30% glycerol, 0.05% bromophenol

blue) was added and samples were separated on a 4-20% TGX gel (Biorad) prior to staining with Coomassie Brilliant Blue. We have modeled the heptameric GT1b J4 isolate p7 complex31 with lumenal His17.35 We extended these studies to include a low-pH, open form wherein His17 protonation GDC-0449 mouse caused p7 protomers to rotate, inducing channel opening (Fig. 1A). This is consistent with p7 opening

being stimulated at low pH,33 as well as cellular proton conductance.19 We also generated a GT2a JFH-1 Fulvestrant purchase model (Fig. 1B) with similar structural characteristics to the J4 channel, despite significant sequence diversity. Autodock 4.0 was used to model binding sites (residue interactions <4 Å) on J4 and JFH-1 channels for amantadine (Ama), rimantadine (Rim), and NN-DNJ. Adamantanes bound to a peripheral, membrane-exposed

region of the channel complex (Fig. 1B, left panel), preventing channel opening. The location of this pocket agreed with NMR studies of p7-amantadine interactions36 and overlapped with J4 L(50-55)A, a mutation shown to alter amantadine sensitivity in vitro.31NN-DNJ did not interact with channel complexes, instead docking to p7 monomers at the protomer interface (Fig. 1B, right panel), thus potentially disrupting oligomerization. Accordingly, active nonyl-IS derivatives were predicted to bind this site with >10-fold higher affinity than inactive butyl-derivatives15 (data not shown). Although relatively well conserved 上海皓元医药股份有限公司 in other genotypes (Fig. 1C), variation at these positions may alter compound binding, providing a basis for genotype-dependent sensitivity.21 J4 and JFH-1 adamantane binding sites contained L20, which mutated to F20 in GT1b patients unresponsive to IFN/Rib/Ama.29 Comparison of predicted binding affinities (Autodock) revealed that Rim bound to wild-type channels with higher affinity compared with Ama, explaining its increased potency.19, 21 Ama-resistant JFH-1 p7 provided a threshold value for effective drug binding (Kd>7.41 μM). L20F increased predicted Kd values for both Ama and Rim above 7.41 μM (Fig. 2A), with one exception.

Five micrograms of MeOH-solubilized flu antigen–p7 protein was dried by evaporation, then resolubilized overnight at room temperature in 20 mM sodium phosphate buffer (pH 7.0) containing 100 mM lyso-myristoylphosphatidylglycerol (LMPG) (monomeric) or 100 mM 1,2-diheptanoyl-sn-glycero-3-phosphocholine (DHPC) (oligomeric),31 incorporating 4 mM rimantadine-HCl (Sigma) or 4 mM N-nonyl deoxynojirimycin (NN-DNJ) (Toronto Biochemicals); 2× native polyacrylamide gel electrophoresis (PAGE) loading dye (150 mM Tris-Cl (pH 7.0), 30% glycerol, 0.05% bromophenol

blue) was added and samples were separated on a 4-20% TGX gel (Biorad) prior to staining with Coomassie Brilliant Blue. We have modeled the heptameric GT1b J4 isolate p7 complex31 with lumenal His17.35 We extended these studies to include a low-pH, open form wherein His17 protonation check details caused p7 protomers to rotate, inducing channel opening (Fig. 1A). This is consistent with p7 opening

being stimulated at low pH,33 as well as cellular proton conductance.19 We also generated a GT2a JFH-1 Proteasome inhibitor model (Fig. 1B) with similar structural characteristics to the J4 channel, despite significant sequence diversity. Autodock 4.0 was used to model binding sites (residue interactions <4 Å) on J4 and JFH-1 channels for amantadine (Ama), rimantadine (Rim), and NN-DNJ. Adamantanes bound to a peripheral, membrane-exposed

region of the channel complex (Fig. 1B, left panel), preventing channel opening. The location of this pocket agreed with NMR studies of p7-amantadine interactions36 and overlapped with J4 L(50-55)A, a mutation shown to alter amantadine sensitivity in vitro.31NN-DNJ did not interact with channel complexes, instead docking to p7 monomers at the protomer interface (Fig. 1B, right panel), thus potentially disrupting oligomerization. Accordingly, active nonyl-IS derivatives were predicted to bind this site with >10-fold higher affinity than inactive butyl-derivatives15 (data not shown). Although relatively well conserved MCE公司 in other genotypes (Fig. 1C), variation at these positions may alter compound binding, providing a basis for genotype-dependent sensitivity.21 J4 and JFH-1 adamantane binding sites contained L20, which mutated to F20 in GT1b patients unresponsive to IFN/Rib/Ama.29 Comparison of predicted binding affinities (Autodock) revealed that Rim bound to wild-type channels with higher affinity compared with Ama, explaining its increased potency.19, 21 Ama-resistant JFH-1 p7 provided a threshold value for effective drug binding (Kd>7.41 μM). L20F increased predicted Kd values for both Ama and Rim above 7.41 μM (Fig. 2A), with one exception.

Certain steps can be taken to minimize the risk Cobimetinib of transmission of viral pathogens. These include: Quarantining plasma until the donor has been tested or even retested for antibodies to HIV, hepatitis C, and HBsAg – a practice that is difficult to implement in countries where the proportion of repeat donors is low. Nucleic acid testing (NAT) to detect viruses – a technology that has a potentially much greater relevance for the production of cryoprecipitate than for factor concentrates, as the latter are subjected to viral inactivation steps [20]. Allergic reactions are

more common following infusion of cryoprecipitate than concentrate [21]. As FFP contains all the coagulation factors, it is sometimes used to treat coagulation factor deficiencies. Cryoprecipitate is preferable to FFP for the treatment of hemophilia A and VWD. (Level 4) [[22]] Due to concerns about the safety and quality of FFP, its use is not recommended, if avoidable (Level 4) [[23]]. However, as FFP and cryo-poor plasma contain FIX, they can be used for the treatment of hemophilia B in countries unable to afford plasma-derived FIX concentrates. It is possible to apply some forms of virucidal

treatment to packs of FFP (including solvent/detergent treatment) and the use of treated packs is recommended. However, virucidal treatment may have some impact on coagulation factors. The large scale preparation of pooled solvent/detergent-treated plasma has also been shown to reduce the proportion of the largest multimers Selleckchem Doxorubicin of VWF [24, 25]. One ml of fresh frozen plasma contains 1 unit of factor activity. It is generally difficult to achieve FVIII levels higher than 30 IU dL−1 with FFP alone. FIX levels

above 25 IU dL−1 are difficult 上海皓元 to achieve. An acceptable starting dose is 15–20 mL kg−1. (Level 4) [[22]] Cryoprecipitate is prepared by slow thawing of fresh frozen plasma (FFP) at 4°C for 10–24 h. It appears as an insoluble precipitate and is separated by centrifugation. Cryoprecipitate contains significant quantities of FVIII (about 3–5 IU mL−1), VWF, fibrinogen, and FXIII, but not FIX or FXI. The resultant supernatant is called cryo-poor plasma and contains other coagulation factors such as factors VII, IX, X, and XI. Due to concerns about the safety and quality of cryoprecipitate, its use in the treatment of congenital bleeding disorders is not recommended and can only be justified in situations where clotting factor concentrates are not available. (Level 4) [ [26, 1, 22] ] Although the manufacture of small pool, viral-inactivated cryoprecipitate has been described, it is uncertain whether it offers any advantage with respect to overall viral safety or cost benefit over conventionally manufactured large pool concentrates [27].

2). Hepatic insulin resistance induces suppressed insulin clearance as well as increased insulin secretion from pancreatic β-cells, which leads to hyperinsulinemia and represses whole-body insulin

sensitivity.[61] Hepatic steatosis is also one of the pathophysiological features of HCV-associated chronic liver disease.[15, 16] It is characterized by the cytoplasmic accumulation of lipid droplets, mainly composed of triglyceride and cholesterol ester. The composition of triglycerides in the liver is uniquely and significantly enriched in carbon monosaturated (C18:1) fatty acids in chronic hepatitis C,[62] which is distinct from what occurs in obese patients. The mechanisms underlying HCV-related steatosis are diverse: decreased lipoprotein secretion from hepatocytes, increased synthesis of fatty acids, decreased buy RAD001 fatty acid oxidation and increased fatty acid uptake by hepatocytes. Angiogenesis inhibitor The HCV core protein has been demonstrated to inhibit microsomal transfer protein activity[63] and to upregulate transcriptional activity of sterol regulatory element-binding protein 1, a transcription factor involved in lipid synthesis.[64] These observations

underscore the importance of the core as a direct and principal regulator of HCV-associated steatosis. On the other hand, decreased fatty acid oxidation and increased fatty acid uptake are related to mitochondrial dysfunction and hyperinsulinemia, medchemexpress respectively. Indeed, we previously demonstrated impaired mitochondrial fatty acid oxidation concomitant with increased ROS production in iron-overloaded transgenic mice expressing the HCV polyprotein.[65] Hyperinsulinemia derived from insulin resistance inhibits lipolysis in the liver and increases fatty acid uptake by hepatocytes. As described above, mitochondrial ROS production is presumed to induce insulin resistance. Thus, inhibited fatty acid oxidation and increased fatty acid uptake are potentially related to mitochondrial ROS production induced by the core

protein. Elevated iron-related serum markers and increased hepatic iron accumulation are relatively common and correlate with the severity of hepatic inflammation and fibrosis in patients with chronic hepatitis C. Excess divalent iron can be highly toxic, mainly via the Fenton reaction producing hydroxyl radicals.[66] This is particularly relevant for chronic hepatitis C, in which oxidative stress has been proposed as a major mechanism of liver injury. Oxidative stress and increased iron levels strongly favor DNA damage, genetic instability and tumorigenesis. Indeed, a significant correlation between 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidatively generated DNA damage,[67] and hepatic iron excess has been shown in patients with chronic hepatitis C.

Conclusion: These

findings Copanlisib mouse implicate ENT1 in liver protection from ischemia and reperfusion injury and suggest ENT inhibitors may be of benefit in the prevention or treatment of ischemic liver injury. (Hepatology 2013;58:1766–1778) Ischemia and reperfusion is a pathologic condition characterized by an initial restriction of blood supply to an organ, followed by the subsequent restoration of perfusion and concomitant reoxygenation.[1, 2] In its classic manifestation, occlusion of the arterial blood supply is caused by an embolus and results in a severe imbalance of metabolic supply and demand causing tissue hypoxia. In the second stage of the disease, blood flow is rapidly restored. Somewhat surprisingly, the restoration of blood flow along with reoxygenation is frequently associated with an exacerbation of tissue injury and a profound inflammatory response click here (so-called reperfusion injury).[3] While ischemia and reperfusion contribute significantly to a wide range of pathologies, its functional contribution during liver surgery is particularly severe. For example, ischemia and

reperfusion is a frequent cause of acute liver failure during orthotopic liver transplantation. Similarly, ischemia and reperfusion 上海皓元 injury can contribute to immunologic consequences during human liver transplantation, as it is implicated in early rejection of the transplanted liver graft or the recurrence of hepatitis C in patients undergoing liver transplantation for the treatment of chronic hepatitis. Moreover, treatment modalities that would prevent hepatic ischemia and reperfusion injury are very limited and studies that aim to identify novel therapeutic approaches for hepatic ischemia and reperfusion are an area of intense investigation.[4, 5] Previous studies had shown that ischemia and reperfusion is associated with increased adenosine production from its precursor molecules—particularly

the nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP).[1, 6] Furthermore, it has been shown that activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A regulates local inflammation and prevents hepatocyte death.[7] Extracellular adenosine can signal through four distinct adenosine receptors (ARs), Adora1, Adora2a, Adora2b, or Adora3.[1] Studies of hepatic ischemia and reperfusion had shown a functional role for extracellular adenosine production,[8, 9] and signaling events through ARs—such as Adora2a[10] and Adora2b[11]—in liver protection from ischemia.

Conclusion: These

findings GSK126 clinical trial implicate ENT1 in liver protection from ischemia and reperfusion injury and suggest ENT inhibitors may be of benefit in the prevention or treatment of ischemic liver injury. (Hepatology 2013;58:1766–1778) Ischemia and reperfusion is a pathologic condition characterized by an initial restriction of blood supply to an organ, followed by the subsequent restoration of perfusion and concomitant reoxygenation.[1, 2] In its classic manifestation, occlusion of the arterial blood supply is caused by an embolus and results in a severe imbalance of metabolic supply and demand causing tissue hypoxia. In the second stage of the disease, blood flow is rapidly restored. Somewhat surprisingly, the restoration of blood flow along with reoxygenation is frequently associated with an exacerbation of tissue injury and a profound inflammatory response Pexidartinib research buy (so-called reperfusion injury).[3] While ischemia and reperfusion contribute significantly to a wide range of pathologies, its functional contribution during liver surgery is particularly severe. For example, ischemia and

reperfusion is a frequent cause of acute liver failure during orthotopic liver transplantation. Similarly, ischemia and reperfusion MCE公司 injury can contribute to immunologic consequences during human liver transplantation, as it is implicated in early rejection of the transplanted liver graft or the recurrence of hepatitis C in patients undergoing liver transplantation for the treatment of chronic hepatitis. Moreover, treatment modalities that would prevent hepatic ischemia and reperfusion injury are very limited and studies that aim to identify novel therapeutic approaches for hepatic ischemia and reperfusion are an area of intense investigation.[4, 5] Previous studies had shown that ischemia and reperfusion is associated with increased adenosine production from its precursor molecules—particularly

the nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP).[1, 6] Furthermore, it has been shown that activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A regulates local inflammation and prevents hepatocyte death.[7] Extracellular adenosine can signal through four distinct adenosine receptors (ARs), Adora1, Adora2a, Adora2b, or Adora3.[1] Studies of hepatic ischemia and reperfusion had shown a functional role for extracellular adenosine production,[8, 9] and signaling events through ARs—such as Adora2a[10] and Adora2b[11]—in liver protection from ischemia.