We thank Dr. Pavel Strnad for valuable comments. Additional Supporting Information may be found in the online version of this article. “
“Hepatocyte proliferation early after liver resection is critical in restoring liver mass and preserving function as the liver regenerates. Carbon monoxide (CO) generated by heme oxygenase-1 (HO-1) strongly influences cellular proliferation and both HO-1 and CO are accepted hepatoprotective molecules. Mice lacking functional HO-1 were unable to mount an appropriate regenerative response following partial hepatectomy (PHTx) compared to wildtype controls. We therefore hypothesized that exogenous administration of CO

at low, nontoxic concentrations Tanespimycin solubility dmso would modulate hepatocyte (HC) proliferation and liver regeneration. Animals treated with a low concentration of CO 1 hour prior to 70% hepatectomy demonstrated enhanced expression of hepatocyte growth factor (HGF) in the liver compared to controls that correlated with a more rapid onset of HC proliferation as measured by phospho-histone3 staining, increased expression of cyclins D1 and E, phosphorylated retinoblastoma, and decreased

expression of the mitotic inhibitor p21. PHTx also increased activation of the HGF receptor c-Met, which was detected more then 9 hours earlier in the livers of CO-treated mice. Blockade of c-Met resulted in abrogation of the CO effects SB203580 order on HC proliferation. Corresponding with increased HC proliferation, treatment with CO maintained liver function with normal prothrombin times versus a 2-fold prolongation in controls. In a lethal 85% PHTx, CO-treated mice showed a greater survival rate compared to controls. In vitro, CO increased HGF expression in hepatic stellate cells, but not HC, and when cocultured together led to increased HC proliferation. In summary,

we demonstrate that administration of exogenous CO enhances rapid and early HC proliferation and, importantly, preserves function following PHTx. Taken together, CO may offer a viable therapeutic Carbohydrate option to facilitate rapid recovery following PHTx. (HEPATOLOGY 2011;) Under normal conditions, hepatocytes are quiescent, yet possess the unique and powerful ability to regenerate after hepatic resection or injury.1-4 Once surgical procedures such as partial hepatectomy (PHTx) or living donor liver transplantation (LDLT) are performed, mitosis of the hepatocytes begins within 24-48 hours and the residual liver hypertrophies to compensate for the resected liver volume and impaired function. This hypertrophy occurs rapidly, reaching 90% of its preresection volume within 4-6 weeks in humans.5 The clinical application of PHTx or LDLT for the treatment of primary or metastatic liver tumors and endstage liver disease depends on this fundamental ability of the liver to regenerate.

Our series of 24 well-characterized patients is by far the largest study on the clinical aspects of drug-induced AIH. No previous study has been able to assess the proportion of DIAIH out of AIH cases in general. We found that 9.2% of AIH patients were by definition induced by drugs. It is conceivable that this reflects referral

bias, but no significant difference was found between the proportion of referral patients among the DIAIH versus the other AIH patients. Nitrofurantoin can lead to a broad spectrum of liver injury with mild liver test abnormalities, acute liver failure with fatal outcome, or need for liver transplantation9, 12, 19-21 and also liver cirrhosis.21 Nitrofurantoin is still widely used in CP 868596 many countries and was recently found to be one of the most common single agents associated with drug-induced liver injury (DILI) in a recent prospective study in the United States.21 Nitrofurantoin has been documented to induce AIH previously in a number of reports.8,

9, 12, 13, 22-24 All cases in the current series with laboratory parameters available to score the AIH by the new simplified criteria17 had a score of at least “probable.” Zone 3 necrosis was observed in our DIAIH cohort and has been described in nitrofurantoin-induced liver injury12 but has also been reported in AIH without drug involvement.25, 26 It seems that DIAIH caused by other drugs than nitrofurantoin and minocycline is a rare cause of AIH. Interestingly, one of the two other drugs suspected to have caused AIH, cephalexin, was also taken by one patient with minocycline-induced AIH in one series.10 Cirrhosis was not found Pexidartinib datasheet to develop in any of the DIAIH cases Methamphetamine in the current study, whereas this was found in 20% of the other AIH patients at baseline. Our results are in agreement with Stricker et al.,9 who found no cases of nitrofurantoin-induced cirrhosis among 52 reported cases of suspected liver injury reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs. Most

of the patients with DIAIH in our study had been treated for a long period with the drug, with a median duration of 24 and 12 months in the nitrofurantoin-induced and minocycline-induced AIH, respectively. This long duration of treatment has been the experience in other series.9, 12 Interestingly, severe abnormalities were seen on imaging in 8 of 11 (73%) of the nitrofurantoin cases, whereas this was not found to occur in the other DIAIH cases. This has not been reported previously, but a recent case report revealed low attenuation patches in the liver parenchyma.27 This unusual pattern of fibrosis was seen in the nitrofurantoin cases with confluent fibrosis and massive fibrotic bands not seen in other AIH patients. The appearance of this type of fibrotic process on imaging might raise a suspicion of nitrofurantoin-induced liver injury. However, it is not clear whether these changes are specific for nitrofurantoin-induced liver damage.

In a follow-up to the Moore et al. (2002) study, Fisher & Hoekstra (2010) showed that even when two male Peromyscus mice inseminated a female in rapid succession, sperm formed trains predominantly with sperm from the same ejaculate, which is consistent with the theoretical prediction that sperm should cooperate only with closely related sperm. Sperm were even able to discriminate

between sperm from their own male and sperm of a brother. LY2157299 purchase Comparison with a monogamous mouse species in which sperm competition is absent showed that such discrimination is absent. This remarkable study provides additional evidence that sperm cooperation is an adaptation to sperm competition. The mechanisms of sperm competition in insects are, as one might expect from their diversity of behaviours and morphologies, remarkably varied (Simmons, 2001). One of the simplest mechanisms, which occurs in dragonflies and damselflies, is sperm removal. In a pioneering study, Waage (1979) showed how male damselflies Calopteryx maculata use the hooks on their phallus, to remove previously stored sperm from the female bursa and spermatheca before inseminating their own. In the giant water bug Abedus herberti, males copulate

repeatedly with females as they are egg laying, and by doing so, fertilize the majority of eggs, even though the female has been inseminated previously by other males. The precise mechanism is not known, but it seems likely that by repeated insemination, the male find more Baricitinib ensures either that his sperm are closest to the point at which fertilization

occurs, just as the egg is being laid, or are numerically dominant (Smith, 1979). A particularly sophisticated form of sperm displacement occurs in the rove beetle Aleochara curtula. The male transfers sperm to the female in a spermatophore that, once the couple has separated, takes on a life of its own. A tube emerges from the spermatophore and enters the female’s spermatheca, where its tip then inflates like a balloon completely filling the female’s sperm store. The swelling spermatophore forces any previously stored sperm out of the store, before its own sperm are released, by two knife-like structures inside the female tract that puncture the ‘balloon’ (Gack & Peschke, 1994). The mechanisms of last male sperm precedence in the yellow dungfly took rather longer to elucidate. Using detailed dissections and radio-tracers to follow the fate of sperm inside the female reproductive tract, Simmons and colleagues eventually revealed that when a male dungfly inseminates a virgin female, he deposits his sperm into the female’s bursa, a bag-like structure connected to the spermatheca (the main sperm storage structure), by a narrow duct. Soon after insemination, a piston-like device sucks up the sperm, transferring it to the spermatheca.

5F). Previous studies have shown that long-lived Little mice HDAC activity assay have increased levels of genes involved in the xenobiotic detoxification and that crossing these mice with FXR KO mice corrected their expression.17 We performed western

blot analysis and found a four- to five-fold elevation of FXR in 24- to 36-month-old Little mice (Fig. 6A,B). It has been shown that the frequency of liver tumors increases with age and reaches around 30% at the age of 24 months.5 However, Little mice do not develop liver cancer with age. Therefore, we tested the hypothesis that high levels of FXR in old Little mice protect the liver from development of cancer. WT and Little mice were treated with DEN, and liver tumors were examined 35-36 weeks after DEN injection. We examined five WT mice and five Little mice and found that all WT animals developed advanced liver cancer, whereas only two Little mice find more had few tumor nodules of a very small size (Fig. 6C). Three other Little mice did not have liver cancer. Examination of liver sections via hematoxylin and eosin staining revealed that the livers of WT mice contained multiple diverse nodules of proliferating hepatocytes, including enlarged cells with moderate anisonucleosis on the left and a cluster of small, uniform, deeply

basophilic cells on the right (Fig. 6D). In contrast, livers of Little mice treated with DEN showed unremarkable architecture and cytology, with uniform hepatocytes containing minimal cytoplasmic lipid and glycogen. We found that the number of replicating hepatocytes increased significantly in WT mice (up to 25%-30%), while around 5% of hepatocytes were BrdU-positive

in the livers of Little mice (Fig. 6E,F). These data show that Little mice are resistant to the development of liver cancer after DEN treatment. We next determined the molecular mechanisms by which Little mice are protected from liver cancer. A recent report showed that gankyrin causes degradation of the liver-specific transcription factor hepatocyte nuclear factor 4α (HNF4α).22 Therefore, we included this Endonuclease protein in our studies. We found that gankyrin was elevated and that it caused reduction of C/EBPα, Rb, HNF4α, and p53 in control WT mice (Fig. 7A,B). FXR was slightly reduced in WT mice; however, in Little mice, FXR levels remained at high levels, leading to the lack of activation of the gankyrin and to no reduction of C/EBPα, Rb, HNF4α, or p53. The reduction of the tumor repressor proteins in WT mice took place on the levels of protein degradation, since levels of mRNA were not changed significantly (Fig. 7C). To determine whether gankyrin is responsible for the degradation of tumor suppressor proteins, we examined interactions of these proteins with gankyrin. In these experiments, we used up to 1 mg of nuclear extracts for the co-immunoprecipitation studies.

, 2012). The efficient operation of the saccade system

depends on the ability to exert voluntary control (an endogenous process) over the automatic response to sensory events (an exogenous process). The antisaccade and memory-guided saccade tasks, which have traditionally been used to investigate saccade initiation in PD, involve competition between contradictory processes: subjects must simultaneously suppress and generate an CHIR-99021 clinical trial eye movement. This makes it difficult to establish the origin of impairments in these tasks. To clarify the effect of PD in the saccade system, we elected to use a saccade task that allows the separate measurement of endogenous and exogenous processes in the saccade system and that does

not require suppression of saccades. We adapted a well-known task (Deubel, 2008), in which saccades can be performed with or without a concurrent perceptual discrimination task. Participants are instructed to make a voluntary saccade to a peripheral target location, which HKI-272 mw is indicated by a central arrow cue. Shortly after the onset of the arrow cue, before the saccade is initiated, symbols can appear briefly at the target location and at distractor locations. After each saccade, observers are asked to report the identity of the symbol that appeared at the target location. It has been shown that the concurrent performance of a discrimination task can facilitate saccade initiation (Montagnini & Chelazzi, 2005; Trottier & Pratt, 2005). The brief, pre-saccadic, peripheral symbol-changes can also modulate saccade latencies in this Urease paradigm (Deubel, 2008; van Stockum et al., 2011a). The effect of the discrimination task can be attributed to endogenous processes, because it is due solely to the task instructions and the observer’s intention. The effect of the peripheral symbol-changes can be attributed to exogenous processes, because it is due solely to a change in visual input. When a group of PD patients

and a control group performed reflexive (visually guided) saccades in a variant of this paradigm, the discrimination task reduced saccade latencies more in the PD group than in the control group (van Stockum et al., 2011b). This observation is consistent with reports of hyper-reflexivity in PD (Chan et al., 2005; van Stockum et al., 2008; van Koningsbruggen et al., 2009; Cameron et al., 2012). Moreover, the discrimination task facilitated saccade initiation in the PD group especially in trials with an overlap, where the ongoing presence of the central fixation point (the overlap) had a smaller inhibitory effect in the PD group than in the control group. We suggested therefore that the discrimination task reveals a source of abnormal endogenous saccadic facilitation in PD, which may affect the saccade system globally (van Stockum et al., 2011b).

1C,D). To confirm the expression of

the antigen, mice that were given the AAV2-ova vector were infused with OT-1 T cells, a CD8+ T cell population specific for the SIINFEKL peptide (ova257-264). These T cells divided and down-regulated CD62L (Fig. 1B, right panels), verifying that the antigen was expressed. We conclude that AAV-2-ova vector stimulated CD8+ but not CD4+ T cell responses. Two different T cell receptor transgenic CD4+ T cells failed to respond to AAV-OVA (Fig. 1). To test whether endogenous see more CD4+ T cells were helping the CD8+ cells, MHC class II–deficient mice, which lack CD4+ T cells, were given AAV2-ova vector and then OT-1 T cells. Figure 2A shows the response of OT-1 T cells, selleck chemicals llc measured using CFSE, at day 3 (D3), day 5 (D5), and week 8 (W8) after adoptive transfer (shaded profiles). In the liver, OT-1 cells divided as early as day 3, and almost all of the cells were CFSE-low by day 5; these cells were also present at week 8. In control mice given the AAV2-gfp vector (nonshaded profiles), there was very little OT-1 T cell division at days 3 and 5, although the cells were subject to some loss of CFSE staining by week 8. Strikingly, there was no

difference in the division of OT-1 T cells between normal B6 mice and MHC class II–deficient mice. In the spleen and the PLN, there was essentially no cell division in any of the mice at day 3, but divided cells appeared in these tissues on day 5, as previously reported14;

again, there was no difference between normal and MHC class II–deficient mice. Figure 2B shows the outcome of these experiments in terms of the numbers of Reverse transcriptase OT-1 T cells in the liver (left panel of Fig. 2B), spleen (center), and PLN of normal B6 versus MHC class II–deficient mice at day 3, day 5, and week 8 after adoptive transfer. In liver, there was a statistically significant expansion of OT-1 T cells at all three time points, but no significant difference between B6 and MHC class II–deficient mice. In spleen, we observed significant clonal expansion only on day 5, but not later. Again, there was no difference between normal B6 and MHC class II–deficient mice. In PLN, we observed no clear effects on overall OT-1 T cell numbers on days 3 and 5, although there was a significant increase in the numbers of OT-1 T cells in MHC class II–deficient mice on day 5, followed by a significant loss of OT-1 T cells in the AAV2-ova–transduced mice at week 8. The overall conclusion is that MHC class II–restricted helper T cells did not influence the response of OT-1 CD8+ T cells to the AAV2-ova vector.

1C,D). To confirm the expression of

the antigen, mice that were given the AAV2-ova vector were infused with OT-1 T cells, a CD8+ T cell population specific for the SIINFEKL peptide (ova257-264). These T cells divided and down-regulated CD62L (Fig. 1B, right panels), verifying that the antigen was expressed. We conclude that AAV-2-ova vector stimulated CD8+ but not CD4+ T cell responses. Two different T cell receptor transgenic CD4+ T cells failed to respond to AAV-OVA (Fig. 1). To test whether endogenous R428 research buy CD4+ T cells were helping the CD8+ cells, MHC class II–deficient mice, which lack CD4+ T cells, were given AAV2-ova vector and then OT-1 T cells. Figure 2A shows the response of OT-1 T cells, SP600125 ic50 measured using CFSE, at day 3 (D3), day 5 (D5), and week 8 (W8) after adoptive transfer (shaded profiles). In the liver, OT-1 cells divided as early as day 3, and almost all of the cells were CFSE-low by day 5; these cells were also present at week 8. In control mice given the AAV2-gfp vector (nonshaded profiles), there was very little OT-1 T cell division at days 3 and 5, although the cells were subject to some loss of CFSE staining by week 8. Strikingly, there was no

difference in the division of OT-1 T cells between normal B6 mice and MHC class II–deficient mice. In the spleen and the PLN, there was essentially no cell division in any of the mice at day 3, but divided cells appeared in these tissues on day 5, as previously reported14;

again, there was no difference between normal and MHC class II–deficient mice. Figure 2B shows the outcome of these experiments in terms of the numbers of Flavopiridol (Alvocidib) OT-1 T cells in the liver (left panel of Fig. 2B), spleen (center), and PLN of normal B6 versus MHC class II–deficient mice at day 3, day 5, and week 8 after adoptive transfer. In liver, there was a statistically significant expansion of OT-1 T cells at all three time points, but no significant difference between B6 and MHC class II–deficient mice. In spleen, we observed significant clonal expansion only on day 5, but not later. Again, there was no difference between normal B6 and MHC class II–deficient mice. In PLN, we observed no clear effects on overall OT-1 T cell numbers on days 3 and 5, although there was a significant increase in the numbers of OT-1 T cells in MHC class II–deficient mice on day 5, followed by a significant loss of OT-1 T cells in the AAV2-ova–transduced mice at week 8. The overall conclusion is that MHC class II–restricted helper T cells did not influence the response of OT-1 CD8+ T cells to the AAV2-ova vector.

2). We also examined the effects of miR-370 on migration and invasion JQ1 nmr of the highly

invasive MHCC-LM3 and YY-8103 cells. miR-370 overexpression markedly reduced, whereas miR-370 inhibition increased, migration and invasion of these cells (Fig. 1E,F and Supporting Fig. 3A-D). Interestingly, miR-370 inhibition also markedly enhanced migration and invasion of IMH cells (Supporting Fig. 3E,F). To further investigate the effect of miR-370 on tumorigenesis of HCC cells in vivo, MHCC-97H or YY-8103 cells infected with Ad-miR-370 or control adenovirus Ad-GFP were SC transplanted into the flanks of Balb/c nude mice. Xenografts were detected in 37.5% (3 of 8) of mice as early as day 14 and in all subjects by day 33 after inoculation in mice receiving MHCC-97H cells infected with Ad-GFP (Fig. 2A). No xenografts were observed until day 33 in mice receiving MHCC-97H cells infected with Ad-miR-370, and only small nodules were identified in 50% (4 of 8) of mice by day 38 (Fig. 2A). Xenografts were significantly smaller in the Ad-miR-370 group, compared to the control group, at every time point (Supporting see more Fig. 4A). Consistently, xenograft weight was significantly reduced in the Ad-miR-370 group (Fig. 2B). Real-time polymerase chain reaction (PCR) analysis showed a significant increase in

miR-370 levels in the Ad-miR-370 group, relative to the Ad-GFP control (Supporting Fig. 4B). Similar results were obtained with YY-8103 cells (Supporting Fig. 4C,D). We further investigated the effect of miR-370 on HCC metastasis in vivo in NOD/SCID mice injected

with luciferase-labeled MHCC-LM3 cells infected with Ad-miR-370 or Ad-GFP. Luciferase signals were detected in lungs in www.selleck.co.jp/products/Docetaxel(Taxotere).html all mice in the Ad-GFP group by ex vivo imaging, but in only 2 of 5 mice in the Ad-miR-370 group 8 weeks after cell transplantation (Fig. 2C and Supporting Fig. 4E). Number of tumor foci on lungs was also significantly reduced in the Ad-miR-370 group (Fig. 2D). Histologic analysis confirmed reduced tumor foci, which were composed of paratypic HCC cells in the Ad-miR-370 group (Fig. 2D). We then explored the antitumor effect of miR-370 on an established HCC cell transplanted SC tumor model in Balb/c nude mice. Intratumoral injection of Ad-miR-370 significantly reduced the growth and weight of MHCC-97H xenografts (Fig. 2E and Supporting Fig. 4F). Real-time PCR confirmed the increased expression of miR-370 in Ad-miR-370-treated tumor nodules (Supporting Fig. 4G). Histological analysis revealed that the tumor nodules were composed of HCC cells arranged in a trabecular pattern, as proved by H&E staining (Fig. 2F). Additionally, Ad-miR-370-treated tumor nodules displayed decreased Ki-67 expression (Fig. 2F) and contained more apoptotic cells (Supporting Fig. 5).

We www.selleckchem.com/products/3-deazaneplanocin-a-dznep.html show that in the CCl4 model, administration of the CB2 agonist JWH-133 reduces the extent

of liver injury, whereas CB2−/− mice are more susceptible to the toxic insult. These findings corroborate previous studies demonstrating hepatoprotective properties of CB2 receptors in experimental models of acute liver injury elicited by ischemia/reperfusion injury, thioacetamide or concanavalin A.6, 19, 34 In addition, we identify iNOS as a central mediator in the beneficial effects mediated by CB2 receptors. Indeed, CCl4-treated CB2−/− mice show impaired induction of hepatic iNOS, and treatment of these mice with the NO donor SIN-1 reduces their exacerbated susceptibility to liver injury. These findings are in line with the reported protective effects of hepatocyte iNOS on liver injury. Thus, iNOS−/− mice display enhanced hepatocyte apoptosis when exposed to either CCl4,26, 27 or to partial hepatectomy.28 In addition, cultured hepatocytes are more resistant to apoptosis in the presence of NO donors, or following induction of iNOS with cytokines, such as TNF-α.29 Interestingly,

our data also indicate that CCl4-treated CB2−/− mice show decreased induction of TNF-α, a well-characterized inducer of iNOS expression. Whether TNF-α release triggered by CB2 receptors in nonparenchymal cells may contribute selleckchem to the iNOS-dependent antiapoptotic effects in hepatocytes remains to be determined. It is well demonstrated that liver injury triggered by CCl4 is followed by a regenerative response orchestrated by the activation (-)-p-Bromotetramisole Oxalate of multiple coordinated pathways, involving cross-talk between hepatocytes and nonparenchymal cells.25 We demonstrate that CB2 receptors display beneficial effects on liver regeneration in this model, as well as in the partial hepatectomy model. We also demonstrate that beneficial effects of CB2 receptors are mediated by a pathway distinct from its protective effects against hepatocyte apoptosis, that involves IL-6. Thus, CCl4-treated CB2−/− mice display reduced hepatic expression of IL-6, and administration of IL-6 to these animals partially

restores PCNA expression. Interestingly, CB2−/− mice and IL-6−/− mice behave similarly in response to acute and chronic liver injury, with increased liver damage, decreased liver regeneration and increased fibrogenesis.17, 35 However, our data indicate that although IL-6 mediates CB2 receptor impact on liver regeneration, the cytokine is not involved in CB2 receptor-dependent antiapoptotic effect. These data are in line with the reported beneficial effects of IL-6 on liver regeneration,25 but contrast with studies reporting the protective role of IL-6 against liver damage.31, 36, 37 The mechanisms underlying these discrepancies, although not fully elucidated, may rely on the duration of IL-6 treatment, as suggested in a recent study.

We Protein Tyrosine Kinase inhibitor show that in the CCl4 model, administration of the CB2 agonist JWH-133 reduces the extent

of liver injury, whereas CB2−/− mice are more susceptible to the toxic insult. These findings corroborate previous studies demonstrating hepatoprotective properties of CB2 receptors in experimental models of acute liver injury elicited by ischemia/reperfusion injury, thioacetamide or concanavalin A.6, 19, 34 In addition, we identify iNOS as a central mediator in the beneficial effects mediated by CB2 receptors. Indeed, CCl4-treated CB2−/− mice show impaired induction of hepatic iNOS, and treatment of these mice with the NO donor SIN-1 reduces their exacerbated susceptibility to liver injury. These findings are in line with the reported protective effects of hepatocyte iNOS on liver injury. Thus, iNOS−/− mice display enhanced hepatocyte apoptosis when exposed to either CCl4,26, 27 or to partial hepatectomy.28 In addition, cultured hepatocytes are more resistant to apoptosis in the presence of NO donors, or following induction of iNOS with cytokines, such as TNF-α.29 Interestingly,

our data also indicate that CCl4-treated CB2−/− mice show decreased induction of TNF-α, a well-characterized inducer of iNOS expression. Whether TNF-α release triggered by CB2 receptors in nonparenchymal cells may contribute GSK2126458 cost to the iNOS-dependent antiapoptotic effects in hepatocytes remains to be determined. It is well demonstrated that liver injury triggered by CCl4 is followed by a regenerative response orchestrated by the activation cAMP of multiple coordinated pathways, involving cross-talk between hepatocytes and nonparenchymal cells.25 We demonstrate that CB2 receptors display beneficial effects on liver regeneration in this model, as well as in the partial hepatectomy model. We also demonstrate that beneficial effects of CB2 receptors are mediated by a pathway distinct from its protective effects against hepatocyte apoptosis, that involves IL-6. Thus, CCl4-treated CB2−/− mice display reduced hepatic expression of IL-6, and administration of IL-6 to these animals partially

restores PCNA expression. Interestingly, CB2−/− mice and IL-6−/− mice behave similarly in response to acute and chronic liver injury, with increased liver damage, decreased liver regeneration and increased fibrogenesis.17, 35 However, our data indicate that although IL-6 mediates CB2 receptor impact on liver regeneration, the cytokine is not involved in CB2 receptor-dependent antiapoptotic effect. These data are in line with the reported beneficial effects of IL-6 on liver regeneration,25 but contrast with studies reporting the protective role of IL-6 against liver damage.31, 36, 37 The mechanisms underlying these discrepancies, although not fully elucidated, may rely on the duration of IL-6 treatment, as suggested in a recent study.