Difference between revisions of "Article:Diabetes Mellitus and Liver Surgery: The Effect of Diabetes on Oxidative Stress and Inflammation. (5964489)"

From ScienceSource
Jump to: navigation, search
(Created page with "{{articleheader | Wikidata_code = Q54939023 | title = Diabetes Mellitus and Liver Surgery: The Effect of Diabetes on Oxidative Stress and Inflammation. | publication_date = 20...")
(No difference)

Revision as of 11:49, 16 April 2019

This page is the ScienceSource HTML version of the scholarly article described at https://www.wikidata.org/wiki/Q54939023. Its title is Diabetes Mellitus and Liver Surgery: The Effect of Diabetes on Oxidative Stress and Inflammation. and the publication date was 2018-05-08. The initial author is Mariana Mendes-Braz.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.

Converted JATS paper:

Journal Information

Title: Mediators of Inflammation

Diabetes Mellitus and Liver Surgery: The Effect of Diabetes on Oxidative Stress and Inflammation

  • Mariana Mendes-Braz
  • Joilson O. Martins

Laboratory of Immunoendocrinology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences of University Sao Paulo (FCF/USP), São Paulo, SP, Brazil

Publication date (collection): /2018

Publication date (epub): 5/2018


Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycaemia and high morbidity worldwide. The detrimental effects of hyperglycaemia include an increase in the oxidative stress (OS) response and an enhanced inflammatory response. DM compromises the ability of the liver to regenerate and is particularly associated with poor prognosis after ischaemia-reperfusion (I/R) injury. Considering the growing need for knowledge of the impact of DM on the liver following a surgical procedure, this review aims to present recent publications addressing the effects of DM (hyperglycaemia) on OS and the inflammatory process, which play an essential role in I/R injury and impaired hepatic regeneration after liver surgery.


1. Introduction

To extirpate a macroscopic lesion or accomplish a transplant, the blood flow to the liver must be interrupted to avoid the haemorrhagic process. Despite the safety of surgical procedures that involve the interruption of blood flow to the liver (ischaemia), this interruption contributes to tissue damage, which is potentiated by the restoration of blood flow (reperfusion). This phenomenon, known as ischaemia-reperfusion (I/R) injury [[1], [2]], is associated with inflammation and oxidative stress (OS) [[3]].

Diabetes mellitus (DM) is a metabolic disorder resulting from deficient insulin secretion and/or insulin action, leading to hyperglycaemia (high blood glucose) [[4]], which causes oxidative damage and activates inflammatory signalling cascades [[5]], in addition to acting as a damaging agent exacerbating the pathological conditions of DM [[6], [7]]. Considering the growing need for knowledge about the impact of DM on livers undergoing a surgical procedure, the present review aims to present recent data concerning the effects of DM (hyperglycaemia) on OS and the inflammatory process.

2. Oxidative Stress

Under normal conditions, the hepatic production of prooxidants, such as reactive oxygen species (ROS), is counterbalanced by antioxidants. An imbalance in favour of prooxidants corresponds to OS, and the direct action of ROS on cell viability and function is directly related to the occurrence of several pathological processes in the liver [[8]]. OS plays an essential role in liver surgery [[9]], and diabetes is generally followed by increased free radical production [[10][13]] or reduced antioxidant protection [[14], [15]]. To better understand the effect of DM (hyperglycaemia) on OS, this section will describe research findings that help clarify the association of DM with liver surgery.

2.1. Diabetes Mellitus and Ischaemia-Reperfusion Injury

Hydrogen peroxide (H2O2), a mild and relatively stable oxidant that is formed in tissues exposed to I/R, has been considered a representative ROS for evaluating the response of cells to OS [[16]]. Although H2O2 is not a free radical, its accumulation may promote the formation of more toxic species, such as hydroxyl radicals (•OH), through the Fenton reaction [[17]]. H2O2 can cause permanent growth arrest [[18], [19]] and apoptosis [[20][22]] in a number of cell types. Nuclear (8-hydroxy-2′-deoxyguanosine) 8-OHdG formation indicates the presence of OS in nuclei [[23]]. The liver is a major organ affected by ROS [[24]] and is susceptible to the effects of OS induced by hyperglycaemia, causing liver injury [[25][27]]. Zhang et al. [[28]] found that serum H2O2 and nuclear 8-OHdG levels were higher in streptozotocin- (STZ-) induced diabetic rats subjected to I/R compared with the diabetic control group. ROS induce lipid peroxidation, which causes membrane injury, in addition to changes in ion permeability, enzyme activity, and, ultimately, cell death. Malondialdehyde (MDA), an indicator of oxidative injury produced via lipid peroxidation [[29]], is significantly enhanced in STZ-induced diabetic rats compared with normal rats and increases after I/R [[28], [30]] (Figure 1).

Apoptosis and necrosis can occur after I/R. An intense injury leads to initial necrotic killing, whereas late apoptosis may follow moderate injury [[31]]. STZ-induced diabetic rats exposed to an ischaemic period present significantly increased hepatocyte degeneration, sinusoidal dilatation, nuclear pyknosis, and cellular necrosis compared with the diabetes sham group [[30]]. In spite of this experimental difference, Behrends et al. [[32]] reported that necrosis is the preferential form of cell death in the liver of hyperglycemic rats (due to intraperitoneal injection of 25% glucose) subjected to I/R. The authors [[32]] noted that this increased injury may be associated with the inhibition of heat shock proteins (HSPs), which is only possible through the association of hyperglycaemia and I/R. The hyperglycaemia alone was not enough for HSP32 and HSP70 downregulation. HSPs are considered to be an indispensable protective agent against I/R injury because they are able to protect the liver from OS [[33]] (Figure 1).

Cell adaptation to OS is a consequence of the upregulation of distinct cytoprotective genes responsible for buffering the antioxidant capacity of the cell [[34]]. Under physiological conditions, an antioxidant defence system protects the body against the harmful effects of free radicals [[35]]. Diabetic livers are vulnerable to attack by oxygen free radicals because they present overall antioxidant depression [[14]]. Release of ROS and the concurrent consumption of endogenous antioxidants and cell death (apoptosis or necrosis) occur during hepatic I/R [[36]]. After I/R, nuclear factor (erythroid-derived 2)-like-2 factor (Nrf2), a transcription factor that mediates the expression of many endogenous antioxidants plays an important role in opposing hepatic injury [[37]]. Zhang et al. [[28]] reported that, after I/R injury, hepatocytes pretreated with high glucose (25 mM) exhibited a reduction in the antioxidative ability of the Nrf2 pathway and a substantial increase in nuclear factor kappa B (NF-κB) translocation; however, NF-κB activation was already enhanced in these hepatocytes before I/R injury. Interestingly, NF-κB, a transcription factor that reacts to redox signals, may directly repress Nrf2 signalling at the transcriptional level [[38], [39]]. Zhang et al. [[28]] postulated that high glucose-induced ROS overproduction could initiate the inhibitory interaction between NF-κB and Nrf2 (Figure 1). However, the precise mechanisms involved in the NF-κB and Nrf2 interaction under hyperglycaemic conditions require further elucidation.

Under normal conditions, the body presents a potent antioxidant system that is responsible for protecting it from the harmful effects of ROS [[40]]. Endogenous antioxidant enzymes attenuate I/R injury in the liver [[36]]. In both type 1 and type 2 DM, antioxidant defence enzymes are deficient, and there is an increase in oxidative damage [[41]]. High levels of ROS such as superoxide (O2−) are found in diabetes and especially during I/R injury [[42]]. Cem Sezen et al. [[30]] showed that there is an increase in glutathione s-transferase (GST) in STZ-induced diabetic mice post-I/R with respect to diabetic rats. Between these two groups, there was no difference in the level of superoxide dismutase (SOD); however, compared with the sham group (nondiabetic), there was a marked decrease in SOD levels. The orchestrated actions of several antioxidants in mammalian cells are essential for efficiently detoxifying free radicals. Therefore, any impairment in this pathway will influence the activities of other enzymes [[43], [44]]. Reduction in the activity of SOD will result in an increased level of O2− [[45]]. GST is known to be an early and sensitive marker of liver injury and has been shown to increase after liver ischaemia/reperfusion [[46]]. This increased activity of GST could be explained as a compensatory mechanism to protect the organism against injury [[47]]. These findings are not only in accord with the diverse signalling pathways related to postoperative liver injury associated with DM (Figure 1) but also indicate the importance of the determination of increased ROS production and its characteristic consequences in postischaemic tissues, permitting the identification of interventions that stimulates ROS detoxification, and consequently protect against reperfusion injury [[16]], mainly in a diabetic context (Figure 1).

2.2. Diabetes Mellitus and Liver Regeneration

An increase in lipid peroxidation was found to be important for a normal proliferative process to occur in the liver remnant after partial hepatectomy (PH) [[48], [49]]. Francés et al. [[50]] reported that OS is increased by hyperglycaemia and is juxtaposed with the effect of PH in STZ-induced diabetic rats. Postoperative recovery depends on the regenerative capacity of the residual liver. The liver presents altered intracellular signalling pathways in type 1 DM specimens [[51][53]] and a consequent deficient regenerative response [[54]]. STZ-induced diabetic rats were found to present an increase in •OH production, which could result in DNA damage [[55], [56]] (Figure 1). Hyperglycaemia in STZ-induced diabetic rats leads to an increase in hepatic ROS production and is further enhanced after PH. STZ-induced diabetic rats subjected to PH present a decrease in the level of proliferating cell nuclear antigen (PCNA) and a significant decrease in cyclin D1 levels, suggesting that few hepatocytes are capable of entering the cell cycle [[50]].

Hyperglycaemia enhances •OH radical levels and consequent Bax protein induction. After PH, STZ-induced diabetic rats were found to present an increase in proapoptotic events (Bax/Bcl-xL ratio, caspase-3 activity, and cytosolic cytochrome c) compared with the diabetic group [[50]] (Figure 1). The diversity of the results of different studies [[30], [32], [50], [55]] shows that the association of hyperglycaemia with different surgical modalities leads to differences in the type of cell death. It is imperative to identify the effects of diabetes on cell death after more complex surgical procedures leading to pronounced liver injury, such as liver transplantation and PH under I/R.

3. Inflammation

Hepatic inflammation is a complex process that is initiated in response to stressful conditions to protect hepatocytes from injury. However, overly intense inflammatory responses are followed by massive hepatocyte loss, causing irreversible parenchymal damage [[57]]. Liver damage is a serious complication in DM [[58]]. Surgical procedures induce acute inflammation, which is characterized by the production and release of various chemical mediators, including cytokines [[59]]. In the next section, the effects of DM (hyperglycaemia) on the hepatic inflammatory process after a surgical procedure will be discussed.

3.1. Diabetes Mellitus and Ischaemia-Reperfusion Injury

The pathophysiology of hepatic I/R injury is not only related to the direct cell impairment caused by ischaemic insult but also results from the restoration of blood flow, which triggers the proinflammatory environment. Diabetic patients present a variety of deficient immune cell functions [[60], [61]], and diabetic animals exhibit abnormalities in the course of the inflammatory response, with a consequent decrease in the number of leukocytes in inflammatory injuries [[62], [63]], the airway inflammatory response to antigen challenge [[64], [65]], mast cell degranulation [[66], [67]], superoxide generation, and tumour necrosis factor- (TNF-) α release by leukocytes upon exposure to lipopolysaccharides [[68]]. The difficulty in arriving at any consistent conclusion is due to the conflicting views regarding the impact of hyperglycaemia on inflammatory responses between different reports. Since clinical observations have revealed that the association between hyperglycaemia and immune alterations could increase the risk for rejection in transplantation, the substantial inflammatory response associated with I/R injury appears to be mediated by an exaggerated adhesion of leukocytes to the endothelium [[69], [70]].

The hyperinflammatory phenotype associated with DM may induce a liver immune response against I/R, which could favour an increase in parenchymal damage [[71]]. In the initial phase of liver injury, different events trigger a complex inflammatory pathway that leads to hepatic accumulation of neutrophils [[72]]. Through the release of oxidants and proteases, hepatocytes are directly damaged by recruited neutrophils, which are involved in by the later phase of liver injury induced by I/R [[73]]. In the livers of hyperglycaemic rats subjected to I/R, Behrends et al. [[32]] observed an increase in neutrophil infiltration (Figure 2). Interestingly, in association with microvascular dysfunction in response to I/R, neutrophil infiltration is exacerbated in DM, suggesting that DM predisposes tissues to the detrimental consequences of I/R, which is a deleterious process that is broadly mediated by neutrophils [[69]].

The immune system responds to liver injury and/or stress through the activation of resident Kupffer cells (KCs), which release proinflammatory cytokines and other factors [[74]]. A prominent feature of liver injury is an increase in the hepatic macrophage population [[75]]. Considering cellular and molecular mechanisms, Yue et al. [[71]] showed that I/R stimulates the release of advanced glycation end products (AGE) into the blood of STZ-induced diabetic mice and that KCs express higher levels of the receptor for AGE (RAGE). The authors [[71]] proposed that RAGE may exhibit different functions in a cell type-specific manner. In normal mice, RAGE regulates hepatocyte proliferation during the restoration phase of I/R, whereas in diabetic mice, RAGE activates the hepatic immune system. These findings support the hypothesis that DM may be a factor involved in the course and evolution of I/R injury after liver surgery.

Activated KCs respond with a classic inflammatory reaction and consequent production of proinflammatory cytokines [[76][80]]. At 6 hours after reperfusion, TNF-α and interleukin- (IL-) 6 levels were found to be increased, while the IL-10 level was decreased on STZ-induced diabetic mice [[71], [81]] (Figure 2), whereas in control mice, KCs not only presented increases in TNF-α and IL-6 but also an increase in IL-10 [[81]]. The activation of IL-10 during a proinflammatory response may represent an important agent in the regulation of intensive inflammation in a stressful situation. These findings not only illustrate the defensive role of KCs during liver I/R injury in opposing the hyperinflammatory response through IL-10 expression but also show that hyperglycemic mice subjected to I/R present a significant decrease in IL-10 secretion, by KCs, which is related to uncontrolled inflammation and robust hepatic I/R injury [[81]].

Several studies suggest that endoplasmic reticulum stress and CHOP signalling could be upregulated by RAGE signalling [[82][85]]. After 6 hours of reperfusion, C/EBP homologous protein (CHOP) levels in KCs were found to be stimulated by I/R and were further increased in STZ-induced hyperglycemic mice. In hyperglycemic KCs, overactivation of CHOP is related to the inhibition of STAT3 and STAT6 activation. The signal transducers and activators of transcription (STATs) regulate the polarization of macrophages [[86]], and diabetic mice present M2 KC phenotype inhibition, which results in increased inflammation under hepatic I/R when the rodents exhibit interruption of IL-10-secreting M2 differentiation [[81]]. Additionally, mice that are only subjected to ischaemia show development of M2-type macrophages, which protect livers from I/R via an IL-10-dependent mechanism [[87]] (Figure 2).

In the pathogenesis of DM, activated innate immunity and inflammation are important factors. Type 2 DM involves inflammatory elements [[88], [89]], and type 1 DM is regarded as an inflammatory process [[90]]. NF-κB is a transcription factor that is activated in the diabetic liver [[91][93]] and is involved in events that lead to inflammation [[94]]. NF-κB regulates the expression of many inflammatory cytokines, including monocyte chemotactic protein- (MCP-) 1, IL-6, and TNF-α [[95], [96]], which are proinflammatory cytokines that may activate neutrophils and KCs [[97]]. Zhang et al. [[28]] showed that after 6 hours of reperfusion, the levels of these hepatic cytokines were significantly higher in STZ-induced diabetic rats and further increased after the ischaemic period. These results suggested that NF-κB might also be involved in hepatic I/R in diabetic rats (Figure 2). The investigation of NF-κB activation in diabetic livers subjected to surgical procedures should be extended to cell death. Between NF-κB and TNF-α, there is an autocrine-reinforcing loop [[98], [99]]. The hepatic increase of TNF-α in STZ-induced diabetic rats leads to pronounced upregulation of the NF-κB pathway [[100]], and NF-κB activation induced by hyperglycaemia mediates cell apoptosis [[101], [102]].

Several inflammatory cytokines (e.g., TNF-α) and arachidonic acid metabolites (prostaglandins and thromboxanes) are involved in liver injury induced by I/R. Cyclooxygenase (COX) regulates the production of prostanoids [[103]], and inhibition of COX-2 protects against hepatic I/R injury [[104], [105]], which suggests that COX-2 is associated with organ injury and contributes to hepatic microvascular and hepatocellular injuries through TNF-α production [[103]]. Hepatocyte apoptosis stimulated by TNF is associated with c-Jun N-terminal kinase (JNK) activation [[106]]. Conversely, Francés et al. [[107]] showed that STZ-induced diabetic COX-2 transgenic mice presented a substantial decrease in apoptosis and that COX-2 overexpression could prevent the increase in JNK activity stimulated by high glucose. The authors [[107]] also showed that the increased expression of COX-2 in diabetic COX-2 transgenic mice induces an increase of phosphoinositide 3-kinase (PI3K) activity compared with diabetic wild-type mice, in addition to favouring the activation of Akt and producing an antiapoptotic signal [[107]]. These studies call attention not only to the contradictory roles of diabetes in orchestrating hepatocyte activity but also to the necessity of clearly understanding the consequences of diabetes for cell death after liver surgery (Figure 2).

3.2. Diabetes Mellitus and Liver Regeneration

In a model of type 2 DM (ob/ob murine), liver regeneration was found to be impaired after 70% PH, which resulted in 90% mortality [[108]]. The regenerative ability of the liver is compromised in type 1 diabetic rats subjected to PH [[51], [52], [109]]. In patients subjected to a major hepatectomy, DM tends to induce postoperative liver failure [[110]]. Considering the mechanisms of regeneration failure, diabetic and obese KK-Ay mice exhibit abnormal responses after PH [[111]] and present excessive induction of hepatic TNF-α expression. Although TNF-α is important for the initiation of normal hepatic regeneration [[112], [113]], excess induction of TNF-α in KCs might interfere with the regenerative process [[111]] (Figure 2).

Adipose tissue is involved in a number of biological functions, including inflammation, and acts as an endocrine organ through the secretion of several biologically active substances known as “adipokines” [[114]]. During liver regeneration, systemic adipose stores are required as a source of various adipokines, such as adiponectin, which is an essential signal for liver regeneration [[115]]. Aoyama et al. [[111]] showed that the serum adiponectin level was significantly reduced in KK-Ay mice before PH and tended to decrease gradually after PH. Adiponectin has been found to inhibit the lipopolysaccharide-dependent activation of macrophages [[116], [117]]. The significant hypoadiponectinemia presented by KK-Ay mice could be related to the fact that the KCs of these animals are more susceptible to certain stimuli; moreover, the hypoadiponectinemia caused by this susceptibility could be further associated with the increased production of TNF-α by KCs, which may interfere with regenerative responses [[111]] (Figure 2). Adiponectin mediates anti-inflammatory effects. However, since this role for adiponectin was found to depend on surgical conditions, the function of adiponectin in the inflammatory process is a controversial issue [[118]]. While injurious effects of adiponectin on steatotic livers subjected to warm ischaemia (60 minutes) were identified by Massip-Salcedo et al. [[119]], the beneficial (anti-inflammatory) effects of adiponectin on small fatty grafts subjected to cold ischaemia (40 minutes) were observed by Man et al. [[120]]. Although these findings were obtained in steatotic livers, these results suggest opportunities for investigation of the effect of adiponectin on diabetic livers subjected to different surgical procedures.

IL-6 is a protein synthesized by fibroblasts, monocytes, macrophages, T cells, and endothelial cells [[121]] that plays an important role in hepatic regeneration [[122], [123]]. Adipokines exhibit proinflammatory or anti-inflammatory activities [[124]], and leptin presents proinflammatory properties [[125], [126]]. IL-6 and leptin function in the Janus kinase- (JAK-) STAT3 signalling pathway [[111]]. KK-Ay mice present a substantial increase in the levels of IL-6 and leptin following PH [[111]]. Despite the important role of the JAK-STAT pathway in hepatic protection against different hepatic injuries [[127], [128]] and the evidence that IL-6, leptin, and the JAK-STAT signalling pathway are essential to liver regeneration [[129][132]], Aoyama et al. [[111]] showed that the role of the JAK-STAT pathway in hepatic regeneration seems to be complex and dependent on the intensity of the stimulus, showing that hyperphosphorylation of STAT3 favours poor hepatic regeneration as a result of direct downregulation of cyclin D1 expression (Figure 2).

4. Diabetes Mellitus in Clinical Situations

There is an absence of clinical studies elucidating signalling pathways related to liver damage and impaired regeneration in diabetic patients undergoing surgery. Nevertheless, it is indispensable to discuss and generate hypotheses about this issue, which is quite controversial because some studies have shown that DM patients present a poorer prognosis after hepatic surgery in comparison with non-DM patients, whereas others show no difference [[133]].

Focusing on the issues addressed in this review (OS and inflammation), Li et al. [[133]] and Shields et al. [[134]] described the typical change in microcirculation that occurs in diabetic patients after liver surgery. The ischaemic period and liver perfusion recovery are important factors related to hepatocellular damage because microcirculatory collapse is followed by a pronounced reduction of tissue oxygenation [[135]], which might result in degeneration and necrosis of hepatocytes and consequent liver dysfunction [[136]]. Experimental models of I/R injury have offered evidence that insufficient hepatic microcirculatory perfusion, inflammatory cell activation, and consequent generation of ROS, cytokines, and chemokines can be considered essential in I/R syndrome [[137]]. Although the authors [[133], [134]] did not report the relationship between diabetic liver failure after liver surgery and microcirculation collapse, we take this opportunity to raise this question for the development of future studies.

The alterations of hepatic haemodynamics are also related to hepatic steatosis, and a decrease in portal vein haemodynamics is observed in patients with a fatty liver disease [[138], [139]]. Moreover, experimental animals with steatosis present decreased parenchymal microcirculation [[140]]. Hepatic steatosis has long been reported in type 1 [[141]] and type 2 DM [[142]]. Steatosis is common in diabetic patients (36% incidence) [[143]], and increased steatosis raises the sensibility of the liver parenchyma to I/R injury [[144]]. In steatotic livers, the parenchymal regeneration ability is impaired, particularly after a surgical procedure [[115]], which may partially explain the incapacity of some diabetic patients to resist liver surgery. The high mortality observed in diabetic patients is absent in nondiabetic patients with steatosis [[143]]. In hepatocytes, increased accumulation of fatty acids induces OS arising from mitochondria, peroxisomes, or microsomes. ROS and lipid peroxidation products can influence KCs and stimulate NF-κB activation, which in turn stimulates the production of TNF-α and several proinflammatory cytokines, such as IL-6 [[143]], which are presented in this review as factors involved in decreased regeneration and increased liver damage.

5. Conclusion

The purpose of this review was to discuss the literature addressing the damaging effect of DM on liver recovery after a surgical procedure and, especially, to highlight the need to expand knowledge of this issue to benefit patients with DM subjected to surgical procedures, which are increasing in clinical practice. Extensive work is still necessary to assess the differences between the diabetic and nondiabetic liver after a surgical procedure. Exploring this subject will enable the development of new treatments that will improve the success of diabetic liver recovery after surgery.



The authors apologize to the many researchers whose work they have not been able to discuss in this limited review. The authors are supported by Grants 2016/24992-0 and 2017/11540-7 from the São Paulo Research Foundation (FAPESP), Grant 301617/2016-3 from the National Counsel of Technological and Scientific Development (CNPq, PQ-1D), and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).


  1. D. J. PownerFactors during donor care that may affect liver transplantation outcome200414324124910.1177/152692480401400310
  2. J. M. HendersonLiver transplantation and rejection: an overview199946Supplement 21482148410431709
  3. F. Serracino-InglottN. A. HabibR. T. MathieHepatic ischemia-reperfusion injury2001181216016610.1016/S0002-9610(00)00573-02-s2.0-003504358211425059
  4. S. CelikS. ErdoganM. TuzcuCaffeic acid phenethyl ester (CAPE) exhibits significant potential as an antidiabetic and liver-protective agent in streptozotocin-induced diabetic rats200960427027610.1016/j.phrs.2009.03.0172-s2.0-6924920382019717012
  5. M. BrownleeBiochemistry and molecular cell biology of diabetic complications2001414686581382010.1038/414813a2-s2.0-003585698011742414
  6. A. GuvenO. YavuzM. CamEffects of melatonin on streptozotocin-induced diabetic liver injury in rats20061082859310.1016/j.acthis.2006.03.0052-s2.0-3374500924616714049
  7. M. RomagnoliM. C. Gomez-CabreraM. G. PerrelliXanthine oxidase-induced oxidative stress causes activation of NF-κB and inflammation in the liver of type I diabetic rats201049217117710.1016/j.freeradbiomed.2010.03.0242-s2.0-7795353868420362663
  8. L. A. VidelaR. RodrigoM. OrellanaOxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients2004106326126810.1042/CS200302852-s2.0-1214429155014556645
  9. T. FukudaK. IkejimaM. HiroseY. TakeiS. WatanabeN. SatoTaurine preserves gap junctional intercellular communication in rat hepatocytes under oxidative stress200035536136810.1007/s0053500503612-s2.0-003412217010832671
  10. J. W. BaynesS. R. ThorpeRole of oxidative stress in diabetic complications: a new perspective on an old paradigm19994811910.2337/diabetes.48.1.12-s2.0-00329133099892215
  11. J. W. BaynesRole of oxidative stress in development of complications in diabetes199140440541210.2337/diab.40.4.4052-s2.0-00257329482010041
  12. K. C. ChangS. Y. ChungW. S. ChongPossible superoxide radical-induced alteration of vascular reactivity in aortas from streptozotocin-treated rats199326629921000
  13. I. S. YoungS. TateJ. H. LightbodyD. McMasterE. R. TrimbleThe effects of desferrioxamine and ascorbate on oxidative stress in the streptozotocin diabetic rat199518583384010.1016/0891-5849(94)00202-U2-s2.0-00289343347797090
  14. A. K. SaxenaP. SrivastavaR. K. KaleN. Z. BaquerImpaired antioxidant status in diabetic rat liver. Effect of vanadate199345353954210.1016/0006-2952(93)90124-f2-s2.0-00274754718442752
  15. S. V. McLennanS. HeffernanL. WrightChanges in hepatic glutathione metabolism in diabetes199140334434810.2337/diab.40.3.3442-s2.0-00259781941671844
  16. D. N. GrangerP. R. KvietysReperfusion injury and reactive oxygen species: the evolution of a concept2015652455110.1016/j.redox.2015.08.0202-s2.0-8494468314626484802
  17. W. JassemS. V. FuggleM. RelaD. D. H. KooN. D. HeatonThe role of mitochondria in ischemia/reperfusion injury200273449349910.1097/00007890-200202270-000012-s2.0-003718111111889418
  18. Q. ChenB. N. AmesSenescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells199491104130413410.1073/pnas.91.10.41302-s2.0-0028345161
  19. D. A. CloptonP. SaltmanLow-level oxidative stress causes cell-cycle specific arrest in cultured cells1995210118919610.1006/bbrc.1995.16452-s2.0-00290321547741740
  20. G. B. CorcoranL. FixD. P. JonesApoptosis: molecular control point in toxicity1994128216918110.1006/taap.1994.11952-s2.0-00280921547940532
  21. D. P. de BonoW. D. YangExposure to low concentrations of hydrogen peroxide causes delayed endothelial cell death and inhibits proliferation of surviving cells1995114223524510.1016/0021-9150(94)05488-52-s2.0-00289483937605392
  22. E. R. WhittemoreD. T. LooC. W. CotmanExposure to hydrogen peroxide induces cell death via apoptosis in cultured rat cortical neurons19945121485148810.1097/00001756-199407000-000192-s2.0-00279315587948844
  23. V. N. AnisimovAgeing and the mechanisms of carcinogenesis: some practical implications19981732632689894760
  24. V. Sanchez-ValleN. C. Chavez-TapiaM. UribeN. Mendez-SanchezRole of oxidative stress and molecular changes in liver fibrosis: a review201219284850486010.2174/0929867128033415202-s2.0-8487046164822709007
  25. E. BugianesiA. J. McCulloughG. MarchesiniInsulin resistance: a metabolic pathway to chronic liver disease2005425987100010.1002/hep.209202-s2.0-3094445514516250043
  26. P. MannaJ. DasJ. GhoshP. C. SilContribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IκBα/NF-κB, MAPKs, and mitochondria-dependent pathways: prophylactic role of arjunolic acid201048111465148410.1016/j.freeradbiomed.2010.02.0252-s2.0-7795255195220188823
  27. P. PalsamyS. SivakumarS. SubramanianResveratrol attenuates hyperglycemia-mediated oxidative stress, proinflammatory cytokines and protects hepatocytes ultrastructure in streptozotocin-nicotinamide-induced experimental diabetic rats2010186220021010.1016/j.cbi.2010.03.0282-s2.0-7795354567720307516
  28. Y. ZhangD. YuanW. YaoHyperglycemia aggravates hepatic ischemia reperfusion injury by inducing chronic oxidative stress and inflammation201620161610.1155/2016/39196272-s2.0-849878969643919627
  29. T. ŞahinZ. BegeçH. İ. ToprakThe effects of dexmedetomidine on liver ischemia-reperfusion injury in rats2013183138539010.1016/j.jss.2012.11.0342-s2.0-8487907475923321519
  30. S. Cem SezenB. IşıkM. BilgeEffect of dexmedetomidine on ischemia-reperfusion injury of liver and kidney tissues in experimental diabetes and hepatic ischemia-reperfusion injury induced rats2016202143149
  31. H. MalhiG. J. GoresJ. J. LemastersApoptosis and necrosis in the liver: a tale of two deaths?200643Supplement 1S31S4410.1002/hep.210622-s2.0-33644524120
  32. M. BehrendsG. Martinez-PalliC. U. NiemannS. CohenR. RamachandranR. HiroseAcute hyperglycemia worsens hepatic ischemia/reperfusion injury in rats201014352853510.1007/s11605-009-1112-32-s2.0-7795051841919997981
  33. H. YamamotoY. YamamotoK. YamagamiHeatshock preconditioning reduces oxidative protein denaturation and ameliorates liver injury by carbon tetrachloride in rats2000199630931810945649
  34. M. E. Rinaldi TosiV. BocanegraW. ManuchaA. Gil LorenzoP. G. VallésThe Nrf2–Keap1 cellular defense pathway and heat shock protein 70 (Hsp70) response. Role in protection against oxidative stress in early neonatal unilateral ureteral obstruction (UUO)2011161576810.1007/s12192-010-0221-y2-s2.0-7995167876620734248
  35. B. HalliwellJ. M. GutteridgeLipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy198418391139613976145845
  36. G. K. GlantzounisH. J. SalacinskiW. YangB. R. DavidsonA. M. SeifalianThe contemporary role of antioxidant therapy in attenuating liver ischemia-reperfusion injury: a review20051191031104710.1002/lt.205042-s2.0-2514446353916123965
  37. K. KudohH. UchinamiM. YoshiokaE. SekiY. YamamotoNrf2 activation protects the liver from ischemia/reperfusion injury in mice2014260111812710.1097/SLA.00000000000002872-s2.0-8490226230724368646
  38. M. Buelna-ChontalC. ZazuetaRedox activation of Nrf2 & NF-κB: a double end sword?201325122548255710.1016/j.cellsig.2013.08.0072-s2.0-8488434486123993959
  39. G. H. LiuJ. QuX. ShenNF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK20081783571372710.1016/j.bbamcr.2008.01.0022-s2.0-4194914129618241676
  40. D. E. FrancésP. I. IngaramoM. T. RoncoC. E. CarnovaleDiabetes, an inflammatory process: oxidative stress and TNF-alpha involved in hepatic complication20136664565310.4236/jbise.2013.66079
  41. I. C. WestRadicals and oxidative stress in diabetes200017317118010.1046/j.1464-5491.2000.00259.x2-s2.0-003399440910784220
  42. J. W. ElrodM. R. DuranskiW. LangstoneNOS gene therapy exacerbates hepatic ischemia-reperfusion injury in diabetes: a role for eNOS uncoupling2006991788510.1161/01.RES.0000231306.03510.772-s2.0-3374623476616763164
  43. P.-M. SinetP. GarberInactivation of the human CuZn superoxide dismutase during exposure to O2− and H2O21981212241141610.1016/0003-9861(81)90382-92-s2.0-00198118156275795
  44. Y. KonoI. FridovichSuperoxide radical inhibits catalase198225710575157546279612
  45. A. T. H. MossaA. A. RefaieA. RamadanJ. BouajilaAmelioration of prallethrin-induced oxidative stress and hepatotoxicity in rat by the administration of Origanum majorana essential oil201320131185908510.1155/2013/8590852-s2.0-84893813641
  46. A. ChoukérA. MartignoniR. J. Schauerα-Gluthathione S-transferase as an early marker of hepatic ischemia/reperfusion injury after liver resection200529452853410.1007/s00268-004-7431-32-s2.0-2344445616615776301
  47. C. E. CarnovaleJ. A. MontiC. FavreC. ScapiniM. C. CarrilloIs intestinal cytosolic glutathione S-transferase an alternative detoxification pathway in two-thirds hepatectomized rats?199557990391010.1016/0024-3205(95)02024-D2-s2.0-00291481737630320
  48. M. T. RoncoM. L. de AlvarezJ. MontiModulation of balance between apoptosis and proliferation by lipid peroxidation (LPO) during rat liver regeneration200281280881712606815
  49. I. Aguilar-DelfínF. López-BarreraR. Hernández-MuñozSelective enhancement of lipid peroxidation in plasma membrane in two experimental models of liver regeneration: partial hepatectomy and acute CC14 administration199624365766210.1002/hep.5102403318781339
  50. D. E. FrancésM. T. RoncoP. I. IngaramoRole of reactive oxygen species in the early stages of liver regeneration in streptozotocin-induced diabetic rats201145101143115310.3109/10715762.2011.6023452-s2.0-8005274558621740310
  51. S. ChinS. RamirezL. E. GreenbaumA. NajiR. TaubBlunting of the immediate-early gene and mitogenic response in hepatectomized type 1 diabetic animals19952694E691E70010.1152/ajpendo.1995.269.4.e691
  52. A. A. AznarC. T. SanchezM. L. B. RemachaA. A. LopezP. L. DiazEffect of alloxan-induced diabetes on hepatic regeneration1991793133191867918
  53. P. W. MolaB. SudhaC. S. PauloseEffect of insulin on DNA synthesis and kinetic parameters of thymidine kinase during liver regeneration19964051067107510.1080/152165496002017038955897
  54. S. S. DeviH. M. MehendaleDisrupted G1 to S phase clearance via cyclin signaling impairs liver tissue repair in thioacetamide-treated type 1 diabetic rats200520728910210.1016/j.taap.2005.02.0072-s2.0-2364445876315953624
  55. D. E. FrancésM. T. RoncoJ. A. MontiHyperglycemia induces apoptosis in rat liver through the increase of hydroxyl radical: new insights into the insulin effect2010205218720010.1677/JOE-09-04622-s2.0-7795067198420164374
  56. G. AndicanG. BurçakOxidative damage to nuclear DNA in streptozotocin-diabetic rat liver200532866366610.1111/j.0305-1870.2005.04247.x2-s2.0-2264443794516120194
  57. C. BrennerL. GalluzziO. KeppG. KroemerDecoding cell death signals in liver inflammation201359358359410.1016/j.jhep.2013.03.0332-s2.0-8488282749523567086
  58. J. MohamedA. H. Nazratun NfizahA. H. ZariyanteyS. B. BudinMechanisms of diabetes-induced liver damage: the role of oxidative stress and inflammation2016162e132e14110.18295/squmj.2016.16.02.0022-s2.0-8496710366527226903
  59. E. FaistC. SchinkelS. ZimmerUpdate on the mechanisms of immune suppression of injury and immune modulation199620445445910.1007/s0026899000712-s2.0-00298724868662134
  60. K. K. S. SunaharaP. SannomiyaJ. O. MartinsBriefs on insulin and innate immune response2012291-21810.1159/0003375792-s2.0-8485986195622415069
  61. S. C. TrevelinD. CarlosM. BerettaJ. S. da SilvaF. Q. CunhaDiabetes mellitus and sepsis: a challenging association201747327628710.1097/SHK.00000000000007782-s2.0-8499269943227787406
  62. I. GavrylenkoM. KhomenkoMorphological and functional state of immune organs in rats with experimental type 1 diabetes mellitus (DM-1)201741610
  63. F. SpillerD. CarlosF. O. Soutoα1-Acid glycoprotein decreases neutrophil migration and increases susceptibility to sepsis in diabetic mice20126161584159110.2337/db11-08252-s2.0-8486188468822415874
  64. D. M. AndréM. C. CalixtoC. SollonHigh-fat diet-induced obesity impairs insulin signaling in lungs of allergen-challenged mice: improvement by resveratrol201771p. 1729610.1038/s41598-017-17558-w29229986
  65. D. M. AndréM. C. CalixtoC. SollonTherapy with resveratrol attenuates obesity-associated allergic airway inflammation in mice20163829830510.1016/j.intimp.2016.06.0172-s2.0-8497629400727344038
  66. B. L. DiazM. F. SerraA. C. AlvesAlloxan diabetes reduces pleural mast cell numbers and the subsequent eosinophil influx induced by allergen in sensitized rats19961111364310.1159/0002373432-s2.0-0029834654
  67. S. C. Cavalher-MachadoW. T. de LimaA. S. DamazoDown-regulation of mast cell activation and airway reactivity in diabetic rats: role of insulin200424455255810.1183/09031936.04.001308032-s2.0-644423772115459132
  68. E. BoichotP. SannomiyaN. EscofierN. GermainZ. B. FortesV. LagenteEndotoxin-induced acute lung injury in rats. Role of insulin199912528529010.1006/pupt.1999.02122-s2.0-003274520310545284
  69. J. PanésI. KuroseM. D. Rodriguez-VacaDiabetes exacerbates inflammatory responses to ischemia-reperfusion199693116116710.1161/01.CIR.93.1.1612-s2.0-00300393908616923
  70. J. ParekhC. U. NiemannK. DangR. HiroseIntraoperative hyperglycemia augments ischemia reperfusion injury in renal transplantation: a prospective study20112011710.1155/2011/652458
  71. S. YueH. M. ZhouJ. J. ZhuHyperglycemia and liver ischemia reperfusion injury: a role for the advanced glycation endproduct and its receptor pathway201515112877288710.1111/ajt.133602-s2.0-8494549420926112980
  72. H. JaeschkeA. FarhoodC. W. SmithNeutrophils contribute to ischemia/reperfusion injury in rat liver in vivo19904153355335910.1096/fasebj.4.15.22538502253850
  73. A. B. LentschA. KatoH. YoshidomeK. M. McMastersM. J. EdwardsInflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury200032216917310.1053/jhep.2000.93232-s2.0-003385380110915720
  74. M. ShuhH. BohorquezLoss GE JrA. J. CohenTumor necrosis factor-α: life and death of hepatocytes during liver ischemia/reperfusion injury201313111913023531747
  75. K. R. KarlmarkR. WeiskirchenH. W. ZimmermannHepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis200950126127410.1002/hep.229502-s2.0-6765117483719554540
  76. N. HisamaY. YamaguchiN. MiyanariIschemia-reperfusion injury: the role of Kupffer cells in the production of cytokine induced neutrophil chemoattractant, a member of the interleukin-8 family1995272160416067725421
  77. N. HisamaY. YamaguchiT. IshikoKupffer cell production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion injury in rats19962451193119810.1002/hep.5102405358903397
  78. G. A. WannerP. E. MüllerW. ErtelM. BauerM. D. MengerK. MessmerDifferential effect of anti-TNF-alpha antibody on proinflammatory cytokine release by Kupffer cells following liver ischemia and reperfusion199911639139510454827
  79. A. NakamitsuE. HiyamaY. ImamuraY. MatsuuraT. YokoyamaKupffer cell function in ischemic and nonischemic livers after hepatic partial ischemia/reperfusion200131214014810.1007/s0059501701982-s2.0-003511797811291708
  80. B. MosherR. DeanJ. HarkemaD. RemickJ. PalmaE. CrockettInhibition of Kupffer cells reduced CXC chemokine production and liver injury200199220121010.1006/jsre.2001.62172-s2.0-003489509011469888
  81. Z. RaoJ. SunX. PanHyperglycemia aggravates hepatic ischemia and reperfusion injury by inhibiting liver-resident macrophage M2 polarization via C/EBP homologous protein-mediated endoplasmic reticulum stress2017811010.3389/fimmu.2017.012992-s2.0-85032859014
  82. Y. T. ZhaoY. W. QiC. Y. HuS. H. ChenY. LiuAdvanced glycation end products inhibit testosterone secretion by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress201638265966510.3892/ijmm.2016.26452-s2.0-8497879548427315604
  83. C. AdamopoulosE. FarmakiE. SpiliotiH. KiarisC. PiperiA. G. PapavassiliouAdvanced glycation end-products induce endoplasmic reticulum stress in human aortic endothelial cells201452115116010.1515/cclm-2012-08262-s2.0-8489138710523454718
  84. J. XuM. XiongB. HuangH. ChenAdvanced glycation end products upregulate the endoplasmic reticulum stress in human periodontal ligament cells201586344044710.1902/jop.2014.1404462-s2.0-8492496896325415248
  85. S. YamabeJ. HiroseY. UeharaIntracellular accumulation of advanced glycation end products induces apoptosis via endoplasmic reticulum stress in chondrocytes201328071617162910.1111/febs.121702-s2.0-8487581804723374428
  86. T. LawrenceG. NatoliTranscriptional regulation of macrophage polarization: enabling diversity with identity2011111175076110.1038/nri30882-s2.0-8035514639922025054
  87. S. YueJ. RaoJ. ZhuMyeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation2014192115343535310.4049/jimmunol.14002802-s2.0-8490124640524771857
  88. S. MüllerS. MartinW. KoenigImpaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors200245680581210.1007/s00125-002-0829-22-s2.0-1874441429212107724
  89. M. CrookType 2 diabetes mellitus: a disease of the innate immune system? An update200421320320710.1046/j.1464-5491.2003.01030.x2-s2.0-154234490215008827
  90. K. I. AlexandrakiC. PiperiP. D. ZiakasCytokine secretion in long-standing diabetes mellitus type 1 and 2: associations with low-grade systemic inflammation200828431432110.1007/s10875-007-9164-12-s2.0-4674911008618224429
  91. G. BodenP. SheM. MozzoliFree fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-κB pathway in rat liver200554123458346510.2337/diabetes.54.12.34582-s2.0-2904444729216306362
  92. Y. IwasakiM. KambayashiM. AsaiM. YoshidaT. NigawaraK. HashimotoHigh glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro2007211566210.1016/j.jdiacomp.2006.02.0012-s2.0-3384566368817189875
  93. Y. BiW. P. SunX. ChenEffect of early insulin therapy on nuclear factor κB and cytokine gene expressions in the liver and skeletal muscle of high-fat diet, streptozotocin-treated diabetic rats200845316717810.1007/s00592-008-0038-72-s2.0-4854910479918500427
  94. U. SiebenlistG. FranzosoK. BrownStructure, regulation and function of NF-κB199410140545510.1146/annurev.cb.10.110194.002201
  95. M. J. MorganZ. G. LiuCrosstalk of reactive oxygen species and NF-κB signaling201121110311510.1038/cr.2010.1782-s2.0-7865089431921187859
  96. M. NiwaA. HaraY. KanamoriNuclear factor-κB activates dual inhibition sites in the regulation of tumor necrosis factor-α-induced neutrophil apoptosis2000407321121910.1016/S0014-2999(00)00735-42-s2.0-003460192011068016
  97. R. F. SaidiS. K. H. KenariLiver ischemia/reperfusion injury: an overview201427636637910.3109/08941939.2014.9324732-s2.0-8491004212125058854
  98. A. R. BrasierJ. LiMechanisms for inducible control of angiotensinogen gene transcription199627346547510.1161/01.HYP.27.3.465
  99. J. LiA. R. BrasierAngiotensinogen gene activation by angiotensin II is mediated by the rel A (nuclear factor-kappaB p65) transcription factor: one mechanism for the renin angiotensin system positive feedback loop in hepatocytes199610325226410.1210/mend.10.3.88336548833654
  100. P. I. IngaramoM. T. RoncoD. E. A. FrancésTumor necrosis factor alpha pathways develops liver apoptosis in type 1 diabetes mellitus20114812-131397140710.1016/j.molimm.2011.03.0152-s2.0-7995786458221481476
  101. P. DandonaA. ChaudhuriH. GhanimP. MohantyProinflammatory effects of glucose and antiinflammatory effect of insulin: relevance to cardiovascular disease2007994A15B26B10.1016/j.amjcard.2006.11.0032-s2.0-3384693161817307055
  102. F. M. HoW. W. LinB. C. ChenHigh glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-κB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway200618339139910.1016/j.cellsig.2005.05.0092-s2.0-2784459374015970429
  103. Y. ItoH. KatagiriK. IshiiA. KakitaI. HayashiM. MajimaEffects of selective cyclooxygenase inhibitors on ischemia/reperfusion-induced hepatic microcirculatory dysfunction in mice200335540841610.1159/0000721742-s2.0-004238643612928598
  104. Y. SunoseI. TakeyoshiS. OhwadaThe effect of cyclooxygenase-2 inhibitor FK3311 on ischemia-reperfusion injury in a canine total hepatic vascular exclusion model20011921546210.1016/S1072-7515(00)00773-02-s2.0-003514856111192923
  105. I. TakeyoshiY. SunoseS. IwazakiThe effect of a selective cyclooxygenase-2 inhibitor in extended liver resection with ischemia in dogs20011001253110.1006/jsre.2001.62112-s2.0-003487884711516201
  106. A. WullaertK. HeyninckR. BeyaertMechanisms of crosstalk between TNF-induced NF-κB and JNK activation in hepatocytes20067291090110110.1016/j.bcp.2006.07.0032-s2.0-3374907645516934229
  107. D. E. A. FrancésP. I. IngaramoR. MayoralCyclooxygenase-2 over-expression inhibits liver apoptosis induced by hyperglycemia2013114366968010.1002/jcb.244092-s2.0-8487276768723059845
  108. M. TorbensonS. Q. YangH. Z. LiuJ. HuangW. GageA. M. DiehlSTAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers2002161115516110.1016/S0002-9440(10)64167-32-s2.0-003631466212107100
  109. T. MatsumotoM. YamaguchiM. KuzumeInsulin gene transfer improves posthepatectomized status of diabetic rats20003272378237910.1016/S0041-1345(00)01707-32-s2.0-003366502711120208
  110. K. ShirabeM. ShimadaT. GionPostoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern era with special reference to remnant liver volume1999188330430910.1016/S1072-7515(98)00301-92-s2.0-003296512410065820
  111. T. AoyamaK. IkejimaK. KonK. OkumuraK. AraiS. WatanabePioglitazone promotes survival and prevents hepatic regeneration failure after partial hepatectomy in obese and diabetic KK-Ay mice20094951636164410.1002/hep.228282-s2.0-6614908566519205029
  112. P. AkermanP. CoteS. Q. YangAntibodies to tumor necrosis factor-alpha inhibit liver regeneration after partial hepatectomy19922634G579G58510.1152/ajpgi.1992.263.4.G5791415718
  113. A. M. DiehlS. Q. YangM. YinH. Z. LinS. NelsonG. BagbyTumor necrosis factor-alpha modulates CCAAT/enhancer binding proteins-DNA binding activities and promotes hepatocyte-specific gene expression during liver regeneration19952212522617601419
  114. S. NepalP. H. ParkModulation of cell death and survival by adipokines in the liver201538796196510.1248/bpb.b15-001882-s2.0-8493677394226133703
  115. M. Mendes-BrazM. Elias-MiróB. KleuserThe effects of glucose and lipids in steatotic and non-steatotic livers in conditions of partial hepatectomy under ischaemia-reperfusion2014347e271e28910.1111/liv.123482-s2.0-8490447449124107124
  116. T. MasakiS. ChibaH. TatsukawaAdiponectin protects LPS-induced liver injury through modulation of TNF-α in KK-Ay obese mice200440117718410.1002/hep.202822-s2.0-304269935315239101
  117. H. MatsumotoS. TamuraY. KamadaAdiponectin deficiency exacerbates lipopolysaccharide/D-galactosamine induced liver injury in mice200612213352335810.3748/wjg.v12.i21.335216733851
  118. M. B. Jiménez-CastroA. Casillas-RamírezM. Mendes-BrazAdiponectin and resistin protect steatotic livers undergoing transplantation20135961208121410.1016/j.jhep.2013.07.0152-s2.0-8488800185823867317
  119. M. Massip-SalcedoM. A. ZaoualiS. Padrissa-AltésActivation of peroxisome proliferator-activated receptor-α inhibits the injurious effects of adiponectin in rat steatotic liver undergoing ischemia-reperfusion200847246147210.1002/hep.219352-s2.0-3954911104918098300
  120. K. ManY. ZhaoA. XuFat-derived hormone adiponectin combined with FTY720 significantly improves small-for-size fatty liver graft survival20066346747610.1111/j.1600-6143.2005.01201.x2-s2.0-3364488524616468955
  121. D. Schmidt-ArrasS. Rose-JohnIL-6 pathway in the liver: from physiopathology to therapy20166461403141510.1016/j.jhep.2016.02.0042-s2.0-8496354154126867490
  122. R. TaubLiver regeneration: from myth to mechanism200451083684710.1038/nrm14892-s2.0-504423201715459664
  123. N. FaustoJ. S. CampbellK. J. RiehleLiver regeneration200643Supplement 1S45S5310.1002/hep.209692-s2.0-32044436238
  124. N. OuchiJ. L. ParkerJ. J. LugusK. WalshAdipokines in inflammation and metabolic disease2011112859710.1038/nri29212-s2.0-7915148470421252989
  125. S. LoffredaS. Q. YangH. Z. LinLeptin regulates proinflammatory immune responses1998121576510.1096/fasebj.12.1.579438411
  126. G. FantuzziR. FaggioniLeptin in the regulation of immunity, inflammation, and hematopoiesis200068443744611037963
  127. K. L. StreetzF. TackeL. LeifeldInterleukin 6/gp130-dependent pathways are protective during chronic liver diseases200338121822910.1053/jhep.2003.502682-s2.0-003778423012830005
  128. C. KleinT. WüstefeldU. AssmusThe IL-6-gp130-STAT3 pathway in hepatocytes triggers liver protection in T cell-mediated liver injury2005115486086910.1172/JCI2364015761498
  129. D. E. CressmanL. E. GreenbaumR. A. DeAngelisLiver failure and defective hepatocyte regeneration in interleukin-6-deficient mice199627452911379138310.1126/science.274.5291.13792-s2.0-00298467568910279
  130. K. StreetzT. LueddeM. MannsC. TrautweinInterleukin 6 and liver regeneration200047230931210.1136/gut.47.2.3092-s2.0-003392857210896929
  131. T. WüstefeldT. RakemannS. KubickaM. P. MannsC. TrautweinHyperstimulation with interleukin 6 inhibits cell cycle progression after hepatectomy in mice200032351452210.1053/jhep.2000.166042-s2.0-003383976910960443
  132. I. A. LeclercqJ. FieldG. C. FarrellLeptin-specific mechanisms for impaired liver regeneration in ob/ob mice after toxic injury200312451451146410.1016/S0016-5085(03)00270-12-s2.0-003762195212730884
  133. Q. LiY. WangT. MaY. LvR. WuClinical outcomes of patients with and without diabetes mellitus after hepatectomy: a systematic review and meta-analysis2017122, article e017112910.1371/journal.pone.01711292-s2.0-8501210892128182632
  134. P. L. ShieldsH. TangJ. M. NeubergerB. K. GunsonP. McMasterJ. PirennePoor outcome in patients with diabetes mellitus undergoing liver transplantation199968453053510.1097/00007890-199908270-000152-s2.0-003285873310480412
  135. B. VollmarS. RichterM. D. MengerLiver ischemia/reperfusion induces an increase of microvascular leukocyte flux, but not heterogeneity of leukocyte trafficking199717293989138279
  136. Y. WanJ. GarnerN. WuRole of stem cells during diabetic liver injury201620219520310.1111/jcmm.127232-s2.0-8495573087426645107
  137. H. JaeschkeMolecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning20032841G15G2610.1152/ajpgi.00342.200212488232
  138. A. BalciS. KarazincirH. SumbasY. OterE. EgilmezT. InandiEffects of diffuse fatty infiltration of the liver on portal vein flow hemodynamics200836313414010.1002/jcu.204402-s2.0-4114916032118196595
  139. B. ErdogmusA. TamerR. BuyukkayaPortal vein hemodynamics in patients with non-alcoholic fatty liver disease20082151899310.1620/tjem.215.892-s2.0-4484909114918509239
  140. A. M. SeifalianC. PiaseckiA. AgarwalB. R. DavidsonThe effect of graded steatosis on flow in the hepatic parenchymal microcirculation199968678078410.1097/00007890-199909270-000092-s2.0-003361027310515377
  141. S. E. RegnellÅ. LernmarkHepatic steatosis in type 1 diabetes20118445446710.1900/RDS.2011.8.4542-s2.0-8486250068722580727
  142. K. G. TolmanV. FonsecaA. DalpiazM. H. TanSpectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease200730373474310.2337/dc06-15392-s2.0-3384762970917327353
  143. S. A. LittleW. R. JarnaginR. P. DeMatteoL. H. BlumgartY. FongDiabetes is associated with increased perioperative mortality but equivalent long-term outcome after hepatic resection for colorectal cancer200261889410.1016/S1091-255X(01)00019-12-s2.0-003636010511986023
  144. M. SelznerH. RüdigerD. SindramJ. MaddenP. ClavienMechanisms of ischemic injury are different in the steatotic and normal rat liver20003261280128810.1053/jhep.2000.205282-s2.0-003364604011093735
The underlying source XML for this text is taken from https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5964489/fullTextXML. The license for the article is Creative Commons Attribution 4.0 International. The main subject has been identified as experimental diabetes mellitus.