Home Life Sciences Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook
Article Open Access

Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook

  • Yang Liu EMAIL logo , Huiqin Hao and Tiezheng Hou
Published/Copyright: February 28, 2022
Download Article (PDF)
Open Life Sciences
From the journal Open Life Sciences Volume 17 Issue 1

Abstract

The concanavalin A (Con A)-induced liver injury mouse model is a typical animal model focusing on T cell-dependent hepatic damage in the field of autoimmune hepatitis (AIH). However, the underlying mechanism of hepatic dysfunction due to cell activation or signaling pathways triggered by Con A has not been fully clarified. Therefore, the controversy on this model remains in the academic community. In this article, we first summarized the merit and demerit of this contentious model from the perspectives of cell dysfunction, microcirculation disturbance, involved signaling pathways, as well as the properties of Con A. Then, we summed up the scientific implications of the model in elucidating the pathogenesis of AIH, and the shortcomings of this model were also summarized to elucidate the pathogenesis and application prospect of this classical liver injury mouse model in the study of AIH.

Keywords: autoimmune hepatitis; concanavalin A; experimental animal models; inflammation; pathogenesis

1 Introduction

Autoimmune hepatitis (AIH), originally named “active chronic and lupoid hepatitis” by Ian R. Mackay and F. Macfarlane Burnet in 1963, is a type of chronic progressive inflammation of liver parenchyma mediated by autoimmune response [1]. It is closely related to the abnormal proliferation and activation of T lymphocytes and is distinguished by interfacial hepatitis in histology and by elevation of immunoglobulin G level and presence of autoantibodies in serology. Moreover, it eventually may cause fibrosis and cirrhosis if the inflammation process cannot be controlled [2]. AIH occurs globally in all ages and ethnicities with a strong female predominance [3], and its incidence and prevalence are still increasing in recent years [4,5]. Establishing an ideal experimental animal model to mimic the progress of human AIH in the laboratory is thought to be helpful in better studying the specific pathogenesis of this disorder and exploring more effective clinical treatment methods. Many researchers have devoted themselves to the evolution of animal models related to AIH since the early 1970s [6]. Notwithstanding a variety of animal models that have been applied to the study on the etiopathogenesis of AIH in different phases, the concanavalin A (Con A)-induced liver injury mouse model is regarded as the most important one [7,8]. It was successfully established in 1992 by Tiegs G [9] and was commonly used in such research fields from the 1990s to 2020s [10,11,12,13]. Not only this model is easy, convenient, inexpensive, and repeatable to establish [14,15] but also its histological features (including periportal and intralobular lymphocytes infiltrates as well as interface hepatitis) and serological changes (i.e., high levels of transaminase) are similar to human AIH patients [16]. However, this widely applicated mouse model is still debatable with the deepening of research on the mechanisms causing liver injury [17]. An in-depth summary of the controversies over this model, together with its pros and cons, will be conducive to illustrate its status and meet the future challenge in the study of AIH.

2 Multiple populations of cells participating in the hepatic injury in this model

Initially, the Con A-induced liver injury mouse model was regarded as a well-established CD4+ T helper cell (Th) activated model focusing merely on the dysfunctional Th involved in the pathogenesis of AIH [9]. However, as the research moved along, it was revealed that, except for Th, a variety of other immunocytes and hepatic nonparenchymal cells were related to the development of hepatocellular injury, including cytotoxic CD8 + T lymphocyte (CTL) [18], natural killer T cell (NKT) [19,20], neutrophil [21], kuffer cell (KC) [22,23], and sinusoid endothelial cell (SEC) [24,25]. As shown in Figure 1, Con A is capable of attaching not only to the major histocompatibility complex (MHC) class II expressed on KC [26] but also to the mannose receptor (MR) located on the surface of SEC [9], KC [27,28], and neutrophil [29]. We have confirmed that the effect on macrophage induced by Con A was related to the MRs by performing a series of in vivo experiments (the data have not been reported). The MRs, which are located on the macrophage surface, contain multiple C-type lectin-like domains (CTLD), and the N-acetylglucosamine of Con A can combinate to the MRs to induce receptor-mediated endocytosis and phagocytosis to maintain the stability of the internal environment. At the same time, Con A also can lead to the activation of macrophages via MRs, to increase the release of superoxide anions and induce the synthesis of cytokines. These cells participate in hepatic damage in direct or indirect ways. For example, Th0 cells will be activated by recognizing the MHC class II-Con A complex via T cell receptor (TCR) and differentiated into Th1, Th2, Th17, and regulatory T cell (Treg). Th1 and Th17 are characterized by secreting tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukins (IL)-17, IL-22 to induce hepatocyte necrosis and apoptosis [30]. At the same time, Th2 and Treg are featured by secreting IL-10 and expressing cytotoxic T lymphocyte antigen (CTLA)-4, which are supposed to induce tolerance toward Con A-induced liver damage [31]. Th0 can also migrate to the inflamed tissue by the recognition of CXC chemokine ligands (CXCLs) expressed on the cytomembrane of injured hepatocytes via CXC chemokine receptor motif 3 (CXCR3) [32,33]. Although CTL does not have an immediate relationship with Con A, the activization of CTL is deemed to be induced by the Con A-mediated expression of TNF-α and IFN-γ, and CTLs will infiltrate the necrotic area by the recognition of MHC class I expressed on the surface of damaged liver cells, which is absent from the healthy liver tissue [34]. That is why CD4+ T cells are reported to be particularly numerous in periportal areas, while CTLs constitute the major cell type in the area of interface lymphocytic infiltration [35], and the ratio of CD4+ T cell to CTL in Con A-induced AIH mice model is higher than in other liver diseases [36,37]. Both CTLs and NKTs contribute to the apoptosis of hepatic cells via the Fas/FasL pathway [34]. Unlike T cells, the KC, neutrophil, and NKT are able to directly induce the death of hepatocytes or SECs by expressing TNF-α, IFN-γ, IL-1β, macrophage inflammatory protein (MIP)-2, and reactive oxygen species (ROS) after being activated by this lectin through TCR or MR [19]. Con A increases the expression of β 2-integrin on neutrophils as well, and the recruitment of neutrophils is a β 2-integrin-dependent process [38]. Moreover, SECs are capable of binding to Con A at 4 h after intravenous injection via MR, MHC II, and intracellular adhesion molecule (ICAM)-1 on its surface. This attachment will lead to the breakdown of the SEC’s membrane and bleb formation and eventually give rise to their detachment, facilitating the adhesion of Con A to KCs [14]. So numerous cells are involved in constructing this model that it is like getting blood from a stone to improve the hepatic injury by interfering with the abnormal activation of a particular type of cell. It is probably the main reason why this model’s etiopathogenesis is still obscure, and no appropriate and acknowledged in vitro model was able to identically imitate the pathogenetic process of this hepatitis model, unlike other autoimmune diseases, such as rheumatoid arthritis [39].

Figure 1 The multicellular participation mechanism participated in establishing the Con A-induced liver injury mouse model. Con A was capable of attaching to MHC class II, MR, and ICMA-1. Th0 cell differentiated into Th1, Th2, Th17, and Treg by the recognition of MHC class II-Con A complex via TCR, and Th1 and Th17 induced the hepatocyte necrosis and apoptosis by secreting TNF-α, IFN-γ, IL-17, and IL-22, while Th2 and Treg would induce tolerance toward Con A by secreting IL-10 or expressing CTLA. Th0 could also migrate to the inflamed tissue by adhering to CXCLs via CXCR3. The NKT directly induced the death of hepatocytes or SECs by expressing TNF-α and IFN-γ after combining with this lectin through TCR. The MRs, located on the surface of macrophages and neutrophils, contain multiple CTLD, and the N-acetylglucosamine of Con A can combinate to the MRs to induce the receptor-mediated endocytosis and phagocytosis to maintain the stability of the internal environment. At the same time, Con A also can lead to the activation of macrophages and neutrophils via MRs, to increase the release of superoxide anions and induce the synthesis of cytokines (including TNF-α, IFN-γ, IL-1β, MIP-2, and ROS). Con A promoted the expression of β 2-integrin on neutrophils, which was essential for neutrophil recruitment. The attachment of SECs to Con via MR, MHC class II, and ICAM-1 could give rise to their death, facilitating the adhesion of Con A to KCs. CTLs would activate by the Con A-mediated expression of TNF-α and IFN-γ and infiltrate to the necrotic area by recognizing MHC class I expressed on the surface of damaged hepatocytes, which is absent from the normal liver tissue. Both CTLs and NKTs contributed to the apoptosis of hepatic cells via the Fas/FasL pathway.
Figure 1

The multicellular participation mechanism participated in establishing the Con A-induced liver injury mouse model. Con A was capable of attaching to MHC class II, MR, and ICMA-1. Th0 cell differentiated into Th1, Th2, Th17, and Treg by the recognition of MHC class II-Con A complex via TCR, and Th1 and Th17 induced the hepatocyte necrosis and apoptosis by secreting TNF-α, IFN-γ, IL-17, and IL-22, while Th2 and Treg would induce tolerance toward Con A by secreting IL-10 or expressing CTLA. Th0 could also migrate to the inflamed tissue by adhering to CXCLs via CXCR3. The NKT directly induced the death of hepatocytes or SECs by expressing TNF-α and IFN-γ after combining with this lectin through TCR. The MRs, located on the surface of macrophages and neutrophils, contain multiple CTLD, and the N-acetylglucosamine of Con A can combinate to the MRs to induce the receptor-mediated endocytosis and phagocytosis to maintain the stability of the internal environment. At the same time, Con A also can lead to the activation of macrophages and neutrophils via MRs, to increase the release of superoxide anions and induce the synthesis of cytokines (including TNF-α, IFN-γ, IL-1β, MIP-2, and ROS). Con A promoted the expression of β 2-integrin on neutrophils, which was essential for neutrophil recruitment. The attachment of SECs to Con via MR, MHC class II, and ICAM-1 could give rise to their death, facilitating the adhesion of Con A to KCs. CTLs would activate by the Con A-mediated expression of TNF-α and IFN-γ and infiltrate to the necrotic area by recognizing MHC class I expressed on the surface of damaged hepatocytes, which is absent from the normal liver tissue. Both CTLs and NKTs contributed to the apoptosis of hepatic cells via the Fas/FasL pathway.

However, this model’s “unexpected” multicellular participation mechanism opens a gate to closely mirror most of the pathogenic properties in AIH human patients [40]. On the other hand, it is because of the abundant “unintended” hepatic nonparenchymal cells (such as SECs and KCs) involved in the establishment of this model that the binding of Con A to the liver seemed to be very specific [41]. It has been demonstrated that the organotropism of FITC-labeled Con A for the liver was remarkable, while fluorescence in other tissues was so weak that it was undetectable, including the lung (the organ that Con A passed first after intravenous injection) and kidney (the organ has the largest blood flow). The selective organ damage induced by Con A results from the MRs significantly expressed on the SECs and KCs, and Con A-inducible lesions were absent in macrophage-depleted animals [26,42]. Therefore, although it is not consistent with the original purpose of establishing this model, it is still widely used now.

3 Genetic background and gender preference of animal deserving to be taken into consideration

As more and more experiments were carried out in different mouse strains, including C57BL/6 [43], C3H [44], BALB/c [45], NMRI [46], and FVB/N [47], it was demonstrated that the dosage of Con A needed to trigger hepatic injury varied significantly according to the genetic background of mice. Generally, Th1-biased C57BL/6 and C3H mice are most susceptible to Con A and normally require lower doses of Con A only around 15–20 mg/kg body weight, while mice with Th2-biased immune response, such as BALB/c or NMRI mice, commonly need higher doses of this lectin up to >30 mg/kg body weight [48]. Therefore, the genetic background of animals needs to be considered when establishing this hepatitis model, due to that Con A is prone to induce a Th1-biased immune response.

Though AIH shows the female preponderance with a female-to-male ratio of 4:1 [49], it is preferable to implement the Con A-induced liver injury experiment exclusively using male mice in order to minimize the number of animals required for reaching statistically significant results. The prime reason is that the immune response induced by Con A is considerably dependent on the hormonal state of the animal, and the female mice are more sensitive to Con A than male ones and show a greater variation in the degree of liver injury and level of cytokine production [50]. Nevertheless, it is helpful to study the gender-related differences in the development of human AIH patients by taking advantage of the gender preference of the model.

4 Intricate signal transduction pathways involved in the pathogenesis of this model

Along with the deepening of the research, a complicated network of signal transduction pathways referring to provoking or exacerbating the impairment of liver function in this model was gradually disclosed, including “Toll like receptor (TLR) signaling pathway” [51,52], “MAPK signaling pathway” [53], “PI3K/Akt signaling pathway” [54,55], “Ferroptosis” [56], “Notch signaling pathway” [57], “Wnt signaling pathway” [58,59], “Endocytosis” [60], and so on. The data in one of our earlier experiments also showed that the differentially expressed mRNAs (DEMs) filtered out by microarray with this model were significantly enriched in these pathways [61]. Furthermore, many new therapeutic antibodies, drugs, or monomers targeting these validated pathways have been increasingly developed to attenuate hepatic damage. For instance, fucosterol and nobiletin were confirmed to alleviate the acute liver lesion through regulating the “MAPK signaling pathway” [62,63], ghrelin and salidroside were deemed to improve liver function in this model via “PI3K/Akt signaling pathway” [64,65], while Hu23C3 (a humanized murine monoclonal antibody against human osteopontin) and CpG-containing oligodeoxynucleotides were supposed to mitigate the hepatic injury and enhance the survival rate of mice by interfering with “NF-κB signaling pathway” [66,67]. Nevertheless, the complexity of the interaction of these pathways exceeded the expectation so that the nosogenesis of this model became more and more incomprehensible, and there is still no specific drug that is able to thoroughly improve the inflammatory damage to liver.

According to the published literature, we found that NF-κB is a vital hub gene associated with the setting up of this hepatitis model because this transcription factor is likely to be the intersection of numerous signal transduction pathways [68,69,70]. Parts of the pathways probably related to NF-κB were exhibited in Figure 2. NF-κB was initially reported as a B-cell-specific transcription factor that binds the κB site in the Igκ light chain enhancer [71]. It can be activated by a variety of inflammatory signals. Pro-inflammatory cytokines and pathogen-associated molecular patterns, working through different receptors, including TNF receptor (TNFR), TLR, and IL-1 receptor (IL-1R) superfamilies, cause the activation of inhibitory κB kinase (IKK) complex and translocation of NF-κB dimers from the cytoplasm to the nucleus, resulting in synergistic expression of multiple inflammatory and innate immune genes eventually. The IL-1β, IL-6, and TNF-α activate NF-κB. Meanwhile, expressions of these pro-inflammatory cytokines are also modulated in response to the activation of NF-κB, thus forming an amplifying feed-forward loop [72,73]. Therefore, drug development targeting this hub gene may be more promising.

Figure 2 The signal transduction pathways targeting NF-κB are involved in building the Con A-induced AIH mouse model. Numerous inflammatory signals (such as IL-1β, IL-6, TNF-α, and some other pro-inflammatory cytokines) could give rise to the activation of IKKs and translocation of NF-κB dimers from the cytoplasm to the nucleus, through multiple signal transduction pathways, including “TLR signaling pathway”, “MAPK signaling pathway”, and “PI3K/Akt signaling pathway”. The nuclear translocation of NF-κB resulted in the synergistic expression of multiple inflammatory and innate immune genes eventually, involving IL-1β, IL-6, and TNF-α as well. Thus, IL-1β, IL-6, TNF-α, and NF-κB formed an amplifying feed-forward loop. (1) PI3K/Akt signaling pathway, (2) TLR-2 and 4 signaling pathway, (3) TNF-α signaling pathway, and (4) MAPK signaling pathway.
Figure 2

The signal transduction pathways targeting NF-κB are involved in building the Con A-induced AIH mouse model. Numerous inflammatory signals (such as IL-1β, IL-6, TNF-α, and some other pro-inflammatory cytokines) could give rise to the activation of IKKs and translocation of NF-κB dimers from the cytoplasm to the nucleus, through multiple signal transduction pathways, including “TLR signaling pathway”, “MAPK signaling pathway”, and “PI3K/Akt signaling pathway”. The nuclear translocation of NF-κB resulted in the synergistic expression of multiple inflammatory and innate immune genes eventually, involving IL-1β, IL-6, and TNF-α as well. Thus, IL-1β, IL-6, TNF-α, and NF-κB formed an amplifying feed-forward loop. (1) PI3K/Akt signaling pathway, (2) TLR-2 and 4 signaling pathway, (3) TNF-α signaling pathway, and (4) MAPK signaling pathway.

5 Acute inflammation process and no detectable autoantibodies

Admittedly, AIH starts with an episode of acute hepatitis in some cases. However, most of the patients are typical of progressive chronic hepatitis, and hepatic fibrosis or cirrhosis will ultimately be caused if the autoimmune process is not well-controlled [2,74]. Whereas Con A-induced liver inflammation is typical acute hepatitis. The hepatocyte apoptosis and elevated transaminase levels in serum can be detected as early as 5 h after administration, and it is sufficient to investigate the inflammatory phenotype at 8–12 h after receiving an injection [48]. In addition, it is not feasible to perform long-term follow-up experiments or mimic a chronic inflammatory process through a repetitive application of Con A because mice are able to develop protective immune tolerance against hepatitis induced by this lectin, and IL-10 plays an important role in this course [31]. As time goes by, once Con A is metabolized, the self-repair of the liver will initiate, which can be manifested by declined transaminase levels in serology and hepatocyte regeneration in histology. At last, the pathological process of AIH terminates, and liver damage will be restored. Con A-induced liver damage is transient and unsustainable, so it is not suitable for exploring the pathogenic mechanism of chronic hepatitis.

The presence of specific antibodies to particular liver autoantigens in serum is regarded as one of the core diagnostic criteria of AIH [75,76], including anti-nuclear antibody, anti-smooth muscle antibody, anti-liver-kidney microsomal antibody, and anti-liver cytosol type 1 antibody [77,78]. Nonetheless, no circulating autoantibody is produced in the Con A-induced liver injury mice model. For one thing, it is a lack of requirement for antigen specificity in this model, owing to that Con A is the unique agent to activate and recruit T lymphocytes into the liver tissue [9]. For another, the low levels of IL-4, IL-10, and IL-13 also contribute to the shortage of autoimmune antibodies. Because these cytokines, which are mainly secreted by Th2 cells, are essential for B cells maturation to plasma cells to secrete autoantibodies [2,79]. Under the healthy condition, the ratio of Th1 to Th2 is in dynamic equilibrium and controlled by the transcription factor T-bet and GATA-binding factor type 3 (GATA3) [80]. Con A promotes the skewing of Th1 by increasing the expression of T-bet and suppressing the differentiation of Th2 via decreasing the expression of GATA3 [81]. As mentioned before, the Th1-biased C57BL/6 and C3H mice are most susceptible to Con A-induced liver injury. In contrast, mice with a Th2-biased immune response, such as BALB/c or NMRI mice, require higher doses of Con A. Without the participation of B cells and no generation of autoantibodies are deemed to be the biggest obstacle in translating this model into the investigation on human AIH.

6 The side-effect for Con A as a lectin

6.1 Microcirculation disturbance

As previously mentioned, the original intention on the foundation of this hepatitis mouse model was to investigate the T cell-dependent mechanisms of liver injury. Nevertheless, as a lectin with coagulation activity, if administered intravenously, Con A will first cause a significant decrease in blood flow in the hepatic sinusoid rather than hepatocellular injury [82]. After that, SECs, KCs, and abnormally activated T cells will work in coordination to lead to the formation of numerous microthrombi and bring about the necrosis of hepatocytes [83]. The microcirculation disturbance mechanism induced by Con A was visualized in Figure 3, which would explain why it is different to fully interrupt the immunologic injury induced by Con A only depending on the immunosuppressor, and heparin, an important anti-clotting agent with no immunomodulatory function, has significant protective effects on hepatic injury induced by this lectin without reducing the production of IFN-γ and TNF-α [84]. Hence, microcirculation disturbances induced by Con A is an unintended mechanism on the liver damage, and to some extent, it will interfere with the judgment on the outcome of new drugs associated with the immunologic mechanism.

Figure 3 The microcirculation disturbance mechanism related to the foundation of Con A-induced AIH mouse model. Con A first caused a significant decrease in blood flow in the hepatic sinusoid after being administrated. Thereafter, abnormally activated T cells immediately produce a large amount of IFN-γ and TNF-α, and then the STAT1 signaling pathway is activated to promote the SECs and KCs to synergistically express tissue factor (TF). TF facilitated the fibrinogen agglutinating into fibrin clots as a type of starting factor of coagulation reaction. TNF-α triggered the production of plasminogen activator inhibitor type 1 to inhibit the anticoagulant pathway by suppressing the degradation of fibrin clots into fibrinogen degradation product. SECs and KCs could also express TF after adhering to Con A directly. All of them worked together to result in hypercoagulation and form numerous microthrombi, which would eventually contribute to the necrosis of hepatocytes. The anti-clotting agent, such as heparin, has significant protective effects on the hepatic injury induced by lectin through inhibiting the clotting activity.
Figure 3

The microcirculation disturbance mechanism related to the foundation of Con A-induced AIH mouse model. Con A first caused a significant decrease in blood flow in the hepatic sinusoid after being administrated. Thereafter, abnormally activated T cells immediately produce a large amount of IFN-γ and TNF-α, and then the STAT1 signaling pathway is activated to promote the SECs and KCs to synergistically express tissue factor (TF). TF facilitated the fibrinogen agglutinating into fibrin clots as a type of starting factor of coagulation reaction. TNF-α triggered the production of plasminogen activator inhibitor type 1 to inhibit the anticoagulant pathway by suppressing the degradation of fibrin clots into fibrinogen degradation product. SECs and KCs could also express TF after adhering to Con A directly. All of them worked together to result in hypercoagulation and form numerous microthrombi, which would eventually contribute to the necrosis of hepatocytes. The anti-clotting agent, such as heparin, has significant protective effects on the hepatic injury induced by lectin through inhibiting the clotting activity.

6.2 Environmental sensitivity

Since Con A is a water-soluble tetrameric protein complex purified from the crude extract of Canavalia ensiformis seeds, its biological activity shows batch-dependent variations [85]. It is sensitive to environmental decay once not stored under protected conditions, so repeated freeze-thaw cycles should be avoided to circumvent protein degradation [86]. Meanwhile, serving as the sole inducer in this model, the levels of transaminase and pro-inflammatory cytokine, considered as the valid index of the severity of the liver injury, change in a Con A-dose-dependent manner [87]. If the intake of Con A is too high, liver damage will be irreversible so that some mice will have the symptom of acute liver failures such as encephalopathy or ascites and die in a short time. Therefore, the dose of Con A needed to induce liver injury has to be tested for each batch before an experimental series, and it is necessary to titrate the Con A dosage accurately to minimize the number of animals succumbing to hypohepatia. Ordinarily, 5–10 mg/kg dose of Con A for 18 h are safe for mice, while 15, 20, and 25 mg/kg will induce 20, 40, and 60% death of mice, respectively [88].

7 Application prospect and possible improvements

Although there are some deficiencies in the Con A-induced liver injury mouse model to completely mimic the pathogenesis and pathological process of AIH in human patients, it is still a well-established and easy to replicate animal model focusing on T cell-mediated hepatic damage (Table 1). In addition, this model is also of great significance to develop new therapeutic drugs or other treatment measures just targeting T cell activation. To cover the model shortage, the following improvements could be taken into account to implement.

Table 1

The most distinctive features of the Con A-induced AIH mouse model

Features Refs.
Kinds of cells participating
 CD4 + T cell [9,30,31,32]
 CTL [18,34,35]
 NKT [19,20,34]
 Neutrophil [19,21,38]
 KC [19,22,23,26,27,28]
 SEC [14,24,25,42]
Male Th1-biased mice are more suitable for establishing this model [48,50]
Intricate signal transduction pathways involved in the development of this model [51,52,53,54,55,56,57,58,59,60,61]
Acute inflammation process [2,31,48,74]
No detectable autoantibodies [2,9,79,80,81]
Microcirculation disturbance as a lectin [82,83,84]
Environmental sensitivity [85,86,87,88]

First, high-throughput detection techniques on screening the differentially expressed genes (involving the coding RNA and non-coding RNA) can be applied to this model, just like the research we are doing, to further explain the interaction between signal transduction pathways [61,89,90]. In particular, much more attention should be paid to the differentially expressed genes enriched in signaling pathways associated with T cell activation and NF-κB transcription.

Second, some kinds of in vitro models could be considered to verify the experimental results obtained from this Con A related in vivo model. For example, the Con A-mediated macrophage activation model is conducive to further interpret the role of KCs in the pathogenesis of AIH, which are primarily found in mice experiments [91,92]. Due to the dominant role in the development of AIH played by Th1-biased immune response, the Th1 cell in vitro model established in accordance with the Th1-skewing condition will serve the purpose of investigating the effects of Th1 cells on liver injury [93,94].

Third, it seems that the utilization of transgenic animals will make up its defects to some extent and is helpful in the discovery of novel biomarkers and potentially new therapeutic targets [95,96,97,98,99].

Furthermore, in view of the agglutination activity of Con A as a lectin, certain kinds of anticoagulant drugs, such as heparin, can be considered to prophylactically administrate to as far as possible mitigate the effects of microcirculation disturbance on the experiments principally aiming at exploring the mechanism of immune disorders.

To sum up, parts of the mechanisms of hepatotoxicity by Con A have been revealed in this article, i.e., Con A, as a kind of lectin, can lead to the activation of macrophage and neutrophil via MRs to increase the release of superoxide anions and induce the synthesis of cytokines, as well as activate Th0 cell via TCR by forming the MHC class II-Con A complex. Con A can also promote the formation of hypercoagulation and form numerous microthrombi in the hepatic sinusoid, which would eventually contribute to hepatocyte necrosis. Moreover, numerous inflammatory signals can be activated after the administration of Con A. Therefore, there is a reasonable prospect that, with continuous improvement and optimization, the research related to the Con A-induced liver injury mouse model will achieve a significant breakthrough and innovation, which will be conducive to a further study in the field of AIH in the future.

Co-corresponding authors.

tel: +86-351-3179734

  1. Funding information: This study was funded by Basic applied study of Shanxi Province (Grant Number: 201901D111333, Grant Recipient: Yang Liu); Innovative projects of Universities in Shanxi Province (Grant Number: 2020L0423, Grant Recipient: Yang Liu); Science and Technology Innovation Program of Shanxi University of Chinese Medicine (Grant Number: 2020PY-JC-07, Grant Recipient: Yang Liu); The Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Chinese Medicine.

  2. Author contributions: Yang Liu wrote the original draft. Tiezheng Hou and Huiqin Hao conceived and designed the project, reviewed, and edited the article.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

[1] Gershwin ME, Krawitt EL. Autoimmune hepatitis: 50 years of (slow) progress. Hepatology. 2014;59(3):754–6.10.1002/hep.26682Search in Google Scholar

[2] Mieli-Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, et al. Autoimmune hepatitis. Nat Rev Dis Primers. 2018;4:18017.10.1017/CBO9780511547409.020Search in Google Scholar

[3] Schwinge D, Schramm C. Sex-related factors in autoimmune liver diseases. Semin Immunopathol. 2019;41(2):165–75.10.1007/s00281-018-0715-8Search in Google Scholar

[4] Valgeirsson KB, Hreinsson JP, Björnsson ES. Increased incidence of autoimmune hepatitis is associated with wider use of biological drugs. Liver Int: Off J Int Assoc Study Liver. 2019;39(12):2341–9.10.1111/liv.14224Search in Google Scholar

[5] Sharma R, Verna EC, Söderling J, Roelstraete B, Hagström H, Jonas F, et al. Increased mortality risk in autoimmune hepatitis: a nationwide population-based cohort study with histopathology. Clin Gastroenterol Hepatol. 2020;S1542–3565(20):31395.10.1016/j.cgh.2020.10.006Search in Google Scholar

[6] Büschenfelde KH, Kössling FK, Miescher PA. Experimental chronic active hepatitis in rabbits following immunization with human liver proteins. Clin Exp Immunol. 1972;11:1.Search in Google Scholar

[7] Czaja AJ. Animal models of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol. 2010;4(4):429–43.10.1586/egh.10.42Search in Google Scholar

[8] El-Kashef DH, Abdelrahman RS. Montelukast ameliorates Concanavalin A-induced autoimmune hepatitis in mice via inhibiting TNF-α/JNK signaling pathway. Toxicol Appl Pharmacol. 2020;393:114931.10.1016/j.taap.2020.114931Search in Google Scholar

[9] Tiegs G, Hentschel J, Wendel AA. T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest. 1992;90(1):196–203.10.1172/JCI115836Search in Google Scholar

[10] Nishikage T, Seki S, Toyabe S, Abo T, Kagata Y, Iwai T, et al. Inhibition of concanavalin A-induced hepatic injury of mice by bacterial lipopolysaccharide via the induction of IL-6 and the subsequent reduction of IL-4: the cytokine milieu of concanavalin A hepatitis. J Hepatol. 1999;31(1):18–26.10.1016/S0168-8278(99)80159-7Search in Google Scholar

[11] Hoffmann F, Sass G, Zillies J, Zahler S, Tiegs G, Hartkorn A, et al. A novel technique for selective NF-kappaB inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion. Gut. 2009;58(12):1670–8.10.1136/gut.2008.165647Search in Google Scholar PubMed

[12] Xu C, Zhang C, Ji J, Wang C, Yang J, Geng B, et al. CD36 deficiency attenuates immune-mediated hepatitis in mice by modulating the proapoptotic effects of CXC chemokine ligand 10. Hepatology. 2018;67(5):1943–55.10.1002/hep.29716Search in Google Scholar PubMed

[13] Yan B, Ai Y, Sun Q, Ma Y, Cao Y, Wang J, et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol Cell. 2021;81(2):355–69.10.1016/j.molcel.2020.11.024Search in Google Scholar PubMed

[14] Wang H-X, Liu M, Weng S-Y, Li J-J, Xie C, He H-L, et al. Immune mechanisms of Concanavalin A model of autoimmune hepatitis. World J Gastroenterol. 2012;18(2):119–25.10.3748/wjg.v18.i2.119Search in Google Scholar PubMed PubMed Central

[15] Christen U, Hintermann E. Immunopathogenic mechanisms of autoimmune hepatitis: how much do we know from animal models? Int J Mol Sci. 2016;17(12):2007.10.3390/ijms17122007Search in Google Scholar PubMed PubMed Central

[16] Jaeckel E, Hardtke-Wolenski M, Fischer K. The benefit of animal models for autoimmune hepatitis. Best Pract Res Clin Gastroenterol. 2011;25(6):643–51.10.1016/j.bpg.2011.10.006Search in Google Scholar PubMed

[17] Wang H, Yan W, Feng Z, Gao Y, Zhang L, Feng X, et al. Plasma proteomic analysis of autoimmune hepatitis in an improved AIH mouse model. J Transl Med. 2020;18(1):3.10.1186/s12967-019-02180-3Search in Google Scholar PubMed PubMed Central

[18] Salas JR, Chen BY, Wong A, Cheng D, Van Arnam JS, Witte ON, et al. 18F-FAC PET selectively images liver-infiltrating CD4 and CD8 T cells in a mouse model of autoimmune hepatitis. J Nucl Med. 2018;59(10):1616–23.10.2967/jnumed.118.210328Search in Google Scholar PubMed PubMed Central

[19] Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009;30(2):180–92.10.1016/j.immuni.2009.01.001Search in Google Scholar PubMed PubMed Central

[20] Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA. 2000;97(10):5498–503.10.1073/pnas.040566697Search in Google Scholar PubMed PubMed Central

[21] Bonder CS, Ajuebor MN, Zbytnuik LD, Kubes P, Swain MG. Essential role for neutrophil recruitment to the liver in concanavalin A-induced hepatitis. J Immunol. 2004;172(1):45–53.10.4049/jimmunol.172.1.45Search in Google Scholar PubMed

[22] Hatano M, Sasaki S, Ohata S, Shiratsuchi Y, Yamazaki T, Nagata K, et al. Effects of Kupffer cell-depletion on Concanavalin A-induced hepatitis. Cell Immunol. 2008;251(1):25–30.10.1016/j.cellimm.2008.02.003Search in Google Scholar PubMed

[23] Yang Y, Yan M, Zhang H, Wang X. Substance P participates in immune-mediated hepatic injury induced by concanavalin A in mice and stimulates cytokine synthesis in Kupffer cells. Exp Ther Med. 2013;6(2):459–64.10.3892/etm.2013.1152Search in Google Scholar PubMed PubMed Central

[24] Magnusson S, Berg T. Extremely rapid endocytosis mediated by the mannose receptor of sinusoidal endothelial rat liver cells. Biochem J. 1989;257(3):651–6.10.1042/bj2570651Search in Google Scholar PubMed PubMed Central

[25] Knolle PA, Gerken G, Loser E, Dienes HP, Gantner F, Tiegs G, et al. Role of sinusoidal endothelial cells of the liver in concanavalin A-induced hepatic injury in mice. Hepatology. 1996;24(4):824–9.10.1002/hep.510240413Search in Google Scholar PubMed

[26] Tsui T-Y, Obed A, Siu Y-T, Yet S-F, Prantl L, Schlitt HJ, et al. Carbon monoxide inhalation rescues mice from fulminant hepatitis through improving hepatic energy metabolism. Shock. 2007;27(2):165–71.10.1097/01.shk.0000239781.71516.61Search in Google Scholar PubMed

[27] Takahashi K, Donovan MJ, Rogers RA, Ezekowitz RA. Distribution of murine mannose receptor expression from early embryogenesis through to adulthood. Cell Tissue Res. 1998;292(2):311–23.10.1007/s004410051062Search in Google Scholar PubMed

[28] Linehan SA. The mannose receptor is expressed by subsets of APC in non-lymphoid organs. BMC Immunol. 2005;6:4.10.1186/1471-2172-6-4Search in Google Scholar PubMed PubMed Central

[29] Weinbaum DL, Sullivan JA, Mandell GL. Receptors for concanavalin A cluster at the front of polarized neutrophils. Nature. 1980;286(5774):725–7.10.1038/286725a0Search in Google Scholar PubMed

[30] Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and molecular mechanisms of autoimmune hepatitis. Annu Rev Pathol. 2018;13:247–92.10.1146/annurev-pathol-020117-043534Search in Google Scholar PubMed

[31] Erhardt A, Biburger M, Papadopoulos T, Tiegs G. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology. 2007;45(2):475–85.10.1002/hep.21498Search in Google Scholar PubMed

[32] Hashimoto E, Lindor KD, Homburger HA, Dickson ER, Czaja AJ, Wiesner RH, et al. Immunohistochemical characterization of hepatic lymphocytes in primary biliary cirrhosis in comparison with primary sclerosing cholangitis and autoimmune chronic active hepatitis. Mayo Clin Proc. 1993;68(11):1049–55.10.1016/S0025-6196(12)60897-0Search in Google Scholar

[33] Wen L, Peakman M, Lobo-Yeo A, McFarlane BM, Mowat AP, Mieli-Vergani G, et al. T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet. 1990;336(8730):1527–30.10.1016/0140-6736(90)93306-ASearch in Google Scholar

[34] Ge W, Gao Y, Zhao Y, Yang Y, Sun Q, Yang X, et al. Decreased T-cell mediated hepatic injury in concanavalin A-treated PLRP2-deficient mice. Int Immunopharmacol. 2020;85:106604.10.1016/j.intimp.2020.106604Search in Google Scholar PubMed

[35] De Biasio MB, Periolo N, Avagnina A, García de Dávila MT, Ciocca M, Goñi J, et al. Liver infiltrating mononuclear cells in children with type 1 autoimmune hepatitis. J Clin Pathol. 2006;59(4):417–23.10.1136/jcp.2005.028613Search in Google Scholar PubMed PubMed Central

[36] Löhr HF, Schlaak JF, Gerken G, Fleischer B, Dienes HP, Meyer, et al. Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. Liver. 1994;14(3):161–6.10.1111/j.1600-0676.1994.tb00067.xSearch in Google Scholar PubMed

[37] Senaldi G, Portmann B, Mowat AP, Mieli-Vergani G, Vergani D. Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis. Arch Dis Child. 1992;67(12):1447–53.10.1136/adc.67.12.1447Search in Google Scholar PubMed PubMed Central

[38] Gujral JS, Farhood A, Bajt ML, Jaeschke H. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice. Hepatology. 2003;38(2):355–63.10.1053/jhep.2003.50341Search in Google Scholar PubMed

[39] Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233(1):233–55.10.1111/j.0105-2896.2009.00859.xSearch in Google Scholar PubMed PubMed Central

[40] Floreani A, Restrepo-Jiménez P, Secchi MF, De Martin S, Leung PSC, Krawitt E, et al. Etiopathogenesis of autoimmune hepatitis. J Autoimmun. 2018;95:133–43.10.1016/j.jaut.2018.10.020Search in Google Scholar PubMed

[41] Gantner F, Leist M, Lohse AW, Germann PG, Tiegs G. Concanavalin A-induced T-cell-mediated hepatic injury in mice: the role of tumor necrosis factor. Hepatology. 1995;21(1):190–8.10.1002/hep.1840210131Search in Google Scholar

[42] Tsutsui H, Nishiguchi S. Importance of Kupffer cells in the development of acute liver injuries in mice. Int J Mol Sci. 2014;15(5):7711–30.10.3390/ijms15057711Search in Google Scholar PubMed PubMed Central

[43] Massaguer A, Perez-Del-Pulgar S, Engel P, Serratosa J, Bosch J, Pizcueta P. Concanavalin A-induced liver injury is severely impaired in mice deficient in P-selectin. J Leukoc Biol. 2002;72(2):262–70.10.1189/jlb.72.2.262Search in Google Scholar

[44] Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, et al. Lethal effect of the anti-Fas antibody in mice. Nature. 1993;364(6440):806–9.10.1038/364806a0Search in Google Scholar

[45] Trautwein C, Rakemann T, Malek NP, Plümpe J, Tiegs G, Manns MP. Concanavalin A-induced liver injury triggers hepatocyte proliferation. J Clin Invest. 1998;101(9):1960–9.10.1172/JCI504Search in Google Scholar

[46] Tiegs G, Wolter M, Wendel A. Tumor necrosis factor is a terminal mediator in galactosamine/endotoxin-induced hepatitis in mice. Biochem Pharmacol. 1989;38(4):627–31.10.1016/0006-2952(89)90208-6Search in Google Scholar

[47] Tomiyama C, Watanabe H, Izutsu Y, Watanabe M, Abo T. Suppressive role of hepatic dendritic cells in concanavalin A-induced hepatitis. Clin Exp Immunol. 2011;166(2):258–68.10.1111/j.1365-2249.2011.04458.xSearch in Google Scholar

[48] Heymann F, Hamesch K, Weiskirchen R, Tacke F. The concanavalin A model of acute hepatitis in mice. Lab Anim. 2015;49(1 Suppl):12–20.10.1177/0023677215572841Search in Google Scholar

[49] Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol. 2015;21(1):60–83.10.3748/wjg.v21.i1.60Search in Google Scholar

[50] Takamoto S, Nakamura K, Yoneda M, Makino I. Gender-related differences in concanavalin A-induced liver injury and cytokine production in mice. Hepatol Res. 2003;27(3):221–9.10.1016/S1386-6346(03)00263-8Search in Google Scholar

[51] Chi G, Feng XX, Ru YX, Xiong T, Gao Y, Wang H, et al. TLR2/4 ligand-amplified liver inflammation promotes initiation of autoimmune hepatitis due to sustained IL-6/IL-12/IL-4/IL-25 expression. Mol Immunol. 2018;99:171–81.10.1016/j.molimm.2018.05.005Search in Google Scholar PubMed

[52] Mo R, Feng XX, Wu YN, Wang H, He YP, Sun HH, et al. Hepatocytes paradoxically affect intrahepatic IFN-gamma production in autoimmune hepatitis due to Gal-9 expression and TLR2/4 ligand release. Mol Immunol. 2020;123:106–15.10.1016/j.molimm.2020.05.014Search in Google Scholar PubMed

[53] Zhang M, Li Q, Zhou C, Zhao Y, Li R, Zhang Y. Demethyleneberberine attenuates concanavalin A-induced autoimmune hepatitis in mice through inhibition of NF-κB and MAPK signaling. Int Immunopharmacol. 2020;80:106137.10.1016/j.intimp.2019.106137Search in Google Scholar PubMed

[54] Xu S, Wu L, Zhang Q, Feng J, Li S, Li J, et al. Pretreatment with propylene glycol alginate sodium sulfate ameliorated concanavalin A-induced liver injury by regulating the PI3K/Akt pathway in mice. Life Sci. 2017;185:103–13.10.1016/j.lfs.2017.07.033Search in Google Scholar PubMed

[55] Fan X, Men R, Wang H, Shen M, Wang T, Ye T, et al. Methylprednisolone decreases mitochondria-mediated apoptosis and autophagy dysfunction in hepatocytes of experimental autoimmune hepatitis model via the Akt/mTOR signaling. Front Pharmacol. 2019;10:1189.10.3389/fphar.2019.01189Search in Google Scholar PubMed PubMed Central

[56] Zeng T, Deng G, Zhong W, Gao Z, Ma S, Mo C, et al. Indoleamine 2, 3-dioxygenase 1enhances hepatocytes ferroptosis in acute immune hepatitis associated with excess nitrative stress. Free Radic Biol Med. 2020;152:668–79.10.1016/j.freeradbiomed.2020.01.009Search in Google Scholar PubMed

[57] Hao X, Li Y, Wang J, Ma J, Zhao S, Ye X, et al. Deficient O-GlcNAc glycosylation impairs regulatory T cell differentiation and notch signaling in autoimmune hepatitis. Front Immunol. 2018;9:2089.10.3389/fimmu.2018.02089Search in Google Scholar PubMed PubMed Central

[58] Tan K, Xie X, Shi W, Miao L, Dong X, Yang W, et al. Deficiency of canonical Wnt/β-catenin signalling in hepatic dendritic cells triggers autoimmune hepatitis. Liver Int: Off J Int Assoc Study Liver. 2020;40(1):131–40.10.1111/liv.14246Search in Google Scholar PubMed

[59] Raïch-Regué D, Glancy M, Thomson AW. Regulatory dendritic cell therapy: from rodents to clinical application. Immunol Lett. 2014;161(2):216–21.10.1016/j.imlet.2013.11.016Search in Google Scholar PubMed PubMed Central

[60] Chandran SS, Klebanoff CA. T cell receptor-based cancer immunotherapy: emerging efficacy and pathways of resistance. Immunol Rev. 2019;290(1):127–47.10.1111/imr.12772Search in Google Scholar PubMed PubMed Central

[61] Liu Y, Chen H, Hao J-H, Li Z-C, Hou T, Hao H-Q. Microarray-based transcriptional profiling of a mouse model of autoimmune hepatitis. FEBS Open Bio. 2020;10(10):2040–54.10.1002/2211-5463.12953Search in Google Scholar PubMed PubMed Central

[62] Mo W, Wang C, Li J, Chen K, Xia Y, Li S, et al. Fucosterol protects against concanavalin A-induced acute liver injury: Focus on P38 MAPK/NF-κB pathway activity. Gastroenterol Res Pract. 2018;2018:1–13.10.1155/2018/2824139Search in Google Scholar PubMed PubMed Central

[63] Li M, Zhao H, Wu J, Wang L, Wang J, Lv K, et al. Nobiletin protects against acute liver injury via targeting c-Jun N-terminal kinase (JNK)-induced apoptosis of hepatocytes. J Agric Food Chem. 2020;68(27):7112–20.10.1021/acs.jafc.0c01722Search in Google Scholar PubMed

[64] Feng J, Niu P, Chen K, Wu L, Liu T, Xu S, et al. Salidroside mediates apoptosis and autophagy inhibition in concanavalin A-induced liver injury. Exp Ther Med. 2018;15(6):4599–614.10.3892/etm.2018.6053Search in Google Scholar PubMed PubMed Central

[65] Mao Y, Wang J, Yu F, Cheng J, Li H, Guo C, et al. Ghrelin reduces liver impairment in a model of concanavalin A-induced acute hepatitis in mice. Drug Des Devel Ther. 2015;9:5385–96.10.2147/DDDT.S89096Search in Google Scholar PubMed PubMed Central

[66] Zhang H, Gong Q, Li J-H, Kong X-L, Tian L, Duan L-H, et al. CpG ODN pretreatment attenuates concanavalin A-induced hepatitis in mice. Int Immunopharmacol. 2010;10(1):79–85.10.1016/j.intimp.2009.09.025Search in Google Scholar PubMed

[67] Fan K, Zhang B, Yang H, Wang H, Tan M, Hou S, et al. A humanized anti-osteopontin antibody protects from Concanavalin A induced-liver injury in mice. Eur J Pharmacol. 2011;657(1–3):144–51.10.1016/j.ejphar.2011.01.041Search in Google Scholar PubMed

[68] Liu Y, Perego M, Xiao Q, He Y, Fu S, He J, et al. Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice. J Clin Invest. 2019;129(10):4261–75.10.1172/JCI128164Search in Google Scholar PubMed PubMed Central

[69] Zheng W, Du S, Tian M, Xu W, Tian Y, Li T, et al. Lepidium meyenii walp exhibits anti-inflammatory activity against con A-induced acute hepatitis. Mediators Inflamm. 2018;2018:1–11.10.1155/2018/8982756Search in Google Scholar

[70] Guo MZ, Meng M, Feng CC, Wang X, Wang CL. A novel polysaccharide obtained from Craterellus cornucopioides enhances immunomodulatory activity in immunosuppressive mice models via regulation of the TLR4-NF-kappaB pathway. Food Funct. 2019;10(8):4792–801.10.1039/C9FO00201DSearch in Google Scholar

[71] Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225–60.10.1146/annurev.immunol.16.1.225Search in Google Scholar PubMed

[72] Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004;25(6):280–8.10.1016/j.it.2004.03.008Search in Google Scholar PubMed

[73] Luo Q, Ding J, Zhu L, Chen F, Xu L. Hepatoprotective effect of wedelolactone against Concanavalin A-induced liver injury in mice. Am J Chin Med. 2018;46(4):819–33.10.1142/S0192415X1850043XSearch in Google Scholar PubMed

[74] Webb GJ, Rana A, Hodson J, Akhtar MZ, Ferguson JW, Neuberger JM, et al. Twenty-year comparative analysis of patients with autoimmune liver diseases on transplant waitlists. Clin Gastroenterol Hepatol. 2018;16(2):278–87.10.1016/j.cgh.2017.09.062Search in Google Scholar PubMed

[75] Hennes EM, Zeniya M, Czaja AJ, Pares A, Dalekos GN, Krawitt EL, et al. International autoimmune Hepatitis G. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48(1):169–76.10.1002/hep.22322Search in Google Scholar PubMed

[76] Liberal R, Mieli-Vergani G, Vergani D. Clinical significance of autoantibodies in autoimmune hepatitis. J Autoimmun. 2013;46:17–24.10.1016/j.jaut.2013.08.001Search in Google Scholar PubMed

[77] Christen U. The role of autoantibodies in autoimmune hepatitis type 2. Immunotherapy. 2013;5(3):247–56.10.2217/imt.13.5Search in Google Scholar PubMed

[78] Muratori P, Lalanne C, Fabbri A, Cassani F, Lenzi M, Muratori L. Type 1 and type 2 autoimmune hepatitis in adults share the same clinical phenotype. Aliment Pharmacol Ther. 2015;41(12):1281–7.10.1111/apt.13210Search in Google Scholar PubMed

[79] Nascimento WC, Silva RP, Fernandes ES, Silva MC, Holanda GC, Santos PA, et al. Immunomodulation of liver injury by Ascaris suum extract in an experimental model of autoimmune hepatitis. Parasitol Res. 2014;113(9):3309–17.10.1007/s00436-014-3994-6Search in Google Scholar PubMed

[80] Tian X, Liu Y, Liu X, Gao S, Sun X. Glycyrrhizic acid ammonium salt alleviates Concanavalin A-induced immunological liver injury in mice through the regulation of the balance of immune cells and the inhibition of hepatocyte apoptosis. Biomed Pharmacother. 2019;120:109481.10.1016/j.biopha.2019.109481Search in Google Scholar PubMed

[81] Liang M, Liwen Z, Yun Z, Yanbo D, Jianping C. The imbalance between Foxp3Tregs and Th1/Th17/Th22 cells in patients with newly diagnosed autoimmune hepatitis. J Immunol Res. 2018;2018:3753081.10.1155/2018/3753081Search in Google Scholar PubMed PubMed Central

[82] Miyazawa Y, Tsutsui H, Mizuhara H, Fujiwara H, Kaneda K. Involvement of intrasinusoidal hemostasis in the development of concanavalin A-induced hepatic injury in mice. Hepatology. 1998;27(2):497–506.10.1002/hep.510270225Search in Google Scholar PubMed

[83] Kato J, Okamoto T, Motoyama H, Uchiyama R, Kirchhofer D, Van Rooijen N, et al. Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice. Hepatology. 2013;57(1):362–72.10.1002/hep.26027Search in Google Scholar PubMed

[84] Weerasinghe SV, Moons DS, Altshuler PJ, Shah YM, Omary MB. Fibrinogen-gamma proteolysis and solubility dynamics during apoptotic mouse liver injury: heparin prevents and treats liver damage. Hepatology. 2011;53(4):1323–32.10.1002/hep.24203Search in Google Scholar PubMed PubMed Central

[85] Cavada BS, Osterne VJS, Lossio CF, Pinto-Junior VR, Oliveira MV, Silva MTL, et al. One century of ConA and 40 years of ConBr research: a structural review. Int J Biol Macromol. 2019;134:901–11.10.1016/j.ijbiomac.2019.05.100Search in Google Scholar PubMed

[86] Li WW, Yu JY, Xu HL, Bao JK. Concanavalin A: a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics. Biochem Biophys Res Commun. 2011;414(2):282–6.10.1016/j.bbrc.2011.09.072Search in Google Scholar PubMed

[87] Sass G, Heinlein S, Agli A, Bang R, Schümann J, Tiegs G. Cytokine expression in three mouse models of experimental hepatitis. Cytokine. 2002;19(3):115–20.10.1006/cyto.2002.1948Search in Google Scholar PubMed

[88] Ye T, Wang T, Yang X, Fan X, Wen M, Shen Y, et al. Comparison of Concanavalin A-induced murine autoimmune hepatitis models. Cell Physiol Biochem. 2018;46(3):1241–51.10.1159/000489074Search in Google Scholar PubMed

[89] Liu Y, Chen H, Hao J, Li Z, Hou T, Hao H. Characterization and functional prediction of the MicroRNAs differentially expressed in a mouse model of Concanavalin A-induced autoimmune Hepatitis. Int J Med Sci. 2020;17(15):2312–27.10.7150/ijms.47766Search in Google Scholar PubMed PubMed Central

[90] Liu Y, Li Z, Hao J, Chen H, Hou T, Hao H. Circular RNAs associated with a mouse model of concanavalin A-induced autoimmune hepatitis: preliminary screening and comprehensive functional analysis. FEBS Open Bio. 2020;10(11):2350–62.10.1002/2211-5463.12981Search in Google Scholar PubMed PubMed Central

[91] Yang F, Lou G, Zhou X, Zheng M, He J, Chen Z. MicroRNA-223 acts as an important regulator to Kupffer cells activation at the early stage of Con A-induced acute liver failure via AIM2 signaling pathway. Cell Physiol Biochem. 2014;34(6):2137–52.10.1159/000369658Search in Google Scholar PubMed

[92] Ke Q-H, Chen H-Y, He Z-L, Lv Z, Xu X-F, Qian Y-G, et al. Silencing of microRNA-375 affects immune function in mice with liver failure by upregulating astrocyte elevated gene-1 through reducing apoptosis of Kupffer cells. J Cell Biochem. 2019;120(1):253–63.10.1002/jcb.27338Search in Google Scholar PubMed

[93] Collier SP, Collins PL, Williams CL, Boothby MR, Aune TM. Influence of Tmevpg1, a long intergenic non-coding RNA, on the expression of Ifng by Th1 cells. J Immunol. 2012;189(5):2084–8.10.4049/jimmunol.1200774Search in Google Scholar PubMed PubMed Central

[94] Collier SP, Henderson MA, Tossberg JT, Aune TM. Regulation of the Th1 genomic locus from Ifng through Tmevpg1 by T-bet. J Immunol. 2014;193(8):3959–65.10.4049/jimmunol.1401099Search in Google Scholar PubMed PubMed Central

[95] Zhuang Y, Li Y, Li X, Xie Q, Wu M. Atg7 knockdown augments Concanavalin A-induced acute Hepatitis through an ROS-mediated p38/MAPK pathway. PLoS ONE. 2016;11(3):e0149754.10.1371/journal.pone.0149754Search in Google Scholar PubMed PubMed Central

[96] Wang J, Cao X, Zhao J, Zhao H, Wei J, Li Q, et al. Critical roles of conventional dendritic cells in promoting T cell-dependent hepatitis through regulating natural killer T cells. Clin Exp Immunol. 2017;188(1):127–37.10.1111/cei.12907Search in Google Scholar PubMed PubMed Central

[97] Umeda N, Endo-Umeda K, Nakashima H, Kato S, Seki S, Makishima M. Frontline science: Concanavalin A-induced acute hepatitis is attenuated in vitamin D receptor knockout mice with decreased immune cell function. J Leukoc Biol. 2019;106(4):791–801.10.1002/JLB.3HI0219-048RSearch in Google Scholar PubMed

[98] Rani R, Kumar S, Sharma A, Mohanty SK, Donnelly B, Tiao GM, et al. Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: distinct roles of interferon regulatory factor-1 in liver injury. J Biol Chem. 2018;293(48):18466–76.10.1074/jbc.RA118.005583Search in Google Scholar PubMed PubMed Central

[99] He GW, Gunther C, Kremer AE, Thonn V, Amann K, Poremba C, et al. PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury. Gut. 2017;66(4):716–23.10.1136/gutjnl-2015-311247Search in Google Scholar PubMed

Received: 2021-08-18
Revised: 2021-11-29
Accepted: 2022-01-03
Published Online: 2022-02-28

© 2022 Yang Liu et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Biomedical Sciences
  2. Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits
  3. The mother of all battles: Viruses vs humans. Can humans avoid extinction in 50–100 years?
  4. Knockdown of G1P3 inhibits cell proliferation and enhances the cytotoxicity of dexamethasone in acute lymphoblastic leukemia
  5. LINC00665 regulates hepatocellular carcinoma by modulating mRNA via the m6A enzyme
  6. Association study of CLDN14 variations in patients with kidney stones
  7. Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook
  8. Regulation of miR-30b in cancer development, apoptosis, and drug resistance
  9. Informatic analysis of the pulmonary microecology in non-cystic fibrosis bronchiectasis at three different stages
  10. Swimming attenuates tumor growth in CT-26 tumor-bearing mice and suppresses angiogenesis by mediating the HIF-1α/VEGFA pathway
  11. Characterization of intestinal microbiota and serum metabolites in patients with mild hepatic encephalopathy
  12. Functional conservation and divergence in plant-specific GRF gene family revealed by sequences and expression analysis
  13. Application of the FLP/LoxP-FRT recombination system to switch the eGFP expression in a model prokaryote
  14. Biomedical evaluation of antioxidant properties of lamb meat enriched with iodine and selenium
  15. Intravenous infusion of the exosomes derived from human umbilical cord mesenchymal stem cells enhance neurological recovery after traumatic brain injury via suppressing the NF-κB pathway
  16. Effect of dietary pattern on pregnant women with gestational diabetes mellitus and its clinical significance
  17. Potential regulatory mechanism of TNF-α/TNFR1/ANXA1 in glioma cells and its role in glioma cell proliferation
  18. Effect of the genetic mutant G71R in uridine diphosphate-glucuronosyltransferase 1A1 on the conjugation of bilirubin
  19. Quercetin inhibits cytotoxicity of PC12 cells induced by amyloid-beta 25–35 via stimulating estrogen receptor α, activating ERK1/2, and inhibiting apoptosis
  20. Nutrition intervention in the management of novel coronavirus pneumonia patients
  21. circ-CFH promotes the development of HCC by regulating cell proliferation, apoptosis, migration, invasion, and glycolysis through the miR-377-3p/RNF38 axis
  22. Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma
  23. Lacunar infarction aggravates the cognitive deficit in the elderly with white matter lesion
  24. Hydroxysafflor yellow A improved retinopathy via Nrf2/HO-1 pathway in rats
  25. Comparison of axon extension: PTFE versus PLA formed by a 3D printer
  26. Elevated IL-35 level and iTr35 subset increase the bacterial burden and lung lesions in Mycobacterium tuberculosis-infected mice
  27. A case report of CAT gene and HNF1β gene variations in a patient with early-onset diabetes
  28. Study on the mechanism of inhibiting patulin production by fengycin
  29. SOX4 promotes high-glucose-induced inflammation and angiogenesis of retinal endothelial cells by activating NF-κB signaling pathway
  30. Relationship between blood clots and COVID-19 vaccines: A literature review
  31. Analysis of genetic characteristics of 436 children with dysplasia and detailed analysis of rare karyotype
  32. Bioinformatics network analyses of growth differentiation factor 11
  33. NR4A1 inhibits the epithelial–mesenchymal transition of hepatic stellate cells: Involvement of TGF-β–Smad2/3/4–ZEB signaling
  34. Expression of Zeb1 in the differentiation of mouse embryonic stem cell
  35. Study on the genetic damage caused by cadmium sulfide quantum dots in human lymphocytes
  36. Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis
  37. Assessment of the anesthetic effect of modified pentothal sodium solution on Sprague-Dawley rats
  38. Genetic susceptibility to high myopia in Han Chinese population
  39. Potential biomarkers and molecular mechanisms in preeclampsia progression
  40. Silencing circular RNA-friend leukemia virus integration 1 restrained malignancy of CC cells and oxaliplatin resistance by disturbing dyskeratosis congenita 1
  41. Endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime for advanced pulmonary large-cell neuroendocrine carcinoma as a first-line treatment: A case report
  42. The significance of PAK4 in signaling and clinicopathology: A review
  43. Sorafenib inhibits ovarian cancer cell proliferation and mobility and induces radiosensitivity by targeting the tumor cell epithelial–mesenchymal transition
  44. Characterization of rabbit polyclonal antibody against camel recombinant nanobodies
  45. Active legumain promotes invasion and migration of neuroblastoma by regulating epithelial-mesenchymal transition
  46. Effect of cell receptors in the pathogenesis of osteoarthritis: Current insights
  47. MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction
  48. Study of hsa_circRNA_000121 and hsa_circRNA_004183 in papillary thyroid microcarcinoma
  49. BuyangHuanwu Decoction attenuates cerebral vasospasm caused by subarachnoid hemorrhage in rats via PI3K/AKT/eNOS axis
  50. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
  51. Monosodium iodoacetate-induced subchondral bone microstructure and inflammatory changes in an animal model of osteoarthritis
  52. A rare presentation of type II Abernethy malformation and nephrotic syndrome: Case report and review
  53. Rapid death due to pulmonary epithelioid haemangioendothelioma in several weeks: A case report
  54. Hepatoprotective role of peroxisome proliferator-activated receptor-α in non-cancerous hepatic tissues following transcatheter arterial embolization
  55. Correlation between peripheral blood lymphocyte subpopulations and primary systemic lupus erythematosus
  56. A novel SLC8A1-ALK fusion in lung adenocarcinoma confers sensitivity to alectinib: A case report
  57. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes
  58. Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer
  59. BTBD10 inhibits glioma tumorigenesis by downregulating cyclin D1 and p-Akt
  60. Mucormycosis co-infection in COVID-19 patients: An update
  61. Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report
  62. Long non-coding RNA HOXB-AS1 is a prognostic marker and promotes hepatocellular carcinoma cells’ proliferation and invasion
  63. Preparation and evaluation of LA-PEG-SPION, a targeted MRI contrast agent for liver cancer
  64. Proteomic analysis of the liver regulating lipid metabolism in Chaohu ducks using two-dimensional electrophoresis
  65. Nasopharyngeal tuberculosis: A case report
  66. Characterization and evaluation of anti-Salmonella enteritidis activity of indigenous probiotic lactobacilli in mice
  67. Aberrant pulmonary immune response of obese mice to periodontal infection
  68. Bacteriospermia – A formidable player in male subfertility
  69. In silico and in vivo analysis of TIPE1 expression in diffuse large B cell lymphoma
  70. Effects of KCa channels on biological behavior of trophoblasts
  71. Interleukin-17A influences the vulnerability rather than the size of established atherosclerotic plaques in apolipoprotein E-deficient mice
  72. Multiple organ failure and death caused by Staphylococcus aureus hip infection: A case report
  73. Prognostic signature related to the immune environment of oral squamous cell carcinoma
  74. Primary and metastatic squamous cell carcinoma of the thyroid gland: Two case reports
  75. Neuroprotective effects of crocin and crocin-loaded niosomes against the paraquat-induced oxidative brain damage in rats
  76. Role of MMP-2 and CD147 in kidney fibrosis
  77. Geometric basis of action potential of skeletal muscle cells and neurons
  78. Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review
  79. Role of cerebellar cortex in associative learning and memory in guinea pigs
  80. Application of metagenomic next-generation sequencing technique for diagnosing a specific case of necrotizing meningoencephalitis caused by human herpesvirus 2
  81. Case report: Quadruple primary malignant neoplasms including esophageal, ureteral, and lung in an elderly male
  82. Long non-coding RNA NEAT1 promotes angiogenesis in hepatoma carcinoma via the miR-125a-5p/VEGF pathway
  83. Osteogenic differentiation of periodontal membrane stem cells in inflammatory environments
  84. Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway
  85. Continuous renal replacement therapy combined with double filtration plasmapheresis in the treatment of severe lupus complicated by serious bacterial infections in children: A case report
  86. Simultaneous triple primary malignancies, including bladder cancer, lymphoma, and lung cancer, in an elderly male: A case report
  87. Preclinical immunogenicity assessment of a cell-based inactivated whole-virion H5N1 influenza vaccine
  88. One case of iodine-125 therapy – A new minimally invasive treatment of intrahepatic cholangiocarcinoma
  89. S1P promotes corneal trigeminal neuron differentiation and corneal nerve repair via upregulating nerve growth factor expression in a mouse model
  90. Early cancer detection by a targeted methylation assay of circulating tumor DNA in plasma
  91. Calcifying nanoparticles initiate the calcification process of mesenchymal stem cells in vitro through the activation of the TGF-β1/Smad signaling pathway and promote the decay of echinococcosis
  92. Evaluation of prognostic markers in patients infected with SARS-CoV-2
  93. N6-Methyladenosine-related alternative splicing events play a role in bladder cancer
  94. Characterization of the structural, oxidative, and immunological features of testis tissue from Zucker diabetic fatty rats
  95. Effects of glucose and osmotic pressure on the proliferation and cell cycle of human chorionic trophoblast cells
  96. Investigation of genotype diversity of 7,804 norovirus sequences in humans and animals of China
  97. Characteristics and karyotype analysis of a patient with turner syndrome complicated with multiple-site tumors: A case report
  98. Aggravated renal fibrosis is positively associated with the activation of HMGB1-TLR2/4 signaling in STZ-induced diabetic mice
  99. Distribution characteristics of SARS-CoV-2 IgM/IgG in false-positive results detected by chemiluminescent immunoassay
  100. SRPX2 attenuated oxygen–glucose deprivation and reperfusion-induced injury in cardiomyocytes via alleviating endoplasmic reticulum stress-induced apoptosis through targeting PI3K/Akt/mTOR axis
  101. Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients
  102. Relationship between CRP gene polymorphisms and ischemic stroke risk: A systematic review and meta-analysis
  103. Effects of growth hormone on lipid metabolism and sexual development in pubertal obese male rats
  104. Cloning and identification of the CTLA-4IgV gene and functional application of vaccine in Xinjiang sheep
  105. Antitumor activity of RUNX3: Upregulation of E-cadherin and downregulation of the epithelial–mesenchymal transition in clear-cell renal cell carcinoma
  106. PHF8 promotes osteogenic differentiation of BMSCs in old rat with osteoporosis by regulating Wnt/β-catenin pathway
  107. A review of the current state of the computer-aided diagnosis (CAD) systems for breast cancer diagnosis
  108. Bilateral dacryoadenitis in adult-onset Still’s disease: A case report
  109. A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma
  110. The role of erythrocytes and erythroid progenitor cells in tumors
  111. Relationship between platelet activation markers and spontaneous abortion: A meta-analysis
  112. Abnormal methylation caused by folic acid deficiency in neural tube defects
  113. Silencing TLR4 using an ultrasound-targeted microbubble destruction-based shRNA system reduces ischemia-induced seizures in hyperglycemic rats
  114. Plant Sciences
  115. Seasonal succession of bacterial communities in cultured Caulerpa lentillifera detected by high-throughput sequencing
  116. Cloning and prokaryotic expression of WRKY48 from Caragana intermedia
  117. Novel Brassica hybrids with different resistance to Leptosphaeria maculans reveal unbalanced rDNA signal patterns
  118. Application of exogenous auxin and gibberellin regulates the bolting of lettuce (Lactuca sativa L.)
  119. Phytoremediation of pollutants from wastewater: A concise review
  120. Genome-wide identification and characterization of NBS-encoding genes in the sweet potato wild ancestor Ipomoea trifida (H.B.K.)
  121. Alleviative effects of magnetic Fe3O4 nanoparticles on the physiological toxicity of 3-nitrophenol to rice (Oryza sativa L.) seedlings
  122. Selection and functional identification of Dof genes expressed in response to nitrogen in Populus simonii × Populus nigra
  123. Study on pecan seed germination influenced by seed endocarp
  124. Identification of active compounds in Ophiopogonis Radix from different geographical origins by UPLC-Q/TOF-MS combined with GC-MS approaches
  125. The entire chloroplast genome sequence of Asparagus cochinchinensis and genetic comparison to Asparagus species
  126. Genome-wide identification of MAPK family genes and their response to abiotic stresses in tea plant (Camellia sinensis)
  127. Selection and validation of reference genes for RT-qPCR analysis of different organs at various development stages in Caragana intermedia
  128. Cloning and expression analysis of SERK1 gene in Diospyros lotus
  129. Integrated metabolomic and transcriptomic profiling revealed coping mechanisms of the edible and medicinal homologous plant Plantago asiatica L. cadmium resistance
  130. A missense variant in NCF1 is associated with susceptibility to unexplained recurrent spontaneous abortion
  131. Assessment of drought tolerance indices in faba bean genotypes under different irrigation regimes
  132. The entire chloroplast genome sequence of Asparagus setaceus (Kunth) Jessop: Genome structure, gene composition, and phylogenetic analysis in Asparagaceae
  133. Food Science
  134. Dietary food additive monosodium glutamate with or without high-lipid diet induces spleen anomaly: A mechanistic approach on rat model
  135. Binge eating disorder during COVID-19
  136. Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model
  137. FTO gene expression in diet-induced obesity is downregulated by Solanum fruit supplementation
  138. Physical activity enhances fecal lactobacilli in rats chronically drinking sweetened cola beverage
  139. Supercritical CO2 extraction, chemical composition, and antioxidant effects of Coreopsis tinctoria Nutt. oleoresin
  140. Functional constituents of plant-based foods boost immunity against acute and chronic disorders
  141. Effect of selenium and methods of protein extraction on the proteomic profile of Saccharomyces yeast
  142. Microbial diversity of milk ghee in southern Gansu and its effect on the formation of ghee flavor compounds
  143. Ecology and Environmental Sciences
  144. Effects of heavy metals on bacterial community surrounding Bijiashan mining area located in northwest China
  145. Microorganism community composition analysis coupling with 15N tracer experiments reveals the nitrification rate and N2O emissions in low pH soils in Southern China
  146. Genetic diversity and population structure of Cinnamomum balansae Lecomte inferred by microsatellites
  147. Preliminary screening of microplastic contamination in different marine fish species of Taif market, Saudi Arabia
  148. Plant volatile organic compounds attractive to Lygus pratensis
  149. Effects of organic materials on soil bacterial community structure in long-term continuous cropping of tomato in greenhouse
  150. Effects of soil treated fungicide fluopimomide on tomato (Solanum lycopersicum L.) disease control and plant growth
  151. Prevalence of Yersinia pestis among rodents captured in a semi-arid tropical ecosystem of south-western Zimbabwe
  152. Effects of irrigation and nitrogen fertilization on mitigating salt-induced Na+ toxicity and sustaining sea rice growth
  153. Bioengineering and Biotechnology
  154. Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes
  155. Development of alkaline phosphatase-scFv and its use for one-step enzyme-linked immunosorbent assay for His-tagged protein detection
  156. Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma
  157. Agriculture
  158. Effects of chemical-based fertilizer replacement with biochar-based fertilizer on albic soil nutrient content and maize yield
  159. Genome-wide identification and expression analysis of CPP-like gene family in Triticum aestivum L. under different hormone and stress conditions
  160. Agronomic and economic performance of mung bean (Vigna radiata L.) varieties in response to rates of blended NPS fertilizer in Kindo Koysha district, Southern Ethiopia
  161. Influence of furrow irrigation regime on the yield and water consumption indicators of winter wheat based on a multi-level fuzzy comprehensive evaluation
  162. Discovery of exercise-related genes and pathway analysis based on comparative genomes of Mongolian originated Abaga and Wushen horse
  163. Lessons from integrated seasonal forecast-crop modelling in Africa: A systematic review
  164. Evolution trend of soil fertility in tobacco-planting area of Chenzhou, Hunan Province, China
  165. Animal Sciences
  166. Morphological and molecular characterization of Tatera indica Hardwicke 1807 (Rodentia: Muridae) from Pothwar, Pakistan
  167. Research on meat quality of Qianhua Mutton Merino sheep and Small-tail Han sheep
  168. SI: A Scientific Memoir
  169. Suggestions on leading an academic research laboratory group
  170. My scientific genealogy and the Toronto ACDC Laboratory, 1988–2022
  171. Erratum
  172. Erratum to “Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study”
  173. Erratum to “A two-microRNA signature predicts the progression of male thyroid cancer”
  174. Retraction
  175. Retraction of “Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis”
https://doi.org/10.1515/biol-2022-0013
Keywords for this article
autoimmune hepatitis; concanavalin A; experimental animal models; inflammation; pathogenesis
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits
  3. The mother of all battles: Viruses vs humans. Can humans avoid extinction in 50–100 years?
  4. Knockdown of G1P3 inhibits cell proliferation and enhances the cytotoxicity of dexamethasone in acute lymphoblastic leukemia
  5. LINC00665 regulates hepatocellular carcinoma by modulating mRNA via the m6A enzyme
  6. Association study of CLDN14 variations in patients with kidney stones
  7. Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook
  8. Regulation of miR-30b in cancer development, apoptosis, and drug resistance
  9. Informatic analysis of the pulmonary microecology in non-cystic fibrosis bronchiectasis at three different stages
  10. Swimming attenuates tumor growth in CT-26 tumor-bearing mice and suppresses angiogenesis by mediating the HIF-1α/VEGFA pathway
  11. Characterization of intestinal microbiota and serum metabolites in patients with mild hepatic encephalopathy
  12. Functional conservation and divergence in plant-specific GRF gene family revealed by sequences and expression analysis
  13. Application of the FLP/LoxP-FRT recombination system to switch the eGFP expression in a model prokaryote
  14. Biomedical evaluation of antioxidant properties of lamb meat enriched with iodine and selenium
  15. Intravenous infusion of the exosomes derived from human umbilical cord mesenchymal stem cells enhance neurological recovery after traumatic brain injury via suppressing the NF-κB pathway
  16. Effect of dietary pattern on pregnant women with gestational diabetes mellitus and its clinical significance
  17. Potential regulatory mechanism of TNF-α/TNFR1/ANXA1 in glioma cells and its role in glioma cell proliferation
  18. Effect of the genetic mutant G71R in uridine diphosphate-glucuronosyltransferase 1A1 on the conjugation of bilirubin
  19. Quercetin inhibits cytotoxicity of PC12 cells induced by amyloid-beta 25–35 via stimulating estrogen receptor α, activating ERK1/2, and inhibiting apoptosis
  20. Nutrition intervention in the management of novel coronavirus pneumonia patients
  21. circ-CFH promotes the development of HCC by regulating cell proliferation, apoptosis, migration, invasion, and glycolysis through the miR-377-3p/RNF38 axis
  22. Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma
  23. Lacunar infarction aggravates the cognitive deficit in the elderly with white matter lesion
  24. Hydroxysafflor yellow A improved retinopathy via Nrf2/HO-1 pathway in rats
  25. Comparison of axon extension: PTFE versus PLA formed by a 3D printer
  26. Elevated IL-35 level and iTr35 subset increase the bacterial burden and lung lesions in Mycobacterium tuberculosis-infected mice
  27. A case report of CAT gene and HNF1β gene variations in a patient with early-onset diabetes
  28. Study on the mechanism of inhibiting patulin production by fengycin
  29. SOX4 promotes high-glucose-induced inflammation and angiogenesis of retinal endothelial cells by activating NF-κB signaling pathway
  30. Relationship between blood clots and COVID-19 vaccines: A literature review
  31. Analysis of genetic characteristics of 436 children with dysplasia and detailed analysis of rare karyotype
  32. Bioinformatics network analyses of growth differentiation factor 11
  33. NR4A1 inhibits the epithelial–mesenchymal transition of hepatic stellate cells: Involvement of TGF-β–Smad2/3/4–ZEB signaling
  34. Expression of Zeb1 in the differentiation of mouse embryonic stem cell
  35. Study on the genetic damage caused by cadmium sulfide quantum dots in human lymphocytes
  36. Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis
  37. Assessment of the anesthetic effect of modified pentothal sodium solution on Sprague-Dawley rats
  38. Genetic susceptibility to high myopia in Han Chinese population
  39. Potential biomarkers and molecular mechanisms in preeclampsia progression
  40. Silencing circular RNA-friend leukemia virus integration 1 restrained malignancy of CC cells and oxaliplatin resistance by disturbing dyskeratosis congenita 1
  41. Endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime for advanced pulmonary large-cell neuroendocrine carcinoma as a first-line treatment: A case report
  42. The significance of PAK4 in signaling and clinicopathology: A review
  43. Sorafenib inhibits ovarian cancer cell proliferation and mobility and induces radiosensitivity by targeting the tumor cell epithelial–mesenchymal transition
  44. Characterization of rabbit polyclonal antibody against camel recombinant nanobodies
  45. Active legumain promotes invasion and migration of neuroblastoma by regulating epithelial-mesenchymal transition
  46. Effect of cell receptors in the pathogenesis of osteoarthritis: Current insights
  47. MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction
  48. Study of hsa_circRNA_000121 and hsa_circRNA_004183 in papillary thyroid microcarcinoma
  49. BuyangHuanwu Decoction attenuates cerebral vasospasm caused by subarachnoid hemorrhage in rats via PI3K/AKT/eNOS axis
  50. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
  51. Monosodium iodoacetate-induced subchondral bone microstructure and inflammatory changes in an animal model of osteoarthritis
  52. A rare presentation of type II Abernethy malformation and nephrotic syndrome: Case report and review
  53. Rapid death due to pulmonary epithelioid haemangioendothelioma in several weeks: A case report
  54. Hepatoprotective role of peroxisome proliferator-activated receptor-α in non-cancerous hepatic tissues following transcatheter arterial embolization
  55. Correlation between peripheral blood lymphocyte subpopulations and primary systemic lupus erythematosus
  56. A novel SLC8A1-ALK fusion in lung adenocarcinoma confers sensitivity to alectinib: A case report
  57. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes
  58. Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer
  59. BTBD10 inhibits glioma tumorigenesis by downregulating cyclin D1 and p-Akt
  60. Mucormycosis co-infection in COVID-19 patients: An update
  61. Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report
  62. Long non-coding RNA HOXB-AS1 is a prognostic marker and promotes hepatocellular carcinoma cells’ proliferation and invasion
  63. Preparation and evaluation of LA-PEG-SPION, a targeted MRI contrast agent for liver cancer
  64. Proteomic analysis of the liver regulating lipid metabolism in Chaohu ducks using two-dimensional electrophoresis
  65. Nasopharyngeal tuberculosis: A case report
  66. Characterization and evaluation of anti-Salmonella enteritidis activity of indigenous probiotic lactobacilli in mice
  67. Aberrant pulmonary immune response of obese mice to periodontal infection
  68. Bacteriospermia – A formidable player in male subfertility
  69. In silico and in vivo analysis of TIPE1 expression in diffuse large B cell lymphoma
  70. Effects of KCa channels on biological behavior of trophoblasts
  71. Interleukin-17A influences the vulnerability rather than the size of established atherosclerotic plaques in apolipoprotein E-deficient mice
  72. Multiple organ failure and death caused by Staphylococcus aureus hip infection: A case report
  73. Prognostic signature related to the immune environment of oral squamous cell carcinoma
  74. Primary and metastatic squamous cell carcinoma of the thyroid gland: Two case reports
  75. Neuroprotective effects of crocin and crocin-loaded niosomes against the paraquat-induced oxidative brain damage in rats
  76. Role of MMP-2 and CD147 in kidney fibrosis
  77. Geometric basis of action potential of skeletal muscle cells and neurons
  78. Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review
  79. Role of cerebellar cortex in associative learning and memory in guinea pigs
  80. Application of metagenomic next-generation sequencing technique for diagnosing a specific case of necrotizing meningoencephalitis caused by human herpesvirus 2
  81. Case report: Quadruple primary malignant neoplasms including esophageal, ureteral, and lung in an elderly male
  82. Long non-coding RNA NEAT1 promotes angiogenesis in hepatoma carcinoma via the miR-125a-5p/VEGF pathway
  83. Osteogenic differentiation of periodontal membrane stem cells in inflammatory environments
  84. Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway
  85. Continuous renal replacement therapy combined with double filtration plasmapheresis in the treatment of severe lupus complicated by serious bacterial infections in children: A case report
  86. Simultaneous triple primary malignancies, including bladder cancer, lymphoma, and lung cancer, in an elderly male: A case report
  87. Preclinical immunogenicity assessment of a cell-based inactivated whole-virion H5N1 influenza vaccine
  88. One case of iodine-125 therapy – A new minimally invasive treatment of intrahepatic cholangiocarcinoma
  89. S1P promotes corneal trigeminal neuron differentiation and corneal nerve repair via upregulating nerve growth factor expression in a mouse model
  90. Early cancer detection by a targeted methylation assay of circulating tumor DNA in plasma
  91. Calcifying nanoparticles initiate the calcification process of mesenchymal stem cells in vitro through the activation of the TGF-β1/Smad signaling pathway and promote the decay of echinococcosis
  92. Evaluation of prognostic markers in patients infected with SARS-CoV-2
  93. N6-Methyladenosine-related alternative splicing events play a role in bladder cancer
  94. Characterization of the structural, oxidative, and immunological features of testis tissue from Zucker diabetic fatty rats
  95. Effects of glucose and osmotic pressure on the proliferation and cell cycle of human chorionic trophoblast cells
  96. Investigation of genotype diversity of 7,804 norovirus sequences in humans and animals of China
  97. Characteristics and karyotype analysis of a patient with turner syndrome complicated with multiple-site tumors: A case report
  98. Aggravated renal fibrosis is positively associated with the activation of HMGB1-TLR2/4 signaling in STZ-induced diabetic mice
  99. Distribution characteristics of SARS-CoV-2 IgM/IgG in false-positive results detected by chemiluminescent immunoassay
  100. SRPX2 attenuated oxygen–glucose deprivation and reperfusion-induced injury in cardiomyocytes via alleviating endoplasmic reticulum stress-induced apoptosis through targeting PI3K/Akt/mTOR axis
  101. Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients
  102. Relationship between CRP gene polymorphisms and ischemic stroke risk: A systematic review and meta-analysis
  103. Effects of growth hormone on lipid metabolism and sexual development in pubertal obese male rats
  104. Cloning and identification of the CTLA-4IgV gene and functional application of vaccine in Xinjiang sheep
  105. Antitumor activity of RUNX3: Upregulation of E-cadherin and downregulation of the epithelial–mesenchymal transition in clear-cell renal cell carcinoma
  106. PHF8 promotes osteogenic differentiation of BMSCs in old rat with osteoporosis by regulating Wnt/β-catenin pathway
  107. A review of the current state of the computer-aided diagnosis (CAD) systems for breast cancer diagnosis
  108. Bilateral dacryoadenitis in adult-onset Still’s disease: A case report
  109. A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma
  110. The role of erythrocytes and erythroid progenitor cells in tumors
  111. Relationship between platelet activation markers and spontaneous abortion: A meta-analysis
  112. Abnormal methylation caused by folic acid deficiency in neural tube defects
  113. Silencing TLR4 using an ultrasound-targeted microbubble destruction-based shRNA system reduces ischemia-induced seizures in hyperglycemic rats
  114. Plant Sciences
  115. Seasonal succession of bacterial communities in cultured Caulerpa lentillifera detected by high-throughput sequencing
  116. Cloning and prokaryotic expression of WRKY48 from Caragana intermedia
  117. Novel Brassica hybrids with different resistance to Leptosphaeria maculans reveal unbalanced rDNA signal patterns
  118. Application of exogenous auxin and gibberellin regulates the bolting of lettuce (Lactuca sativa L.)
  119. Phytoremediation of pollutants from wastewater: A concise review
  120. Genome-wide identification and characterization of NBS-encoding genes in the sweet potato wild ancestor Ipomoea trifida (H.B.K.)
  121. Alleviative effects of magnetic Fe3O4 nanoparticles on the physiological toxicity of 3-nitrophenol to rice (Oryza sativa L.) seedlings
  122. Selection and functional identification of Dof genes expressed in response to nitrogen in Populus simonii × Populus nigra
  123. Study on pecan seed germination influenced by seed endocarp
  124. Identification of active compounds in Ophiopogonis Radix from different geographical origins by UPLC-Q/TOF-MS combined with GC-MS approaches
  125. The entire chloroplast genome sequence of Asparagus cochinchinensis and genetic comparison to Asparagus species
  126. Genome-wide identification of MAPK family genes and their response to abiotic stresses in tea plant (Camellia sinensis)
  127. Selection and validation of reference genes for RT-qPCR analysis of different organs at various development stages in Caragana intermedia
  128. Cloning and expression analysis of SERK1 gene in Diospyros lotus
  129. Integrated metabolomic and transcriptomic profiling revealed coping mechanisms of the edible and medicinal homologous plant Plantago asiatica L. cadmium resistance
  130. A missense variant in NCF1 is associated with susceptibility to unexplained recurrent spontaneous abortion
  131. Assessment of drought tolerance indices in faba bean genotypes under different irrigation regimes
  132. The entire chloroplast genome sequence of Asparagus setaceus (Kunth) Jessop: Genome structure, gene composition, and phylogenetic analysis in Asparagaceae
  133. Food Science
  134. Dietary food additive monosodium glutamate with or without high-lipid diet induces spleen anomaly: A mechanistic approach on rat model
  135. Binge eating disorder during COVID-19
  136. Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model
  137. FTO gene expression in diet-induced obesity is downregulated by Solanum fruit supplementation
  138. Physical activity enhances fecal lactobacilli in rats chronically drinking sweetened cola beverage
  139. Supercritical CO2 extraction, chemical composition, and antioxidant effects of Coreopsis tinctoria Nutt. oleoresin
  140. Functional constituents of plant-based foods boost immunity against acute and chronic disorders
  141. Effect of selenium and methods of protein extraction on the proteomic profile of Saccharomyces yeast
  142. Microbial diversity of milk ghee in southern Gansu and its effect on the formation of ghee flavor compounds
  143. Ecology and Environmental Sciences
  144. Effects of heavy metals on bacterial community surrounding Bijiashan mining area located in northwest China
  145. Microorganism community composition analysis coupling with 15N tracer experiments reveals the nitrification rate and N2O emissions in low pH soils in Southern China
  146. Genetic diversity and population structure of Cinnamomum balansae Lecomte inferred by microsatellites
  147. Preliminary screening of microplastic contamination in different marine fish species of Taif market, Saudi Arabia
  148. Plant volatile organic compounds attractive to Lygus pratensis
  149. Effects of organic materials on soil bacterial community structure in long-term continuous cropping of tomato in greenhouse
  150. Effects of soil treated fungicide fluopimomide on tomato (Solanum lycopersicum L.) disease control and plant growth
  151. Prevalence of Yersinia pestis among rodents captured in a semi-arid tropical ecosystem of south-western Zimbabwe
  152. Effects of irrigation and nitrogen fertilization on mitigating salt-induced Na+ toxicity and sustaining sea rice growth
  153. Bioengineering and Biotechnology
  154. Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes
  155. Development of alkaline phosphatase-scFv and its use for one-step enzyme-linked immunosorbent assay for His-tagged protein detection
  156. Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma
  157. Agriculture
  158. Effects of chemical-based fertilizer replacement with biochar-based fertilizer on albic soil nutrient content and maize yield
  159. Genome-wide identification and expression analysis of CPP-like gene family in Triticum aestivum L. under different hormone and stress conditions
  160. Agronomic and economic performance of mung bean (Vigna radiata L.) varieties in response to rates of blended NPS fertilizer in Kindo Koysha district, Southern Ethiopia
  161. Influence of furrow irrigation regime on the yield and water consumption indicators of winter wheat based on a multi-level fuzzy comprehensive evaluation
  162. Discovery of exercise-related genes and pathway analysis based on comparative genomes of Mongolian originated Abaga and Wushen horse
  163. Lessons from integrated seasonal forecast-crop modelling in Africa: A systematic review
  164. Evolution trend of soil fertility in tobacco-planting area of Chenzhou, Hunan Province, China
  165. Animal Sciences
  166. Morphological and molecular characterization of Tatera indica Hardwicke 1807 (Rodentia: Muridae) from Pothwar, Pakistan
  167. Research on meat quality of Qianhua Mutton Merino sheep and Small-tail Han sheep
  168. SI: A Scientific Memoir
  169. Suggestions on leading an academic research laboratory group
  170. My scientific genealogy and the Toronto ACDC Laboratory, 1988–2022
  171. Erratum
  172. Erratum to “Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study”
  173. Erratum to “A two-microRNA signature predicts the progression of male thyroid cancer”
  174. Retraction
  175. Retraction of “Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis”
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2026 De Gruyter Brill
Downloaded on 23.1.2026 from https://www.degruyterbrill.com/document/doi/10.1515/biol-2022-0013/html
Scroll to top button