Home Interleukin-35 in autoimmune dermatoses: Current concepts
Article Open Access

Interleukin-35 in autoimmune dermatoses: Current concepts

  • Yuming Xie , Huilin Zhang , Junke Huang and Qing Zhang EMAIL logo
Published/Copyright: March 21, 2022
Download Article (PDF)
Open Medicine
From the journal Open Medicine Volume 17 Issue 1

Abstract

Interleukin-35 (IL-35) is a lately observed cytokine and is part of the IL-12 cytokine family. IL-35 includes two subunits, p35 and Epstein-Barr virus-induced gene 3, and activates subsequent signaling pathways by binding to receptors to mediate signal transduction, thereby modulating the immunoregulatory functions of T cells, B cells, macrophages, and other immune cell types. Although there is currently limited research on the roles of IL-35 in human autoimmunity, many studies have demonstrated that IL-35 may mediate immunosuppression. Therefore, it plays an essential role in some autoimmune dermatoses, including systemic lupus erythematosus, psoriasis, systemic sclerosis, and dermatomyositis. We will introduce the structure and biological characteristics of IL-35 and summarize its effects on the occurrence and development of autoimmune dermatoses in this article. It is suggested that IL-35 is a possible target for therapy in the aforementioned diseases.

Keywords: dermatomyositis; interleukin-35; psoriasis; systemic lupus erythematosus; systemic sclerosis

1 Introduction

As described recently, interleukin-35 (IL-35) is a new member of the IL-12 cytokine family, which also contains IL-12, IL-23, and IL-27 [1,2]. The members of the IL-12 cytokine family are all heterodimers made up of an α-subunit and a β-subunit. IL-12 consists of p40 and p35 subunits, IL-23 consists of p40 and p19, while IL-27 is made up of p28 and Epstein-Barr virus-induced gene 3 (Ebi3) [1,3,4]. It is reported that p35 and Ebi3 form IL-35 [1,2]. The two subunits of IL-35 can both regulate the immune activities independently, while p35 is the main subunit of IL-35 that plays an immunological role, and Ebi3 can form a heterodimer with p35 to enhance its function [5]. Mouse IL-35 can be expressed by non-stimulated CD4+Foxp3+ regulatory T cells (Tregs) [1]. However, human IL-35 is undetectable in non-stimulated Tregs but can be produced by Tregs after activation [6,7,8,9]. IL-35 is inducible in regulatory B cells (Bregs) [10], tolerogenic dendritic cells [11], and placental trophoblast cells [12].

IL-35 receptors are heterodimers or homodimers that are composed of IL-12Rβ2, gp130, or IL-27Rα, including two heterodimers, IL-12Rβ2-gp130 and IL-12Rβ2-IL-27Rα, and two homodimers, IL-12Rβ2–IL-12Rβ2 and gp130–gp130 [13,14]. Among these subunits, IL-12Rβ2 is mainly expressed by activated natural killer cells and T cells [15,16]. Gp130 is expressed by most immune cells [17], and IL-27Rα is primarily expressed by activated CD8+ T cells, CD4+ T cells, and monocytes [18]. Once IL-35 binds to the corresponding receptors, signal transduction begins, and signal transducer and activator of transcription (STAT) family members and Janus kinase (JAK) family members are activated. In T cells, its signal transduction involves three receptors, including IL-12Rβ2-gp130, IL-12Rβ2–IL-12Rβ2, and gp130–gp130, and the process is mainly accomplished by activating STAT1 and STAT4 [13]. The two homodimeric receptors can only suppress T cell proliferation, while the IL-12Rβ2-gp130 heterodimeric receptor is able to reduce T cell multiplication and mediate the induction of a potent Treg subset, IL-35-induced regulatory T cells (iTr35) [13]. In Bregs, recombinant IL-35 activates STAT1 and STAT3 pathways by binding with IL-12Rβ2-IL-27Rα, which can produce two Breg subsets that secrete IL-35 (IL-35+ Bregs) and IL-10 (IL-10+ Bregs) (Table 1) [14,19]. These results show that IL-35 is capable of binding to different receptors in different cell types.

Table 1

The expression, signaling pathways, and functions of IL-35

Position Receptor STATs Function
T cells gp130–gp130 STAT1 Suppressing T cell proliferation
IL-12Rβ2–IL-12Rβ2 STAT4 Suppressing T cell proliferation
IL-12Rβ2–gp130 STAT1 Suppressing T cell proliferation
STAT1, STAT4 Inducing iTr35 generation
B cells IL-12Rβ2–IL-27Rα STAT1, STAT3 Promoting conversion of IL-10+ Bregs and IL-35+ Bregs

2 Biological functions of IL-35 in autoimmunity

IL-35 is significant in the progression of inflammation and immune reactions, and IL-35 can mediate immunosuppressive and immunoregulatory functions.

In mice, IL-35 expressed by T cells can reduce effector T cell (Teff) multiplication [1]. Furthermore, mouse recombinant IL-35, a functional heterodimer genetically engineered by combining p35 and Ebi3, can strengthen the inhibitory effect of CD8+CTLA-4+ Tregs on the propagation of autologous T cells [20]. IL-35 inhibits CD8+ T cells by influencing cellular immunosuppressive regulation and external regulatory protein stimulation [21]. It has been reported that mesenchymal stem cells, transfected with lentivirus carrying IL-35, stimulate CD4+CD25+ Tregs proliferation and inhibit CD4+ T cells propagation. And in the supernatant of the coculture system containing these three cell subpopulations, the levels of IL-10 and IL-35 increased, while the secretion of IL-17 decreased compared to control groups with non-transfected mesenchymal stem cells or phosphate buffer saline (PBS) [22]. IL-35 inhibits the activation and differentiation of IL-17A+ T helper (Th17) cells [23,24]. To investigate the effect of IL-35 on Th17-related transcription factors, a study found that Th17-related transcription factors T-bet and retinoic acid receptor-associated orphan receptor (ROR)γ T were significantly inhibited in mice treated with IL-35 [25]. Another study in PBMC showed that recombinant IL-35 regulates Th17 cell differentiation by inhibiting RORα and RORγ T transcription factors, and inhibits IL-17 mRNA transcription, thereby reducing IL-17 secretion [26]. Inducible costimulator-positive Tregs are able to produce IL-35 to suppress IL-17 production [23]. Tregs are in a position to reduce the propagation of Th17 cells; moreover, IL-35 strengthens the inhibition of Tregs [27]. Additionally, it was observed that IL-35 can maintain the Treg phenotype and inhibit Th17 cell differentiation [24] (Figure 1a). These findings suggest that IL-35 plays an important role in regulating the balance between Tregs and Th17 cells.

Figure 1 Biological functions of IL-35. (a) IL-35 regulates T cell-mediated immune responses. IL-35 can induce iTr35 generation, and the resulting iTr35 cells produce additional IL-35. IL-35 suppresses Teff proliferation. By upregulating the suppressive function of Tregs, IL-35 can suppress Th17 cell differentiation and IL-17 secretion. (b) IL-35 regulates B cell-mediated immune responses. IL-35 induces IL-10+ Bregs and IL-35+ Bregs. Moreover, IL-10+ Bregs inhibit the propagation of CD19+ B cells, and IL-35+ Bregs suppress the expansion of B220hi cells. iTr35: IL-35-induced regulatory T cells, Teff: effector T cell, Treg: regulatory T cell, ROR: retinoic acid receptor-related orphan receptor, IL-10+ Breg: regulatory B cells secreting IL-10, IL-35+ Breg: regulatory B cells secreting IL-35.
Figure 1

Biological functions of IL-35. (a) IL-35 regulates T cell-mediated immune responses. IL-35 can induce iTr35 generation, and the resulting iTr35 cells produce additional IL-35. IL-35 suppresses Teff proliferation. By upregulating the suppressive function of Tregs, IL-35 can suppress Th17 cell differentiation and IL-17 secretion. (b) IL-35 regulates B cell-mediated immune responses. IL-35 induces IL-10+ Bregs and IL-35+ Bregs. Moreover, IL-10+ Bregs inhibit the propagation of CD19+ B cells, and IL-35+ Bregs suppress the expansion of B220hi cells. iTr35: IL-35-induced regulatory T cells, Teff: effector T cell, Treg: regulatory T cell, ROR: retinoic acid receptor-related orphan receptor, IL-10+ Breg: regulatory B cells secreting IL-10, IL-35+ Breg: regulatory B cells secreting IL-35.

As previously mentioned, IL-35 is capable of inducing iTr35 generation, which produces IL-35 in both humans and mice [28]. Induced regulatory T cells are different from thymus-derived natural Treg cells in that they are produced by IL-10 or transforming growth factor-beta (TGF-β) induction [29,30]. However, iTr35 cells mediate immunological suppression only through IL-35, rather than by proven cytokines, including TGF-β and IL-10 [28]. Unlike the currently known TGF-β-induced regulatory T cells, which express Foxp3, iTr35 cells do not express Foxp3 [28,31]. Furthermore, iTr35 cells and IL-35 generate a positive feedback loop in which IL-35 induces iTr35 cell proliferation, and the produced iTr35 cells produce additional IL-35 [28] (Figure 1a).

IL-35 also mediates the immunoregulatory function of Bregs. Recombinant IL-35 induces Bregs and promotes their conversion to IL-10+ Bregs and IL-35+ Bregs. As mentioned above, this process is accomplished by activating STAT1/STAT3 pathways through the IL-35 receptor, made up of IL-12Rβ2 and IL-27Rα [14,19]. Meanwhile, IL-10+ Bregs downregulate the propagation of CD19+ B cells, and IL-35+ Bregs show a suppressive function of the expansion of B220hi cells [14] (Figure 1b). Tonsil-derived mesenchymal stem cells from humans increase the number of IL-10-producing Bregs through Ebi3, thus reducing the immune response mediated by B cells in mice [32].

IL-35 does not directly affect the viability of human mast cell line cells, but significantly inhibits the viability of human mast cell line cells stimulated by phorbol 12-myristate 13-acetate and A23187 (calcium ionophore) [33]. In addition, IL-35 suppresses histamine release, IL-6 and IL-17 mRNA expression, and mitogen-activated protein kinase (MAPK) phosphorylation in human mast cell line cells stimulated by phorbol 12-myristate 13-acetate and A23187 [33]. All these facts show that IL-35 mediates significant functions in immunological regulation.

3 Roles of IL-35 in autoimmune dermatoses

3.1 Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiorgan and multisystem involvement, such as skin, kidney, and vascular dysfunctions. The imbalance of CD8+ T cells and CD4+ T cells in SLE patients results in continued B cell activation to produce various types of autoantibodies and result in the persistence of autoimmunity [34,35,36]. A study found that in Murphy Roths Large (MRL)/lpr mice, a spontaneous lupus-like disease model, the reduction of IL-10+ Breg cells and serum IL-10 were accompanied by reduced serum IL-35, prompting that IL-35 may be involved in the regulatory function of Breg cells from lupus [37]. The immune imbalance between Th17 cells and Tregs leads to the destruction of immune homeostasis, which is closely correlated with the development of SLE [38,39,40]. Therefore, it is speculated that IL-35 may help restore the immune balance of SLE patients by limiting the functions of Th17 cells and CD4+ T cells and promoting Treg proliferation. Research on juvenile SLE has shown that leukocyte-associated-immunoglobulin-like receptor 1 (LAIR1), one of the observably downregulated differential expression proteins in juvenile SLE patients, binds to the Src homologue 2 domain of protein tyrosine phosphatase non-receptor type 11 (PTPN11) through its two cytoplasmic tyrosine inhibitory motifs, and has a potential inhibitory effect on lymphocytes and leads to dephosphorylation of subsequent kinases. IL-35 leads to the inhibition of the JAK/STAT and MAPK signaling pathways by increasing LAIR1 levels. Then, it adjusts the LAIR1-PTPN11-JAK-STAT-fibronectin 1 interaction network, and ultimately, may mitigate juvenile SLE nephritis [41].

A study by Cai et al. in female MRL/lpr mice showed that in comparison with PBS-treated mice, nephritis and lupus diseases in IL-35-treated mice were obviously remissive [42]. The mRNA levels of Foxp3, IL-35 subunits (p35 and Ebi3), free subunits of IL-35 receptors (IL-12Rβ2 and gp130) from splenic and thymic cells were distinctly elevated in MRL/lpr mice after IL-35 therapy in comparison with PBS-treated MRL/lpr mice [42]. Subsequently, plasma concentrations of gp130 and IL-35 of MRL/lpr mice with mild disease, IL-12Rβ2 and gp130 of MRL/lpr mice with moderate disease, and IL-12Rβ2 of MRL/lpr mice with severe disease after IL-35 therapy were found to be elevated relative to those of PBS-treated MRL/lpr mice [42]. CD4+CD25+Foxp3+ Treg cells were upgraded in the spleen, thymus, and peripheral blood of lupus mice treated with IL-35, so that the CD4+CD25+Foxp3+ Treg/CD4+CD25− Teff ratio was obviously upregulated in all groups after IL-35 therapy, and the proportion of IL-10+ Bregs obviously increased with IL-35 treatment [42]. The percentage and absolute number of Tregs in the spleen, thymus, and peripheral blood of lupus mice treated with IL-35 overexpression plasmid were higher [41]. Concentrations of pro-inflammatory cytokines in plasma containing IL-17A, IL-6, interferon-gamma (IFN-γ), and tumour necrosis factor-alpha (TNF-α) were significantly decreased, and IL-10, an anti-inflammatory cytokine, was significantly increased in plasma of IL-35-treated mice [42]. It was also shown that SLE-related plasma antibodies (antinuclear antibody and anti-double-stranded DNA antibody) concentrations were significantly reduced, demonstrating that IL-35 probably mediates the suppression of SLE through the immunoregulatory functions of Tregs and Bregs [42]. A separated peripheral blood mononuclear cell (PBMC) culture experiment revealed lower IL-35 levels in active SLE patients relative to healthy controls (HCs) [43]. IL-35 levels in the serum of active SLE patients were lower than those of non-active SLE patients, and a negative relationship between SLE Disease Activity Index (SLEDAI)-2k scores and serum IL-35 levels was observed [44,45]. The proportion of CD4+ T cells expressing EBI3 in peripheral blood of patients with active SLE was lower than that of HCs and inactive SLE patients and was negatively correlated with the SLEDAI score [45]. These results may indicate that IL-35 and Ebi3-expressing CD4+ T cells may play a protective part in the development of SLE, and their IL-35 levels may be used as a measure of SLE activity. IL-35 levels in the serum of SLE patients with lupus nephritis were obviously lower than those of SLE patients without lupus nephritis, and IL-35 might be a possible biomarker for kidney damage related to SLE [44]. IL-35 levels in the plasma of newly diagnosed SLE patients were significantly decreased compared with HCs [46]. The decrease of IL-35 quantity in patients with newly diagnosed SLE probably occurs since the plasma concentrations of IL-35 and the number of circulating IL-35+ Bregs are both decreased [46]. The expression levels of gp130 on CD4+ helper T (Th) cell surface of patients with severe SLE were lower and were negatively related to SLEDAI, and the elevation of soluble forms of gp130 may be related to the reduced expression of gp130 on CD4+ T cell surface in patients with SLE [47]. The amounts of CD4+CD25+ Tregs were in smaller quantities in moderate and severe SLE patients in comparison with HCs [47]. Data in this research revealed that the proliferation of Tregs is related to the gp130 expression level on the surface of CD4+ Th cells, which may suggest that the decreased gp130 expression on CD4+ Th cells was associated with the downregulated population of Tregs [47].

However, contrary to the studies mentioned above, some researchers reported that IL-35 levels in serum of active SLE patients were higher than those in HCs [48,49]. Qiu et al. observed that higher levels of IL-35 in serum of active SLE patients were reduced after treatment with large doses of prednisone [48]. Therefore, we hypothesized that the reason for the difference in the serum IL-35 concentration compared with the aforementioned studies might partly be related to the fact that active SLE patients in those studies had been treated with glucocorticoids. IL-35 levels in serum were also found obviously increased in newly diagnosed SLE patients in comparison with HCs [50]. In another study, soluble gp130 and IL-35 levels in plasma were increased in newly diagnosed severe SLE patients in comparison with HCs, and Ebi3 and p35 mRNA levels in PBMCs of severe SLE patients were also increased [47]. It is shown that the mRNA level of Ebi3 and p35 in B cells had a considerable increasing trend in the SLE patients compared with HCs [50]. A study that examined subsets of CD3+CD4+, CD3+CD4−, and CD3−CD4− lymphocytes in patients with SLE found no significant differences in the levels of IL-12Rβ2 and gp130 on the surface of the subsets studied [49]. However, the study did not distinguish between living and dead cells, nor did it distinguish Treg independently. The possible reasons for these different results may be that different samples, including PBMCs, plasma, and serum, were tested, different kits were used, and only Chinese patients were studied [51]. Therefore, future experiments with larger sample size and experiments in other ethnic groups are needed for verification.

3.2 Roles of IL-35 in psoriasis

Psoriasis is a chronic disease featuring inflammation. Its characteristics include abnormal infiltration, activation of T cells, and excessive propagation of keratinocytes. The IL-23/IL-17 axis and Th17 cells are both significant in the pathological process of psoriasis [52,53,54]. The IL-35 levels in the serum of psoriasis vulgaris patients before treatment were prominently lower than those in HCs, but the IL-35 levels in serum were obviously upregulated with routine treatment [55]. Plasma IL-35 levels were lower in psoriasis patients in comparison with HCs [56,57]. The level of IL-35 in psoriatic skin biopsies was lower than that in the surrounding skin and normal controls [58]. The study of plaque psoriasis found that the skin lesion of plaque psoriasis patients gradually recovered after treatment with adalimumab; however, the plasma IL-35 level was lower in the adalimumab group [57]. The possible reason for the contrary result is that the observation time is short and the skin lesions in patients with adalimumab treatment are more severe. Expression levels of plasma IL-35 were negatively correlated with IL-17, IL-22, IL-23, TNF-α, and IFN-γ [56]. Meanwhile, its expression was positively related to the levels of IL-10 and TGF-β in psoriasis patients [56]. It is suggested that IL-35 may influence the pathogenesis of psoriasis by regulating the generation of cytokines related to Th17 cells or Tregs.

Similar results were seen in keratin 14-vascular endothelial growth factor A (VEGF-A)-transgenic mouse models. Compared with the control group, which was transfected with the pcDNA3.1 vector, the IL-6 and IL-17A levels in ear tissues and serum supernatant were lower, there were fewer IL-17-secreting CD4+ T cells of lymph nodes and spleen, and the number of CD4+ T cells that secrete IL-10 in lymph nodes and spleen were increased in mice that were transfected with the plasmid coding human IL-35 (pIL-35) group [59]. The levels of classically inflammatory macrophages (M1) in ear tissues and spleens of the pIL-35 group were decreased, while the level of alternatively anti-inflammatory macrophages (M2) was increased, and the M1/M2 ratio was decreased. M1 and M2 are considered to be linked with the inflammatory response in wound healing [60]. IL-35 induced immunosuppression in keratin 14-VEGF-A-transgenic mice via the reduction of the local infiltration of macrophages and the decrease in the M1/M2 proportion [59]. The treatment of IL-35 improved the redness, scaliness, severe ear thickening and swelling, and other psoriatic lesions in psoriasis mice models [59,61]. Rather, it has been reported that no IL-35 was present in the serum in an experiment conducted in Brazilian psoriasis patients [62]. IL-35 may be a potential target to monitor or treat psoriasis, but more studies are needed to confirm its effects in psoriasis.

3.3 Systemic sclerosis

Systemic sclerosis (SSc), an autoimmune connective tissue disease, develops due to abnormal activation of fibroblasts, which produce excessive collagen, resulting in skin and internal visceral fibrosis.

Macrophages, T cells, B cells, and other immune cells are implicated in SSc [63]. The role of IL-35 in the pathogenesis of SSc is unclear. Results of a study on SSC showed that IL-35 was elevated in patients compared to controls, and IL-35 inhibited CD4+ T lymphocyte proliferation and induced Treg differentiation [64]. IL-35 can inhibit type I collagen expression in normal fibroblasts and SSc dermal fibroblasts, and reduce the stability of collagen mRNA in normal fibroblasts [65]. These effects of IL-35 were realized by subunit Ebi3, while another subunit p35 was found to have no such effect in the study [65]. Skin injection of Ebi3 improved skin fibrosis in SSc mice models, further suggesting that IL-35 may have potential therapeutic effects to improve fibrosis during the pathogenesis of SSc [65].

However, other studies suggested that IL-35 promotes collagen production during the pathogenesis of SSc. According to the injury level of the skin, SSc is classified as either diffuse cutaneous SSc or limited cutaneous SSc [66]. These two kinds of SSc patients had higher IL-35 concentrations in serum than that in HCs, while no differences were found in serum IL-35 production between the two types of patients, and patients with lung fibrosis had higher IL-35 levels relative to those without fibrosis [67]. In another study, there was significant upregulation of p35, Ebi3, and IL-35 in lesioned skin from SSc patients in comparison with HCs at both the protein and the mRNA levels [68]. IL-35 expresses and releases increasingly under stimulation of TGF-β, and IL-35 can induce resting fibroblasts to differentiate into myofibroblasts, thereby increasing the release of collagen protein [68]. It has also been observed that IL-35 levels in the serum of SSc patients had a negative relationship with disease duration, and the results of capillary microscopy showed that early SSc patients have higher serum IL-35 levels in comparison with active or late SSc patients [68]. Likewise, Tang et al. observed that the IL-35 levels in the serum of SSc patients were obviously higher than those of the HCs, but after 3 months of treatment, the IL-35 levels in the serum of SSc patients were reduced primarily [69]. It can be inferred that the elevation of serum IL-35 was correlated with the early skin and pulmonary fibrosis of SSc, results that are opposite to the anti-inflammatory effects of IL-35 in other mentioned diseases. Yayla et al. also discovered higher concentrations of IL-35 in SSc patients’ serum, but they found that it was negatively related to C-reactive protein (CRP), Medsger disease severity score, and modified Rodnan skin score [70]. However, IL-35 levels were not different between the SSc patients with or without lung fibrosis in this study; therefore, more studies need to be performed to verify these results. In a word, IL-35 might be one of the serologic biomarkers indicating the inflammatory status of SSc.

3.4 Dermatomyositis

Dermatomyositis (DM) is an autoimmune disease involving the skin and striated muscle. There are different lymphocyte subsets that accumulate in different regions of the muscle in DM patients [71]. The membrane attack complex is composed of B cells and C5-9 complement bodies. T cells, macrophages, dendritic cells, and B cells are all possibly relevant to the pathogenesis of DM [71]. However, there are still few studies exploring the relationship between DM and IL-35. It has been observed that serum concentrations of IL-35 of DM patients are overexpressed relative to HCs [72,73,74]. Surprisingly, the results of the research revealed that IL-35 levels in serum were not correlated to peripheral blood lymphocyte subgroup counts in idiopathic inflammatory myopathy patients [72]. The results of previous experiments showed that the populations of Tregs in the peripheral blood of DM patients were decreased in comparison to HCs [75,76]. There were also decreases in populations of CD3+ cells, CD3+CD8+ cells, and CD3+CD4+ cells in active DM patients compared with patients with inactive DM and HCs [77]. These might mean that the source of IL-35 may come from non-T cell sources but not peripheral blood T cells.

Higher serum expression of IL-35 was found in active DM patients than in remissive individuals [73]. It is observed that serum levels of IL-35 were the highest in DM patients whose disease durations were shorter than 6 months, while the lowest serum frequency of IL-35 was in DM patients with disease duration longer than 12 months compared with HCs. Moreover, the IL-35 frequency in the serum of untreated patients was also higher than in those who relapsed [73]. Additionally, the serum concentrations of IL-35 in idiopathic inflammatory myopathy patients were negatively correlated with the disease course [72,74]. Serum IL-35 quantity had a positive relationship with erythrocyte sedimentation rate (ESR), CRP, lactate dehydrogenase (LDH), creatine kinase, and visual analogue scale [73]. As these measures are correlated with disease activity, and creatine kinase and LDH are the indicators to estimate muscle damage, therefore, serum IL-35 may be a potential biomarker to assess disease activity or muscle damage of DM. Exogenous human recombinant IL-35 downregulated IL-17 and TNF-α production in PBMCs stimulated by lipopolysaccharide from DM patients compared with HCs [73]. These findings suggest that IL-35 may have the effect of immune suppression on DM. However, the possibility that elevated IL-35 probably mediates a pro-inflammatory role in DM patients cannot yet be ruled out. The function of IL-35 in DM pathogenesis still needs to be explored in the future. The experimental results of the above-mentioned diseases in each article are summarized in Table 2.

Table 2

IL-35 levels and biological functions in autoimmune dermatoses

Disease Source Control group Sample Findings Function Ref.
SLE MRL/lpr mice PBS-treated MRL/lpr mice Peripheral blood, splenic, and thymic cells Tregs increased in IL-35-treated MRL/lpr mice Suppress inflammation [41]
— Nephritis and lupus diseases in IL-35-treated MRL/lpr mice were remissive Suppress inflammation [42]
Splenic and thymic cells Foxp3, p35, Ebi3, and free gp130 and IL-12Rβ2 increased in IL-35-treated MRL/lpr mice [42]
Plasma IL-35, gp130, and IL-12Rβ2 increased in IL-35-treated MRL/lpr mice [42]
Peripheral blood, splenic, and thymic cells CD4+CD25+Foxp3+ Tregs and IL-10+ Bregs increased in IL-35-treated MRL/lpr mice [42]
Plasma IFN-γ, TNF-α, IL-6, and IL-17A decreased, and IL-10 increased in IL-35-treated MRL/lpr mice [42]
Plasma Antinuclear antibody and anti-double-stranded DNA antibody decreased in IL-35-treated MRL/lpr mice [42]
Human Healthy individuals PBMC supernatants IL-35 decreased in active SLE patients Suppress inflammation [43]
Plasma IL-35 decreased in newly diagnosed SLE patients Suppress inflammation [46]
PBMCs IL-35+ B cells decreased in newly diagnosed SLE patients [46]
Inactive SLE patients Serum IL-35 decreased in active SLE patients Suppress inflammation [44,45]
Serum IL-35 levels were negatively correlated with SLEDAI-2 k [44,45]
SLE patients without lupus nephritis Serum IL-35 decreased in SLE patients with lupus nephritis [44]
Healthy individuals Serum IL-35 increased in active SLE patients Promote inflammation [48,49]
Serum IL-35 increased in newly diagnosed SLE patients Promote inflammation [50]
B cells P35 and Ebi3 increased in SLE patients [50]
Plasma IL-35 and soluble gp130 increased in severe SLE patients Promote inflammation [47]
PBMCs P53 and Ebi3 increased in severe SLE patients [47]
Th cells Gp130 decreased in severe SLE patients [47]
Th cells Gp130 levels were negatively correlated with SLEDAI [47]
PBMCs CD4+CD25+ Tregs decreased in severe and moderate SLE patients [47]
Psoriasis Human Healthy individuals Serum IL-35 decreased in patients with psoriasis vulgaris Suppress inflammation [55,56]
Plasma IL-35 decreased in psoriasis patients Suppress inflammation [56,57]
Plasma IL-35 levels were negatively correlated with IFN-γ, TNF-α, IL-23, IL-17, IL-22, and positively correlated with TGF-β and IL-10 Suppress inflammation [56]
Skin IL-35 decreased in psoriatic skin biopsies Suppress inflammation [58]
Keratin 14-VEGF-A-transgenic mice Mice transfected with pcDNA3.1 vector Serum and ear tissues supernatant IL-6 and IL-17A decreased in mice transfected with pIL-35 Suppress inflammation [59]
Spleen and lymph node IL-17 secreting CD4+ T cells decreased and IL-10 secreting CD4+ T cells increased in mice transfected with pIL-35 [59]
Spleen and ear tissues M1 decreased and M2 increased in mice transfected with pIL-35 [59]
— Psoriatic lesions were improved in mice transfected with pIL-35 [59]
SSc Human Healthy individuals Serum IL-35 increased in SSc patients, inhibited CD4+ T lymphocyte proliferation, and induced Treg differentiation Suppress inflammation [64]
Serum IL-35 increased in SSc patients Promote inflammation [67,68,69,70]
Serum IL-35 levels were negatively correlated with disease duration, modified Rodnan skin score, Medsger disease severity score, and CRP [68,70]
Skin IL-35 increased in SSc patients, and upregulated differentiation of myofibroblasts [68]
Fibroblasts without IL-35 — Type I collagen expression were inhibited by IL-35 in normal fibroblasts and SSc dermal fibroblasts Suppress inflammation [65]
SSc mice model Balb/c mice injected with PBS Skin Skin fibrosis was improved in mice skin injected with Ebi3 Suppress inflammation [65]
DM Human Healthy individuals Serum IL-35 increased in DM patients Suppress inflammation [72,73,74]
Serum IL-35 levels were negatively correlated with disease duration [72,74]
Serum IL-35 levels were positively correlated with ESR, CRP, visual analogue scale, creatine kinase, and LDH [73]
Recurrent patients Serum IL-35 increased in untreated DM patients [73]
Patients in remission Serum IL-35 increased in active DM patients [73]
Healthy individuals PBMCs Human recombinant IL-35 inhibited IL-17 and TNF-α productions of PBMCs stimulated by lipopolysaccharide from DM patients [73]

SLE – systemic lupus erythematosus, SSc – systemic sclerosis, PBMC – peripheral blood mononuclear cell, SLEDAI-2k – systemic lupus erythematosus disease activity index-2k, pIL-35 – plasmid coding human IL-35 sequence, CRP – C-reactive protein, DM – dermatomyositis, ESR – erythrocyte sedimentation rate, LDH – lactate dehydrogenase.

4 Conclusions

IL-35 acts as a significant inhibitory cytokine in the immunity system, modulating dysfunctional B cells and T cells and regulating various immune-related inflammatory factors. For this reason, IL-35 is important in autoimmune dermatosis. In SLE and psoriasis, a large amount of evidence supports a protective immunosuppressive effect of IL-35; however, it may promote fibrosis, which may suggest the development of inflammation in SSc. IL-35 might play an immunosuppressive role in DM, but this hypothesis remains to be verified. Therefore, its role in immune regulation may vary greatly in different autoimmune diseases, and more studies are needed in the future to elucidate its function of the occurrence and development of different diseases. Although IL-35 plays different roles in the immune regulation of different diseases, it can still be regarded as a treatment target for autoimmune diseases. If IL-35 expression is decreased in a disease, recombinant IL-35 can be used for treatment. If IL-35 expression is significantly upregulated in some diseases, treatment can be performed by reducing the expression of IL-35. With further research on IL-35 in the future, IL-35 is expected to be a new therapeutic target for autoimmune diseases.

Abbreviation list

Breg

regulatory B cell

CRP

C-reactive protein

DM

dermatomyositis

Ebi3

Epstein-Barr virus-induced gene 3

ESR

erythrocyte sedimentation rate

HC

healthy control

IFN-γ

interferon-gamma

IL-10+Breg

regulatory B cells secreting IL-10

IL-35+Breg

regulatory B cells secreting IL-35

IL-35

interleukin-35

iTr35

IL-35-induced regulatory T cells

JAK

Janus kinase

LAIR1

leukocyte-associated-immunoglobulin-like receptor 1

LDH

lactate dehydrogenase

M1

inflammatory macrophages

M2

anti-inflammatory macrophages

MAPK

mitogen-activated protein kinase

MRL

Murphy Roths Large

PBMC

separated peripheral blood mononuclear cell

PBS

phosphate buffer saline

pIL-35

plasmid coding human IL-35

PTPN11

protein tyrosine phosphatase non-receptor type 11

ROR

receptor-related orphan receptor

SLE

systemic lupus erythematosus

SLEDAI

systemic lupus erythematosus disease activity index

SSc

systemic sclerosis

STAT

signal transducer and activator of transcription

Teff

effector T cell

TGF-β

transforming growth factor beta

Th cell

T helper cell

TNF-α

tumour necrosis factor-alpha

Treg

regulatory T cell

VEGF

vascular endothelial growth factor

tel: +86-13574890509

  1. Funding information: This work was supported by research funding from the National Natural Science Foundation of China (No. 81872533 to Qing Zhang), the Hunan Provincial Natural Science Foundation of China (No. 2019JJ40427 to Qing Zhang and No. 2019JJ50855 to Huilin Zhang), and the Hunan Provincial Health Commission Scientific Research Project (No. 20201192 to Huilin Zhang).

  2. Author contributions: Yuming Xie wrote the manuscript, Huilin Zhang and Junke Huang edited the manuscript，and Qing Zhang revised the content. All authors read and approved the final manuscript.

  3. Conflict of interest: The authors declare that they have no competing interests.

  4. Data availability statement: All data generated or analysed during this study are included in this published article.

References

[1] Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566–9. 10.1038/nature06306.Search in Google Scholar

[2] Devergne O, Birkenbach M, Kieff E. Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc Natl Acad Sci U S A. 1997;94(22):12041–6. 10.1073/pnas.94.22.12041.Search in Google Scholar

[3] Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989;170(3):827–45. 10.1084/jem.170.3.827.Search in Google Scholar

[4] Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715–25. 10.1016/s1074-7613(00)00070-4.Search in Google Scholar

[5] Dambuza IM, He C, Choi JK, Yu CR, Wang R, Mattapallil MJ, et al. IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease. Nat Commun. 2017;8(1):719. 10.1038/s41467-017-00838-4.Search in Google Scholar PubMed PubMed Central

[6] Bardel E, Larousserie F, Charlot-Rabiega P, Coulomb-L’Hermine A, Devergne O. Human CD4 + CD25 + Foxp3 + regulatory T cells do not constitutively express IL-35. J Immunol. 2008;181(10):6898–905. 10.4049/jimmunol.181.10.6898.Search in Google Scholar PubMed

[7] Collison LW, Pillai MR, Chaturvedi V, Vignali DA. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol. 2009;182(10):6121–8. 10.4049/jimmunol.0803646.Search in Google Scholar PubMed PubMed Central

[8] Guttek K, Reinhold D. Stimulated human peripheral T cells produce high amounts of IL-35 protein in a proliferation-dependent manner. Cytokine. 2013;64(1):46–50. 10.1016/j.cyto.2013.04.037.Search in Google Scholar PubMed

[9] Allan SE, Song-Zhao GX, Abraham T, McMurchy AN, Levings MK. Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3. Eur J Immunol. 2008;38(12):3282–9. 10.1002/eji.200838373.Search in Google Scholar PubMed

[10] Shen P, Roch T, Lampropoulou V, O’Connor RA, Stervbo U, Hilgenberg E, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507(7492):366–70. 10.1038/nature12979.Search in Google Scholar PubMed PubMed Central

[11] Dixon KO, van der Kooij SW, Vignali DA, van Kooten C. Human tolerogenic dendritic cells produce IL-35 in the absence of other IL-12 family members. Eur J Immunol. 2015;45(6):1736–47. 10.1002/eji.201445217.Search in Google Scholar PubMed PubMed Central

[12] Mao H, Gao W, Ma C, Sun J, Liu J, Shao Q, et al. Human placental trophoblasts express the immunosuppressive cytokine IL-35. Hum Immunol. 2013;74(7):872–7. 10.1016/j.humimm.2013.04.010.Search in Google Scholar PubMed

[13] Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, et al. The composition and signaling of the IL-35 receptor are unconventional. Nat Immunol. 2012;13(3):290–9. 10.1038/ni.2227.Search in Google Scholar PubMed PubMed Central

[14] Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20(6):633–41. 10.1038/nm.3554.Search in Google Scholar PubMed PubMed Central

[15] Szabo SJ, Dighe AS, Gubler U, Murphy KM. Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med. 1997;185(5):817–24. 10.1084/jem.185.5.817.Search in Google Scholar PubMed PubMed Central

[16] Peritt D, Robertson S, Gri G, Showe L, Aste-Amezaga M, Trinchieri G. Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol. 1998;161(11):5821–4. https://www.ncbi.nlm.nih.gov/pubmed/9834059.10.4049/jimmunol.161.11.5821Search in Google Scholar

[17] Saito M, Yoshida K, Hibi M, Taga T, Kishimoto T. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992;148(12):4066–71. https://www.ncbi.nlm.nih.gov/pubmed/1602143.10.4049/jimmunol.148.12.4066Search in Google Scholar

[18] Dietrich C, Candon S, Ruemmele FM, Devergne O. A soluble form of IL-27Ralpha is a natural IL-27 antagonist. J Immunol. 2014;192(11):5382–9. 10.4049/jimmunol.1303435.Search in Google Scholar PubMed

[19] Liu J, Chen X, Hao S, Zhao H, Pang L, Wang L, et al. Human chorionic gonadotropin and IL-35 contribute to the maintenance of peripheral immune tolerance during pregnancy through mediating the generation of IL-10(+) or IL-35(+) Breg cells. Exp Cell Res. 2019;383(2):111513. 10.1016/j.yexcr.2019.111513.Search in Google Scholar PubMed

[20] Olson BM, Jankowska-Gan E, Becker JT, Vignali DA, Burlingham WJ, McNeel DG. Human prostate tumor antigen-specific CD8 + regulatory T cells are inhibited by CTLA-4 or IL-35 blockade. J Immunol. 2012;189(12):5590–601. 10.4049/jimmunol.1201744.Search in Google Scholar PubMed PubMed Central

[21] Li X, Dong Y, Tu K, Wang W. Proteomics analysis reveals the interleukin-35-dependent regulatory mechanisms affecting CD8(+) T-cell functions. Cell Immunol. 2020;348:104022. 10.1016/j.cellimm.2019.104022.Search in Google Scholar PubMed

[22] Guo H, Zhao N, Gao H, He X. Mesenchymal stem cells overexpressing interleukin-35 propagate immunosuppressive effects in mice. Scand J Immunol. 2017;86(5):389–95. 10.1111/sji.12613.Search in Google Scholar PubMed

[23] Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol. 2012;129(1):207–15. e1–5 10.1016/j.jaci.2011.08.009.Search in Google Scholar PubMed PubMed Central

[24] Singh K, Kadesjo E, Lindroos J, Hjort M, Lundberg M, Espes D, et al. Interleukin-35 administration counteracts established murine type 1 diabetes--possible involvement of regulatory T cells. Sci Rep. 2015;5:12633. 10.1038/srep12633.Search in Google Scholar PubMed PubMed Central

[25] Wirtz S, Billmeier U, McHedlidze T, Blumberg RS, Neurath MF. Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology. 2011;141(5):1875–86. 10.1053/j.gastro.2011.07.040.Search in Google Scholar PubMed PubMed Central

[26] Okada K, Fujimura T, Kikuchi T, Aino M, Kamiya Y, Izawa A, et al. Effect of interleukin (IL)-35 on IL-17 expression and production by human CD4(+) T cells. PeerJ. 2017;5:e2999. 10.7717/peerj.2999.Search in Google Scholar PubMed PubMed Central

[27] Zongyi Y, Funian Z, Hao L, Xin W, Ying C, Jialin Z, et al. Interleukin-35 mitigates the function of murine transplanted islet cells via regulation of Treg/Th17 ratio. PLoS One. 2017;12(12):e0189617. 10.1371/journal.pone.0189617.Search in Google Scholar PubMed PubMed Central

[28] Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010;11(12):1093–101. 10.1038/ni.1952.Search in Google Scholar PubMed PubMed Central

[29] Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, et al. A CD4 + T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997;389(6652):737–42. 10.1038/39614.Search in Google Scholar PubMed

[30] Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4 + CD25-precursors. J Immunol. 2002;169(8):4183–9. 10.4049/jimmunol.169.8.4183.Search in Google Scholar PubMed

[31] Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4 + CD25- naive T cells to CD4 + CD25 + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198(12):1875–86. 10.1084/jem.20030152.Search in Google Scholar PubMed PubMed Central

[32] Cho KA, Lee JK, Kim YH, Park M, Woo SY, Ryu KH. Mesenchymal stem cells ameliorate B-cell-mediated immune responses and increase IL-10-expressing regulatory B cells in an EBI3-dependent manner. Cell Mol Immunol. 2017;14(11):895–908. 10.1038/cmi.2016.59.Search in Google Scholar PubMed PubMed Central

[33] Fu LX, Chen T, Sun QM, Zhou PM, Guo ZP. Interleukin-35 inhibited the production of histamine and pro-inflammatory cytokines through suppression MAPKs pathway in HMC-1 cells. Allergy Asthma Clin Immunol. 2021;17(1):38. 10.1186/s13223-021-00543-4.Search in Google Scholar PubMed PubMed Central

[34] Finzel S, Schaffer S, Rizzi M, Voll RE. [Pathogenesis of systemic lupus erythematosus]. Z Rheumatol. 2018;77(9):789–98. 10.1007/s00393-018-0541-3.Search in Google Scholar PubMed

[35] Zheng LT, Zhao LD, Zhao C, Zhao Y, Zhang X, Zhang FC, et al. Effect of serum interleukin-21 on B cell secretory capacity and apoptosis in patients with systemic lupus erythematosus. Zhonghua Nei Ke Za Zhi. 2017;56(2):116–20. 10.3760/cma.j.issn.0578-1426.2017.02.007.Search in Google Scholar PubMed

[36] Araujo JA, Mesquita Jr. D, de Melo Cruvinel W, Salmazi KI, Kallas EG, Andrade LE. Th17 cells and CD4(+) multifunctional T cells in patients with systemic lupus erythematosus. Rev Bras Reumatol Engl Ed. 2016;56(1):28–36. 10.1016/j.rbre.2015.10.003.Search in Google Scholar PubMed

[37] Mu Q, Edwards MR, Swartwout BK, Cabana Puig X, Mao J, Zhu J, et al. Gut Microbiota and Bacterial DNA Suppress Autoimmunity by Stimulating Regulatory B Cells in a Murine Model of Lupus. Front Immunol. 2020;11:593353. 10.3389/fimmu.2020.593353.Search in Google Scholar PubMed PubMed Central

[38] Yang J, Chu Y, Yang X, Gao D, Zhu L, Yang X, et al. Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum. 2009;60(5):1472–83. 10.1002/art.24499.Search in Google Scholar PubMed

[39] Szmyrka-Kaczmarek M, Kosmaczewska A, Ciszak L, Szteblich A, Wiland P. Peripheral blood Th17/Treg imbalance in patients with low-active systemic lupus erythematosus. Postepy Hig Med Dosw (Online). 2014;68:893–8. 10.5604/17322693.1111127.Search in Google Scholar PubMed

[40] Alvarez-Rodriguez L, Martinez-Taboada V, Calvo-Alen J, Beares I, Villa I, Lopez-Hoyos M. Altered Th17/Treg ratio in peripheral blood of systemic lupus erythematosus but not primary antiphospholipid syndrome. Front Immunol. 2019;10:391. 10.3389/fimmu.2019.00391.Search in Google Scholar PubMed PubMed Central

[41] Cai Z, Zhang S, Wu P, Ren Q, Wei P, Hong M, et al. A novel potential target of IL-35-regulated JAK/STAT signaling pathway in lupus nephritis. Clin Transl Med. 2021;11(2):e309. 10.1002/ctm2.309.Search in Google Scholar PubMed PubMed Central

[42] Cai Z, Wong CK, Dong J, Chu M, Jiao D, Kam NW, et al. Remission of systemic lupus erythematosus disease activity with regulatory cytokine interleukin (IL)-35 in Murphy Roths Large (MRL)/lpr mice. Clin Exp Immunol. 2015;181(2):253–66. 10.1111/cei.12639.Search in Google Scholar PubMed PubMed Central

[43] Sonmez C, Yucel AA, Yesil TH, Kucuk H, Sezgin B, Mercan R, et al. Correlation between IL-17A/F, IL-23, IL-35 and IL-12/-23 (p40) levels in peripheral blood lymphocyte cultures and disease activity in Behcet’s patients. Clin Rheumatol. 2018;37(10):2797–2804. 10.1007/s10067-018-4049-7.Search in Google Scholar PubMed

[44] He D, Liu M, Liu B. Interleukin-35 as a new biomarker of renal involvement in lupus nephritis patients. Tohoku J Exp Med. 2018;244(4):263–70. 10.1620/tjem.244.263.Search in Google Scholar PubMed

[45] Ouyang H, Shi YB, Liu ZC, Wang Z, Feng S, Kong SM, et al. Decreased interleukin 35 and CD4 + EBI3 + T cells in patients with active systemic lupus erythematosus. Am J Med Sci. 2014;348(2):156–61. 10.1097/MAJ.0000000000000215.Search in Google Scholar PubMed

[46] Ye Z, Jiang Y, Sun D, Zhong W, Zhao L, Jiang Z. The plasma interleukin (IL)-35 level and frequency of circulating IL-35(+) regulatory B cells are decreased in a cohort of chinese patients with new-onset systemic lupus erythematosus. Sci Rep. 2019;9(1):13210. 10.1038/s41598-019-49748-z.Search in Google Scholar PubMed PubMed Central

[47] Cai Z, Wong CK, Kam NW, Dong J, Jiao D, Chu M, et al. Aberrant expression of regulatory cytokine IL-35 in patients with systemic lupus erythematosus. Lupus. 2015;24(12):1257–66. 10.1177/0961203315585815.Search in Google Scholar PubMed

[48] Qiu F, Song L, Yang N, Li X. Glucocorticoid downregulates expression of IL-12 family cytokines in systemic lupus erythematosus patients. Lupus. 2013;22(10):1011–6. 10.1177/0961203313498799.Search in Google Scholar PubMed

[49] Mohd Shukri ND, Farah Izati A, Wan Ghazali WS, Che Hussin CM, Wong KK. CD3(+)CD4(+)gp130(+) T cells are associated with worse disease activity in systemic lupus erythematosus patients. Front Immunol. 2021;12:675250. 10.3389/fimmu.2021.675250.Search in Google Scholar PubMed PubMed Central

[50] Abbasifard M, Kamiab Z, Hasani M, Rahnama A, Saeed-Askari P, Khorramdelazad H. Assessing the expression of immunosuppressive cytokines in the newly diagnosed systemic lupus Erythematosus patients: a focus on B cells. BMC Immunol. 2020;21(1):58. 10.1186/s12865-020-00388-3.Search in Google Scholar PubMed PubMed Central

[51] Su LC, Liu XY, Huang AF, Xu WD. Emerging role of IL-35 in inflammatory autoimmune diseases. Autoimmun Rev. 2018;17(7):665–73. 10.1016/j.autrev.2018.01.017.Search in Google Scholar PubMed

[52] Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128(5):1207–11. 10.1038/sj.jid.5701213.Search in Google Scholar PubMed

[53] Haider AS, Lowes MA, Suarez-Farinas M, Zaba LC, Cardinale I, Khatcherian A, et al. Identification of cellular pathways of “type 1,” Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis. J Immunol. 2008;180(3):1913–20. 10.4049/jimmunol.180.3.1913.Search in Google Scholar PubMed

[54] Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199(1):125–30. 10.1084/jem.20030451.Search in Google Scholar PubMed PubMed Central

[55] Chen J, Du J, Han Y, Wei Z. Correlation analysis between IL-35, IL-36gamma, CCL27 and psoriasis vulgaris. J Dermatolog Treat. 2021;32(6):621–4. 10.1080/09546634.2019.1689226.Search in Google Scholar PubMed

[56] Li T, Gu M, Liu P, Liu Y, Guo J, Zhang W, et al. Clinical significance of decreased interleukin-35 expression in patients with psoriasis. Microbiol Immunol. 2018;62(7):454–61. 10.1111/1348-0421.12605.Search in Google Scholar PubMed

[57] Zdanowska N, Owczarczyk-Saczonek A, Czerwinska J, Nowakowski JJ, Kozera-Zywczyk A, Owczarek W, et al. Adalimumab and methotrexate affect the concentrations of regulatory cytokines (interleukin-10, transforming growth factor-beta1, and interleukin-35) in patients with plaque psoriasis. Dermatol Ther. 2020;333(6):e14153. 10.1111/dth.14153.Search in Google Scholar PubMed

[58] Owczarczyk-Saczonek A, Czerwinska J, Orylska M, Placek W. Evaluation of selected mechanisms of immune tolerance in psoriasis. Postepy Dermatol Alergol. 2019;36(3):319–28. 10.5114/ada.2019.85641.Search in Google Scholar PubMed PubMed Central

[59] Zhang J, Lin Y, Li C, Zhang X, Cheng L, Dai L, et al. IL-35 decelerates the inflammatory process by regulating inflammatory cytokine secretion and M1/M2 macrophage ratio in psoriasis. J Immunol. 2016;197(6):2131–44. 10.4049/jimmunol.1600446.Search in Google Scholar PubMed

[60] Zheng XF, Hong YX, Feng GJ, Zhang GF, Rogers H, Lewis MA, et al. Lipopolysaccharide-induced M2 to M1 macrophage transformation for IL-12p70 production is blocked by Candida albicans mediated up-regulation of EBI3 expression. PLoS One. 2013;8(5):e63967. 10.1371/journal.pone.0063967.Search in Google Scholar PubMed PubMed Central

[61] Wang Y, Mao Y, Zhang J, Shi G, Cheng L, Lin Y, et al. IL-35 recombinant protein reverses inflammatory bowel disease and psoriasis through regulation of inflammatory cytokines and immune cells. J Cell Mol Med. 2018;22(2):1014–25. 10.1111/jcmm.13428.Search in Google Scholar PubMed PubMed Central

[62] Cardoso PR, Lima EV, Lima MM, Rego MJ, Marques CD, Pitta Ida R, et al. Clinical and cytokine profile evaluation in Northeast Brazilian psoriasis plaque-type patients. Eur Cytokine Netw. 2016;27(1):1–5. 10.1684/ecn.2016.0371.Search in Google Scholar PubMed

[63] Sakkas LI, Bogdanos DP. Systemic sclerosis: new evidence re-enforces the role of B cells. Autoimmun Rev. 2016;15(2):155–61. 10.1016/j.autrev.2015.10.005.Search in Google Scholar PubMed

[64] Yang C, Lei L, Pan J, Zhao C, Wen J, Qin F, et al. Altered CD4 + T cell and cytokine levels in peripheral blood and skin samples from systemic sclerosis patients and IL35 in CD4 + T cell growth. Rheumatology (Oxford). 2022;61(2):794–805. 10.1093/rheumatology/keab359.Search in Google Scholar PubMed

[65] Kudo H, Wang Z, Jinnin M, Nakayama W, Inoue K, Honda N, et al. EBI3 downregulation contributes to type i collagen overexpression in scleroderma skin. J Immunol. 2015;195(8):3565–73. 10.4049/jimmunol.1402362.Search in Google Scholar PubMed

[66] LeRoy EC, Medsger Jr. TA. Criteria for the classification of early systemic sclerosis. J Rheumatol. 2001;28(7):1573–6, https://www.ncbi.nlm.nih.gov/pubmed/11469464.Search in Google Scholar

[67] Dantas AT, Goncalves SM, Pereira MC, Goncalves RS, Marques CD, Rego MJ, et al. Increased IL-35 serum levels in systemic sclerosis and association with pulmonary interstitial involvement. Clin Rheumatol. 2015;34(9):1621–5. 10.1007/s10067-015-3006-y.Search in Google Scholar PubMed

[68] Tomcik M, Zerr P, Palumbo-Zerr K, Storkanova H, Hulejova H, Spiritovic M, et al. Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease. Rheumatology (Oxford). 2015;54(12):2273–82. 10.1093/rheumatology/kev260.Search in Google Scholar PubMed

[69] Tang J, Lei L, Pan J, Zhao C, Wen J. Higher levels of serum interleukin-35 are associated with the severity of pulmonary fibrosis and Th2 responses in patients with systemic sclerosis. Rheumatol Int. 2018;38(8):1511–9. 10.1007/s00296-018-4071-8.Search in Google Scholar PubMed

[70] Yayla ME, Torgutalp M, Okatan IE, Yurteri EU, Kucuksahin O, Dincer ABK, et al. Serum interleukin 35 levels in systemic sclerosis and relationship with clinical features. J Clin Rheumatol. 2020;26(3):83–6. 10.1097/RHU.0000000000000947.Search in Google Scholar PubMed

[71] Thompson C, Piguet V, Choy E. The pathogenesis of dermatomyositis. Br J Dermatol. 2018;179(6):1256–62. 10.1111/bjd.15607.Search in Google Scholar PubMed

[72] Yin L, Ge Y, Yang H, Peng Q, Lu X, Zhang Y, et al. The clinical utility of serum IL-35 in patients with polymyositis and dermatomyositis. Clin Rheumatol. 2016;35(11):2715–21. 10.1007/s10067-016-3347-1.Search in Google Scholar PubMed

[73] Jiang Q, Li Y, Xia L, Shen H, Lu J. Interleukin-35: a serological biomarker for patients with polymyositis/dermatomyositis. J Interferon Cytokine Res. 2019;39(11):720–5. 10.1089/jir.2019.0063.Search in Google Scholar PubMed

[74] Mann H, Krystufkova O, Zamecnik J, Hacek J, Hulejova H, Filkova M, et al. Interleukin-35 in idiopathic inflammatory myopathies. Cytokine. 2020;137:155350. 10.1016/j.cyto.2020.155350.Search in Google Scholar PubMed

[75] Antiga E, Kretz CC, Klembt R, Massi D, Ruland V, Stumpf C, et al. Characterization of regulatory T cells in patients with dermatomyositis. J Autoimmun. 2010;35(4):342–50. 10.1016/j.jaut.2010.07.006.Search in Google Scholar PubMed

[76] Banica L, Besliu A, Pistol G, Stavaru C, Ionescu R, Forsea AM, et al. Quantification and molecular characterization of regulatory T cells in connective tissue diseases. Autoimmunity. 2009;42(1):41–9. 10.1080/08916930802282651.Search in Google Scholar PubMed

[77] Wang DX, Lu X, Zu N, Lin B, Wang LY, Shu XM, et al. Clinical significance of peripheral blood lymphocyte subsets in patients with polymyositis and dermatomyositis. Clin Rheumatol. 2012;31(12):1691–7. 10.1007/s10067-012-2075-4.Search in Google Scholar PubMed

Received: 2021-08-27
Revised: 2022-02-13
Accepted: 2022-02-16
Published Online: 2022-03-21

© 2022 Yuming Xie 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. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
https://doi.org/10.1515/med-2022-0455
Keywords for this article
dermatomyositis; interleukin-35; psoriasis; systemic lupus erythematosus; systemic sclerosis
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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.
© 2025 De Gruyter Brill
Downloaded on 18.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/med-2022-0455/html
Scroll to top button