miR-141-3p attenuates RSL3-induced ferroptosis and intestinal epithelial-mesenchymal transition via directly inhabits ZEB1 in intestinal Behçet's syndrome.

The aims of this study were to investigate whether the ferroptosis is involved in intestinal Behçet's syndrome (IBS), and to identify if miR-141-3p could attenuate RAS-selective lethal 3 (RSL3)-induced ferroptosis and intestinal epithelial to mesenchymal transition (EMT) via directly inhabits zinc fnger E-box binding homeobox 1 (ZEB1). The expressions of ferroptosis-related proteins in the intestinal tissues of patients with IBS were investigated by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Malondialdehyde (MDA) contents of the intestinal tissues and cells were detected. Serum from IBS patients and RSL3 were co-cultured with intestinal epithelial cells in vitro. In order to investigate whether RSL3-induced ferroptosis can be ameliorated by miR-141-3p, the intestinal epithelial cells were firstly stimulated with RSL3 and then incubated with miR-141-3p mimics. Western blot was used to measure the expression of EMT and ferroptosis-related proteins. Expression of GPX4 (22.51% ± 2.05%, 51.75% ± 3.47%, t = - 7.77, p = 0.000) and xCT (17.49% ± 1.57%, 28.73% ± 1.75%, t = - 4.38, p = 0.003) were significantly lower in intestinal mucosal tissues of patients with IBS compared with HC group. Compared with the HC samples, the IBS specimens had significantly higher MDA (t = 4.32, p = 0.01). Moreover, the relative mRNA levels of ferritin light chain (FTL) (t = 4.07, p = 0.02) and ferritin heavy chain (FTH) (t = 8.82, p = 0.001) in the intestinal tissues were significant higher in IBS patients than in HC group. Serum from IBS patients could induce intestinal epithelial cell ferroptosis in vitro. Moreover, miR-141-3p could attenuate intestinal epithelial cell ferroptosis-induced by RSL3 and intestinal EMT via targeting ZEB1 in vitro. Ferroptosis were induced in patients with IBS. Moreover, the serum from IBS patients could induce ferroptosis in vitro. miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1. Therefore, miR-141-3p may open new avenues for the treatment of IBS in the future. Key Points • Ferroptosis in IBS is first reported in this study. • In this study, we explored that the serum from IBS patients could induce ferroptosis in vitro and miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1.

CD80-Fc fusion protein as a potential cancer immunotherapy strategy.

The activation of T lymphocytes is a crucial component of the immune response, and the presence of CD80, a membrane antigen, is necessary for T-cell activation. CD80 is usually expressed on antigen-presenting cells (APCs), which can interact with cluster of differentiation 28 (CD28) or programmed cell death ligand 1 (PD-L1) to promote T-cell proliferation, differentiation and function by activating costimulatory signal or blocking inhibitory signal. Simultaneously, CD80 on the APCs also interacts with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T cells to suppress the response of specific effector T cells, particularly in the context of persistent antigenic stimulation. Due to the pivotal role of CD80 in the immune response, the CD80-Fc fusion protein has emerged as a promising approach for cancer immunotherapy. This review primarily focused on the crucial role of CD80 in the cancer immunotherapy. We also reviewed the current advancements in the research of CD80-Fc fusion proteins. Finally, we deliberated on the challenges encountered by CD80-Fc fusion proteins and proposed the potential strategies that could yield the benefits for patients.

Serum food specific IgG antibodies are associated with small bowel inflammation in patients with Crohn's disease.

BACKGROUND/AIMS: Food antigens are thought to play a vital role in the initiation and perpetuation of Crohn's disease (CD). The main purpose of this study was to evaluate the potential association of serum food specific IgG antibodies and small bowel (SB) inflammation in CD patients. METHODS: We conducted a prospective observational study with 96 CD patients. Demographic, disease-related data and inflammatory parameters were collected. Serum food IgG antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Capsule endoscopy was performed to detect SB inflammation quantified by the Lewis Score. RESULTS: Seventy-eight of (81.3%) CD patients were detected positive for at least one food-specific antibody. The five most prevalent food antibodies in CD patients were tomato, egg, corn, rice, and soybean. Patients with SB inflammation had a higher positive rate of food IgG antibodies (P = 0.010) and more IgG-positive food items (P = 0.010) than those without. Specifically, patients with SB inflammation were more likely to have positive food-specific IgG against egg (P = 0.014), corn (P = 0.014), and wheat (P = 0.048). Additionally, the number of positive food IgGs ≥ 3 and elevated ESR were independently associated with concurrent SB inflammation (P = 0.015 and P = 0.013, respectively). CONCLUSION: Our study confirmed that CD patients with SB inflammation had a higher positive rate of food IgG antibodies and more IgG-positive food items. The number of food positive IgGs ≥ 3 and elevated ESR were independently associated with concurrent SB inflammation.

Targeting collagen in tumor extracellular matrix as a novel targeted strategy in cancer immunotherapy.

Collagen, the most abundant protein in mammal, is widely expressed in tissues and organs, as well as tumor extracellular matrix. Tumor collagen mainly accumulates in tumor stroma or beneath tumor blood vessel endothelium, and is exposed due to the fragmentary structure of tumor blood vessels. Through the blood vessels with enhanced permeability and retention (EPR) effect, collagen-binding macromolecules could easily bind to tumor collagen and accumulate within tumor, supporting tumor collagen to be a potential tumor-specific target. Recently, numerous studies have verified that targeting collagen within tumor extracellular matrix (TEM) would enhance the accumulation and retention of immunotherapy drugs at tumor, significantly improving their anti-tumor efficacy, as well as avoiding severe adverse effects. In this review, we would summarize the known collagen-binding domains (CBD) or proteins (CBP), their mechanism and application in tumor-targeting immunotherapy, and look forward to future development.

A collagen-binding SIRPαFc fusion protein for targeted cancer immunotherapy.

Collagen is abundant but exposed in tumor due to the abnormal tumor blood vessels, thus is considered as a tumor-specific target. The A3 domain of von Willebrand factor (vWF A3) is a kind of collagen-binding domain (CBD) which could bind collagen specifically. Previously we reported a chemosynthetic CBD-SIRPαFc conjugate, which could block CD47 and derived tumor-targeting ability by CBD. CBD-SIRPαFc conjugate represented improved anti-tumor efficacy with increased MHC II+ M1 macrophages, but the uncertain coupling ratio remained a problem. Herein, we produced a vWF A3-SIRPαFc fusion protein through eukaryotic expression system. It was examined at both molecular and cellular levels with its collagen affinity, uninfluenced original affinity to targets and phagocytosis-promoting function compared to unmodified SIRPαFc. Living imaging showed that vWF A3-SIRPαFc fusion protein derived the improved accumulation and retention in tumor than SIRPαFc. In the MC38 allograft model, vWF A3-SIRPαFc demonstrated a superior tumor-suppressing effect, characterized by increased MHC II+ M1 macrophages and T cells (particularly CD4+ T cells). These results revealed that vWF A3-SIRPαFc fusion protein derived tumor-targeting ability, leading to improved anti-tumor immunotherapeutic efficacy compared to SIRPαFc. Altogether, vWF A3 improved the anti-tumor efficacy and immune-activating function of SIRPαFc, supporting targeting tumor collagen as a possible targeted strategy.

Discoidin domain receptor 1 is a potential target correlated with tumor invasion and immune infiltration in gastric cancer.

Discoidin domain receptor 1 (DDR1) has been demonstrated to be able to promote tumor invasion and metastasis and being closely related to tumor immune infiltration. However, DDR1 has rarely been studied in gastric cancer. Here, we primarily evaluated DDR1 expression in gastric cancer and its cell lines using multiple databases. Subsequently, the cancer prognosis was investigated in relation to DDR1 expression. After analysis, we discovered that DDR1 was highly expressed and significantly connected with poor prognosis in gastric cancer. To comprehensively understand the molecular mechanism of DDR1, we explored genes and proteins interacting with DDR1 in gastric cancer using databases. Additionally, we found that the expression level of DDR1 was inversely correlated with immune infiltration and significantly relative to various immune cell markers. Overall, DDR1 was implicated in invasion, metastasis, and immune infiltration of gastric cancer. Inhibition of DDR1 may have the potential to alleviate the strong invasiveness and metastasis of advanced gastric cancer. Meanwhile, immune exclusion by DDR1 may also provide a new strategy for improving the efficacy of immune checkpoints inhibitors (ICIs), such as programmed cell death protein 1 (PD-1) antibody.

A SIRPαFc Fusion Protein Conjugated With the Collagen-Binding Domain for Targeted Immunotherapy of Non-Small Cell Lung Cancer.

The SIRPαFc fusion protein can block the immunosuppressive CD47-SIRPα signal between macrophages and tumor cells as a decoy receptor and has demonstrated its immunotherapeutic efficacy in various tumors. However, its clinical application was limited because of the potential hematologic toxicity. The heptapeptide "TKKTLRT" is a collagen-binding domain (CBD) which can bind collagen specifically. Herein, we aim to improve the tumor targeting of SIRPαFc and therefore avoid its unnecessary exposure to normal cells through synthesizing a TKKTLRT-SIRPαFc conjugate. Experiments at molecular and cellular levels indicate that the TKKTLRT-SIRPαFc conjugate-derived collagen-binding affinity and the introduction of CBD did not impact the CD47-binding affinity as well as its phagocytosis-promoting effect on NSCLC cells. In vivo distribution experiments showed that CBD-SIRPαFc accumulated in tumor tissue more effectively compared to unmodified SIRPαFc, probably due to the exposed collagen in the tumor vascular endothelium and stroma resulting from the abnormal vessel structure. On an A549 NSCLC nude mouse xenograft model, CBD-SIRPαFc presented more stable and effective antitumor efficacy than SIRPαFc, along with significantly increased CD11b+F4/80+ macrophages especially MHC II+ M1 macrophages within tumors. All of these results revealed that CBD brought a tumor-targeting ability to the SIRPαFc fusion protein, which contributed to the enhanced antitumor immune response. Altogether, the CBD-SIRPαFc conjugate may have the potential to be an effective tumor immunotherapy with improved antitumor efficacy but less non-tumor-targeted side effect.

Association between ABO blood group and risk of Crohn's disease: A case-control study in the Chinese Han population.

BACKGROUND: Blood group O has been reported to be a potentially protective factor for Crohn's disease (CD) susceptibility in Caucasian and Korean populations, but a similar conclusion was not found in a Chinese study. The present study investigated the potential association in the Chinese Han population. METHODS: We included 275 CD patients, 132 ulcerative colitis (UC) patients and 1201 healthy individuals in this case-control study. The demographic characteristics and ABO blood group were compared among the three groups. The clinical characteristics and treatment of CD were further investigated according to the blood group distribution. RESULTS: The blood group distribution in CD patients was significantly different from healthy controls, and the frequency of O blood in CD patients was significantly lower compared to healthy controls. After adjusting for age and gender, the non-O blood groups remained significantly associated with CD susceptibility in propensity score-adjusted and propensity score-matched analyses. Compared to CD patients with non-O blood groups, patients with O blood were at a lower risk of developing penetrating disease, more likely to receive immunosuppressant treatment and less likely to receive biological treatment. CONCLUSION: Our results confirmed that non-O blood groups were significantly associated with an increased risk of CD in the Chinese Han population.

Risk factors for the flare of systemic lupus erythematosus and its influence on prognosis: a single-center retrospective analysis.

OBJECTIVES: To explore the risk factors for systemic lupus erythematosus (SLE) flare and their impact on prognosis. METHODS: The clinical characteristics, laboratory results, and treatment plans of 121 patients with SLE flare were retrospectively analyzed. Ninety-eight SLE outpatients with sustained remission during the same period were selected as controls. Logistic multivariate regression analysis was employed to screen for risk factors for SLE flare. RESULTS: Infection, thrombocytopenia, arthritis, anti-nucleosome antibodies positive, anti-ß2-glycoprotein I (IgG) antibodies positive, and patient's self-discontinuation of medicine maintenance therapy might be risk factors for SLE flare. Patients who discontinued medicine maintenance therapy by themselves had a significantly higher rate of severe SLE flare than patients with regular medicine maintenance therapy (P = 0.033). The incidence of anemia associated with SLE (P = 0.001), serositis (P = 0.005), and pulmonary hypertension (P = 0.003) in patients who discontinued medicine maintenance therapy were significantly higher than patients with regular medicine maintenance therapy. SLE patients with regular medicine maintenance therapy for less than 3 years had a higher risk of pulmonary hypertension than those with regular medicine maintenance therapy longer than 3 years (P = 0.034). CONCLUSIONS: The accompanying thrombocytopenia, arthritis, anti-nucleosome antibodies positive and anti-ß2-glycoprotein I (IgG) antibodies positive at the onset of SLE may affect the prognosis of SLE. Patient's self-discontinuation of medicine maintenance therapy is the main cause of SLE flare, which may induce severe flare in SLE patients and lead to a significantly higher incidence of pulmonary hypertension.

[Corrigendum] Combination treatment of adipose­derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway.

Following the publication of the above article, an interested reader drew the authors' attention that the data featured in Fig. 1B (for adipogenic differentiation of adipose­derived stem cells) and Fig. 1F (for expression of green fluorescent protein of adipose­derived stem cells) of the above article appeared to have already been published as Fig. 1A (for adipogenic differentiation of adipose­derived stem cells) and Fig. 2D (for expression of green fluorescent protein of adipose­derived stem cells) in the following article: Luo L, Lin T, Zheng S, Xie Z, Chen M, Lian G, Xu C, Wang H and Xie L: Adipose­derived stem cells attenuate pulmonary arterial hypertension and ameliorate pulmonary arterial remodeling in monocrotaline­induced pulmonary hypertensive rats. Clin Exp Hypertens 37: 241­248, 2015. The authors consulted their original data and were able to determine that the duplication of these figure parts had arisen inadvertently during the process of compiling the figure. The revised version of Fig. 1, featuring the corrected data panels for the above­mentioned experiments in Fig. 1B and F, is shown on the next page. The authors confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum. Furthermore, they apologize to the readership of the Journal for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 41: 51­60, 2018; DOI: 10.3892/ijmm.2017.3226].

Predictive Value of Active Sacroiliitis in MRI for Flare Among Chinese Patients with Axial Spondyloarthritis in Remission.

INTRODUCTION: In recent axSpAx patients with remission lasting at least 3 months and later followed-up monthly for a median of 8 months, we compared the predictive value of baseline MRI of sacroiliac joints and constructed a nomogram model for predicting flare. METHODS: This study included 251 patients with axial spondyloarthritis, according to the ASAS axSpA classification criteria, who achieved Low Disease Activity (ASDAS) and underwent MRI examination. A total of 144 patients from the First Affiliated Hospital of Xiamen University were used as the nomogram training set; 107 from the First Affiliated Hospital of Fujian Medical University were for external validation. RESULTS: The median time of relapse was 8.705 months (95% CI 8.215-9.195) and 7.781 months (95% CI 7.075-8.486) for MRI-positive patients and 9.8 months (95% CI 9.273-10.474) for MRI negative patients, respectively. Both active sacroiliitis on MRI (HR 1.792, 95% CI 1.230-2.611) and anti-TNF-α treatments (HR 0.507, 95% CI 0.349-0.736) were significantly associated with disease flares. Gender, disease duration, HLA-B27, MRI, and anti-TNF-α treatment were selected as predictors of the nomogram. The areas under the ROC curve (AUROCs) of the 1-year remission probability in the training and validation groups were 0.71 and 0.729, respectively. Nomogram prediction models present better AUROCs, C-indices, and decision curve analysis cure than the clinical experience model. CONCLUSIONS: Active sacroiliitis in MRI requires weighting in order to estimate remission and disease flares, when axSpA patients achieve low disease activity. The simple nomogram might be able to discriminate and calibrate in clinical practice. TRIAL REGISTRATION: ClinicalTrials, NCT03425812, Registered 8 February 2018, https://clinicaltrials.gov.

Risk factors for the flare of systemic lupus erythematosus and its influence on prognosis: a single-center retrospective analysis

Abstract Objectives: To explore the risk factors for systemic lupus erythematosus (SLE) flare and their impact on prognosis. Methods: The clinical characteristics, laboratory results, and treatment plans of 121 patients with SLE flare were retrospectively analyzed. Ninety-eight SLE outpatients with sustained remission during the same period were selected as controls. Logistic multivariate regression analysis was employed to screen for risk factors for SLE flare. Results: Infection, thrombocytopenia, arthritis, anti-nucleosome antibodies positive, anti-β2-glycoprotein I (IgG) antibodies positive, and patient's self-discontinuation of medicine maintenance therapy might be risk factors for SLE flare. Patients who discontinued medicine maintenance therapy by themselves had a significantly higher rate of severe SLE flare than patients with regular medicine maintenance therapy ( P = 0.033). The incidence of anemia associated with SLE ( P = 0.001), serositis ( P = 0.005), and pulmonary hypertension ( P = 0.003) in patients who discontinued medicine maintenance therapy were significantly higher than patients with regular medicine maintenance therapy. SLE patients with regular medicine maintenance therapy for less than 3years had a higher risk of pulmonary hypertension than those with regular medicine maintenance therapy longer than 3years ( P = 0.034). Conclusions: The accompanying thrombocytopenia, arthritis, anti-nucleosome antibodies positive and anti-β2-glycoprotein I (IgG) antibodies positive at the onset of SLE may affect the prognosis of SLE. Patient's self-discontinuation of medicine maintenance therapy is the main cause of SLE flare, which may induce severe flare in SLE patients and lead to a significantly higher incidence of pulmonary hypertension.

Combination treatment of adipose-derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway.

The present study aimed to assess the effects of therapy with adiponectin (APN) gene-modified adipose-derived stem cells (ADSCs) on pulmonary arterial hypertension (PAH) in rats and the underlying cellular and molecular mechanisms. ADSCs were successfully isolated from the rats and characterized. ADSCs were effectively infected with the green fluorescent protein (GFP)-empty (ADSCs-V) or the APN-GFP (ADSCs-APN) lentivirus and the APN expression was evaluated by ELISA. Sprague-Dawley rats were administered monocrotaline (MCT) to develop PAH. The rats were treated with MCT, ADSCs, ADSCs-V and ADSCs-APN. Then ADSCs-APN in the lung were investigated by confocal laser scanning microscopy and western blot analysis. Engrafted ADSCs in the lung were located around the vessels. Mean pulmonary arterial pressure (mPAP) and the right ventricular hypertrophy index (RVHI) in the ADSCs-APN-treated mice were significantly decreased as compared with the ADSCs and ADSCs-V treatments. Pulmonary vascular remodeling was assessed. Right ventricular (RV) function was evaluated by echocardiography. We found that pulmonary vascular remodeling and the parameters of RV function were extensively improved after ADSCs-APN treatment when compared with ADSCs and ADSCs-V treatment. Pulmonary artery smooth muscle cells (PASMCs) were isolated from the PAH rats. The antiproliferative effect of APN on PASMCs was assayed by Cell Counting Kit-8. The influence of APN and specific inhibitors on the levels of bone morphogenetic protein (BMP), adenosine monophosphate activated protein kinase (AMPK), and small mothers against decapentaplegia (Smad) pathways was detected by western blot analysis. We found that APN suppressed the proliferation of PASMCs isolated from the PAH rats by regulating the AMPK/BMP/Smad pathway. This effect was weakened by addition of the AMPK inhibitor (compound C) and BMP2 inhibitor (noggin). Therefore, combination treatment with ADSCs and APN effectively attenuated PAH in rats by inhibiting PASMC proliferation and regulating the AMPK/BMP/Smad pathway.