Phytic acid/tannic acid reinforced hydrogels with ultra-high strength for human motion monitoring and arrays.

Conductive hydrogels have been widely researched for their potential applications in soft electronic devices. Creating environmentally friendly and multifunctional high-strength hydrogels for high-performance devices remains a significant challenge. This study employs the biodegradable material polyvinyl alcohol (PVA) as the primary component, with phytic acid (PA) and tannic acid (TA) as reinforcing phases, to create a multifunctional, high-strength "green" hydrogel. Through the multiple complexations of two bio-enhancing phases with the PVA main chain, this hydrogel attains ultra-high tensile strength (9.341 MPa), substantial toughness (4.262 MJ m-3), and extensive fracture strain (> 1000%), making it a representative with both mechanical performance and antibacterial capabilities. Additionally, it exhibits a low strain sensing limit (0.5%) and excellent durability (500 cycles under 50% strain). This work introduces a novel strategy of combining biodegradable materials with biomass to fabricate multifunctional hydrogels suitable for human motion monitoring and 2D pressure distribution.

Inhibition of the RBMS1/PRNP axis improves ferroptosis resistance-mediated oxaliplatin chemoresistance in colorectal cancer.

The majority of patients with advanced colorectal cancer have chemoresistance to oxaliplatin, and studies on oxaliplatin resistance are limited. Our research showed that RNA-binding motif single-stranded interacting protein 1 (RBMS1) caused ferroptosis resistance in tumor cells, leading to oxaliplatin resistance. We employed bioinformatics to evaluate publically accessible data sets and discovered that RBMS1 was significantly upregulated in oxaliplatin-resistant colorectal cancer cells, in tandem with ferroptosis suppression. In vivo and in vitro studies revealed that inhibiting RBMS1 expression caused ferroptosis in colorectal cancer cells, restoring tumor cell sensitivity to oxaliplatin. Mechanistically, this is due to RBMS1 inducing prion protein translation, resulting in ferroptosis resistance in tumor cells. Validation of clinical specimens revealed that RBMS1 is similarly linked to tumor development and a poor prognosis. Overall, RBMS1 is a potential therapeutic target with clinical translational potential, particularly for oxaliplatin chemoresistance in colorectal cancer.

Interleukin-37 contributes to endometrial regenerative cell-mediated immunotherapeutic effect on chronic allograft vasculopathy.

BACKGROUND AIMS: Chronic allograft vasculopathy (CAV) remains a predominant contributor to late allograft failure after organ transplantation. Several factors have already been shown to facilitate the progression of CAV, and there is still an urgent need for effective and specific therapeutic approaches to inhibit CAV. Human mesenchymal-like endometrial regenerative cells (ERCs) are free from the deficiencies of traditional invasive acquisition methods and possess many advantages. Nevertheless, the exact immunomodulation mechanism of ERCs remains to be elucidated. METHODS: C57BL/6 (B6) mouse recipients receiving BALB/c mouse donor abdominal aorta transplantation were treated with ERCs, negative control (NC)-ERCs and interleukin (IL)-37-/-ERCs (ERCs with IL-37 ablation), respectively. Pathologic lesions and inflammatory cell infiltration in the grafts, splenic immune cell populations, circulating donor-specific antibody levels and cytokine profiles were analyzed on postoperative day (POD) 40. The proliferative capacities of Th1, Th17 and Treg subpopulations were assessed in vitro. RESULTS: Allografts from untreated recipients developed typical pathology features of CAV, namely endothelial thickening, on POD 40. Compared with untreated and IL-37-/-ERC-treated groups, IL-37-secreting ERCs (ERCs and NC-ERCs) significantly reduced vascular stenosis, the intimal hyperplasia and collagen deposition. IL-37-secreting ERCs significantly inhibited the proliferation of CD4+T cells, reduced the proportions of Th1 and Th17 cells, but increased the proportion of Tregs in vitro. Furthermore, in vitro results also showed that IL-37-secreting ERCs significantly inhibited Th1 and Th17 cell responses, abolished B-cell activation, diminished donor-specific antibody production and increased Treg proportions. Notably, IL-37-secreting ERCs remarkably downregulated the levels of pro-inflammatory cytokines (interferon-γ, tumor necrosis factor-α, IL-1ß, IL-6 and IL-17A) and increased IL-10 levels in transplant recipients. CONCLUSIONS: The knockdown of IL-37 dramatically abrogates the therapeutic ability of ERCs for CAV. Thus, this study highlights that IL-37 is indispensable for ERC-mediated immunomodulation for CAV and improves the long-term allograft acceptance.

Retrograde type A aortic dissection during or after thoracic endovascular aortic repair: a single center 16-year experience.

Objective: This article aims to investigate the incidence rate of retrograde type A aortic dissection (RTAD) and the risk factors of RTAD in relation to thoracic endovascular aortic repair (TEVAR). Methods: Patients with thoracic aortic disease who underwent TEVAR at Henan Provincial People's Hospital from January 2004 to December 2019 were enrolled in the present research. The risk factors associated with RTAD following TEVAR using univariate and multiple logistic regression analyses. Results: During the study period, A total of 1,688 TEVAR patients were included in this study, and of these, 1,592 cases were included in the type B aortic dissection (TBAD) group, and 96 cases were included in the non-TBAD group. There were 1,230 cases of aortic dissection and 362 cases of aortic intramural hematoma and/or penetrating ulcer in the TBAD group. The non-TBAD group included 68 cases of thoracic aortic aneurysm, 21 cases of thoracic aortic pseudoaneurysm, and seven cases of congenital aortic coarctation. The overall incidence rate of RTAD was 1.1% (18/1,688) in patients, all of which occurred in the TBAD group. The cohort comprised 18 RTAD patients with an average age of 56.78, consisting of 13 males and 5 females. Among them, 13 individuals exhibited hypertension. Ten instances happened within the TEVAR perioperative period, including two cases during the surgery, six cases occurred within three months, two cases occurred after one year, and the longest interval was 72 months following TEVAR. TEVAR was successfully implemented in 17 patients, while the operation technique was temporarily altered in one case. The new entry position for RTAD was identified as the proximal region of the stent graft (SG) in 13 patients, while in five cases, the entry site was more than 2 cm away from the proximal region of the SG. 17 cases were at the greater curvature of the aorta, and one case was at the lesser curvature. Multivariate logistic regression analysis revealed that the SG oversizing ratio is a relevant risk factor for RTAD. However, ascending aortic diameter, aortic arch type, SG type, and anchored region were not directly related to the occurrence of RTAD. Conclusion: RTAD is a rare yet catastrophic complication. It could occur both during the procedure, early and late postoperative periods. Maintaining an appropriate SG oversizing ratio is crucial to minimize the risk of RTAD.

MPs-ACT, an Assay to Evaluate the Procoagulant Activity of Microparticles.

The procoagulant effect of microparticles (MPs) contributes to hypercoagulability-induced thrombosis. We provide preliminary findings of the MPs-Activated Clotting Time (MPs-ACT) assay to determine the procoagulant activity of MPs. MPs-rich plasma was obtained and recalcified. Changes in plasma viscoelasticity were evaluated and the time to the peak viscoelastic changes was defined as the MPs-ACT. MPs concentration was measured by flow cytometry. Coagulation products produced during plasma clotting were identified by fibrin and fibrinopeptide A. MPs were prepared in vitro and added to standard plasma to simulate pathological samples. In addition, reproducibility and sensitivity were evaluated. We confirmed the linear relationship between MPs-ACT and MP concentrations. Dynamic changes in fibrin production were depicted. We simulated the correlation between MPs-ACT and standard plasma containing MPs prepared in vitro. The reproducibility of high-value and low-value samples was 6.0% and 10.8%, respectively. MPs-ACT sensitively detected hypercoagulable samples from patients with pre-eclampsia, hip fractures, and lung tumors. MPs-ACT largely reflects the procoagulant effect of MPs. MPs-ACT sensitively and rapidly detects hypercoagulability with MPs-rich plasma. It may be promising for the diagnosis of hypercoagulable states induced by MPs.

A nomogram risk assessment model to predict the possibility of type II endoleak-related re-intervention after endovascular aneurysm repair (EVAR).

This study aimed to develop and validate a novel nomogram risk assessment model to predict the possibility of type II endoleak (T2EL)-related re-intervention. The data of 455 patients with abdominal aortic aneurysms who underwent elective endovascular aneurysm repair (EVAR) procedures between January 2018 and December 2021 at our single center were retrospectively reviewed. Following the implementation of exclusion criteria, 283 patients were finally included and divided into T2EL-related re-intervention (n = 42) and non-T2EL (n = 241) groups. The overall T2EL-related re-intervention rate for 283 patients was 14.8% (42/283). Using multivariate analysis, significant risk factors for re-intervention included age (OR, 1.172; 95% CI, 1.051-1.307; P = 0.004), smoking (OR, 13.418; 95% CI, 2.362-76.215; P = 0.003), diameter of inferior mesenteric artery (IMA) (OR, 21.380; 95% CI, 3.060-149.390; P = 0.002), and number of patent lumbar arteries (OR, 9.736; 95% CI, 3.175-29.857; P < 0.001). The discrimination ability of this risk-predictive model was reasonable (concordance index [C-index] = 0.921; 95% CI, 0.878-0.964). The Hosmer-Lemeshow goodness of fit test was performed on the model, and the chi-square value was 3.210 (P = 0.920), presenting an excellent agreement between the model-predicted and observed values. The receiver operating characteristic (ROC) curve identified that the risk thresholds of re-intervention were a diameter of > 2.77 mm for the diameter of the inferior mesenteric artery and a proportion of < 45.5% for thrombus volume in the aneurysm sac. This novel nomogram risk assessment model for predicting the possibility of patients' T2EL-related re-interventions after EVAR should be helpful in discriminating high-risk patients. Two novel risk thresholds may imply a higher possibility of T2EL-related re-intervention after EVAR.

Heterologous Expression of Human Metallothionein Gene HsMT1L Can Enhance the Tolerance of Tobacco (Nicotiana nudicaulis Watson) to Zinc and Cadmium.

Metallothionein (MT) is a multifunctional inducible protein in animals, plants, and microorganisms. MT is rich in cysteine residues (10-30%), can combine with metal ions, has a low molecular weight, and plays an essential biological role in various stages of the growth and development of organisms. Due to its strong ability to bind metal ions and scavenge free radicals, metallothionein has been used in medicine, health care, and other areas. Zinc is essential for plant growth, but excessive zinc (Zn) is bound to poison plants, and cadmium (Cd) is a significant environmental pollutant. A high concentration of cadmium can significantly affect the growth and development of plants and even lead to plant death. In this study, the human metallothionein gene HsMT1L under the control of the CaMV 35S constitutive promoter was transformed into tobacco, and the tolerance and accumulation capacity of transgenic tobacco plants to Zn and Cd were explored. The results showed that the high-level expression of HsMT1L in tobacco could significantly enhance the accumulation of Zn2+ and Cd2+ in both the aboveground parts and the roots compared to wild-type tobacco plants and conferred a greater tolerance to Zn and Cd in transgenic tobacco. Subcellular localization showed that HsMT1L was localized to the nucleus and cytoplasm in the tobacco. Our study suggests that HsMT1L can be used for the phytoremediation of soil for heavy metal removal.

Effects of Phytochelatin-like Gene on the Resistance and Enrichment of Cd2+ in Tobacco.

Phytochelatins (PCs) are class III metallothioneins in plants. They are low molecular-weight polypeptides rich in cysteine residues which can bind to metal ions and affect the physiological metabolism in plants. Unlike other types of metallothioneins, PCs are not the product of gene coding but are synthesized by phytochelatin synthase (PCS) based on glutathione (GSH). The chemical formula of phytochelatin is a mixture of (γ-Glu-Cys)n-Gly (n = 2-11) and is influenced by many factors during synthesis. Phytochelatin-like (PCL) is a gene-encoded peptide (Met-(α-Glu-Cys)11-Gly) designed by our laboratory whose amino acid sequence mimics that of a natural phytochelatin. This study investigated how PCL expression in transgenic plants affects resistance to Cd and Cd accumulation. Under Cd2+ stress, transgenic plants were proven to perform significantly better than the wild-type (WT), regarding morphological traits and antioxidant abilities, but accumulated Cd to higher levels, notably in the roots. Fluorescence microscopy showed that PCL localized in the cytoplasm and nucleus.

IL-37 overexpression promotes endometrial regenerative cell-mediated inhibition of cardiac allograft rejection.

BACKGROUND: Endometrial regenerative cells (ERCs) play an important role in attenuation of acute allograft rejection, while their effects are limited. IL-37, a newly discovered immunoregulatory cytokine of the IL-1 family, can regulate both innate and adaptive immunity. Whether IL-37 overexpression can enhance the therapeutic effects of ERCs in inhibition of acute cardiac allograft rejection remains unknown and will be explored in this study. METHODS: C57BL/6 mice recipients receiving BALB/c mouse heterotopic heart allografts were randomly divided into the phosphate-buffered saline (untreated), ERC treated, negative lentiviral control ERC (NC-ERC) treated, and IL-37 overexpressing ERC (IL-37-ERC) treated groups. Graft pathological changes were assessed by H&E staining. The intra-graft cell infiltration and splenic immune cell populations were analyzed by immunohistochemistry and flow cytometry, respectively. The stimulatory property of recipient DCs was tested by an MLR assay. Furthermore, serum cytokine profiles of recipients were measured by ELISA assay. RESULTS: Mice treated with IL-37-ERCs achieved significantly prolonged allograft survival compared with the ERC-treated group. Compared with all the other control groups, IL-37-ERC-treated group showed mitigated inflammatory response, a significant increase in tolerogenic dendritic cells (Tol-DCs), regulatory T cells (Tregs) in the grafts and spleens, while a reduction of Th1 and Th17 cell population. Additionally, there was a significant upregulation of immunoregulatory IL-10, while a reduction of IFN-γ, IL-17A, IL-12 was detected in the sera of IL-37-ERC-treated recipients. CONCLUSION: IL-37 overexpression can promote the therapeutic effects of ERCs to inhibit acute allograft rejection and further prolong graft survival. This study suggests that gene-modified ERCs overexpressing IL-37 may pave the way for novel therapeutic options in the field of transplantation.

Four-Pyroptosis Gene-Based Nomogram as a Novel Strategy for Predicting the Effect of Immunotherapy in Hepatocellular Carcinoma.

Background: Immunotherapy has been considered as a promising cancer treatment for hepatocellular carcinoma (HCC). However, due to the particular immune environment of the liver, identifying patients who could benefit from immunotherapy is critical in clinical practice. Methods: The pyroptosis gene expression database of 54 candidates from The Cancer Genome Atlas (TCGA) were collected to discover the critical prognostic-related pyroptosis genes. A novel pyroptosis gene model was established to calculate the risk score. Kaplan-Meier analysis and receiver operating characteristic curve (ROC) were used to verify its predictive ability. The International Cancer Genome Consortium (ICGC) data was collected as external validation data to verify the model's accuracy. We employed multiple bioinformatics tools and algorithms to evaluate the tumor immune microenvironment (TIME) and the response to immunotherapy. Results: Our study found that most pyroptosis genes were expressed differently in normal and tumor tissues and that their expression was associated with the prognosis. Then, a precise four-pyroptosis gene model was generated. The one-year area under the curves (AUCs) among the training, internal, and external validation patients were 0.901, 0.727, and 0.671, respectively. An analysis of survival data revealed that individuals had a worse prognosis than patients with low risk. The analysis of TIME revealed that the low-risk group had more antitumor cells, fewer immunosuppressive cells, stronger immune function, less immune checkpoint gene expression, and better immunotherapy response than the high-risk group. Immunophenoscore (IPS) analysis also demonstrated that the low-risk score was related to superior immune checkpoint inhibitors therapy. Conclusion: A nomogram based on the four-pyroptosis gene signature was a novel tool to predict the effectiveness of immunotherapy for HCC. Therefore, individualized treatment targeting the pyroptosis genes may influence TIME and play an essential role in improving the prognosis in HCC patients.

Structural and Temporal Dynamics of Mesenchymal Stem Cells in Liver Diseases From 2001 to 2021: A Bibliometric Analysis.

Background: Mesenchymal stem cells (MSCs) have important research value and broad application prospects in liver diseases. This study aims to comprehensively review the cooperation and influence of countries, institutions, authors, and journals in the field of MSCs in liver diseases from the perspective of bibliometrics, evaluate the clustering evolution of knowledge structure, and discover hot trends and emerging topics. Methods: The articles and reviews related to MSCs in liver diseases were retrieved from the Web of Science Core Collection using Topic Search. A bibliometric study was performed using CiteSpace and VOSviewer. Results: A total of 3404 articles and reviews were included over the period 2001-2021. The number of articles regarding MSCs in liver diseases showed an increasing trend. These publications mainly come from 3251 institutions in 113 countries led by China and the USA. Li L published the most papers among the publications, while Pittenger MF had the most co-citations. Analysis of the most productive journals shows that most are specialized in medical research, experimental medicine and cell biology, and cell & tissue engineering. The macroscopical sketch and micro-representation of the whole knowledge field are realized through co-citation analysis. Liver scaffold, MSC therapy, extracellular vesicle, and others are current and developing areas of the study. The keywords "machine perfusion", "liver transplantation", and "microRNAs" also may be the focus of new trends and future research. Conclusions: In this study, bibliometrics and visual methods were used to review the research of MSCs in liver diseases comprehensively. This paper will help scholars better understand the dynamic evolution of the application of MSCs in liver diseases and point out the direction for future research.

N6-Methyladenine-Related Signature for Immune Microenvironment and Response to Immunotherapy in Hepatocellular Carcinoma.

Background: The prognostic value of m6A-related genes in hepatocellular carcinoma (HCC) and its correlation with the immune microenvironment still requires further investigation. Methods: Consensus clustering by m6A related genes was used to classify 374 patients with HCC from The Cancer Genome Atlas (TCGA) database. Then we performed the least absolute shrinkage and selection operator (LASSO) to construct the m6A related genes model. The International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) datasets were used to verify and evaluate the model. ESTIMATE, CIBERSORTx, the expression levels of immune checkpoint genes, and TIDE were used to investigate the tumor microenvironment (TME) and the response to immunotherapy. Gene set enrichment analyses (GSEA), tumor-associated macrophages (TAMs), and gene-drug sensitivity were also analyzed. Results: By expression value and regression coefficient of five m6A related genes, we constructed the risk score of each patient. The patients with a higher risk score had a considerably poorer prognosis in the primary and validated cohort. For further discussing TME and the response to immunotherapy, we divided the entire set into two groups based on the risk score. Our findings implied that the tumor-infiltrating lymphocytes (TILs) were proportional to the risk scores, which seemed to contradict that patients with higher scores had a poor prognosis. Further, we found that the high-risk group had higher expression of PD-L1, CTLA-4, and PDCD1, indicating immune dysfunction, which may be a fundamental reason for poor prognosis. This was further reinforced by the fact that the low-risk group responded better than the high-risk group to monotherapy and combination therapy. Conclusion: The m6A related risk score is a new independent prognostic factor that correlates with immunotherapy response. It can provide a new therapeutic strategy for improving individual immunotherapy in HCC.

Dual role of IL-37 in the progression of tumors.

Interleukin (IL)-37 is a novel defined cytokine that belongs to IL-1 family, which possesses potent anti-inflammatory and immunosuppressive properties. The IL-37 protein mainly exists in the cytoplasm of monocytes and is also expressed in epithelial cells and T cells. IL-37 is produced as a precursor which works in mature or immature isoforms without a classic signal peptide, and negatively regulates TLR agonist- mediated signaling pathway, proinflammatory cytokines, and IL-1R ligands. IL-37 has been found to be elevated and plays an anti-tumor role in various types of tumors, such as hepatocellular carcinoma, non-small cell lung cancer, and cervical cancer. The tumor microenvironment (TME) refers to the cellular environment where the tumor or cancer stem cells exist. At present, growing evidence shows that changes in TME can regulate metabolism, immunity, secretion, and function, so as to inhibit or promote the progression of the tumor. Therefore, a thorough understanding of the TME is essential for the occurrence and development of tumors. In this review, we will summarize the role of IL-37 in the microenvironment of different tumors, hoping to provide novel perspectives towards the mechanism, prevention, and treatment of tumors.

Endometrial regenerative cells with galectin-9 high-expression attenuate experimental autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation. METHODS: ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4+ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4+ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4+/CD8+ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH. RESULTS: After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4+ T cell proliferation and downregulated CD4+ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4+ and CD8+ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs. CONCLUSIONS: The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.

Identification of Hub Gene TIMP1 and Relative ceRNAs Regulatory Network in Colorectal Cancer.

OBJECTIVE: This study aimed to discover the ceRNAs network in the pathophysiological development of human colorectal cancer (CRC) and to screen biomarkers for target therapy and prognosis by using integrated bioinformatics analysis. METHODS: Data on gene expressions of mRNAs, miRNAs, and circRNAs and clinical information were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases, respectively. Differentially expressed mRNAs (DEmRNAs) were identified by using the DESeq2 package of R software. Functional enrichment analysis was conducted using the ClusterProfiler package of R software. The protein-protein interaction (PPI) network was shown by the STRING website. Survival analysis of hub genes was performed using the survival package in R software. Interactions among hub genes, differentially expressed miRNAs (DEmiRNAs), and differentially expressed circRNAs (DEcircRNAs) were used to construct the ceRNAs network. RESULTS: A total of 412 DEmRNAs including 82 upregulated and 330 downregulated genes were screened out between 473 CRC and 41 normal samples. Two hundred and sixty DEcircRNAs including 253 upregulated and 7 downregulated genes were altered between 23 CRC and 23 normal samples. One hundred and ninety DEmiRNAs including 82 upregulated and 108 downregulated genes were obtained between 450 CRC and 8 normal samples. A ceRNAs and PPI network were successfully constructed, and TIMP1 associated with prognosis was employed. CONCLUSION: The present study identified a novel circRNAs-miRNAs-mRNA ceRNAs network, which implied that TIMP1 and related miRNAs, circRNAs were potential biomarkers underlying the development of CRC, providing new insights for survival predictions and therapeutic targets.

IL-1ß pre-stimulation enhances the therapeutic effects of endometrial regenerative cells on experimental colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic, relapsing, and non-specific inflammatory bowel disease, and the current treatment strategies were mainly used to relieve symptoms or for maintenance. Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and have been demonstrated to alleviate multiple immune-dysregulation diseases. Pro-inflammatory stimuli were reported to enhance the immunosuppressive functions of ERCs, but the mechanism underlined is not fully understood. Here, we have designed this study to investigate the therapeutic effects of IL-1ß-primed ERCs in the attenuation of experimental colitis. METHODS: BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. PBS (200 µL), ERCs, and IL-1ß-primed ERCs (10ng/mL, 48 h) were injected (1 million/mouse/day, i.v.) on day 2, 5, and 8, respectively. Colonic and splenic samples were harvested on day 10 after DSS induction. RESULTS: It was found that IL-1ß-primed ERC treatment markedly attenuated colonic damage, body weight loss, and colon length shortening in colitis mice. Compared with other treatments, cell populations of CD4+IL-4+Th2 cells, CD4+CD25+FOXP3+ regulatory T cells (Tregs), and CD68+CD206+ macrophages in spleens were also significantly upregulated in the IL-1ß-primed ERC-treated group (p < 0.05). In addition, lower expression of pro-inflammatory (IFN-γ, IL-17, TNF-α, and IL-6), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) were detected in colons in the IL-1ß-primed ERC-treated group (p < 0.05 vs. other groups). Importantly, we also found that different generations of ERCs had an overall lower secretion of Dickkopf-1 (DKK1) by IL-1ß pre-stimulation (p < 0.05) and a higher expression of ß-catenin in colonic and splenic tissues after the administration of IL-1ß-primed ERCs. CONCLUSIONS: This study has demonstrated that IL-1ß pre-stimulation effectively downregulated DKK1 expression in ERCs, which in turn promoted the wnt/ß-catenin pathway activation in colonic and splenic tissues. Consequently, IL-1ß-primed ERCs exhibited an enhanced therapeutic effect in the attenuation of DSS-induced colitis.

Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy.

Background: Chronic rejection characterized by chronic allograft vasculopathy (CAV) remains a major obstacle to long-term graft survival. Due to multiple complicated mechanisms involved, a novel therapy for CAV remains exploration. Although mesenchymal stromal cells (MSCs) have been ubiquitously applied to various refractory immune-related diseases, rare research makes a thorough inquiry in CAV. Meanwhile, melatonin (MT), a wide spectrum of immunomodulator, plays a non-negligible role in transplantation immunity. Here, we have investigated the synergistic effects of MT in combination with MSCs in attenuation of CAV. Methods: C57BL/6 (B6) mouse recipients receiving BALB/c mouse donor aorta transplantation have been treated with MT and/or adipose-derived MSCs. Graft pathological changes, intragraft immunocyte infiltration, splenic immune cell populations, circulating donor-specific antibodies levels, cytokine profiles were detected on post-operative day 40. The proliferation capacity of CD4+ and CD8+ T cells, populations of Th1, Th17, and Tregs were also assessed in vitro. Results: Grafts in untreated recipients developed a typical pathological feature of CAV characterized by intimal thickening 40 days after transplantation. Compared to untreated and monotherapy groups, MT in combination with MSCs effectively ameliorated pathological changes of aorta grafts indicated by markedly decreased levels of intimal hyperplasia and the infiltration of CD4+ cells, CD8+ cells, and macrophages, but elevated infiltration of Foxp3+ cells. MT either alone or in combination with MSCs effectively inhibited the proliferation of T cells, decreased populations of Th1 and Th17 cells, but increased the proportion of Tregs in vitro. MT synergized with MSCs displayed much fewer splenic populations of CD4+ and CD8+ T cells, Th1 cells, Th17 cells, CD4+ central memory T cells (Tcm), as well as effector memory T cells (Tem) in aorta transplant recipients. In addition, the percentage of splenic Tregs was substantially increased in the combination therapy group. Furthermore, MT combined with MSCs markedly reduced serum levels of circulating allospecific IgG and IgM, as well as decreased the levels of pro-inflammatory IFN-γ, TNF-α, IL-1ß, IL-6, IL-17A, and MCP-1, but increased the level of IL-10 in the recipients. Conclusions: These data suggest that MT has synergy with MSCs to markedly attenuate CAV and provide a novel therapeutic strategy to improve the long-term allograft acceptance in transplant recipients.

IL-37 overexpression enhances the therapeutic effect of endometrial regenerative cells in concanavalin A-induced hepatitis.

BACKGROUND AIMS: Mesenchymal stromal cells and immunosuppressive factor IL-37 can both suppress concanavalin A (Con A)-induced hepatitis in mice. Endometrial regenerative cells (ERCs), novel types of mesenchymal-like stromal cells, possess powerful immunomodulatory effects and are effective in treating various diseases. The aim of this study was to explore the effects of ERCs in suppressing Con A-induced hepatitis and determine whether IL-37 overexpression could enhance the therapeutic effect of ERCs in this process. METHODS: ERCs were extracted from the menstrual blood of healthy female volunteer donors. The IL-37 gene was transferred into ERCs, and the expression of IL-37 in cells was detected by western blot and enzyme-linked immunosorbent assay. Hepatitis was induced by Con A in C57BL/6 mice that were randomly divided into groups treated with phosphate-buffered saline, ERCs, IL-37 or ERCs transfected with the IL-37 gene (IL-37-ERCs). Cell tracking, liver function, histopathological and immunohistological changes, immune cell proportions and levels of cytokines were measured 24 h after Con A administration. RESULTS: Compared with ERC or IL-37 treatment, IL-37-ERCs further reduced levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and improved histopathological changes in the liver. In addition, IL-37-ERC treatment further reduced the proportions of M1 macrophages and CD4+ T cells and increased the proportion of regulatory T cells. Moreover, IL-37-ERC treatment resulted in lower levels of IL-12 and interferon gamma, and higher level of transforming growth factor beta. CONCLUSIONS: The results of this study suggest that ERCs can effectively alleviate Con A-induced hepatitis. Furthermore, IL-37 overexpression can significantly enhance the therapeutic efficacy of ERCs by augmenting the immunomodulatory and anti-inflammatory properties of ERCs. This study may provide a promising strategy for treatment of T-cell-dependent hepatitis.

Osteochondroma of the pubic symphysis causing hematuria: a case report and literature review.

BACKGROUND: Osteochondroma is the most common benign bone neoplasm and is sometimes referred to as osteocartilaginous exostosis. The symptoms caused by osteochondroma are rare, especially the urogenital complications. Therefore, this tumour is sometimes misdiagnosed. CASE PRESENTATION: This report described a 70-year-old woman with hematuria who was initially misdiagnosed with a bladder tumour in the outpatient department by a urologist. However, during cystoscopy, we found that the mass did not resemble a bladder tumor. Multidisciplinary approach with careful analysis of the imaging data suggested the diagnosis of osteochondroma. Open surgical excision of the mass was done and histology confirmed the diagnosis of benign osteochondroma. After 6 months of follow-up, the patient was still asymptomatic. CONCLUSIONS: This case illustrates that hematuria is caused by not only urogenital disease but also osteochondroma. We present this case to draw the attention of clinicians to osteochondroma of the pubic symphysis.

CD73 expression is critical to therapeutic effects of human endometrial regenerative cells in inhibition of cardiac allograft rejection in mice.

The newly found mesenchymal-like endometrial regenerative cells (ERCs) have been proved to induce immune tolerance in cardiac allograft transplantation. However, the therapeutic mechanism is not clear. The present study was undertaken to investigate whether ecto-5'-nucleotidase (CD73) expression on ERCs is critical to cardiac allograft protection. C57BL/6 mouse recipients receiving BALB/c mouse cardiac allografts were treated with unmodified ERCs or anti-CD73 monoclonal antibodies (mAb) pretreated ERCs, respectively. It has been found that CD73 expression was critical to ERC-induced attenuation of graft pathology. The blockage of CD73 expression on ERCs was related to the percentage decline of tolerogenic dendritic cells (Tol-DCs), macrophages type 2 (M2), and regulatory T cells (Tregs). As compared with anti-CD73 mAb pretreated ERCs group, CD73 expressing ERCs significantly increased the level of anti-inflammatory cytokine IL-10 but decreased levels of pro-inflammatory cytokines including IFN-γ and TNF-α. In addition, CD73 expressing ERCs showed tissue protective function via the regulation of adenosine receptor expression which was related to the infiltration of CD4+ and CD8+ cells in the allografts. Furthermore, significant increase of A2B receptors in the cardiac allograft was also associated with CD73 expressing ERC-induced prolongation of cardiac allograft survival.