Recombinant human IL-37 attenuates acute cardiac allograft rejection in mice.

BACKGROUND: Allograft rejection remains a major obstacle to long-term graft survival. Although previous studies have demonstrated that IL-37 exhibited significant immunomodulatory effects in various diseases, research on its role in solid organ transplantation has not been fully elucidated. In this study, the therapeutic effect of recombinant human IL-37 (rhIL-37) was evaluated in a mouse cardiac allotransplantation model. METHODS: The C57BL/6 recipients mouse receiving BALB/c donor hearts were treated with rhIL-37. Graft pathological and immunohistology changes, immune cell populations, and cytokine profiles were analyzed on postoperative day (POD) 7. The proliferative capacities of Th1, Th17, and Treg subpopulations were assessed in vitro. Furthermore, the role of the p-mTOR pathway in rhIL-37-induced CD4+ cell inhibition was also elucidated. RESULTS: Compared to untreated groups, treatment of rhIL-37 achieved long-term cardiac allograft survival and effectively alleviated allograft rejection indicated by markedly reduced infiltration of CD4+ and CD11c+ cells and ameliorated graft pathological changes. rhIL-37 displayed significantly less splenic populations of Th1 and Th17 cells, as well as matured dendritic cells. The percentages of Tregs in splenocytes were significantly increased in the therapy group. Furthermore, rhIL-37 markedly decreased the levels of TNF-α and IFN-γ, but increased the level of IL-10 in the recipients. In addition, rhIL-37 inhibited the expression of p-mTOR in CD4+ cells of splenocytes. In vitro, similar to the in vivo experiments, rhIL-37 caused a decrease in the proportion of Th1 and Th17, as well as an increase in the proportion of Treg and a reduction in p-mTOR expression in CD4+ cells. CONCLUSIONS: We demonstrated that rhIL-37 effectively suppress acute rejection and induce long-term allograft acceptance. The results highlight that IL-37 could be novel and promising candidate for prevention of allograft rejection.

High Tensile, Antibacterial, and Conductive Hydrogel Sensor with Multiple Cross-Linked Networks Based on PVA/Sodium Alginate/Zinc Oxide.

Hydrogel sensors have attracted a lot of attention due to their great significance for biosensors and human detection, especially their antibacterial properties when in direct contact with the human body. However, it is challenging to improve mechanical and antibacterial performance simultaneously. In this study, by using ultrasonic dispersion technology to attach zinc oxide to cellulose and adding sodium alginate, a multiple cross-linking network is generated, which effectively solves this problem. The proposed poly(vinyl alcohol)/sodium alginate/zinc oxide/hydrogel sensor exhibits not only excellent biocompatibility but also high tensile properties (strain above 2000%). Besides, the sensor also has an antibacterial function (against Escherichia coli and Staphylococcus aureus). The hydrogel acts as a strain sensor and biosensor; it can also be used as a human health detection sensor; its high tensile properties can detect large tensile deformation and small changes in force, such as finger bending, knee bending, and other joint movements, and can also be used as a sound detection sensor to detect speech and breathing. This study provides a simple method to prepare hydrogel sensors that can be useful for human health detection and biosensor development.

Oxymatrine combined with rapamycin to attenuate acute cardiac allograft rejection.

Background and aim: Solid organ transplantation remains a life-saving therapeutic option for patients with end-stage organ dysfunction. Acute cellular rejection (ACR), dominated by dendritic cells (DCs) and CD4+ T cells, is a major cause of post-transplant mortality. Inhibiting DC maturation and directing the differentiation of CD4+ T cells toward immunosuppression are keys to inhibiting ACR. We propose that oxymatrine (OMT), a quinolizidine alkaloid, either alone or in combination with rapamycin (RAPA), attenuates ACR by inhibiting the mTOR-HIF-1α pathway. Methods: Graft damage was assessed using haematoxylin and eosin staining. Intragraft CD11c+ and CD4+ cell infiltrations were detected using immunohistochemical staining. The proportions of mature DCs, T helper (Th) 1, Th17, and Treg cells in the spleen; donor-specific antibody (DSA) secretion in the serum; mTOR-HIF-1α expression in the grafts; and CD4+ cells and bone marrow-derived DCs (BMDCs) were evaluated using flow cytometry. Results: OMT, either alone or in combination with RAPA, significantly alleviated pathological damage; decreased CD4+ and CD11c+ cell infiltration in cardiac allografts; reduced the proportion of mature DCs, Th1 and Th17 cells; increased the proportion of Tregs in recipient spleens; downregulated DSA production; and inhibited mTOR and HIF-1α expression in the grafts. OMT suppresses mTOR and HIF-1α expression in BMDCs and CD4+ T cells in vitro. Conclusions: Our study suggests that OMT-based therapy can significantly attenuate acute cardiac allograft rejection by inhibiting DC maturation and CD4+ T cell responses. This process may be related to the inhibition of the mTOR-HIF-1α signaling pathway by OMT.

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.

From cerebral ischemia towards myocardial, renal, and hepatic ischemia: Exosomal miRNAs as a general concept of intercellular communication in ischemia-reperfusion injury.

Ischemia-reperfusion injury occurs when blood supply to an organ is disrupted-ischemia-and then restored-reperfusion-and is commonly found under different pathological settings such as cerebral, myocardial, renal, and hepatic ischemia-reperfusion injuries. Despite apparent differences as to the cause of these diseases, emerging evidence suggests that common signaling pathways, such as exosomes and microRNAs (miRNAs), are involved in this context. Although miRNAs are also found in the extracellular milieu, plenty of miRNAs are found in exosomes and are thus protected from degradation. miRNAs selectively sorted into exosomes potentially regulate specific aspects of the onset and progression of ischemic stroke. Such mechanisms involve the regulation of cell survival, inflammation, angiogenesis, and neurogenesis. Likewise, miRNAs shuttled into exosomes are involved in the pathogenesis of myocardial, renal, and hepatic ischemia-reperfusion injuries. This review will discuss recent evidence on the exosome-facilitated progression of four ischemia-reperfusion conditions, particularly concerning miRNAs within these vesicles. The notion is given to miRNAs participating in more than one of the four conditions, indicating a considerable degree of overlap across ischemia-reperfusion conditions. We will conclude the review by highlighting clinical opportunities of such exosome-derived miRNAs both as biomarkers and as therapeutic targets.

Endometrial Regenerative Cell-Derived Exosomes Attenuate Experimental Colitis through Downregulation of Intestine Ferroptosis.

Background: Endometrial regenerative cells (ERCs) have been identified to ameliorate colitis in mice; however, whether exosomes derived from ERCs (ERC-exos) own similar effects on colitis remains unclear. Ferroptosis, an iron-dependent cell programmed death form, has been reported to promote inflammation in UC. Thus, in this study, whether ERC-exos can treat colitis and regulate intestine ferroptosis will be explored. Methods: In this study, iron, malondialdehyde (MDA) production, glutathione (GSH) synthesis, and acyl-CoA synthetase long-chain family member (ACSL) 4 and glutathione peroxidase 4 (GPX4) expressions were measured in colon samples from healthy people and UC patients to explore the effects of ferroptosis. In vitro, ERC-exos were cocultured with ferroptosis inducer erastin-treated NCM460 human intestinal epithelial cell line, and ferroptotic parameters were measured. In vivo, colitis was induced by 3% dextran sulfate sodium (DSS) in BALB/c mice, and animals were randomly assigned to normal, untreated, and ERC-exos-treated groups. The Disease Activity Index (DAI) score, histological features, tissue iron, MDA, GSH, ACSL4, and GPX4 were measured to verify the role of ERC-exos in attenuating UC. Results: Compared with healthy people, UC samples exhibited higher levels of iron, MDA, and ACSL4, while less levels of GSH and GPX4. In vitro, the CCK-8 assay showed that ERC-exos rescued erastin-induced cell death, and ERC-exos treatment significantly increased the levels of GSH and expression of GPX4, while markedly decreasing the levels of iron, MDA, and expression of ACSL4. In vivo, ERC-exos treatment effectively reduced DAI score, ameliorated colon pathological damage, and improved disease symptoms. Moreover, ERC-exos treatment further enhanced the levels of GSH and the expression of GPX4 but reduced the levels of iron, MDA, and expression of ACSL4 in the colon of colitis mice. Conclusions: Ferroptosis was involved in the pathogenesis of UC, and ERC-exos attenuated DSS-induced colitis through downregulating intestine ferroptosis. This study may provide a novel insight into treating UC in the future.

The intellectual base and research fronts of IL-37: A bibliometric review of the literature from WoSCC.

Background: IL-37 is a recently identified cytokine with potent immunosuppressive functions. The research fronts of IL-37 are worth investigating, and there is no bibliometric analysis in this field. The purpose of this study is to construct the intellectual base and predict research hotspots of IL-37 research both quantitatively and qualitatively according to bibliometric analysis. Methods: The articles were downloaded from the Web of Science Core Collection (WoSCC) database from the inception of the database to 1 April 2022. CiteSpace 5.8.R3 (64-bit, Drexel University, Philadelphia, PA, USA) and Online Analysis Platform of Literature Metrology (https://bibliometric.com/) were used to perform bibliometric and knowledge-map analyses. Results: A total of 534 papers were included in 200 academic journals by 2,783 authors in 279 institutions from 50 countries/regions. The journal Cytokine published the most papers on IL-37, while Nature Immunology was the most co-cited journal. The publications belonged mainly to two categories of Immunology and Cell Biology. USA and China were the most productive countries. Meanwhile, the University of Colorado Denver in USA produced the highest number of publications followed by Radboud University Nijmegen in the Netherlands and Monash University in Australia. Charles A. Dinarello published the most papers, while Marcel F. Nold had the most co-citations. Top 10 co-citations on reviews, mechanisms, and diseases were regarded as the knowledge base. The keyword co-occurrence and co-citations of references revealed that the mechanisms and immune-related disorders were the main aspects of IL-37 research. Notably, the involvement of IL-37 in various disorders and the additional immunomodulatory mechanisms were two emerging hotspots in IL-37 research. Conclusions: The research on IL-37 was thoroughly reviewed using bibliometrics and knowledge-map analyses. The present study is a benefit for academics to master the dynamic evolution of IL-37 and point out the direction for future research.

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.

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.

Pterostilbene production of tomato transformed with resveratrol synthase and resveratrol O-methyltransferase genes.

Pterostilbene is a methylated derivative of resveratrol. It has been proved to be effective in preventing many human diseases. However, it is produced and accumulated in only small amounts in natural plant raw materials. Here, two genes coding for resveratrol synthase 3 (AhRS3) in Arachis hypogaea and resveratrol O-methyltransferase (VvROMT) in Vitis vinifera were artificially synthesized considering the codon preference of the tomato. They were linked by LP4/2A to form a fusion gene, controlled by cauliflower mosaic virus 35S promoter, and introduced into tomato via Agrobacterium-mediated transformation. This study aimed to obtain a tomato breeding material enriched with pterostilbene in fruits for a healthy food source. Two transgenic plants with high alien gene expression were selected from the regenerated plants using real-time polymerase chain reaction. High-performance liquid chromatography was used to detect the pterostilbene content in fruits. The highest content reached 146.701 ±â€¯47.771 µg/g dry weight, which was significantly higher than natural levels in all other species tested to date. UPLC-MS/MS was used to analyze the differences in metabolites in fruits between the transgenic and wild-type plants to understand the effect of AhRS3-LP4/2A-VvROMT gene on tomato metabolism. Results showed that the synthesis pathway of stilbenes had little influence on the flavonoid metabolic pathway in tomato fruits.

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.