Melatonin pretreatment improves endometrial regenerative cell-mediated therapeutic effects in experimental colitis.

BACKGROUND: Endometrial regenerative cells (ERCs) have been proven to be an effective strategy for attenuating experimental colitis, but the complex in vivo microenvironment such as oxidative stress may largely limit and weaken ERC efficacy. Melatonin (MT) works as an anti-oxidative agent in a variety of preclinical diseases, and has been identified to promote mesenchymal stem cell-mediated therapeutic effects in different diseases. However, the ability of MT to enhance ERC-mediated effects in colitis is currently poorly understood. METHODS: Menstrual blood was collected from healthy female volunteers to obtain ERCs and identified. In vitro, H2O2-induced oxidative stress was introduced to test if MT could prevent ERCs from damage through detection of intracellular reactive oxidative species (ROS) and apoptosis assay. In vivo, dextran sodium sulfate (DSS)-induced acute colitis was treated by ERCs and MT-primed ERCs, therapeutic effects were assayed by the disease activity index (DAI), histological features, and macrophage and CD4+ T cell in the spleen and colon, and cytokine profiles in the sera and colon were also measured. RESULTS: In vitro, ERCs that underwent MT-precondition were found to possess more anti-oxidative potency in comparison to naïve ERCs, which were characterized by decreased apoptosis rate and intracellular ROS under H2O2 stimulation. In vivo, MT pretreatment can significantly enhance the therapeutic effects of ERCs in the attenuation of experimental colitis, including decreased DAI index and damage score. In addition, MT pretreatment was found to promote ERC-mediated inhibition of Th1, Th17, and M1 macrophage and pro-inflammatory cytokines, increase of Treg, and immunomodulation of cytokines in the spleen and colon. CONCLUSIONS: MT pretreatment facilitates the promotion of cell viability under oxidative stress in vitro, while also enhancing ERC-mediated therapeutic effects in experimental colitis.

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.

On-Chip Liquid Manipulation via a Flexible Dual-Layered Channel Possessing Hydrophilic/Hydrophobic Dichotomy.

The hydrophilic/hydrophobic cooperative interface provides a smart platform to control liquid distribution and delivery. Through the fusion of flexibility and complex structure, we present a manipulable, open, and dual-layered liquid channel (MODLC) for on-demand mechanical control of fluid delivery. Driven by anisotropic Laplace pressure, the mechano-controllable asymmetric channel of MODLC can propel the directional slipping of liquid located between the paired tracks. Upon a single press, the longest transport distance can reach 10 cm with an average speed of ∼3 cm/s. The liquid on the MODLC can be immediately manipulated by pressing or dragging processes, and versatile liquid-manipulating processes on hierarchical MODLC chips have been achieved, including remote droplet magneto-control, continuous liquid distributor, and gas-producing chip. The flexible hydrophilic/hydrophobic interface and its assembly can extend the function and applications of the wettability-patterned interface, which should update our understanding of complex systems for sophisticated liquid transport.

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.

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.

Functional metabolome profiling may improve individual outcomes in colorectal cancer management implementing concepts of predictive, preventive, and personalized medical approach.

Objectives: Colorectal cancer (CRC) is one of the most common solid tumors worldwide, but its diagnosis and treatment are limited. The objectives of our study were to compare the metabolic differences between CRC patients and healthy controls (HC), and to identify potential biomarkers in the serum that can be used for early diagnosis and as effective therapeutic targets. The aim was to provide a new direction for CRC predictive, preventive, and personalized medicine (PPPM). Methods: In this study, CRC patients (n = 30) and HC (n = 30) were recruited. Serum metabolites were assayed using an ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technology. Subsequently, CRC cell lines (HCT116 and HCT8) were treated with metabolites to verify their function. Key targets were identified by molecular docking, thermal shift assay, and protein overexpression/inhibition experiments. The inhibitory effect of celastrol on tumor growth was also assessed, which included IC50 analysis, nude mice xenografting, molecular docking, protein overexpression/inhibition experiments, and network pharmacology technology. Results: In the CRC group, 15 serum metabolites were significantly different in comparison with the HC group. The level of glycodeoxycholic acid (GDCA) was positively correlated with CRC and showed high sensitivity and specificity for the clinical diagnostic reference (AUC = 0.825). In vitro findings showed that GDCA promoted the proliferation and migration of CRC cell lines (HCT116 and HCT8), and Poly(ADP-ribose) polymerase-1 (PARP-1) was identified as one of the key targets of GDCA. The IC50 of celastrol in HCT116 cells was 121.1 nM, and the anticancer effect of celastrol was supported by in vivo experiments. Based on the potential of GDCA in PPPM, PARP-1 was found to be significantly correlated with the anticancer functions of celastrol. Conclusion: These findings suggest that GDCA is an abnormally produced metabolite of CRC, which may provide an innovative molecular biomarker for the predictive identification and targeted prevention of CRC. In addition, PARP-1 was found to be an important target of GDCA that promotes CRC; therefore, celastrol may be a potential targeted therapy for CRC via its effects on PARP-1. Taken together, the pathophysiology and progress of tumor molecules mediated by changes in metabolite content provide a new perspective for predictive, preventive, and personalized medical of clinical cancer patients based on the target of metabolites in vivo.Clinical trials registration number: ChiCTR2000039410. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-021-00269-8.

Endometrial Regenerative Cell-Derived Conditioned Medium Alleviates Experimental Colitis.

BACKGROUND: Traditional interventions can play a certain role in attenuating ulcerative colitis (UC), known as one type of inflammatory bowel diseases, but sometimes are not effective. Endometrial regenerative cells (ERCs) have been shown to exert immunosuppressive effects in different models of inflammation, and stem cell-derived conditioned media (CM) have advantages over cell therapy in terms of easy access and direct action. However, whether ERC-CM could alleviate colitis remains unclear and will be explored in this study. METHODS: Menstrual blood was collected from healthy female volunteers to obtain ERCs and ERC-CM. Acute colitis was induced by 3% dextran sodium sulfate (DSS), and ERC-CM was injected on days 4, 6, and 8, respectively, after induction. The disease activity index was calculated through the record of weight change, bleeding, and fecal viscosity during the treatment process. Histological features, macrophage and CD4+ T cell in the spleen and colon, and cytokine profiles in the sera and colon were measured. In addition, an in vitro lymphocyte proliferation assay was measured by using a CCK-8 kit in this study. RESULTS: ERC-CM treatment significantly improved the symptoms and histological changes in colitis mice. ERC-CM increased the percentage of Tregs in the spleen and colon but decreased the percentages of M1 macrophages and Th1 and Th17 cells in the spleen and decreased the population of Th17 cells in the colon. In addition, ERC-CM treatment decreased the local expression of TNF-α, IL-6, and iNOS in the colon. Furthermore, ERC-CM increased the levels of anti-inflammatory cytokines IL-10 and IL-27 but decreased proinflammatory cytokines IL-6 and IL-17 in the sera. In addition, ERC-CM significantly inhibited ConA-induced mouse lymphocyte proliferation in vitro. CONCLUSION: The results suggest that ERC-CM can exert similar therapeutic effects as ERCs and could be explored for future application of cell-free therapy in the treatment of colitis.

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.

Corrigendum: Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy.

[This corrects the article DOI: 10.3389/fimmu.2021.672849.].

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.

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.

Clinical Efficacy and Safety of Stem Cell-Based Therapy in Treating Asherman Syndrome: A System Review and Meta-Analysis.

Asherman's Syndrome (AS) is an uncommon, acquired, and refractory gynecological disorder. Current treatment was still limited, and stem cell-based therapy has been proposed as a novel strategy for management of AS. Here, we conducted a meta-analysis of self-controlled clinical trials to assess the effectiveness and safety of stem cell-based therapy in Asherman syndrome patients who have failed in conventional treatment. We systematically searched PubMed, Embase, Cochrane, and Web of Science database (published up to October 3, 2020). Our main evaluation outcomes were menses improvement, endometrial thickness changes, pregnancy outcome, and side effects. All analyses were performed by using RevMan5.4 software. 427 studies were identified, eight of which were eligible and included in our analysis. Stem cell combined hormone therapy achieved a higher likelihood of improving menstruation (risk ratio [RR] 22.43, 95% CI: 8.03 to 62.68, P < 0.00001), an enhancement of pregnancy outcome (risk ratio [RR] 11.1, 95% CI: 3.58 to 34.38, P < 0.0001), and a mean increase of 3-month endometrial thickness (standardized mean difference [SMD] 2.43, 95% CI: 1.72 to 3.13, P < 0.00001). Subgroup analysis also indicated that 6-month and 9-month endometrial thickness increased significantly with the stem cell-based treatment. Moreover, no obvious and severe adverse reactions were observed during the process of stem cell therapy. There were 3 patients (3.57%) reported with lost appetite, mild gastritis, vomiting, or abdominal cramps, whereas, these symptoms relieved subsequently. This meta-analysis systematically reviewed and synthesized the outcomes of stem cell-based therapy in treating Asherman syndrome, which suggest that stem cell and hormone combination therapy was safe and more effective in improving menstruation duration, pregnancy outcome, and endometrial thickness. However, further trials with large sample sizes are needed to establish more solid evidence for administrating this therapy in clinic.

[Expression of vasohibin-1 in colorectal cancer tissue and its correlation with vascular endothelial growth factor A and microvessei density].

OBJECTIVE: To explore the clinical significance of vasohibin-1 expression in colorectal cancer tissues and its correlation with vascular endothelial growth factor A(VEGF-A) and microvessel density (MVD). METHODS: Tumor tissues and paired adjacent normal tissue (distance to cancer >5 cm) from 60 colorectal cancer patients undergoing resection in the Second Hospital of Tianjin Medical University from June 2013 to November 2013 were included in this study. The protein expressions of vasohibin-1, VEGF-A and MVD were detected by immunohistochemical staining. The mRNA expressions of vasohibin-1 and VEGF-A were detected by RT-PCR. The protein expressions of vasohibin-1 and VEGF-A were observed by Western blot. Correlation among parameters was examined. RESULTS: Vasohibin-1 expression was mainly localized in the cytoplasm of tumor cells and endothelial cells. VEGF-A expression was mainly localized in the cytoplasm and membrane of tumor cells. The expressions of vasohibin-1, VEGF-A and MVD in colorectal tumor tissues were significantly higher than those in corresponding adjacent tissues [43.3% (26/60) vs. 16.7% (10/60), 51.7%(31/60) vs. 18.3% (11/60), (39.67 ± 16.80)/mm² vs. (17.85 ± 6.43)/mm², all P<0.05]. Higher vasohibin-1 expression was significantly associated with TNM stage and metastasis (P<0.05). Vasohibin-1 expression was positively correlated with VEGF-A and MVD (r=0.378, 0.628, all P<0.05). Vasohibin-1 and VEGF-A mRNA expressions and protein expressions in colorectal cancer tissues were significantly higher than those in corresponding adjacent tissues (all P<0.05). CONCLUSION: Vasohibin-1 expression in colorectal cancer tissues is significantly higher as compared to corresponding adjacent tissues. Vasohibin-1 expression is positively correlated to VEGF-A and MVD, and associated to TNM stage and metastasis. Positive vasohibin-1 expression indicates a poor prognosis of patients with colorectal cancer.