The proliferation/migration ability mediated by CD151/PI3K/AKT pathway determines the therapeutic effect of hUC-MSCs transplantation on rheumatoid arthritis.

OBJECTIVE: To elucidate the underlying mechanism by which the proliferation and migration abilities of human umbilical cord mesenchymal stem cells (hUC-MSCs) determine their therapeutic efficacy in rheumatoid arthritis treatment. METHODS: The DBA/1J mice were utilized to establish a collagen-induced RA (CIA) mouse model and to validate the therapeutic efficacy of hUC-MSCs transfected with CD151 siRNA. RNA-seq, QT-PCR and western blotting were utilized to evaluate the mRNA and protein levels of the PI3K/AKT pathway, respectively. RESULTS: IFN-γ significantly enhanced the proliferation and migration abilities of hUC-MSCs, up-regulating the expression of CD151, a gene related to cell proliferation and migration. Effective inhibition of this effect was achieved through CD151 siRNA treatment. However, IFN-γ did not affect hUC-MSCs differentiation or changes in cell surface markers. Additionally, transplantation of CD151-interfered hUC-MSCs (siRNA-CD151-hUC-MSCs) resulted in decreased colonization in the toes of CIA mice and worse therapeutic effects compared to empty vector treatment (siRNA-NC-hUC-MSCs). CONCLUSION: IFN-γ facilitates the proliferation and migration of hUC-MSCs through the CD151/PI3K/AKT pathway. The therapeutic efficacy of siRNA-CD151-hUC-MSCs was found to be inferior to that of siRNA-NC-hUC-MSCs.

The dual role of mesenchymal stem cells in apoptosis regulation.

Mesenchymal stem cells (MSCs) are widely distributed pluripotent stem cells with powerful immunomodulatory capacity. MSCs transplantation therapy (MSCT) is widely used in the fields of tissue regeneration and repair, and treatment of inflammatory diseases. Apoptosis is an important way for tissues to maintain cell renewal, but it also plays an important role in various diseases. And many studies have shown that MSCs improves the diseases by regulating cell apoptosis. The regulation of MSCs on apoptosis is double-sided. On the one hand, MSCs significantly inhibit the apoptosis of diseased cells. On the other hand, MSCs also promote the apoptosis of tumor cells and excessive immune cells. Furthermore, MSCs regulate apoptosis through multiple molecules and pathways, including three classical apoptotic signaling pathways and other pathways. In this review, we summarize the current evidence on the regulation of apoptosis by MSCs.

B2M is a Biomarker Associated With Immune Infiltration In High Altitude Pulmonary Edema.

BACKGROUND: High altitude pulmonary edema (HAPE) is a serious mountain sickness with certain mortality. Its early diagnosis is very important. However, the mechanism of its onset and progression is still controversial. AIM: This study aimed to analyze the HAPE occurrence and development mechanism and search for prospective biomarkers in peripheral blood. METHODS: The difference genes (DEGs) of the Control group and the HAPE group were enriched by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and then GSEA analysis was performed. After identifying the immune-related hub genes, QPCR was used to verify and analyze the hub gene function and diagnostic value with single-gene GSEA and ROC curves, and the drugs that acted on the hub gene was found in the CTD database. Immune infiltration and its association with the hub genes were analyzed using CIBERSORT. Finally, WGCNA was employed to investigate immune invasion cells' significantly related gene modules, following enrichment analysis of their GO and KEGG. RESULTS: The dataset enrichment analysis, immune invasion analysis and WGCNA analysis showed that the occurrence and early progression of HAPE were unrelated to inflammation. The hub genes associated with immunity obtained with MCODE algorithm of Cytoscape were JAK2 and B2M.. RT-qPCR and ROC curves confirmed that the hub gene B2M was a specific biomarker of HAPE and had diagnostic value, and single-gene GSEA analysis confirmed that it participated in MHC I molecule-mediated antigen presentation ability decreased, resulting in reduced immunity. CONCLUSION: Occurrence and early progression of high altitude pulmonary edema may not be related to inflammation. B2M may be a new clinical potential biomarker for HAPE for early diagnosis and therapeutic evaluation as well as therapeutic targets, and its decrease may be related to reduced immunity due to reduced ability of MCH I to participate in antigen submission.

The expression mechanism of programmed cell death 1 ligand 1 and its role in immunomodulatory ability of mesenchymal stem cells.

Programmed cell death 1 ligand 1 (PD-L1) is an important immunosuppressive molecule, which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1. The PD-L1 expression disorder plays an important role in the occurrence, development, and treatment of sepsis or other inflammatory diseases, and has become an important target for the treatment of these diseases. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with multiple differentiation potential. In recent years, MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases. Moreover, PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases. In this review, we will summarize the main regulatory mechanism of PD-L1 expression, and discuss various biological functions of PD-L1 in the immune regulation of MSCs.

Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression.

BACKGROUND: The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear. AIM: To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis. METHODS: We assessed PD-L1 expression in human umbilical-cord-derived MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γ alone or in combination with TNF-α induces PD-L1 expression. Moreover, we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in both an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium-induced acute colitis. RESULTS: Our results suggest that IFN-γ induction alone upregulates PD-L1 expression in hUC-MSCs while TNF-α alone does not, and that the co-induction of IFN-γ and TNF-α promotes higher expression of PD-L1. IFN-γ induces hUC-MSCs to express PD-L1, in which IFN-γ activates the JAK/STAT1 signaling pathway, up-regulates the expression of the interferon regulatory factor 1 (IRF1) transcription factor, promotes the binding of IRF1 and the PD-L1 gene promoter, and finally promotes PD-L1 mRNA. Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling. Finally, co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation, and significantly ameliorate weight loss, mucosal damage, inflammatory cell infiltration, and up-regulation of inflammatory factors in colitis mice. CONCLUSION: Overall, our results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.

Effects of live attenuated measles vaccine Hu191 strain on epithelial mesenchymal transition,proliferation and migration of 4T1 breast cancer cells / 中国生物制品学杂志

@#Objective To investigate the effects of live attenuated measles vaccine Hu191 strain(MV-Hu191)on epithelial mesenchymal transition(EMT),proliferation and migration of 4T1 breast cancer cells.MethodsCCK-8 and clone formation assay were used to analyze the effect of MV-Hu191 on the proliferation of 4T1 cells;The effect of MV-Hu191 on 4T1cell migration was analyzed by cell scratch test;The expression of EMT pathway proteins(MMP-2,MMP-9,E-cadherin)in4T1 cells was detected by Western blot;4T1 tumor-bearing mouse model was established in female BALB/c mice. The model mice were divided into control group(PBS),MV-Hu191(1 × 106TCID50)group and paclitaxel group(15 mg/kg),with 10 mice in each group,and injected into tumor at the dosage of 100 μL every 2 d for 5 times. At 28 d after administration,the effects of MV-Hu191 on survival time,tumorigenicity and metastasis in vivo were observed;The pathological characteristics of lung tissue and tumor tissue were observed by HE staining under microscope;The expression of EMT pathway proteins(MMP-2,MMP-9 and E-cadherin)in tumor tissue was detected by immunohistochemical staining.Results The results of in vitro experiment showed that,compared with the control group,MV-Hu191 inhibited the proliferation and migration of 4T1 cells(F = 2. 811 and 13. 535,P = 0. 001 and 0. 002,respectively),down regulated the expression of MMP-2 and MMP-9(F = 45. 433 and 9. 744,P = 0. 011 and 0. 038,respectively),and up regulated the expression of Ecadherin(F = 7. 001,P = 0. 032);The results of in vivo experiment showed that MV-Hu191 significantly prolonged the survival time of tumor-bearing mice,and decreased the tumor quality(F = 8. 301,P = 0. 003)and the number of pulmonary nodules metastasis compared with the control group(F = 33. 792,P = 0. 000);MV-Hu191 treated tumor tissue gap was small,the cells were round,and the alveolar contour was clearly visible;The expression of MMP-2 and MMP-9 in MVHu191 treated tumor tissue decreased significantly(F = 6. 705 and 9. 047,P = 0. 028 and 0. 023,respectively),while the expression of E-cadherin increased significantly(F = 3. 468,P = 0. 039).ConclusionMV-Hu191 signi-ficantly inhibits the proliferation and migration of 4T1 breast cancer cells,antagonizes the tumorigenicity and lung meta-stasis of 4T1 tumorbearing mice,and prolongs the survival time of mice. The possible mechanism of MV-Hu191 against breast cancer is closely related to the regulation of EMT pathway protein expression.

Possible mechanism of 191 measles attenuated live vaccine strains inhibiting the proliferation of triple negative breast cancer MDA-MB-231 cells based on proteomics technology / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：基于蛋白质组学技术探讨麻疹减毒活疫苗191株（MV-Hu191）在体内外对三阴性乳腺癌MDA-MB-231、4T1细胞的影响及其作用机制。方法：采用CCK-8法检测MV-Hu191对MDA-MB-231和4T1细胞增殖的影响；液相色谱-质谱联用技术分析MV-Hu191处理对MDA-MB-231细胞中蛋白质谱的影响，多重数据库筛选蛋白质谱中的典型差异蛋白质并进行GO、KEGG、亚细胞定位与功能注释。瘤内注射1×106 TCID50 MV-Hu191干预4T1细胞移植瘤模型小鼠，流式细胞术检测小鼠脾组织中T细胞亚群，ELISA法检测小鼠血清TNF-α和IL-6含量。结果：体外实验结果表明，MV-Hu191具有抑制MDA-MB-231和4T1细胞增殖的作用，差异均具有统计学意义（P<0.01）。蛋白质组学分析结果显示，MV-Hu191作用MDA-MB-231细胞后明显上调蛋白质有38个、下调有12个；差异表达的蛋白质主要参与细胞黏附、信号受体激活、细胞代谢、应激反应等生物学过程，22个差异蛋白质亚细胞定位位于细胞外，KEGG功能分类显示与免疫调节功能相关的差异蛋白质最多且均为上调蛋白，包括C4A、C8B、SERPINF2、A2M、SERPINC1、CTSB、SERPING1、C5；PPI预测发现免疫相关差异蛋白与CD4、CD8、TNF-α及IL-6相互关联。体内实验结果显示，MV-Hu191干预组小鼠脾组织中CD4+ T细胞数量略高于对照组，但差异无统计学意义（P>0.05），CD4+/CD8+ T细胞比值明显高于对照组（P<0.05），血清TNF-α和IL-6含量显著上升（均P<0.01）。结论：MV-Hu191显著抑制MDA-MB-231、4T1细胞增殖及拮抗4T1细胞荷瘤小鼠成瘤性，其机制可能是MV-Hu191通过激活免疫效应分子实现抗肿瘤作用。

Cross talk between glucose metabolism and immunosuppression in IFN-γ-primed mesenchymal stem cells.

The immunosuppressive function "licensed" by IFN-γ is a vital attribute of mesenchymal stem cells (MSCs) widely used in the treatment of inflammatory diseases. However, the mechanism and impact of metabolic reprogramming on MSC immunomodulatory plasticity remain unclear. Here, we explored the mechanism by which glucose metabolism affects the immunomodulatory reprogramming of MSCs "licensed" by IFN-γ. Our data showed that glucose metabolism regulates the immunosuppressive function of human umbilical cord MSCs (hUC-MSCs) challenged by IFN-γ through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Furthermore, ATP facilitated the cross talk between glucose metabolism and the JAK-STAT system, which stimulates the phosphorylation of JAK2 and STATs, as well as the expression of indoleamine 2, 3-dioxygenase and programmed cell death-1 ligand. Moreover, ATP synergistically enhanced the therapeutic efficacy of IFN-γ-primed hUC-MSCs against acute pneumonia in mice. These results indicate a novel cross talk between the immunosuppressive function, glucose metabolism, and mitochondrial oxidation and provide a novel targeting strategy to enhance the therapeutic efficacies of hUC-MSCs.

Fibroblast-like cells Promote Wound Healing via PD-L1-mediated Inflammation Resolution.

Chronic non-healing wounds fail to progress beyond the inflammatory phase, characterized by a disorder of inflammation resolution. PD-1/PD-L1, a major co-inhibitory checkpoint signaling, plays critical roles in tumor immune surveillance and the occurrence of inflammatory or autoimmune diseases, but its roles in wound healing remains unclear. Here, we described a novel function of PD-L1 in fibroblast-like cells as a positive regulator of wound healing. PD-L1 dynamically expressed on the fibroblast-like cells in the granulation tissue during wound healing to form a wound immunosuppressive microenvironment, modulate macrophages polarization from M1-type to M2-type, and initiates resolution of inflammation, finally accelerate wound healing. Loss of PD-L1 delayed wound healing, especially in mice with LPS-induced severe inflammation. Furthermore, the mainly regulatory mechanism is that combination of FGF-2 and TGF-ß1 promotes PD-L1 translation in fibroblasts through enhancing the eIF4E availability regulated by both PI3K-AKT-mTOR-4EBP1 and p38-ERK-MNK signaling pathways. Our results reveal the positive role of PD-L1 in wound healing, and provide a new strategy for the treatment of chronic wounds.

METTL3/IGF2BP3 axis inhibits tumor immune surveillance by upregulating N6-methyladenosine modification of PD-L1 mRNA in breast cancer.

BACKGROUND: Continual expression of PD-L1 in tumor cells is critical for tumor immune escape and host T cell exhaustion, however, knowledge on its clinical benefits through inhibition is limited in breast cancer. N6-methyladenosine (m6A) plays a crucial role in multiple biological activities. Our study aimed to investigate the regulatory role of the m6A modification in PD-L1 expression and immune surveillance in breast cancer. METHODS: MeRIP-seq and epitranscriptomic microarray identified that PD-L1 is the downstream target of METTL3. MeRIP-qPCR, absolute quantification of m6A modification assay, and RIP-qPCR were used to examine the molecular mechanism underlying METTL3/m6A/IGF2BP3 signaling axis in PD-L1 expression. B-NDG and BALB/c mice were used to construct xenograft tumor models to verify the phenotypes upon METTL3 and IGF2BP3 silencing. In addition, breast cancer tissue microarray was used to analyze the correlation between PD-L1 and METTL3 or IGF2BP3 expression. RESULTS: We identified that PD-L1 was a downstream target of METTL3-mediated m6A modification in breast cancer cells. METTL3 knockdown significantly abolished m6A modification and reduced stabilization of PD-L1 mRNA. Additionally, METTL3-mediated PD-L1 mRNA activation was m6A-IGF2BP3-dependent. Moreover, inhibition of METTL3 or IGF2BP3 enhanced anti-tumor immunity through PD-L1-mediated T cell activation, exhaustion, and infiltration both in vitro and in vivo. PD-L1 expression was also positively correlated with METTL3 and IGF2BP3 expression in breast cancer tissues. CONCLUSION: Our study suggested that METTL3 could post-transcriptionally upregulate PD-L1 expression in an m6A-IGF2BP3-dependent manner to further promote stabilization of PD-L1 mRNA, which may have important implications for new and efficient therapeutic strategies in the tumor immunotherapy.

A case report of cervicothoracic penetrating injury with retention of foreign body.

BACKGROUND: Cervicothoracic penetrating injury, considered to be relatively rare, has a complicated mechanism that is difficult to treat. In this report, a special case of cervicothoracic injury caused by foreign body penetration was elucidated. In this case, the injury location and the involved foreign body were exceptionally particular, which induced a challenging process of diagnosis and treatment. CASE PRESENTATION: A male patient suffered from a serious injury caused by a thick branch that pierced through his neck in a traffic accident between an electric car and a tricycle carrying wood. There were also local injuries in the left scapular region. After an emergency multidisciplinary consultation, the patient was diagnosed and subsequently treated with vascular exploration and repair (common carotid artery), intrathoracic foreign body extraction, chest exploration, debridement, and suture. After surgery, he was transferred to the emergency intensive care unit for anticoagulation and anti-infection treatment. Finally, after the improvement of his physical condition, the patient was transferred to the general ward for further treatment and was successfully discharged from the hospital. Once discharged, the patient lived a normal life, free from sequelae or complications. CONCLUSION: It may be an extremely daunting task to cure cervicothoracic penetrating injury due to its rare occurrence in clinical practice. Different from the previous cervicothoracic traumas, the injury location in this case is exceedingly particular. In general, the common cervicothoracic trauma is associated with damage to the trachea, esophagus, throat, and other structures, easily resulting in dyspnea, which, however, does not occur in this case. The insertion position of foreign body is exceptionally particular as it does not pierce the common carotid artery but poses compression on it, which induces ischemia. It is essential for the successful treatment that the treatment plan is formulated via the detailed imaging examination and careful multidisciplinary consultation.

The Association of Single-Nucleotide Polymorphism rs13181 in ERCC2 with Risk and Prognosis of Nasopharyngeal Carcinoma in an Endemic Chinese Population.

OBJECTIVE: We examined whether the single-nucleotide polymorphism (SNP) rs13181 in the gene encoding excision repair cross complementation group 2 (ERCC2) is associated with the risk and prognosis of nasopharyngeal carcinoma (NPC). METHODS: SNPs at rs13181 were genotyped in 439 NPC patients (NPC group) and 431 age- and gender-matched cancer-free controls (control group) from a region of China where NPC is endemic, and frequencies of GG, GT and TT genotypes were compared between the two groups in the case-control study. In a subset of 365 NPC cases, SNPs were examined for potential correlation with tumor-free survival time (TFS) and overall survival (OS). RESULTS: Relative to NPC risk with a TT genotype, NPC risk was similar with GT + GG genotypes (OR 1.052, 95% CI 0.656-1.688), after adjusting for gender, age, smoking history, and immunoglobin A against Epstein-Barr virus capsid antigen (EBV-VCA-IgA) status. Univariate analysis showed that the GG or GT genotype was associated with significantly worse TFS (p<0.001) and OS (p=0.010) than the TT genotype. Prognosis was significantly worse for men than for women (TFS, p=0.045; OS, p=0.031), for T3-T4 classification than for T1-T2 (TFS, p=0.009; OS, p=0.007), for N3 than for N0+N1+N2 (TFS, p<0.001; OS, p<0.001). Based on multivariate analysis, independent risk factors for poor TFS were GG or GT genotype (HR 2.629, 95% CI 1.625-4.254, p<0.001), T3-T4 classification (HR 2.146, 95% CI 1.244-3.701, p=0.006) and N3 (HR 2.527, 95% CI 1.574-4.059, p<0.001). GG or GT genotype (HR 2.217, 95% CI 1.283-3.832, p=0.004), gender (HR 1.989, 95% CI 1.046-3.785, p=0.036), T3-T4 (HR 2.431, 95% CI 1.306-4.526, p=0.005) and N3 (HR 2.693, 95% CI 1.637-4.432, p<0.001) were independent risk factors for poor OS. CONCLUSION: The rs13181 SNP in ERCC2 does not appear to be associated with NPC risk, but it may serve as an independent prognostic factor for NPC recurrence and death.

HDAC2 inhibits EMT-mediated cancer metastasis by downregulating the long noncoding RNA H19 in colorectal cancer.

BACKGROUND: Emerging evidence suggests that epithelial mesenchymal transition (EMT) and epigenetic mechanisms promote metastasis. Histone deacetylases (HDACs) and noncoding RNAs (ncRNAs) are important epigenetic regulators. Here, we elucidated a novel role of histone deacetylase 2 (HDAC2) in regulating EMT and CRC metastasis via ncRNA. METHODS: The expression of HDACs in CRC was analyzed using the public databases and matched primary and metastatic tissues, and CRC cells with different metastatic potentials (DLD1, HCT116, SW480 and SW620). Microarray analysis was used to identify differential genes in parental and HDAC2 knockout CRC cells. EMT and histone modifications were determined using western blot and immunofluorescence. Migration ability was assessed by transwell assay, and metastasis was assessed in vivo using a tail vain injection. Gene expression and regulation was assessed by RT-PCR, chromatin immunoprecipitation and reporter assays. Protein interaction was assessed by immunoprecipitation. Specific siRNAs targeting H19, SP1 and MMP14 were used to validate their role in HDAC2 loss induced EMT and metastasis. RESULTS: Reduced HDAC2 expression was associated with poor prognosis in CRC patients and found in CRC metastasis. HDAC2 deletion or knockdown induced EMT and metastasis by upregulating the long noncoding RNA H19 (LncRNA H19). HDAC2 inhibited LncRNA H19 expression by histone H3K27 deacetylation in its promoter via binding with SP1. LncRNA H19 functioned as a miR-22-3P sponge to increase the expression of MMP14. HDAC2 loss strongly promoted CRC lung metastasis, which was suppressed LncRNA H19 knockdown. CONCLUSION: Our study supports HDAC2 as a CRC metastasis suppressor through the inhibition of EMT and the expression of H19 and MMP14.

[Possibility of mesenchymal stem cell transplantation in the treatment of coronavirus disease 2019].

2019 Novel coronavirus (2019-nCoV) infection has caused a global pandemic. Although researchers have carried out a lot of research on 2019-nCoV, analyzed the molecular structure and conducted evolutionary tree analysis, there is still insufficient understanding of its specific pathogenic mechanism, resulting in the lack of specific and effective therapeutic drugs and method. 2019-nCoV infection can cause inflammation and may deteriorate to acute respiratory distress syndrome (ARDS) and sepsis, which have become the main complication of its death. Therefore, using antiviral and symptomatic treatment with inflammation reduction can have a better therapeutic effect. Mesenchymal stem cells (MSCs) not only have a significant immune-regulation function, but also play a role in regeneration and repair, repairing damaged lungs, so they can be considered as a new effective method for the treatment of coronavirus disease 2019 (COVID-19). This article analyzes the main pathogenic mechanism of 2019-nCoV, and the process of developing into ARDS, combined with the research status of MSCs, to explore its significance and feasibility for the treatment of COVID-19. Finally, it will provide a substantial theoretical basis for clinical treatment now and in the future.

Combination of human umbilical cord mesenchymal stem (stromal) cell transplantation with IFN-γ treatment synergistically improves the clinical outcomes of patients with rheumatoid arthritis.

OBJECTIVES: To clarify the key role of circulating interferon-γ (IFN-γ) and to improve the clinical efficacy of mesenchymal stem cell (MSC) transplantation (MSCT) in patients with rheumatoid arthritis (RA). METHODS: Study of wild-type or IFN-γR-/- MSCT was first evaluated in a murine model of collagen-induced arthritis (CIA) following which a phase 1/2 randomised controlled study was conducted in 63 patients with RA who responded poorly to regular clinical treatments. Subjects were randomly assigned to an MSCT monotherapy group (n=32) or an MSCT plus recombinant human IFN-γ treatment group (n=31), with 1 year of follow-up. The primary end points consisted of efficacy as assessed as good or moderate EULAR response rates and the proportion of patients at 3 months attaining American College of Rheumatology 20 (ACR20) response rates. RESULTS: In the murine studies, wild-type MSCT significantly improved the clinical severity of CIA, while IFN-γR-/- MSCT aggravated synovitis, and joint and cartilage damage. Transitioning from the murine to the clinical study, the 3-month follow-up results showed that the efficacy and ACR20 response rates were attained in 53.3% patients with MSCT monotherapy and in 93.3% patients with MSCT combined with IFN-γ treatment (p<0.05). No new or unexpected safety issues were encountered in 1-year follow-up for either treatment group. CONCLUSIONS: The results of this study show that IFN-γ is a key factor in determining the efficacy of MSCT in the treatment of RA, and that an MSC plus IFN-γ combination therapeutic strategy can greatly improve the clinical efficacy of MSC-based therapy in RA patients.

Beneficial effects of baicalein on a model of allergic rhinitis.

Allergic rhinitis (AR) is a common disease that causes severe inflammation and even disabilities. Previous studies have reported baicalein to have an anti-inflammatory effect. However, the pharmacological action of baicalein on anaphylaxis has not been clarified yet. This study assessed the in vivo protective effect of baicalein post-treatment in an ameliorating ovalbumin (OVA)-sensitized AR rat model. Baicalein attenuated histological alterations, aberrant tissue repair and inflammation after OVA-induced AR. Baicalein reduced the frequency of nasal/ear rubs and sneezes in rats, and inhibited generation of several inflammatory cytokines (TNF-α, IL-1ß, and IL-6) in both blood and nasal lavage of rats. Infiltrations of eosinophils, lymphocyte, and neutrophils were decreased in baicalein-administered rats. Furthermore, baicalein inhibited the expression of STAT3 phosphorylation in the nasal mucosa. In summary, baicalein attenuated OVA-induced AR and inflammation, which suggests it as a promising therapeutic agent for the alleviation of AR-associated inflammation and pathology.

Full title: High glucose protects mesenchymal stem cells from metformin-induced apoptosis through the AMPK-mediated mTOR pathway.

Micro- and macro-vascular events are directly associated with hyperglycemia in patients with type 2 diabetes mellitus (T2DM), but whether intensive glucose control decreases the risk of diabetic cardiovascular complications remains uncertain. Many studies have confirmed that impaired quality and quantity of mesenchymal stem cells (MSCs) plays a pathogenic role in diabetes. Our previous study found that the abundance of circulating MSCs was significantly decreased in patients with T2DM, which was correlated with the progression of diabetic complications. In addition, metformin-induced MSC apoptosis is one of the reasons for the decreased quantity of endogenous or exogenous MSCs during intensive glucose control. However, the role of glucose in metformin-induced MSC apoptosis during intensive glucose control in T2DM remains unknown. In this study, we found that metformin induces MSC apoptosis during intensive glucose control, while high glucose (standard glucose control) could significantly reverse its adverse effect in an AMPK-mTOR pathway dependent manner. Thus, our results indicate that the poorer clinical benefit of the intensive glucose control strategy may be related to an adverse effect due to metformin-induced MSC apoptosis during intensive glucose control therapy in patients with T2DM.

Chondroma of laryngeal cartilage mimicking thyroid tumor: A case report.

RATIONALE: Cartilaginous tumors of the larynx are rare. This report describes an atypical case with chondroma of laryngeal cartilage presenting as cervical mass, which was misdiagnosed as a thyroid tumor. PATIENT CONCERN: A 73-year-old Chinese man with a 1-month history of cervical mass. The neck color Doppler ultrasound and CT of thyroid showed a space-occupying lesion in the upper right pole of the thyroid gland. DIAGNOSES: Chondroma of laryngeal cartilage was confirmed at the time of surgery. INTERVENTIONS: After relevant examinations, subtotal thyroidectomy and excisional biopsy of the neck mass were performed under general anesthesia. However, the rapid pathology of the tumor (thyroid right lateral lobe) indicated chondroma, so the patient underwent laryngeal chondroma resection and tracheotomy under general anesthesia. OUTCOMES: After surgery, given the advanced age of the patient, long surgical duration and poor cardiorespiratory function, the patient suffered sudden cardiac death after the operation. LESSONS: Cartilaginous tumor of the larynx is rare, and approximately 250 cases have been reported till date. It is difficult to diagnose cartilaginous tumors of the larynx in the early stage, and they are easily misdiagnosed. Early diagnosis, radical surgery, and long-term follow-up are key to prolong survival.

Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium.

BACKGROUND: Cardiovascular complications, especially myocardial infarctions (MIs), are the leading mortality cause in diabetic patients. The transplantation of stem cells into damaged hearts has had considerable success as a treatment for MI, although whether antidiabetic drugs affect the therapeutic efficacy of stem cell transplantation is still unknown. This study aims to understand whether and how metformin, one of the first-line drugs used to treat type 2 diabetes mellitus (T2DM), induces mesenchymal stromal cell (MSC) apoptosis and dampens their cardioprotective effect after transplantation into infarcted hearts. METHODS: A mouse MI model was generated via permanent ligation of the left anterior descending (LAD) coronary artery. MSCs with or without metformin treatment were transplanted after MI in diabetic mice. Echocardiography was used to assess cardiac function and determine cardiac remodeling, and TTC staining was performed to evaluate infarction size. A mouse gavage model was performed to evaluate bone marrow MSCs for flow cytometry assay. RESULTS: Metformin dampened MSC therapeutic efficacy, which increased infarct size and restricted functional cardiac recovery. Specifically, metformin induced the activation of AMP-activated protein kinase (AMPK)-mediated apoptosis through the inhibition of S6K1-Bad-Bcl-xL cell survival signaling, resulting in the upregulated expression of apoptosis-associated proteins and increased MSC apoptosis. Accordingly, counteracting AMPK attenuated metformin-induced apoptosis in MSCs and partially restored their cardioprotective effects in diabetic mice with MI. Furthermore, a decrease in peripheral blood MSCs was found in patients with T2DM who had a metformin medication history. CONCLUSIONS: Our results highlight an unexpected adverse effect of metformin-induced MSC apoptosis through AMPK-mediated mTOR suppression, which is attenuated by an AMPK inhibitor. Moreover, AMPK inhibition may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI in diabetes.