ICA/SDF-1α/PBMSCs loaded onto alginate and gelatin cross-linked scaffolds promote damaged cartilage repair.

A three-dimensional alginate-coated scaffold (GAIS) was constructed in the present study to showcase the multidifferentiation potential of peripheral blood mesenchymal stem cells (PBMSCs) and to investigate the role and mechanism by which Icariin (ICA)/stromal cell-derived factor (SDF-1α)/PBMSCs promote damaged articular repair. In addition, the ability of ICA, in combination with SDF-1α, to promote the migration and proliferation of stem cells was validated through the utilization of CCK-8 and migration experiments. The combination of ICA and SDF-1α inhibited the differentiation of PBMSCs into cartilage, as demonstrated by in vivo experiments and histological staining. Both PCR and western blot experiments showed that GAIS could upregulate the expression of particular genes in chondrocytes. In comparison to scaffolds devoid of alginate (G0), PBMSCs seeded into GAIS scaffolds exhibited a greater rate of proliferation, and the conditioned medium derived from scaffolds containing SDF-1α enhanced the capacity for cell migration. Moreover, after a 12-week treatment period, GAIS, when successfully transplanted into osteochondral defects of mice, was found to promote cartilage regeneration and repair. The findings, therefore, demonstrate that GAIS enhanced the in vitro capabilities of PBMSCs, including proliferation, migration, homing and chondrogenic differentiation. In addition, ICA and SDF-1α effectively collaborated to support cartilage formation in vivo. Thus, the ICA/SDF-1α/PBMSC-loaded biodegradable alginate-gelatin scaffolds showcase considerable potential for use in cartilage repair.

TERT assists GDF11 to rejuvenate senescent VEGFR2+/CD133+ cells in elderly patients with myocardial infarction.

Growth differentiation factor 11 (GDF11) is a transforming growth factor ß superfamily member with a controversial role in rejuvenating old stem cells after acute injury in the elderly population. This study aimed to evaluate the effects of telomerase reverse transcriptase (TERT) on GDF11-mediated rejuvenation of senescent late-outgrowth endothelial progenitor cells (EPCs), defined as VEGFR2+/CD133+ cells, in elderly patients with acute myocardial infarction (AMI). We compared the quantity and capabilities of VEGFR2+/CD133+ cells from old (>60 years), middle-aged (45-60 years), and young (<45 years) AMI patients. The decline in circulating count and survival of VEGFR2+/CD133+ cells with age was accompanied by decrease in their TERT and GDF11 expression levels in patients with AMI. Further, upregulation of TERT could trigger GDF11-mediated rejuvenation of old VEGFR2+/CD133+ cells by renewing their survival and angiogenic abilities through activation of canonical (Smad2/3) and noncanonical (eNOS) signaling pathways. Depletion of GDF11 or TERT caused senescence of young VEGFR2+/CD133+ cells leading to impaired vascular function and angiogenesis in vitro and in vivo, whereas adTERT and rhGDF11 rescued this senescence. TERT cooperates with GDF11 to enhance regenerative capabilities of old VEGFR2+/CD133+ cells. When combined with TERT, GDF11 may represent a potential therapeutic target for the treatment of elderly patients with MI.

Clinical Efficiency and Safety of Magnetic-Controlled Capsule Endoscopy for Gastric Diseases in Aging Patients: Our Preliminary Experience.

BACKGROUND: The elderly assess higher incidence of gastric diseases and may meet challenges and contraindications when flexible esophagogastroduodenoscopy intubating. Magnetic-controlled capsule endoscopy (MCE) is declared as a promising alternative, but its applications in elderly population do not attach enough importance. AIMS: To explore MCE's efficiency and safety in the elderly. METHODS: A single-center retrospective study has been conducted. Data from the elderly group (>65 year-old) who underwent MCE examination, including indications, MCE outcomes, gastric conditions, evaluations from MCE manipulators and endoscopists, subjective discomforts, adverse events, etc., had been collected, then analyzed, and compared with the ones from the middle-aged group (>40, ≤ 65 year-old). RESULTS: During April 2015 and September 2018, 98 elderly patients and 72 middle-aged patients underwent MCE examination. In the elderly, the indications included poor physical condition (28.6%), severe angiocardiopathy (39.8%), EGD rejection (13.3%), severe respiratory disorder (8.2%), craniocerebral injury (8.2%), and allergy to anesthetics (2.0%). Rate of complete gastric observation and positive finding were 98.0% and 72.4% (vs. middle-aged group, 94.4%, 56.9%, P = 0.220, 0.035), and gastric conditions showed relatively inferior. Gastric preparation and MCE procedure were generally tolerated, but three elderly patients (3.1%) experienced capsule blockage in stomach. CONCLUSIONS: Our preliminary data support that MCE offers considerable benefit and is general safe for the elderly. We hope such data promote greater awareness of innovative attempts for the specific elderly, and expect multi-center, large-scale trials with randomized controlled design bring optimized strategies for better gastric visibility, efficacy and lower potential risk.

Cell surface-anchored syndecan-1 ameliorates intestinal inflammation and neutrophil transmigration in ulcerative colitis.

Syndecan-1 (SDC1), with a variable ectodomain carrying heparan sulphate (HS) chains between different Syndecans, participates in many steps of inflammatory responses. In the process of proteolysis, the HS chains of the complete extracellular domain can be shed from the cell surface, by which they can mediate most of SDC1's function. However, the exact impact on SDC1 which anchored on the cell surface has not been clearly reported. In our study, we established the models by transfection with the cleavable resistant SDC1 mutant plasmid, in which SDC1 shedding can be suppressed during stimulation. Role of membrane SDC1 in inflammatory pathway, pro-inflammatory cytokine secretion as well as neutrophil transmigration, and how suppressing its shedding will benefit colitis were further investigated. We found that the patients suffered ulcerative colitis had high serum SDC1 levels,presented with increased levels of P65, tumour necrosis factor alpha (TNF-α) and IL-1ß and higher circulating neutrophils. NF-κB pathway was activated, and secretion of TNF-α, interleukin-1beta (IL-1ß), IL-6 and IL-8 were increased upon lipopolysaccharide stimuli in intestinal epithelial cells. Syndecan-1, via its anchored ectodomain, significantly lessened these up-regulation extents. It also functioned in inhibiting transmigration of neutrophils by decreasing CXCL-1 secretion. Moreover, SDC1 ameliorated colitis activity and improved histological disturbances of colon in mice. Taken together, we conclude that suppression of SDC1 shedding from intestinal epithelial cells relieves severity of intestinal inflammation and neutrophil transmigration by inactivating key inflammatory regulators NF-κB, and down-regulating pro-inflammatory cytokine expressions. These indicated that compenstion and shedding suppression of cytomembrane SDC1 might be the optional therapy for intestinal inflammation.

Comparison of Various Strategies for the Prognosis and Outcomes of Ischaemic Dilated Cardiomyopathy in Smokers: Complete Revascularisation and Smoking Cessation Produces a Superior Outcome.

BACKGROUND: Various therapies have been used to improve the symptoms and prognosis of patients with coronary artery disease. However, comparative studies showing more suitable choices for patients with ischaemic dilated cardiomyopathy (IDCM) and who smoke cigarettes are lacking. METHODS: A total of 338 patients were divided into four groups according to whether they received complete revascularisation (CR), and/or underwent smoking cessation (SC). They were followed prospectively for 12 months. The major adverse cardiac and cerebrovascular events (MACCEs: all-cause mortality, non-fatal MI, non-fatal stroke, repeat revascularisation, and AHF) were the primary endpoint, and decompensation necessitating hospitalisation and the combined endpoint thereof were secondary endpoints. RESULTS: During a mean follow-up of 12 months, the prevalence of MACCEs was significantly lower in patients receiving CR plus SC (CRSC) than in patients receiving CR only (CR), SC only (SC), and neither R nor SC (NoRSC) (CRSC 4.4% vs. CR 11.9, p<0.05; vs. SC 26.5%, p<0.001; vs. NoRSC 34.5%, p<0.001, respectively). At 12 months, CR plus SC induced the greatest clinical benefits of the secondary outcomes in the CRSC group (49.1% relative increase in LVEF; 89.8% decrease in NT-proBNP level; 30.9% decrease in LVEDD; 38.3% decrease in LVESD; 51.4% decrease in LVEDVi; 51.2% decrease in LVESVi; 96.4% decrease in hs-cTnT level; 93.5% decrease in CK-MB level; 91.1% decrease in hs-CRP level; 94.0% decrease in IL-6 level; 1.9-fold increase in eNOS level; 1.8-fold increase in NO level; 1.3-fold increase in NOS level, all p<0.001). Absence of revascularisation brought about fewer benefits, and those who continued smoking had worse outcomes. CONCLUSIONS: The combination of CR and SC could be an optimal therapeutic regimen for patients with IDCM who smoke because it improves myocardial blood perfusion and endothelial function.

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-ß1 signaling pathway.

Interlukin-6 (IL-6) is a multifunctional cytokine produced by several cell types that has a role in fibrosis. Fibroblasts (FBs) maintain this underlying pathogenic change through regulation of IL-6 production; however, its potential functional role in regulating surrounding cellular structural changes during ischemic myocardial remodeling remains unexplored. Here, we generated FBs, cardiomyocytes (CMs), and blood vascular endothelial cells (ECs) from the ventricles of neonatal rats. IL-6 was then overexpressed in FBs and the cells were treated with IL-6 receptor inhibitor (IL6RI), TGF-ß1 receptor inhibitor (TßRI), or MMP2/MMP9 inhibitor (MMPI) using monoculture or coculture models under hypoxic conditions. The results indicate that overexpression of IL-6 is sufficient to induce myofibroblastic proliferation, differentiation, and fibrosis, probably via increased TGF-ß1-mediated MMP2/MMP3 signaling. The use of IL6RI, TßRI, or MMPI diminished these effects. In addition, IL-6 activated the apoptosis-associated factors Caspase3 and Smad3, and decreased the expression of anti-apoptotic factor Bcl2, resulting in apoptosis of CMs under hypoxic coculture: IL6RI or TßRI inhibited these effects. Unexpectedly, IL-6-overexpressing FBs significantly increased the angiogenesis of ECs, which involved significant increases in the expression of proangiogenic growth factors. Treatment of FBs with IL6RI or TßRI in coculture with ECs reduced the levels of secreted proangiogenic growth factors, and the angiogenesis of ECs was significantly downregulated. Thus, IL-6 functions in ischemic myocardial remodeling through multifunctional reprogramming of hypoxia-associated FBs towards fibrosis via upregulation of the TGF-ß1 signaling pathway.

High glucose-induced intestinal epithelial barrier damage is aggravated by syndecan-1 destruction and heparanase overexpression.

Syndecan-1 (Sdc1) and its endo-beta-D-glucuronidase heparanase (HPSE) are implicated in maintenance of intestinal epithelial barrier (IEB), but their alterations and roles in high-glucose/hyperglycaemia (HG) conditions have not been fully investigated. This study aimed to determine the expression pattern, the possible regulation mechanism of Sdc1 and HPSE in HG conditions, and their potential effects on IEB. Therefore, diabetic mice/cell models were developed, and tissue/serum samples, cell lysate and culture supernatants were harvested. The expression of Sdc1 and HPSE in control, HG and designated interventions groups were detected. Phosphorylations of mitogen-activated protein kinase signalling pathway (MAPK), the expressions of Occludin and ZO-1, and the levels of transepithelial electrical resistance (TEER) were measured and monitored. The results showed that in HG conditions, intestinal tissue and cellular Sdc1 were significantly decreased, but the expression of HPSE, and soluble Sdc1 in serum and culture supernatants were remarkably increased. Such alterations of Sdc1 and HPSE were associated with solely p38 MAPK activation, and were correlated with the reductions of Occludin, ZO-1 and TEER. Heparin (Sdc1 analogue) and SB203580 (a p38 MAPK inhibitor), instead of insulin, alleviated Sdc1 destruction and HPSE overexpression, and effectively prevented against the reductions of tight junctions and the abnormality of intestinal permeability in HG conditions. In conclusion, we confirm the unique alterations of Sdc1 and HPSE in HG conditions, and found their interactions with p38 MAPK activation and IEB. These indicate that Sdc1/HPSE modulation can be viewed as an important complementary treatment for relieving HG-induced gastrointestinal damage.

Cardioprotection by PI3K-mediated signaling is required for anti-arrhythmia and myocardial repair in response to ischemic preconditioning in infarcted pig hearts.

Although the phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway is essential for conferring cardioprotection in response to ischemic preconditioning (IP), the role of PI3K/Akt signaling in the infarcted heart for mediating the anti-arrhythmic effects in response to IP remains unclear. We explored the involvement of PI3K/Akt in the IP-like effect of connexin 43 and proangiogenic factors with particular regard to its role in protecting against ischemia-induced arrhythmia, heart failure, and myocardial remodeling. Groups of pigs were administered phosphate-buffered saline (PBS) or LY294002 solution. Before induction of myocardial infarction (MI), pigs were grouped according to whether or not they underwent IP. Next, all animals underwent MI induction by ligation of the left anterior descending (LAD) coronary artery. Myocardial tissues from the pig hearts at 7 days after MI were used to assess myocardium myeloperoxidase and reaction oxygen species, infarct size, collagen content, blood vascular density, expression of Akt, connexin 43, and proangiogenic growth factors, using spectrophotometer, histology, immunohistochemistry, real-time RT-PCR, and western blot. At 7 days after MI, IP significantly reduced animal mortality and malignant ventricular arrhythmia, myocardial inflammation, infarct size, and collagen content, and improved cardiac function and remodeling; use of the PI3K inhibitor LY294002 diminished these effects. In parallel with a decline in Akt expression and phosphorylation by MI, LY294002 injection resulted in significant suppression of connexin 43 and proangiogenic factor expression, and a reduction of angiogenesis and collateral circulation. These findings demonstrate that the cardioprotective effects of IP on antiventricular arrhythmia and myocardial repair occur through upregulation of PI3K/Akt-mediated connexin 43 and growth factor signaling.

Generation of an induced pluripotent stem cell line from patient with atrial fibrillation with KCNQ1 p.Ser209Pro mutation.

Gain-of-function mutations in the KCNQ1 gene can cause atrial fibrillation. In this study, we generated an induced stem cell line (GRCHJUi001) from one member of an atrial fibrillation family line, whom had heterozygous mutation in the KCNQ1 gene c.625 T > C (p.Ser209Pro), and the cell line showed maintenance of stem cells characterized by morphology, normal karyotype, and pluripotency.

Comparison of various niches for endothelial progenitor cell therapy on ischemic myocardial repair: coexistence of host collateralization and Akt-mediated angiogenesis produces a superior microenvironment.

OBJECTIVE: Comparative studies are lacking that show the effects of different microenvironments on the activity of engrafted stem cells after myocardial infarction (MI). Here, we analyzed the temporal and spatial variations of angiogenesis, collateralization, and the expression of Akt-related signals after MI to test whether the effects of endothelial progenitor cells (EPCs) were different. METHODS AND RESULTS: After the induction of MI, pigs were selected that did not develop a collateral coronary circulation (R0) or developed a significant collateral coronary circulation (R2). Both sets were allocated randomly to 4 groups: phosphate-buffered saline (intramyocardial injection of phosphate-buffered saline), EPC transplantation, LY294002 (intramyocardial injection of an Akt inhibitor), and EPCs plus LY294002. Infarcted porcine hearts at different time points and under different collateralized conditions exhibited a variety of vascular microenvironments. At 14 days post-MI, angiogenesis and the expression of Akt-mediated angiogenic cytokines predominated in R2 porcine hearts. When grafted into this microenvironment, EPCs induced the greatest effects in impeding the development of heart failure, preserving left ventricular function and dimensions, and inhibiting infarct expansion. LY294002 significantly reduced these effects. CONCLUSIONS: These findings suggest that the microenvironment that coexists with collateralization and Akt-mediated angiogenesis appears to be more beneficial to cardiac repair induced by EPC therapy than other niches after MI.

Rebamipide helps defend against nonsteroidal anti-inflammatory drugs induced gastroenteropathy: a systematic review and meta-analysis.

BACKGROUND: Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) has been perplexing most clinicians and users of NSAIDs. Rebamipide is increasingly advocated as a candidate option for the prevention of NSAIDs induced gastrointestinal mucosal injury. AIMS: To assess the efficacy and the safety of rebamipide for the prevention and treatment of NSAID-induced gastroenteropathy. METHODS: PubMed, Embase, Web of Science, Google Scholar, the Cochrane Library, Japan Science and Technology Information Aggregator, and China Biology Medicine Disc were searched up to December 2011. Randomized controlled trials (RCTs) recruiting subjects with co-prescriptions of NSAIDs and rebamipide were eligible. Efficacy and safety of rebamipide were reevaluated, and dichotomous data were pooled to obtain relative risk (RR) with a 95 % confidence interval. Heterogeneity and publication bias were assessed by the inconsistency index statistic and funnel plot analysis, respectively. RESULTS: The search identified 338 citations, and 15 RCTs including 965 individuals were eligible. In general, rebamipide acted better than placebo against short-term NSAID-induced gastroduodenal injury. Separate studies showed rebamipide was equal to or not superior to traditional strategies (including PPIs, H2RA and misoprostol treatment). Especially, rebamipide showed a beneficial effect against the small bowel damage (total RR = 2.70, 95 % confidence interval = 1.02-7.16, P = 0.045) when compared with placebo group. The average incidence of adverse events was about 36.1 % (0-70.0 %) but no serious event was recorded. CONCLUSIONS: Current evidences show rebamipide is effective and safe for defending against NSAID-induced gastroduodenal and lower-gastrointestinal injuries. However, more well-designed trials should be conducted to fully confirm the practical value of rebamipide.

Icariin activates far upstream element binding protein 1 to regulate hypoxia-inducible factor-1α and hypoxia-inducible factor-2α signaling and benefits chondrocytes.

Icariin (ICA) is a typical flavonoid glycoside derived from epimedium plants. It has both anabolic and anti-catabolic effects to improve bone mineral density and reduce bone microstructural degradation. However, the effect and underlying mechanism of ICA on the proliferation and metabolism of chondrocyte and synthesis of extracellular matrix are still unclear. This study aimed to investigate the role and regulation of far upstream element binding protein 1 (FUBP1) in chondrocytes treated with ICA to maintain homeostasis and suppress inflammatory responses. In the study, the effect of ICA on chondrocytes with overexpressed or silenced FUBP1 was detected by the MTS and single-cell cloning methods. The expression of hypoxia-inducible factor-1/2α (HIF-1/2α), FUBP1, matrix metalloproteinase (MMP)9, SRY-box transcription factor 9 (SOX9), and type II collagen (Col2α) in ATDC5 cells, a mouse chondrogenic cell line, treated with ICA was evaluated by immunoblotting. Western blotting revealed 1 µM ICA to have the most significant effect on chondrocytes. Alcian blue staining and colony formation assays showed that the promoting effect of ICA was insignificant in FUBP1-knockdown cells (P > 0.05) but significantly enhanced in FUBP1-overexpressed cells (P < 0.05). Western blot results from FUBP1-knockdown cells treated with or without ICA showed no significant difference in the expression of FUBP1, HIF-1/2α, MMP9, SOX9, and Col2α proteins, whereas the same proteins showed increased expression in FUBP1-overexpressed chondrocytes; moreover, HIF-2α and MMP9 expression was significantly inhibited in FUBP1-knockdown chondrocytes (P < 0.05). In conclusion, as a bioactive monomer of traditional Chinese medicine, ICA is beneficial to chondrocytes.

Risk factors associated with contrast-associated acute kidney injury in ST-segment elevation myocardial infarction patients: a systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the risk factors for contrast-associated acute kidney injury (CA-AKI) in ST-elevation myocardial infarction patients treated with primary percutaneous coronary intervention. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched the databases of PubMed, Embase and Ovid, up to February 2022, for observational studies that investigated the association between risk factors and CA-AKI. RESULTS: A total of 21 studies were included in the meta-analysis. Of the total 22 015 participants, 2728 developed CA-AKI. Pooled incidence was 11.91% (95% CI 9.69%, 14.14%). Patients with CA-AKI were more likely to be older, female, also had comorbidities (hypertension, diabetes, previous heart failure). Smoking (OR: 0.60; 95% CI 0.52, 0.69) and family history of CAD (coronary artery disease) (OR: 0.76; 95% CI 0.60, 0.95) were associated with lower risk of CA-AKI. Left anterior descending (LAD) artery occlusion (OR: 1.39; 95% CI 1.21, 1.59), left main disease (OR: 4.62; 95% CI 2.24, 9.53) and multivessel coronary disease (OR: 1.33; 95% CI 1.11, 1.60) were risk factors for CA-AKI. Contrast volume (weighted mean difference: 20.40; 95% CI 11.02, 29.79) was associated with increased risk in patients receiving iso-osmolar or low-osmolar non-ionic contrast. CONCLUSIONS: In addition to the known risk factors, LAD artery infarction, left main disease and multivessel disease are risk factors for CA-AKI. The unexpected favourable association between smoking, as well as family history of CAD, and CA-AKI requires further investigation. PROSPERO REGISTRATION NUMBER: CRD42021289868.

Risk factors and clinical outcomes of incomplete endoscopic resection of small rectal neuroendocrine tumors in southern China: a 9-year data analysis.

Background: The histologically complete resection (CR) rate of small rectal neuroendocrine tumors (RNETs) is unsatisfactory at the first endoscopy. Risk factors and clinical outcomes associated with incomplete resection (IR) have not been explicitly elucidated. This study aims to explore the relevant factors of IR. Methods: This retrospective study reviewed patients with small RNETs (≤10 mm) in eight centers from January 2013 to December 2021. Clinicopathological characteristics and clinical outcomes were compared between the CR and IR groups, and the polypectomy and advanced treatment groups. Results: Of the 326 patients included, 83 (25.5%) were diagnosed with IR. Polypectomy (odds ratio [OR] = 16.86), a central depression (OR = 7.50), and treatment in the early period (OR = 2.60) were closely associated with IR. Further analysis revealed that an atypical hyperemic appearance (OR = 7.49) and treatment in the early period (OR = 2.54) were significantly associated with the inappropriate use of polypectomy (both P < 0.05). In addition, a total of 265 (81.3%) were followed up with a median follow-up period of 30.9 months. No death, metastasis, or recurrence was found during the follow-up period. Conclusions: Polypectomy, a central depression, and treatment in the early period were risk factors for IR. Further, an atypical hyperemic appearance and treatment in the early period were significant predisposing factors for inappropriate choice of polypectomy. For histologically incompletely resected small RNETs, follow-up may be a safe and feasible alternative to rigorous salvage therapy.

Treatment and application of stem cells from different sources for cartilage injury: a literature review.

Background and Objective: Cartilage defects and degeneration have a major impact on daily mobility and quality of life for millions of people worldwide. As the most effective seed cells for tissue engineering applications in regenerative medicine, mesenchymal stem cells (MSCs) are pluripotent cells with mesoderm and neural crest origin. The combination of biomaterial scaffolds with stem cells and drugs for cartilage damage repair has brought much hope to the medical field. Methods: We searched and compared the literature on cartilage damage repaired by stem cells through PubMed and Web of Science method, this review summarizes the research progress of mesenchymal stem cells from various tissue sources in repairing articular cartilage injury. Key Content and Findings: We found that peripheral blood, bone marrow, umbilical cord blood, adipose tissue, and umbilical cord are classic stem cell sources. Stem cells can be stimulated by various growth factors, recombinant proteins, or important monomers to generate cartilage in vitro. At the same time, MSCs obtained from various sources can secrete different growth factors to further regulate their own cartilage formation. These stem cells may promote the cartilage damage repair by promoting differentiation and fighting inflammation. Conclusions: This review summarizes and discusses the advantages and disadvantages of the ability of MSCs from different sources to treat cartilage injury, and provides help and identification for the subsequent in-depth research and preclinical application of various MSCs.

Oct4 cooperates with c-Myc to improve mesenchymal-to-endothelial transition and myocardial repair of cardiac-resident mesenchymal stem cells.

BACKGROUND: Cardiac-resident mesenchymal stem cells (cMSCs) can exhibit fibrotic, proinflammatory, and proangiogenic phenotype in response to myocardial ischemia (Isch). How their phenotypic fate decisions are determined remains poorly understood. Here, we demonstrate that the cooperation of Oct4 and c-Myc in cMSCs creates a preferable mesenchymal-to-endothelial transition (MEndoT) to promote angiogenesis and consequent myocardial repair. METHODS: We collected MSCs from cardiac and peripheral blood of rat with left ventricular Isch (LV Isch) 30 days after myocardial infarction (MI) or sham operation. After a comparison of characterization between cMSCs and peripheral blood MSCs (pbMSCs), we conducted transcriptome analysis and RNA sequencing of cMSCs. Using loss/gain-of-function approaches to understand the cooperation of c-Myc and Oct4 on MEndoT of cMSCs under hypoxic condition, we explored the mechanisms through transcriptome and functional experiment, and chromatin immunoprecipitation. Next, we transplanted male cMSCs with overexpression or inhibition of c-Myc/Oct4 into the infarcted myocardium of female rats and evaluated infarct size, cell retention, inflammation, remodeling, and function after 30 days. RESULTS: LV Isch switched cMSCs toward both inflammatory and proangiogenic phenotypes, with increased secretion of inflammatory cytokines as well as decreased expression of proangiogenic factors. The effect of LV Isch on pbMSCs was less remarkable. Gene expression heatmap showed imbalance in expression of Oct4 and c-Myc regulating genes associated with remodeling of cMSCs. We provided evidence that cMSCs-specific c-Myc- versus Oct4-overexpression showed divergent genomic signatures, and their corresponding target genes play an important role in regulating cMSCs phenotypic changes. In particular, Oct4 accelerated angiogenesis induced by c-Myc overexpression in cMSCs and inhibited their phenotypic transition into inflammatory cells and fibroblast. Mechanistically, exogenous Oct4 caused c-Myc to translocate from the nucleus to the cytoplasm and activated some of its target signalings including VEGF signaling. Although transplantation of cMSCs alone did not improve LV remodeling and function, cMSCs co-transfected with c-Myc and Oct4 promoted a more positive effect in their survival and reparative properties, increased animal survival, reduced infarct size, decreased scar thickness, inhibited LV remodeling, and improved heart function 30 days after MI. Significantly, Oct4 promoted MEndoT ("Rescue me" signal) of cMSCs after both c-Myc stimulation in vitro and transplantation into the infarcted heart. CONCLUSIONS: Myocardial Isch drives resident cMSCs toward multiple phenotypes. Oct4 interacts with c-Myc to promote MEndoT capacity of cMSCs and improve their survival and reparative effects through upregulation of angiogenesis-related signaling pathways. These findings may identify novel targets for stem cell therapy.

ß-Catenin promotes long-term survival and angiogenesis of peripheral blood mesenchymal stem cells via the Oct4 signaling pathway.

Stem cell therapy has been extensively studied to improve heart function following myocardial infarction; however, its therapeutic potency is limited by low rates of engraftment, survival, and differentiation. Here, we aimed to determine the roles of the ß-catenin/Oct4 signaling axis in the regulation of long-term survival and angiogenesis of peripheral blood mesenchymal stem cells (PBMSCs). These cells were obtained from rat abdominal aortic blood. We showed that ß-catenin promotes the self-renewal, antiapoptotic effects, and long-term survival of PBMSCs by activating the Oct4 pathway through upregulation of the expression of the antiapoptotic factors Bcl2 and survivin and the proangiogenic cytokine bFGF and suppression of the levels of the proapoptotic factors Bax and cleaved caspase-3. ß-Catenin overexpression increased Oct4 expression. ß-Catenin knockdown suppressed Oct4 expression in PBMSCs. However, ß-catenin levels were not affected by Oct4 overexpression or knockdown. Chromatin immunoprecipitation assays proved that ß-catenin directly regulates Oct4 transcription in PBMSCs. In vivo, PBMSCs overexpressing ß-catenin showed high survival in infarcted hearts and resulted in better myocardial repair. Further functional analysis identified Oct4 as the direct upstream regulator of Ang1, bFGF, HGF, VEGF, Bcl2, and survivin, which cooperatively drive antiapoptosis and angiogenesis of engrafted PBMSCs. These findings revealed the regulation of ß-catenin in PBMSCs by the Oct4-mediated antiapoptotic/proangiogenic signaling axis and provide a breakthrough point for improving the long-term survival and therapeutic effects of PBMSCs.

CADM1/TSLC1 inactivation by promoter hypermethylation is a frequent event in colorectal carcinogenesis and correlates with late stages of the disease.

Cell adhesion molecule 1 (CADM1/TSLC1), a putative tumor suppressor involving in cell adhesion, proliferation and apoptosis, is frequently inactivated in several carcinomas due to promoter hypermethylation. But alterations of CADM1/TSLC1 in colorectal carcinogenesis and clinical significance have not been elucidated yet. The aim of this study was to determine the role of functional inactivation of CADM1/TSLC1 gene in colorectal tumorigenesis and its potential as a novel epigenetic marker for clinical assessment of patients with colorectal cancer. We measured CADM1/TSLC1 expression levels in 8 colorectal cancer cell lines, 54 primary colorectal carcinomas and their corresponding non-cancerous tissues by reverse transcription polymerase chain reaction, western blot analysis and immunohistochemistry. We analyzed CADM1/TSLC1 promoter methylation status by bisulfite genomic sequencing and the methylation special polymerase chain reaction, and evaluated its correlation with clinicopathological characteristics. All statistical tests were 2-sides. Downregulation of CADM1/TSLC1 expression was observed in 7 of 8 (88%) colorectal cancer cell lines and in 39 of 54 (72%) primary colorectal carcinomas. Hypermethylation of CADM1/TSLC1 promoter region occurred in 6 of 8 (75%) colorectal cancer cell lines and 32 of 54 (59%) primary colorectal carcinomas, and was correlated with advanced colorectal carcinoma. Epigenetic inactivation of CADM1/TSLC1 gene is a frequent alteration in development of colorectal cancer and can be a potential biomarker for molecular staging of patients with colorectal cancer.

Activated Syndecan-1 shedding contributes to mice colitis induced by dextran sulfate sodium.

BACKGROUND: Syndecan-1(Sdc1) plays important roles in many steps of inflammatory responses. In ulcerative colitis patients, decreased Sdc1 expression was observed and Sdc1 analogue heparin could improve the disease course. A better understanding of how Sdc1 functions in colitis will benefit the disease intervention. AIMS: To evaluate the role of Sdc1 in dextran sulfate sodium (DSS)-induced colitis. METHODS: BALB/c mice were grouped randomly into control, DSS, and heparin+DSS. The DSS group was given 4% DSS orally and heparin+DSS group was given 4% DSS with heparin (enoxaparin) subcutaneously, while the control was given distilled water orally. All mice were killed at day 7. Disease activities, histopathological changes, membrane-bound and free Sdc1 level and mRNA expression of Sdc1, IL-1, and IL-10 in colon mucosa were detected. RESULTS: Significant colitis was observed in the DSS group, but disease activity index and histological score showed significant lower in the heparin+DSS group than those in the DSS group. Compared to the control group, decreased Sdc1 protein expression was detected in colon mucosa of DSS-induced colitis while Sdc1 ectodomain level in serum was much higher. Inhibited Sdc1 ectodomain shedding was detected in the heparin+DSS group compared to the DSS group. RT-PCR demonstrated that both IL-1 and IL-10 expression were up-regulated in DSS-induced colitis while heparin lessened the up-regulation extent. CONCLUSIONS: Sdc1 shedding is activated in DSS-induced colitis and heparin, which mimics Sdc1 functions, relieves colitis severity by inhibiting Sdc1 shedding and down-regulating cytokines expression.