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.

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.

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.

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.

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.

Baicalin promotes chondrocyte viability and the synthesis of extracellular matrix through TGF-ß/Smad3 pathway in chondrocytes.

BACKGROUND: Osteoarthritis (OA) is common in the elderly. Baicalin (BA) is a flavonoid monomer extracted from Scutellaria baicalensis Georgi, which has been reported to have anti-inflammatory, anti-deformation and anti-bacterial effects. METHODS: Cultures of micromass and 3D alginate beads, Alcian blue and Safranin O (SO)/fast green staining were used to investigate chondrocyte viability and extracellular matrix (ECM) synthesis in chondrocytes of all groups. The expression of SOX9, Smad3, Aggrecan (ACAN), type II collagen (Col2α), matrix metallopetidase 9 (MMP9), MMP13 and ADAMTS5 in chondrocytes of all groups were detected by western blot or qRT-PCR. RESULTS: The present study demonstrates that BA neutralized the IL-1ß-induced downregulation of chondrocyte viability and ECM secretion, including ACAN and Col2α. The downregulation of SOX9, and the upregulation of MMP9, MMP13 and ADAMTS5 induced by IL-1ß were reversed by BA treatment. Moreover, BA increased the nuclear translocation of Smad3 and SOX9 in chondrocytes cultured by micromass and 3D alginate beads. Interestingly, Smad3 inhibitor SIS3 reversed the promoting effect of BA on chondrocyte viability, ECM secretion, SOX9 and Smad3 nuclear translocation, and the inhibiting effect of BA on MMP9 and ADAMTS5 expressions. BA treatment also attenuated the decrease of Smad3 phosphorylation, SOX9 expression and the damage of cartilage integrity in mice which were induced by destabilization of the medial meniscus (DMM). CONCLUSION: BA promotes chondrocyte viability and the cell matrix synthesis through TGF-ß/Smad3 pathway in IL-1ß-treated chondrocytes and DMM treated mice. BA is a potential therapeutic target for OA.

Oct4-dependent FoxC1 activation improves the survival and neovascularization of mesenchymal stem cells under myocardial ischemia.

BACKGROUND: The administration of mesenchymal stem cells (MSCs) remains the most promising approach for cardiac repair after myocardial infarct (MI). However, their poor survival and potential in the ischemic environment limit their therapeutic efficacy for heart repair after MI. The purpose of this study was to investigate the influence of FoxC1-induced vascular niche on the activation of octamer-binding protein 4 (Oct4) and the fate of MSCs under hypoxic/ischemic conditions. METHODS: Vascular microenvironment/niche was induced by efficient delivery of FoxC1 transfection into hypoxic endothelial cells (ECs) or infarcted hearts. MSCs were cultured or injected into this niche by utilizing an in vitro coculture model and a rat MI model. Survival and neovascularization of MSCs regulated by Oct4 were explored using gene transfer and functional studies. RESULTS: Here, using gene expression heatmap, we demonstrated that cardiac ECs rapidly upregulated FoxC1 after acute ischemic cardiac injury, contributing to an intrinsic angiogenesis. In vitro, FoxC1 accelerated tube-like structure formation and increased survival of ECs, resulting in inducing a vascular microenvironment. Overexpression of FoxC1 in ECs promoted survival and neovascularization of MSCs under hypoxic coculture. Overexpression of Oct4, a FoxC1 target gene, in MSCs enhanced their mesenchymal-to-endothelial transition (MEndoT) while knockdown of Oct4 by siRNA altering vascularization. In a rat MI model, overexpression of FoxC1 in ischemic hearts increased post-infarct vascular density and improved cardiac function. The transplantation of adOct4-pretreated MSCs into these ischemic niches augments MEndoT, enhanced vascularity, and further improved cardiac function. Consistently, these cardioprotective effects of FoxC1 was abrogated when Oct4 was depleted in the MSCs and was mimicked by overexpression of Oct4. CONCLUSIONS: Together, these studies demonstrate that the FoxC1/Oct4 axis is an essential aspect for survival and neovascularization of MSCs in the ischemic conditions and represents a potential therapeutic target for enhancing cardiac repair.

Curcumin exerts a protective effect on murine knee chondrocytes treated with IL-1ß through blocking the NF-κB/HIF-2α signaling pathway.

BACKGROUND: Osteoarthritis (OA) is characterized by erosion and degradation of articular cartilage. This study assessed the effects of curcumin on mouse knee cartilage chondrocytes. METHODS: Chondrocytes were treated for 24 hours with interleukin IL-1ß (10 ng/mL) alone, or the combination of curcumin (10, 20, and 50 µM) and IL-1ß. The proliferation, viability, and cytotoxicity of the chondrocytes were evaluated by the MTS assay. Expression of SOX9, AGG, Col2α, MMP9, ADAMTS5, COX2, iNOS, pIκB-α, pNF-κB, and hypoxia-inducible factor-2α (HIF-2α) were detected by western blotting or quantitative polymerase chain reaction (q-PCR). Nuclear translocation of NF-κB and HIF-2α were investigated by immunofluorescence and immunohistochemistry. In in vivo experiments, mice were subjected to destabilization of the medial meniscus (DMM) and given curcumin orally for 6 weeks. Cartilage integrity was evaluated by OARSI (Osteoarthritic Research Society International) scores. RESULTS: Curcumin significantly inhibited the IL-1ß-induced reduction of cell viability, degradation of ECM, and the expression of SOX9, Col2α, and AGG (P<0.01). Western blotting, immunofluorescence and immunohistochemistry experiments demonstrated that curcumin dramatically inhibited the activation of NF-κB/HIF-2α in chondrocytes treated with IL-1ß (P<0.01). The articular scores were significantly lower in the DMM-induced OA mice compared to OA mice treated with curcumin (P<0.01). CONCLUSIONS: Curcumin may have the potential to inhibit OA development, partly through suppressing the activation of the NF-κB/HIF-2α pathway.

Detachable string magnetically controlled capsule endoscopy for detecting high-risk varices in compensated advanced chronic liver disease (CHESS1801): A prospective multicenter study.

BACKGROUND: Gastroesophageal varices is a serious complication of compensated advanced chronic liver disease (cACLD). Primary prophylaxis to reduce the risk of variceal hemorrhage is recommended if high-risk varices (HRV) are detected. We performed this study to compare the accuracy, patients' satisfaction and safety of detection of HRV by detachable string magnetically controlled capsule endoscopy (DS-MCCE) with esophagogastroduodenoscopy (EGD) as the reference. METHODS: We prospectively recruited participants with cACLD from 12 university hospitals (11 in China and one in the United Kingdom) between November 2018 and December 2019 (ClinicalTrials.gov, NCT03749954). All participants underwent DS-MCCE, followed by EGD within a week in a blinded fashion. Following endoscopy, and on the same day, participants were asked to fill in a satisfaction questionnaire regarding their experience. FINDINGS: A total of 105 eligible participants were enrolled. With EGD as the reference standard, the concordance index, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of DS-MCCE in diagnosis of HRV were 0•90 (95% confidence interval [CI]: 0•83-0•95), 92% (95% CI: 78-98%), 88% (95% CI: 78-95%), 80% (95% CI: 70-92%), 95% (95% CI: 90-100%), 7•91 (95% CI: 4•10-15•30), and 0•09 (95% CI: 0•03-0•30), respectively. The kappa score of 0•78 (95% CI: 0•65-0•90) suggested substantial agreement between DS-MCCE and EGD. Moreover, in participants undergoing EGD without sedation, the satisfaction of DS-MCCE was significantly better than that of EGD (p < 0•0001, d = 1•15 [95%CI: 0•88-1•42]). All participants confirmed the excretion of the capsule, and no adverse events occurred. INTERPRETATION: DS-MCCE is an accurate alternative to EGD for detecting HRV in cACLD, which is safe and associated with better satisfaction. FUNDING: A full list of funding can be found in the Funding Support section.

Icariin inhibits the inflammation through down-regulating NF-κB/HIF-2α signal pathways in chondrocytes.

Articular cartilage injury or defect is a common disease and is mainly characterized by cartilage degradation because of chondrocyte inflammation. By now, there are no effective drugs and methods to protect articular cartilage from degradation. Icariin (ICA) is a typical flavonoid compound extracted from Epimedii Folium with anti-inflammatory and bone-protective effects. Our previous studies demonstrate that ICA up-regulates HIF-1α expression and glycolysis in chondrocytes and maintains chondrocyte phenotype. As another member of HIFs family, HIF-2α always plays a key role in inflammation. The effect of ICA on HIF-2α is unclear by now. In the present study, we confirmed the findings in our previous study that ICA promoted not only chondrocyte vitality and extracellular matrix (ECM) synthesis, but also the anti-inflammatory effect of ICA. In bone defect mice, ICA inhibited the expressions of NF-κB and HIF-2α. In TNF-α-treated ADTC5 chondrocytes, ICA neutralized the activation of IKK (IKK phosphorylation), the phosphorylation of IkB and NF-κB and the expression of HIF-2α. Furthermore, ICA inhibited the nucleus transfer of NF-κB and the expressions of MMP9 and ADAMTS5, two key targets of NF-κB/HIF-2α signal pathway. Taken together, the present study demonstrated that ICA may increase the vitality of chondrocytes by suppressing the inflammatory injury through the inhibition on NF-κB/HIF-2α signaling pathway. ICA is one effective candidate drug for the treatment of articular cartilage injury.

FoxC1-Induced Vascular Niche Improves Survival and Myocardial Repair of Mesenchymal Stem Cells in Infarcted Hearts.

AIMS: Forkhead box C1 (FoxC1) is essential for maintaining the hair follicle stem cell niche. The role of FoxC1 in maintaining mesenchymal stem cell (MSC) niches after myocardial infarction (MI) has not been directly determined to date. In this study, we determined to explore the possible roles and mechanisms of FoxC1 on MSC survival and function in the ischemic niche. METHODS AND RESULTS: MI model was established in this study, and expression level of FoxC1 was overexpressed or knocked down through efficient delivery of FoxC1 transfection or siFoxC1. Fifteen days later, the animals were allocated randomly to receive phosphate-buffered saline (PBS) injection or MSC transplantation. We identified FoxC1 as a key regulator of maintaining the vascular niche in the infarcted hearts (IHs) by driving proangiogenic and anti-inflammatory cytokines while repressing inflammatory and fibrotic factor expression. This vascular niche improved MSC survival and capacity in the IHs. Importantly, FoxC1 interacted with MSCs and was required for vessel specification and differentiation of engrafted MSCs in the ischemic niches, promoting myocardial repair. Inhibiting FoxC1 abolished these effects. CONCLUSION: These results definitively implicate FoxC1 signaling in maintaining ischemic vascular niche, which may be helpful in myocardial repair induced by MSC therapy.

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.

HIF-2α and Oct4 have synergistic effects on survival and myocardial repair of very small embryonic-like mesenchymal stem cells in infarcted hearts.

Poor cell survival and limited functional benefits have restricted mesenchymal stem cell (MSC) efficacy for treating myocardial infarction (MI), suggesting that a better understanding of stem cell biology is needed. The transcription factor HIF-2α is an essential regulator of the transcriptional response to hypoxia, which can interact with embryonic stem cells (ESCs) transcription factor Oct4 and modulate its signaling. Here, we obtained very small embryonic-like mesenchymal stem cells (vselMSCs) from MI patients, which possessed the very small embryonic-like stem cells' (VSELs) morphology as well as ESCs' pluripotency. Using microarray analysis, we compared HIF-2α-regulated gene profiles in vselMSCs with ESC profiles and determined that HIF-2α coexpressed Oct4 in vselMSCs similarly to ESCs. However, this coexpression was absent in unpurified MSCs (uMSCs). Under hypoxic condition, vselMSCs exhibited stronger survival, proliferation and differentiation than uMSCs. Transplantation of vselMSCs caused greater improvement in cardiac function and heart remodeling in the infarcted rats. We further demonstrated that HIF-2α and Oct4 jointly regulate their relative downstream gene expressions, including Bcl2 and Survivin; the important pluripotent markers Nanog, Klf4, and Sox2; and Ang-1, bFGF, and VEGF, promoting angiogenesis and engraftment. Importantly, these effects were generally magnified by upregulation of HIF-2α and Oct4 induced by HIF-2α or Oct4 overexpression, and the greatest improvements were elicited after co-overexpressing HIF-2α and Oct4; overexpressing one transcription factor while silencing the other canceled this increase, and HIF-2α or Oct4 silencing abolished these effects. Together, these findings demonstrated that HIF-2α in vselMSCs cooperated with Oct4 in survival and function. The identification of the cooperation between HIF-2α and Oct4 will lead to deeper characterization of the downstream targets of this interaction in vselMSCs and will have novel pathophysiological implications for the repair of infarcted myocardium.

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.

Gastrointestinal malignant neoplasms disguised as pneumatosis cystoids intestinalis: A case report and literature review.

RATIONALE: Pneumatosis cystoids intestinalis (PCI) is a rare disease in which gas develops in the mucosa or submucosa of the digestive tract. The etiology and pathogenesis of this disease, at present, remain unclear, and gastrointestinal malignant neoplasms may be a potentially important cause. Herein, we report a case of mantle cell lymphoma presenting as PCI as well as present a literature review of cases of suspect PCI that was definitively diagnosed as gastrointestinal neoplasms. In doing so, we highlighted cases of neoplastic pathogenesis that present as PCI. PATIENT CONCERNS: A 55-year-old man was referred to our gastrointestinal department with complaints of intermittent abdominal pain, distention, diarrhea, and occasional melena that persisted for 2 months. He has a history of nasopharyngeal carcinoma. DIAGNOSES: Intensive, translucent, grape-like cystoids of the whole colon and small intestine were disguised as PCI upon colonoscopy and capsule endoscopy. INTERVENTIONS: Right hemicolectomy and ileocecectomy were performed for intussusception and to confirm the diagnosis. Final pathology indicated that the mass was mantle cell lymphoma. OUTCOMES: After surgery and subsequent chemotherapy, the patient showed good recovery and no abnormal lesions were detected on colonoscopy. LESSONS: As shown through this case and a literature review of similar cases of apparent PCI that was definitively diagnosed as gastrointestinal neoplasm, gastrointestinal malignant neoplasms might rarely present as PCI and neoplastic etiologies should also be considered once PCI is detected. Because most patients with malignant PCIs might inevitably experience severe complications, abdominal surgery should be considered and applied timely after unsuccessful resolution by conservative medical therapies and symptomatic treatments.