Mesenchymal stem cells (MSCs) repair infarcted heart through paracrine mechanism. We sought to compare the effectiveness of MSCs and MSC-derived exosomes (MSC-Exo) in repairing infarcted hearts and ...to identify how MSC-Exo mediated cardiac repair is regulated. In a rat myocardial infarction model, we found that MSC-Exo inhibited cardiac fibrosis, inflammation, and improved cardiac function. The beneficial effects of MSC-Exo were significantly superior compared to that of MSCs. To explore the potential mechanisms underlying MSC-Exo’s effects, we performed several in vitro experiments and miRNA-sequence analysis. MSC-Exo stimulated cardiomyocyte H9C2 cell proliferation, inhibited apoptosis induced by H2O2, and inhibited TGF-β induced transformation of fibroblast cell into myofibroblast. Importantly, novel miRNA sequencing results indicated that MSC-Exo and MSCs have similar miRNA expression profile, which could be one of the reasons that MSC-Exo can replace MSCs for cardiac repair. In addition, the expression of several miRNAs from MSC-Exo was significantly different from that of MSCs, which may explain why MSC-Exo has better therapeutic effect than MSCs. In conclusion, this study demonstrates that MSC-Exo could be used alone to promote cardiac repair and are superior to MSCs in repairing injured myocardium.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Combined enzymatic and ultrasonic treatment was evaluated for efficient extraction of pectin from sisal waste in comparison with other extraction methods. The sequential treatment with enzyme ...(Celluclast 1.5 L) followed by ultrasound of sisal waste attained a much higher pectin yield of 31.1% than the ultrasound followed by enzyme, 14.6%. The pectin yield attained with the combined enzymatic/ultrasonic extraction was also higher than enzymatic extraction (9.4%), ultrasonic extraction (11.9%) and acidic extraction (5.8%). The pectin attained using the combined enzymatic/ultrasonic extraction (PEU) exhibited a higher galacturonic acid content (62.88%) and a higher degree of esterification (49.64%), indicating a better preserved polymer chain than that using acidic extraction (PA). PEU had a higher molar mass (7.65 × 105 g/mol) and a lower Mw/Mn than PA. Meanwhile, all sisal pectins showed the similar sugar composition regardless of the extraction methods according to FT-IR analysis. The results of rheological test showed that PEU in water turned from gel to liquid with increasing angle-frequency, while PA remained in a gel state. Compared with PA, the viscoelastic properties of PEU were more sensitive to temperature changes. SEM observation of the sisal residues after pectin extraction revealed a synergistic effect of the enzymatic and ultrasonic treatment on the solid structure, which may be contributable to the improved pectin extraction efficiency. The results from the present study suggest that the combination of enzymatic and ultrasonic extraction is an efficient process strategy for production of high quality pectins.
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•Sisal waste is an attractive feedstock for pectin production.•Combined enzymatic/ultrasonic extraction greatly promoted the sisal pectin yield.•Sisal pectin from combined enzymatic/ultrasonic extraction exhibited high galacturonic acid content.•The enzymatic and ultrasonic treatment has a synergistic effect on pectin extraction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Immunotherapy has emerged to play a rapidly expanding role in the treatment of cancers. Currently, many clinical trials of therapeutic agents are on ongoing with majority of immune checkpoint ...inhibitors (ICIs) especially programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1, two main immune checkpoints, are expressed at high levels in thymic epithelial tumors (TETs) and could be predictors of the progression and immunotherapeutic efficacy of TETs. However, despite inspiring efficacy reported in clinical trials and clinical practice, significantly higher incidence of immune-related adverse events (irAEs) than other tumors bring challenges to the administration of ICIs in TETs. To develop safe and effective immunotherapeutic patterns in TETs, understanding the clinical properties of patients, the cellular and molecular mechanisms of immunotherapy and irAEs occurrence are crucial. In this review, the progress of both basic and clinical research on immune checkpoints in TETs, the evidence of therapeutic efficacy and irAEs based on PD-1 /PD-L1 inhibitors in TETs treatment are discussed. Additionally, we highlighted the possible mechanisms underlying irAEs, prevention and management strategies, the insufficiency of current research and some worthy research insights. High PD-1/PD-L1 expression in TETs provides a rationale for ICI use. Completed clinical trials have shown an encouraging efficacy of ICIs, despite the high rate of irAEs. A deeper mechanism understanding at molecular level how ICIs function in TETs and why irAEs occur will help maximize the immunotherapeutic efficacy while minimizing irAEs risks in TET treatment to improve patient prognosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epstein–Barr virus (EBV)‐associated gastric carcinomas (EBVaGCs) may account for 8–9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is ...warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV‐DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat‐sen University Cancer Center for EBER examination. We detected EBV‐DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV‐DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV‐negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3‐year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV‐DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV‐DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV‐DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.
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Epstein–Barr Virus (EBV)‐associated gastric carcinomas (EBVaGC) may account for 8–9% of all gastric cancers (GC). The exact role of EBV status in predicting the prognosis of GC remains to be clarified, however. Here, the authors report a prevalence of EBVaGC in GC in China of 5.1%, as defined by EBER staining in cancerous tissue. EBVaGC patients had a better overall survival than EBV‐negative patients. Though only half of EBVaGC patients gained detectable plasma EBV‐DNA levels, elevated plasma EBV‐DNA predicted relapse and poor response to chemotherapy. Dynamic detection of plasma EBV‐DNA load may offer an easily accessible biomarker to monitor EBVaGC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Over the past decade, lncRNAs have been widely reported in human malignant tumors, including papillary thyroid carcinoma. LncRNA SNHG15 has been validated to be a tumor facilitator in several types ...of malignancies. The present study focused on the biological role of SNHG15 in papillary thyroid carcinoma. Based on the result of qPCR analysis, we identified the strong expression of SNHG15 in human papillary thyroid carcinoma tissues and cell lines. Moreover, Kaplan-Meier method was utilized to analyze the internal relevance between SNHG15 expression and overall survival rate of patients with papillary thyroid carcinoma. Loss-of-function assays were designed and conducted to determine the inhibitory effects of silenced SNHG15 on the cell growth and migration in papillary thyroid carcinoma. The mechanical investigation indicated that SNHG15 upregulated YAP1 by sponging miR-200a-3p. Moreover, results of gain-of-function assays validated the anti-oncogenic function of miR-200a-3p in papillary thyroid carcinoma. Finally, results of rescue assays validated the function of SNHG15-miR-200a-3p-YAP1 axis in papillary thyroid carcinoma. YAP1 is known as an oncogene and a core factor of Hippo pathway. Here, we demonstrated that SNHG15 inactivated Hippo signaling pathway in papillary thyroid carcinoma. In summary, our findings demonstrated that SNHG15 serves as a competitively endogenous RNA (ceRNA) to regulate YAP1-Hippo signaling pathway by sponging miR-200a-3p in papillary thyroid carcinoma.
Diabetic nephropathy is one of the most serious complications in patients with diabetes. At present, there are no satisfactory treatments available for diabetic nephropathy. Stem cells are currently ...the main candidates for the development of new treatments for diabetic nephropathy, as they may exert their therapeutic effects mainly through paracrine mechanisms. Exosomes derived from stem cells have been reported to play an important role in kidney injury. In this article, we try to investigate whether exosomes retrieved from urine stem cells could itself prevent diabetic nephropathy at an early stage in vivo and in vitro.
Exosomes from conditioned medium of urine-derived stem cells (USCs-Exo) were isolated using ultrafiltration-combined purification methods. USCs-Exo were then verified by morphology, size, and specific biomarkers using transmission electron microscopy, tunable resistive pulse sensing analysis, and western blotting. After establishment of the streptozotocin-induced Sprague-Dawley rat model, the effects of USCs-Exo on kidney injury and angiogenesis were observed via weekly tail intravenous injection of USCs-Exo or control until 12 weeks. In vitro, podocytes cultured in high-glucose medium were treated with USCs-Exo to test the protective effect of USCs-Exo on podocytic apoptosis. Meanwhile, the potential factors in promoting vascular regeneration in USCs-Exo and urine-derived stem cell conditioned medium were investigated by enzyme-linked immunosorbent assay.
Urine-derived stem cells were cultured and were verified by positive markers for CD29, CD73, CD90 and CD44 antigens, and negative markers for CD34, CD45 and HLA-DR. USCs-Exo were approximately 50-100 nm spherical vesicles, and the specific markers included CD9, CD63 and CD81. Intravenous injections of USCs-Exo could potentially reduce the urine volume and urinary microalbumin excretion, prevent podocyte and tubular epithelial cell apoptosis, suppress the caspase-3 overexpression and increase glomerular endothelial cell proliferation in diabetic rats. In addition, USCs-Exo could reduce podocytic apoptosis induced by high glucose in vitro. USCs-Exo contained the potential factors, including growth factor, transforming growth factor-β1, angiogenin and bone morphogenetic protein-7, which may be related with vascular regeneration and cell survival.
USCs-Exo may have the potential to prevent kidney injury from diabetes by inhibiting podocyte apoptosis and promoting vascular regeneration and cell survival.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Trace elements have been recognized to play an important role in the development of Parkinson's disease (PD). However, it is difficult to precisely identify the relationship between these elements ...and the progression of PD because of an insufficient number of patients. In this study, quantifications of selenium (Se), copper (Cu), iron (Fe) and zinc (Zn) by atomic absorption spectrophotometry were performed in plasma from 238 PD patients and 302 controls recruited from eastern China, which is so far the largest cohort of PD patients and controls for measuring plasma levels of these elements. We found that plasma Se and Fe concentrations were significantly increased whereas Cu and Zn concentrations decreased in PD patients as compared with controls. Meanwhile, these four elements displayed differential changes with regard to age. Linear and logistic regression analyses revealed that both Fe and Zn were negatively correlated with age in PD patients. Association analysis suggests that lower plasma Se and Fe levels may reduce the risk for PD, whereas lower plasma Zn is probably a PD risk factor. Finally, a model was generated to predict PD patients based on the plasma concentrations of these four trace elements as well as other features such as sex and age, which achieved an accuracy of 80.97±1.34% using 10-fold cross-validation. In summary, our data provide new insights into the roles of Se, Cu, Fe and Zn in PD progression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND AND PURPOSE—Multipotent mesenchymal stromal cell (MSC) harvested exosomes are hypothesized as the major paracrine effectors of MSCs. In vitro, the miR-17–92 cluster promotes ...oligodendrogenesis, neurogenesis, and axonal outgrowth. We, therefore, investigated whether the miR-17–92 cluster–enriched exosomes harvested from MSCs transfected with an miR-17–92 cluster plasmid enhance neurological recovery compared with control MSC-derived exosomes.
METHODS—Rats subjected to 2 hours of transient middle cerebral artery occlusion were intravenously administered miR-17–92 cluster–enriched exosomes, control MSC exosomes, or liposomes and were euthanized 28 days post–middle cerebral artery occlusion. Histochemistry, immunohistochemistry, and Golgi–Cox staining were used to assess dendritic, axonal, synaptic, and myelin remodeling. Expression of phosphatase and tensin homolog and activation of its downstream proteins, protein kinase B, mechanistic target of rapamycin, and glycogen synthase kinase 3β in the peri-infarct region were measured by means of Western blots.
RESULTS—Compared with the liposome treatment, both exosome treatment groups exhibited significant improvement of functional recovery, but miR-17–92 cluster–enriched exosome treatment had significantly more robust effects on improvement of neurological function and enhancements of oligodendrogenesis, neurogenesis, and neurite remodeling/neuronal dendrite plasticity in the ischemic boundary zone (IBZ) than the control MSC exosome treatment. Moreover, miR-17–92 cluster–enriched exosome treatment substantially inhibited phosphatase and tensin homolog, a validated miR-17–92 cluster target gene, and subsequently increased the phosphorylation of phosphatase and tensin homolog downstream proteins, protein kinase B, mechanistic target of rapamycin, and glycogen synthase kinase 3β compared with control MSC exosome treatment.
CONCLUSIONS—Our data suggest that treatment of stroke with tailored exosomes enriched with the miR-17–92 cluster increases neural plasticity and functional recovery after stroke, possibly via targeting phosphatase and tensin homolog to activate the PI3K/protein kinase B/mechanistic target of rapamycin/glycogen synthase kinase 3β signaling pathway.
Polyelectrolyte complex nanoparticles (PEC NPs) were fabricated via electrostatic interactions between positively charged heat-denatured lactoferrin (LF) particles and negatively charged pectin. The ...obtained PEC NPs were then utilized as curcumin carriers. PEC NPs were prepared by mixing 1.0 mg/mL solutions of heat-denatured LF and pectin at a mass ratio of 1:1 (w/w) in the absence of NaCl at pH 4.50. PEC NPs that were prepared under optimized conditions were spherical in shape with a particle size of ∼208 nm and zeta potential of ∼−32 mV. Hydrophobic curcumin was successfully encapsulated into LF/pectin PEC NPs with high encapsulation efficiency (∼85.3%) and loading content (∼13.4%). The in vitro controlled release and prominent antioxidant activities of curcumin from LF/pectin PEC NPs were observed. The present work provides a facile and fast method to synthesize nanoscale food-grade delivery systems for the improved water solubility, controlled release, and antioxidant activity of hydrophobic curcumin.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Summary
In this paper, the overcharge tests of 25 Ah LiFePO4/graphite batteries are conducted in an open environment and the overcharge‐to‐thermal‐runaway characteristics are studied. The effects of ...current rates (C‐rates: 2C, 1C, 0.5C, and 0.3C) and states of health (SOHs: 100%, 80%, 70%, and 60%) on thermal runaway features are discussed in detail. The overcharge process can be summarized into five stages based on the experimental phenomena (C‐rate ≥ 1 and SOH ≥ 80%): expansion, fast venting after safety valve rupture, slow venting, intense jet smoke, and explosion, while the battery cannot explode at lower C‐rates and SOHs. The maximum pressure increases with the increase in C‐rate or SOH. There are five obvious inflection points in the voltage curve during overcharge process. The V1 (point B) of aged battery, corresponding to lithium plating on the anode, changes little with C‐rates. It is slightly lower than that of the new battery. A sharp drop in voltage (point E) is probably due to the internal short circuit (ISC), caused by the local melting and rupture of the separator. It takes more than 2 minutes from the moment of ISC to thermal runaway regardless of the SOH, indicating that there are a few minutes to take safety measures if the voltage is an indication parameter. The onset temperature of thermal runaway decreases first and then increases as the SOH decreases from 100% to 60% during 1C constant overcharge tests. These results can provide guidance for the thermal management of the whole battery life cycle and the reuse of retired batteries.
The overcharge tests of 25 Ah power LiFePO4/graphite batteries with different states of health (SOHs) are conducted under various current rates (C‐rates). The overcharge test is more dangerous as SOH or C‐rate increases. The onset temperature of thermal runaway decreases first and then increases with the SOH decreasing from 100% to 60%.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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