Explore the vast range of titles available.

Exosomes as a unique subtype of small extracellular vesicles (sEVs) have attracted increasing interest in recent years in the fields of mesenchymal stromal cell (MSC) research. Studies have confirmed that exosomes derived from MSCs preserve immunosuppressive phenotype and can mimic therapeutic benefits of their parent cells. This review briefly summarizes most recent findings on the potential of exosomes as an alternative of therapeutic MSCs, focusing on the role of MSCs and their secreted exosomes in regulation of immune cells, preclinical and clinical evidence of therapeutic outcomes of MSC exosomes, and the biodistribution and pharmacokinetic profile of systemically administered exosomes. It is appreciated that exosomes from MSCs of different sources have variable contents including inflammatory mediators, tropic factors, signaling molecules, and nucleic acids (DNA, mRNA, microRNA and long non-coding RNA). Diverse functions of exosomes derived from different sources are expected. More importantly, exosomes isolated in vitro may not mirror that from in vivo, where donor MSCs are exposed to specific disease or injury-related conditions. Simulating in vivo microenvironment by pretreatment of MSCs with relevant chemical mediators may lead to their secretion of therapeutically more efficient exosomes/sEVs. However, we know very little about the key molecules involved and the differences between exosomes released under different conditions. These issues would be of tremendous interest to preclinical research that pursues exosome biology-underlain therapeutic mechanisms of MSCs. Further studies are expected to demonstrate the superiority of MSC-derived exsomes/sEVs as a pharmaceutical entity with regard to efficacy, safety, and practicability.

Extracellular vesicles (EVs) have emerged as important regulators of inter‐cellular and inter‐organ communication, in part via the transfer of their cargo to recipient cells. Although circulating EVs have been previously studied as biomarkers of aging, how circulating EVs change with age and the underlying mechanisms that contribute to these changes are poorly understood. Here, we demonstrate that aging has a profound effect on the circulating EV pool, as evidenced by changes in concentration, size, and cargo. Aging also alters particle function; treatment of cells with EV fractions isolated from old plasma reduces macrophage responses to lipopolysaccharide, increases phagocytosis, and reduces endothelial cell responses to vascular endothelial growth factor compared to cells treated with young EV fractions. Depletion studies indicate that CD63+ particles mediate these effects. Treatment of macrophages with EV‐like particles revealed that old particles increased the expression of EV miRNAs in recipient cells. Transfection of cells with microRNA mimics recapitulated some of the effects seen with old EV‐like particles. Investigation into the underlying mechanisms using bone marrow transplant studies revealed circulating cell age does not substantially affect the expression of aging‐associated circulating EV miRNAs in old mice. Instead, we show that cellular senescence contributes to changes in particle cargo and function. Notably, senolytic treatment of old mice shifted plasma particle cargo and function toward that of a younger phenotype. Collectively, these results demonstrate that senescent cells contribute to changes in plasma EVs with age and suggest a new mechanism by which senescent cells can affect cellular functions throughout the body. Senescent cells accumulate in the body with aging and alter circulating extracellular vesicle microRNA content. This can be replicated in young mice by inducing senescence using sub‐lethal irradiation. Conversely, removal of senescent cells in aged mice by senolytic treatment restores circulating extracellular vesicle microRNA expression to that of a younger phenotype.

Despite great progress in engineering functional tissues for organ repair, including the heart, an invasive surgical approach is still required for their implantation. Here, we designed an elastic and microfabricated scaffold using a biodegradable polymer (poly(octamethylene maleate (anhydride) citrate)) for functional tissue delivery via injection. The scaffold’s shape memory was due to the microfabricated lattice design. Scaffolds and cardiac patches (1 cm × 1 cm) were delivered through an orifice as small as 1 mm, recovering their initial shape following injection without affecting cardiomyocyte viability and function. In a subcutaneous syngeneic rat model, injection of cardiac patches was equivalent to open surgery when comparing vascularization, macrophage recruitment and cell survival. The patches significantly improved cardiac function following myocardial infarction in a rat, compared with the untreated controls. Successful minimally invasive delivery of human cell-derived patches to the epicardium, aorta and liver in a large-animal (porcine) model was achieved. Cardiac repair usually requires highly invasive interventional procedures. Here, the authors develop an injectable shape-memory cardiac patch and demonstrated its applicability in a myocardial infarction model.

The ability to generate epicardial cells from human pluripotent stem cells will facilitate studies of heart regeneration. The epicardium supports cardiomyocyte proliferation early in development and provides fibroblasts and vascular smooth muscle cells to the developing heart. The epicardium has been shown to play an important role during tissue remodeling after cardiac injury, making access to this cell lineage necessary for the study of regenerative medicine. Here we describe the generation of epicardial lineage cells from human pluripotent stem cells by stage-specific activation of the BMP and WNT signaling pathways. These cells display morphological characteristics and express markers of the epicardial lineage, including the transcription factors WT1 and TBX18 and the retinoic acid–producing enzyme ALDH1A2. When induced to undergo epithelial-to-mesenchymal transition, the cells give rise to populations that display characteristics of the fibroblast and vascular smooth muscle lineages. These findings identify BMP and WNT as key regulators of the epicardial lineage in vitro and provide a model for investigating epicardial function in human development and disease.

A bstract We consider two-loop renormalization of high-dimensional Lorentz scalar operators in the gluonic sector of QCD. These operators appear also in the Higgs effective theory obtained by integrating out the top quark loop in the gluon fusion process. We first discuss the classification of operators and how to construct a good set of basis using both off-shell field theory method and on-shell form factor formalism. To study loop corrections, we apply efficient unitarity-IBP strategy and compute the two-loop minimal form factors of length-3 operators up to dimension sixteen. From the UV divergences of form factor results, we extract the renormalization matrices and analyze the operator mixing behavior in detail. The form factors we compute are also equivalent to Higgs plus three-gluon amplitudes that capture high-order top mass corrections in Higgs EFT. We obtain the analytic finite remainder functions which exhibit several universal transcendentality structures.

Environmental barrier coating (EBC) materials that are resistant against molten calcia-magnesia-aluminosilicate (CMAS) corrosion are urgently required. Herein, multicomponent rare-earth (RE) disilicate ((Yb 0.2 Y 0.2 Lu 0.2 Sc 0.2 Gd 0.2 ) 2 Si 2 O 7 , (5RE) 2 Si 2 O 7 ) was investigated with regard to its CMAS interaction behavior at 1400 °C. Compared with the individual RE disilicates, the (5RE) 2 Si 2 O 7 material exhibited improved resistance against CMAS attack. The dominant process involved in the interaction of (5RE) 2 Si 2 O 7 with CMAS was reaction-recrystallization. A dense and continuous reaction layer protected the substrate from rapid corrosion at high temperatures. The results demonstrated that multicomponent strategy of RE species in disilicate can provide a new perspective in the development of promising EBC materials with improved corrosion resistance.

Quercetin is a potent cancer therapeutic agent and dietary antioxidant present in fruit and vegetables. Quercetin prevents tumor proliferation by inducing cell cycle arrest and is a well known cancer therapeutic agent and autophagy mediator. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, gold-quercetin into poly(DL-lactide-co-glycolide) nanoparticles was examined. In this study, we explored the role and possible underlying mechanisms of quercetin nanoparticle in regulation of antitumor activity in liver cancer cells. Treatment with quercetin nanoparticle effectively inhibited the liver cancer cell proliferation, cell migration and colony formation, thus suppressing liver cancer progression. Quercetin nanoparticle also upregulated apoptosis markedly. Further study suggested that quercetin nanoparticle accelerated the cleavage of caspase-9, caspase-3, and induced the up-releasing of cytochrome c (Cyto-c), contributing to apoptosis in liver cancer cells. Quercetin nanoparticles also promoted telomerase reverse transcriptase (hTERT) inhibition through reducing AP-2β expression and decreasing its binding to hTERT promoter. In addition, quercetin nanoparticle had an inhibitory role in cyclooxygenase 2 (COX-2) via suppressing the NF-κB nuclear translocation and its binding to COX-2 promoter. Quercetin nanoparticle also inactivated Akt and ERK1/2 signaling pathway. Taken together, our results suggested that quercetin nanoparticle had an antitumor effect by inactivating caspase/Cyto-c pathway, suppressing AP-2β/hTERT, inhibiting NF-κB/COX-2 and impeding Akt/ERK1/2 signaling pathways. Our results provided new mechanistic basis for further investigation of quercetin nanoparticles to find potential therapeutic strategies and possible targets for liver cancer inhibition.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer (NSCLC), but acquired resistance limits their clinical application. NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy. In this study, we investigated the role of NRF2 in resistance to EGFR-TKIs. We showed that NRF2 protein levels were markedly increased in a panel of EGFR-TKI-resistant NSCLC cell lines due to slow degradation of NRF2 protein. NRF2 knockdown overcame the resistance to EGFR-TKIs in HCC827ER and HCC827GR cells. Furthermore, we demonstrated that NRF2 imparted EGFR-TKIs resistance in HCC827 cells via upregulation of GPX4 and SOD2, and suppression of GPX4 and SOD2 reversed resistance to EGFR-TKIs. Thus, we conclude that targeting NRF2-GPX4/SOD2 pathway is a potential strategy for overcoming resistance to EGFR-TKIs.

Recruited immune cells play a critical role in muscle repair, in part by interacting with local stem cell populations to regulate muscle regeneration. How aging affects their communication during myogenesis is unclear. Here, we investigate how aging impacts the cellular function of these two cell types after muscle injury during normal aging or after immune rejuvenation using a young to old (Y‐O) or old to old (O‐O) bone marrow (BM) transplant model. We found that skeletal muscle from old mice (20 months) exhibited elevated basal inflammation and possessed fewer satellite cells compared with young mice (3 months). After cardiotoxin muscle injury (CTX), old mice exhibited a blunted inflammatory response compared with young mice and enhanced M2 macrophage recruitment and IL‐10 expression. Temporal immune and cytokine responses of old mice were partially restored to a young phenotype following reconstitution with young cells (Y‐O chimeras). Improved immune responses in Y‐O chimeras were associated with greater satellite cell proliferation compared with O‐O chimeras. To identify how immune cell aging affects myoblast function, conditioned media (CM) from activated young or old macrophages was applied to cultured C2C12 myoblasts. CM from young macrophages inhibited myogenesis while CM from old macrophages reduced proliferation. These functional differences coincided with age‐related differences in macrophage cytokine expression. Together, this study examines the infiltration and proliferation of immune cells and satellite cells after injury in the context of aging and, using BM chimeras, demonstrates that young immune cells retain cell autonomy in an old host to increase satellite cell proliferation. This study examined the infiltration and proliferation of immune cells and satellite cells in response to muscle injury during normal aging or after immune rejuvenation using a young to old (Y‐O) or old to old (O‐O) bone marrow transplant model. Old mice exhibited blunted inflammatory and myogenic responses compared to young mice with enhanced M2 macrophage recruitment. Immune rejuvenation in Y‐O chimeras restored the acute immune response in old mice and increased satellite cell proliferation.

Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to an adverse proliferative phenotype is a hallmark of atherosclerosis or vascular restenosis. However, the genetic modulators responsible for this switch have not been fully elucidated in humans nor have they been correlated with clinical abnormalities. This study investigated genetic mechanisms involved in phenotypic switching of VSMCs at non‐defect areas of the aorta in patients with atherosclerosis. Aortic wall samples were obtained from patients with (N = 53) and without (N = 27) atherosclerosis undergoing cardiovascular surgery. Vascular smooth muscle cell cultures were generated, and expression of microRNA‐145 (miR‐145), its target gene Kruppel‐Like Factor 5 (KLF5) and Myocardin (MYOCD, a smooth muscle‐specific transcriptional coactivator) were analysed using RT‐qPCR, along with expression of relevant proteins. Vascular smooth muscle cells were transduced with miR‐145 inhibitor and mimic to determine the effect of miR‐145 expression on VSMC proliferation. miR‐145 expression decreased while KLF5 expression increased in atherosclerotic aortas. Atherosclerotic samples and VSMCs had decreased expression of contractile markers calponin and alpha smooth muscle actin (α‐SMA) and MYOCD. miR‐145 inhibitor‐transduced VSMCs from non‐atherosclerotic patients showed decreased expression of calponin and α‐SMA and increased proliferation compared with non‐transduced controls, and these levels were close to those of atherosclerotic patients. miR‐145 mimic‐transduced VSMCs from atherosclerotic patients showed increased expression of calponin and α‐SMA and decreased proliferation compared with non‐transduced controls, and these levels were close to those found in non‐atherosclerotic patients. These data demonstrate that miR‐145 modulates the phenotypic switch of VSMCs from a contractile to a proliferative state via KLF5 and MYOCD in atherosclerosis.