A XEN-like State Bridges Somatic Cells to Pluripotency during Chemical Reprogramming.

Somatic cells can be reprogrammed into pluripotent stem cells (PSCs) by using pure chemicals, providing a different paradigm to study somatic reprogramming. However, the cell fate dynamics and molecular events that occur during the chemical reprogramming process remain unclear. We now show that the chemical reprogramming process requires the early formation of extra-embryonic endoderm (XEN)-like cells and a late transition from XEN-like cells to chemically-induced (Ci)PSCs, a unique route that fundamentally differs from the pathway of transcription factor-induced reprogramming. Moreover, precise manipulation of the cell fate transition in a step-wise manner through the XEN-like state allows us to identify small-molecule boosters and establish a robust chemical reprogramming system with a yield up to 1,000-fold greater than that of the previously reported protocol. These findings demonstrate that chemical reprogramming is a promising approach to manipulate cell fates.

Identifying MiR-140-3p as a stable internal reference to normalize MicroRNA qRT-PCR levels of plasma small extracellular vesicles in lung cancer patients.

Exploration of a stably expressed gene as a reference is critical for the accurate evaluation of miRNAs isolated from small extracellular vesicles (sEVs). In this study, we analyzed small RNA sequencing on plasma sEV miRNAs in the training dataset (n = 104) and found that miR-140-3p was the most stably expressed candidate reference for sEV miRNAs. We further demonstrated that miR-140-3p expressed most stably in the validation cohort (n = 46) when compared to two other reference miRNAs, miR-451a and miR-1228-3p, and the commonly-used miRNA reference U6. Finally, we compared the capability of miR-140-3p and U6 as the internal reference for sEV miRNA expression by evaluating key miRNAs expression in lung cancer patients and found that miR-140-3p was more suitable as a sEV miRNA reference gene. Taken together, our data indicated miR-140-3p as a stable internal reference miRNA of plasma sEVs to evaluate miRNA expression profiles in lung cancer patients.

Pretreatment with platelet-rich plasma protects against ischemia-reperfusion induced flap injury by deactivating the JAK/STAT pathway in mice.

BACKGROUND: Ischemia-reperfusion (I/R) injury is a major cause of surgical skin flap compromise and organ dysfunction. Platelet-rich plasma (PRP) is an autologous product rich in growth factors, with tissue regenerative potential. PRP has shown promise in multiple I/R-induced tissue injuries, but its effects on skin flap injury remain unexplored. METHODS: We evaluated the effects of PRP on I/R-injured skin flaps, optimal timing of PRP administration, and the involved mechanisms. RESULTS: PRP protected against I/R-induced skin flap injury by improving flap survival, promoting blood perfusion and angiogenesis, suppressing oxidative stress and inflammatory response, and reducing apoptosis, at least partly via deactivating Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signalling pathway. PRP given before ischemia displayed overall advantages over that given before reperfusion or during reperfusion. In addition, PRP pretreatment had a stronger ability to reverse I/R-induced JAK/STAT activation and apoptosis than AG490, a specific inhibitor of JAK/STAT signalling. CONCLUSIONS: This study firstly demonstrates the protective role of PRP against I/R-injured skin flaps through negative regulation of JAK/STAT activation, with PRP pretreatment showing optimal therapeutic effects.

Proline-rich protein PRPL1 enhances Panax notoginseng defence against Fusarium solani by regulating reactive oxygen species balance and strengthening the cell wall barrier.

The root rot mainly caused by Fusarium solani is a bottleneck in the cultivation of Panax notoginseng. In this study, we reported a gene encoding a plant cell wall structural protein, P. notoginseng proline-rich protein (PnPRPL1), whose transcription was upregulated by F. solani and induced by some hormone signals. The PnPRPL1 recombinant protein significantly inhibited the growth and conidial germination of the root rot pathogens. Downregulation of PnPRPL1 by RNA interference (RNAi) in P. notoginseng leaves increased the susceptibility to F. solani, whereas overexpression of PnPRPL1 in tobacco (Nicotiana tabacum) enhanced the resistance to F. solani. Compared with wild-type tobacco, the PnPRPL1-overexpressing transgenic tobacco had higher reactive oxygen species (ROS)-scavenging enzyme activities, lower ROS levels, and more lignin and callose deposition. The opposite results were obtained for the P. notoginseng expressing PnPRPL1 RNAi fragments. Furthermore, the PnPRPL1 promoter transcription activity was induced by several plant hormones and multiple stress stimuli. In addition, the transcription factor PnWRKY27 activated the expression of PnPRPL1 by directly binding to the promoter region. Thus, PnPRPL1, which is positively regulated by a WRKY transcription factor, encodes an antimicrobial protein that also mediates ROS homoeostasis and callose/lignin deposition during the response to F. solani infection.

Operation-robust SiO2-based memristive application in air.

In recent years, neuromorphic computing is recognized as a promising path to further improve the efficiency of integrated computing system in the post-Moore era, relying on its high parallelism. As a key fundamental element in hardware-implementing neuromorphic system, the synaptic device has made substantial research progress. Among these, SiO2 trapping-based memristive devices generally have systematically integrated merits, such as ease of fabrication and high CMOS process compatibility, but electrochemical activity to oxygen makes them unreliable for operating in air. Here, by using ultrathin Si3N4 as a physical isolation layer, we have obtained a robust memristive device based on SiO2 trapping although operating in air. Further study of Si3N4 thickness dependence has demonstrated that 7 nm is suggested as the most favorable thickness for reliable and flexible programming, and that an inherent isolating mechanism is 'switching-on' for an electron but 'switching-off' for large-sized oxygen molecules. Based on a device with 7 nm Si3N4, we have mimicked various modes of synaptic plasticities. These results could thus not only increase the prospects of using SiO2 trapping in memristive applications but also provide an effective path to improve the robustness of these SiO2-based applications against ambient air.

JMJ24 targets CHROMOMETHYLASE3 for proteasomal degradation in Arabidopsis.

H3K9 methylation is usually associated with DNA methylation, and together they symbolize transcriptionally silenced heterochromatin. A number of proteins involved in epigenetic processes have been characterized. However, how the stability of these proteins is regulated at the post-translational level is largely unknown. Here, we show that an Arabidopsis JmjC domain protein, JMJ24, possesses ubiquitin E3 ligase activity. JMJ24 directly targets a DNA methyltransferase, CHROMOMETHYLASE 3 (CMT3), for proteasomal degradation to initiate destabilization of the heterochromatic state of endogenous silenced loci. Our results uncover an additional connection between two conserved epigenetic modifications: histone modification and DNA methylation.

Panax notoginseng transcription factor WRKY15 modulates resistance to Fusarium solani by up-regulating osmotin-like protein expression and inducing JA/SA signaling pathways.

BACKGROUND: Panax notoginseng (Burk) F. H. Chen is a valuable traditional Chinese medicinal plant, but its commercial production is seriously affected by root rot caused by some pathogenic fungi, including Fusarium solani. Nevertheless, the genetic breeding for disease resistance of P. notoginseng remains limited. The WRKY transcription factors have been revealed to play important roles in plant defense responses, which might provide an inspiration for resistance improvement in P. notoginseng. RESULTS: In this study, the regulatory mechanism of transcription factor PnWRKY15 on P. notoginseng resistance to F. solani infection was revealed. The suppressed expression of PnWRKY15 via RNA interference increased the sensitivity of P. notoginseng to F. solani and decreased the expression levels of some defense-related genes, including PnOLP1, which encodes an osmotin-like protein that confers resistance to F. solani. Ectopic expression of PnWRKY15 in the model plant tobacco significantly enhanced the resistance to F. solani. Moreover, the transcriptome sequencing analysis discovered that some pathogenesis-related genes were expressed at higher levels in the PnWRKY15-overexpressing tobacco than that in the wild-type tobacco. In addition, the jasmonic acid (JA) and salicylic acid (SA) signaling pathways were evidently induced by PnWRKY15-overexpression, that was evidenced by that the JA and SA contents were significantly higher in the PnWRKY15-overexpressing tobacco than that in the wild-type. Furthermore, PnWRKY15, which was localized in the nucleus, can trans-activate and up-regulate PnOLP1 expression according to the EMSA, yeast one-hybrid and co-expression assays. CONCLUSIONS: PnWRKY15 contributes to P. notoginseng resistance to F. solani by up-regulating the expression of resistance-related gene PnOLP1 and activating JA/SA signaling pathways. These findings will help to further elucidate the transcriptional regulatory mechanism associated with the P. notoginseng defense response to F. solani.

Tunable couplings between location-insensitive emitters mediated by an epsilon-near-zero plasmonic waveguide.

This work demonstrates the efficient tuning of incoherent and coherent coupling between emitters embedded in an epsilon-near-zero (ENZ) waveguide coated with a multilayer graphene. As a result, a tunable two-qubit quantum phase gate based on the ENZ waveguide is realized at the cutoff frequency. Furthermore, due to the vanishingly small permittivity of the ENZ waveguide, all incoherent coupling between any two identical emitters located in the central area of the slit approaches a maximum, enabling near-ideal bipartite and multipartite entanglement. The coherent coupling between emitters is much larger at an operating frequency far from the ENZ resonance frequency than at the cutoff frequency, and the coherent coupling and resulting energy transfer efficiency can also be effectively tuned by the Fermi level of graphene. These results demonstrate an efficiently tunable electro-optical platform for quantum devices.

Doping-modulated lateral asymmetric Schottky diode as a high-performance self-powered synaptic device.

In the post-Moore era, the gradually saturated computational capability of conventional digital computers showing the opposite trend as the exponentially increasing data volumes imperatively required a platform or technology to break this bottleneck. Brain-inspired neuromorphic computing promises to inherently improve the efficiency of information processing and computation by means of the highly parallel hardware architecture to reduce global data transmission. Here, we demonstrate a compact device technology based on the barrier asymmetry to achieve zero-consumption self-powered synaptic devices. In order to tune the device behaviors, the typical chemical doping is used to tailor the asymmetry for energy harvesting. Finally, in our demonstrated devices, the open-circuit voltage (VOC) and power-conversion efficiency (PCE) can be modulated up to 0.77 V and 6%, respectively. Optimized photovoltaic features affords synaptic devices with an outstanding programming weight states, involving training facilitation, stimulus reinforce and consolidation. Based on self-powered system, this work further presents a highly available modulation scheme, which achieves excellent device behaviors while ensuring the zero-energy consumption.

Adsorption and Sensing of NO2, SO2, and NH3 on a Janus MoSeTe Monolayer Decorated with Transition Metals (Fe, Co, and Ni): A First-Principles Study.

This paper reports the adsorption of toxic gases (NO2, SO2, and NH3) on a MoSeTe structure based on first principles. It was found that the gas (NO2, SO2, and NH3) adsorption on a pure MoSeTe monolayer was weak; however, the adsorption performance of these gas molecules on transition-metal-atom-supported MoSeTe monolayers (TM-MoSeTe) was better than that on pure MoSeTe monolayers. In addition, there was more charge transfer between gas molecules and TM-MoSeTe. By comparing the adsorption energy and charge transfer values, the trend of adsorption energy and charge transfer in the adsorption of NO2 and SO2 was determined to be Fe-MoSeTe > Co-MoSeTe > Ni-MoSeTe. For the adsorption of NH3, the effect trend was as follows: Co-MoSeTe > Ni-MoSeTe > Fe-MoSeTe. Finally, by comparing their response times, the better gas sensor was selected. The Ni-MoSeTe system is suitable for NO2 gas sensors, and the Fe-MoSeTe and Co-MoSeTe systems are suitable for SO2 gas sensors. The Fe-MoSeTe, Co-MoSeTe, and Ni-MoSeTe systems are all suitable for NH3 gas sensors. Janus transition-metal dichalcogenides have the potential to be used as gas-sensing and scavenging materials.

Theoretical study of Mo2N supported transition metal single-atom catalyst for OER/ORR bifunctional electrocatalysis.

The rational design and development of an efficient bifunctional catalyst for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is the key to developing new renewable energy storage and conversion technologies. Transition metal nitrides (TMNs) have shown excellent energy storage and electrochemistry potential due to their unique electronic structure and physicochemical properties. In this paper, based on the first-principles method of density functional theory (DFT), a series of efficient and stable bifunctional single-atom catalysts (SACs) were designed on Mo2N by introducing transition metal atoms as active sites, and the effects of different TM atoms on the catalytic performance of 2D-Mo2N (Two dimensional Mo2N) were evaluated. The calculation results show that TM@Mo2N exhibits excellent stability and good conductivity, which is conducive to electron transfer during the electrocatalytic reaction. Among these SACs, the Au@Mo2N single-atom catalyst has a very low OER overpotential (0.36 V), exhibiting high OER activity. Meanwhile, Au@Mo2N also exhibits excellent ORR performance with a low overpotential of 0.4 V, indicating that Au@Mo2N is the best OER/ORR bifunctional catalyst. This work provides a feasible solution for developing transition metal bifunctional electrocatalysts. Au@Mo2N is expected to replace traditional commercial Pt catalyst materials and become a catalyst with excellent performance in fuel cell modules.

Lilium regale Wilson WRKY3 modulates an antimicrobial peptide gene, LrDef1, during response to Fusarium oxysporum.

BACKGROUND: WRKY transcription factors (TFs) play vital roles in plant growth and development, secondary metabolite synthesis, and response to biotic and abiotic stresses. In a previous transcriptome sequencing analysis of Lilium regale Wilson, we identified multiple WRKY TFs that respond to exogenous methyl jasmonate treatment and lily Fusarium wilt (Fusarium oxysporum). RESULTS: In the present study, the WRKY TF LrWRKY3 was further analyzed to reveal its function in defense response to F. oxysporum. The LrWRKY3 protein was localized in the plant cell nucleus, and LrWRKY3 transgenic tobacco lines showed higher resistance to F. oxysporum compared with wild-type (WT) tobacco. In addition, some genes related to jasmonic acid (JA) biosynthesis, salicylic acid (SA) signal transduction, and disease resistance had higher transcriptional levels in the LrWRKY3 transgenic tobacco lines than in the WT. On the contrary, L. regale scales transiently expressing LrWRKY3 RNA interference fragments showed higher sensitivity to F. oxysporum infection. Moreover, a F. oxysporum-induced defensin gene, Def1, was isolated from L. regale, and the recombinant protein LrDef1 isolated and purified from Escherichia coli possessed antifungal activity to several phytopathogens, including F. oxysporum. Furthermore, co-expression of LrWRKY3 and the LrDef1 promoter in tobacco enhanced the LrDef1 promoter-driven expression activity. CONCLUSIONS: These results clearly indicate that LrWRKY3 is an important positive regulator in response to F. oxysporum infection, and one of its targets is the antimicrobial peptide gene LrDef1.

An MYB Transcription Factor Modulates Panax notoginseng Resistance Against the Root Rot Pathogen Fusarium solani by Regulating the Jasmonate Acid Signaling Pathway and Photosynthesis.

Root rot of Panax notoginseng, a precious Chinese medicinal plant, seriously impacts its sustainable production. However, the molecular regulatory mechanisms employed by P. notoginseng against root rot pathogens, including Fusarium solani, are still unclear. In this study, the PnMYB2 gene was isolated, and its expression was affected by independent treatments with four signaling molecules (methyl jasmonate, ethephon, salicylic acid, and hydrogen peroxide) as assessed by quantitative real-time PCR. Moreover, the PnMYB2 expression level was induced by F. solani infection. The PnMYB2 protein localized to the nucleus and may function as a transcription factor. When overexpressed in transgenic tobacco, the PnMYB2 gene conferred resistance to F. solani. Jasmonic acid (JA) metabolism and disease resistance-related genes were induced in the transgenic tobacco, and the JA content significantly increased compared with in the wild type. Additionally, transcriptome sequencing, Kyoto Encyclopedia of Genes and Genomes annotation enrichment, and metabolic pathway analyses of the differentially expressed genes in the transgenic tobacco revealed that JA metabolic, photosynthetic, and defense response-related pathways were activated. In summary, PnMYB2 is an important transcription factor in the defense responses of P. notoginseng against root rot pathogens that acts by regulating JA signaling, photosynthesis, and disease-resistance genes.

Testin regulates the blood-testis barrier via disturbing occludin/ZO-1 association and actin organization.

The blood-testis barrier (BTB) separates the seminiferous epithelium into the apical and basal compartments. The BTB has to operate timely and accurately to ensure the correct migration of germ cells, meanwhile maintaining the immunological barrier. Testin was first characterized from primary Sertoli cells, it is a secretory protein and a sensitive biomarker to monitor junctions between Sertoli and germ cells. Till now, the functions of testin on BTB dynamics and the involving mechanisms are unknown. Herein, testin acts as a regulatory protein on BTB integrity. In vitro testin knockdown by RNAi caused significant damage to the Sertoli cell barrier with no apparent changes in the protein levels of several major tight junction (TJ), adhesion junction, and gap junction proteins. Also, testin RNAi caused the diffusion of two TJ structural proteins, occludin and ZO-1, diffusing away from the Sertoli cell surface into the cytoplasm. Association and colocalization between ZO-1 and occludin were decreased after testin RNAi, examined by Co-IP and coimmunofluorescent staining, respectively. Furthermore, testin RNAi induced a dramatic disruption on the arrangement of actin filament bundles and a reduced F-actin/G-actin ratio. The actin regulatory protein ARP3 appeared at the Sertoli cell interface after testin RNAi without its protein level change, whereas overexpressing testin in Sertoli cells showed no effect on TJ barrier integrity. The above findings suggest that besides as a monitor for Sertoli-germ cell junction integrity, testin is also an essential molecule to maintain Sertoli-Sertoli junctions.

The Akt/FoxO/p27Kip1 axis contributes to the anti-proliferation of pentoxifylline in hypertrophic scars.

Hypertrophic scars (HS) are characterized by the excessive production and deposition of extracellular matrix (ECM) proteins. Pentoxifylline (PTX), a xanthine derived antioxidant, inhibits the proliferation, inflammation and ECM accumulation of HS. In this study, we aimed to explore the effect of PTX on HS and further clarify the mechanism of PTX-induced anti-proliferation. We found that PTX could significantly attenuate proliferation of HS fibroblasts and fibrosis in an animal HS model. PTX inhibited the proliferation of HSFs in a dose- and time-dependent manner, and this growth inhibition was mainly mediated by cell cycle arrest. Transcriptome sequencing showed that PTX affects HS formation through the PI3K/Akt/FoxO1 signalling pathway to activate p27Kip1 . PTX down-regulated p-Akt and up-regulated p-FoxO1 in TGF-ß1 stimulated fibroblasts at the protein level, and simultaneously, the expression of p27Kip1 was activated. In a mouse model of HS, PTX treatment resulted in the ordering of collagen fibres. The results revealed that PTX regulates TGFß1-induced fibroblast activation and inhibits excessive scar formation. Therefore, PTX is a promising agent for the treatment of HS formation.

Serum level of macrophage migration inhibitory factor predicts severity and prognosis in patients with ischemic stroke.

OBJECTIVE: To evaluate whether the macrophage migration inhibitory factor (MIF) level in serum of ischemic stroke patients was associated with their clinical severity and early outcome. METHODS: During February 2017-March 2018, consecutive patients admitted to our hospital because of first-ever ischemic stroke were identified. The prognostic value of MIF was set for predicting the outcome of these patients at discharge. The results were compared with existing methods, including National Institutes of Health Stroke Scale (NIHSS) score and validated indicators. RESULTS: 289 patients were enrolled. The serum level of all patients was determined (median: 20.6 ng/ml). At admission, 131 patients (45.3%) were evaluated as minor stroke (NIHSS < 5). When serum level of MIF was increased by each 1 ng/ml, the unadjusted and adjusted risk of moderate-to-high clinical severity was elevated by 5% (OR = 1.05 [95% CI: 1.01-1.09], P = 0.006) and 3% (1.03 [1.00-1.08], P = 0.02), respectively. At discharge, 82 patients (28.4%) had poor functional outcomes. The median serum level of MIF was lower in group with good outcomes than that observed in poor outcomes (19.4[15.8-24.2] vs. 24.0[19.9-29.4] ng/ml; P < 0.001). When serum level of MIF was increased by each 1 ng/ml, the unadjusted and adjusted risk of poor outcomes was elevated by 9% (1.09 [1.05-1.13], P < 0.001) and 6% (1.06 [1.02-1.10], P < 0.01), respectively. CONCLUSIONS: High MIF levels are independently related to the moderate to high clinical severity in ischemic stroke patients, as well as the poor outcome at discharge.

SIRT1 activation promotes angiogenesis in diabetic wounds by protecting endothelial cells against oxidative stress.

OBJECTIVE: Chronic wounds are a devastating complication of diabetes and can lead to amputations or even death. Current medical therapies are insufficient to accelerate its repair. The objective of this study was to explore the role of Sirtuin1 (SIRT1) in diabetic wounds. METHODS AND MATERIALS: Perilesional skin tissue samples from diabetic ulcers and normoglycemic trauma wounds were used to detect SIRT1 expression and oxidative stress levels. In a diabetic mouse model, SIRT1 was pharmacologically activated to attenuate angiogenesis and accelerate wound closure. Finally, in vitro experiments were performed to elucidate some of the mechanisms by which SIRT1 activation promotes angiogenesis in diabetic wound healing. RESULTS: We found that skin tissue from diabetes patients showed lower expression of SIRT1 and severe oxidative stress. Decreased SIRT1 expression was observed in skin tissue from streptozocin (STZ)-induced diabetic mice and was associated with impaired wound healing. In addition, the wounds of STZ-induced diabetic mice treated with SRT1720 (a specific SIRT1 activator) demonstrated locally improved wound healing and angiogenesis. In the in vitro experiment, similar results were observed. Under hyperglycemia conditions, human umbilical vein endothelial cells (HUVECs) showed lower expression of SIRT1 and higher levels of reactive oxygen species (ROS) production. Furthermore, the migration, proliferation and in vitro tube formation ability of HUVECs were impaired under hyperglycemia conditions, and SRT1720 treatment rescued these impairments and decreased ROS production in HUVECs. CONCLUSIONS: This study provides experimental evidence that SIRT1 activation could improve angiogenesis in wounds in vitro and in vivo and that sirtuin1 activation accelerates wound healing in diabetic mice by promoting angiogenesis. These positive therapeutic effects may be mediated by protecting vascular endothelial cells from oxidative stress injury. This study suggested that SIRT1 may serve as a potentially important and potent therapeutic target for treating diabetic ulcers.

Uniqueness and multiplicity of clines in an environmental pocket.

The number of clines (i.e., polymorphic equilibria) maintained by a step-environment in a unidimensional pocket at a single diallelic locus is investigated. The monoecious population is locally panmictic; its density is uniform. Migration and viability selection are both weak; the former is homogeneous and symmetric; the latter is directional and usually specified by a unimodal function f(p) of the gene frequency p. If the ratio of the selection intensity to the migration rate exceeds a critical value, at least one cline exists. The general theorems on equilibrium structure determine it in detail for many classes of f(p), including the cubic for frequency-independent selection. Numerical examples demonstrate that for suitable f(p), many equilibria can occur simultaneously.

Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K/Akt signaling pathway.

INTRODUCTION: Adipose tissue-derived stem cells (ADSCs) have been shown to enhance wound healing via their paracrine function. Exosomes, as one of the most important paracrine factors, play an essential role in this process. However, the concrete mechanisms that underlie this effect are poorly understood. In this study, we aim to explore the potential roles and molecular mechanisms of exosomes derived from ADSCs in cutaneous wound healing. METHODS: Normal human skin fibroblasts and ADSCs were isolated from patient skin and adipose tissues. ADSCs were characterized by using flow cytometric analysis and adipogenic and osteogenic differentiation assays. Exosomes were purified from human ADSCs by differential ultracentrifugation and identified by electron microscopy, nanoparticle tracking, fluorescence confocal microscopy and western blotting. Fibroblasts were treated with different concentrations of exosomes, and the synthesis of collagen was analyzed by western blotting; the levels of growth factors were analyzed by real-time quantitative PCR (RT-PCR) and ELISA; and the proliferation and migration abilities of fibroblasts were analyzed by real-time cell analysis, CCK-8 assays and scratch assays. A mouse model with a full-thickness incision wound was used to evaluate the effect of ADSC-derived exosomes on wound healing. The level of p-Akt/Akt was analyzed by western blotting. Ly294002, a phosphatidylinositol 3-kinases (PI3K) inhibitor, was used to identify the underlying mechanisms by which ADSC-derived exosomes promote wound healing. RESULTS: ADSC-derived exosomes were taken up by the fibroblasts, which showed significant, dose-dependent increases in cell proliferation and migration compared to the behavior of cells without exosome treatment. More importantly, both the mRNA and protein levels of type I collagen (Col 1), type III collagen (Col 3), MMP1, bFGF, and TGF-ß1 were increased in fibroblasts after stimulation with exosomes. Furthermore, exosomes significantly accelerated wound healing in vivo and increased the level of p-Akt/Akt in vitro. However, Ly294002 alleviated these exosome-induced changes, suggesting that exosomes from ADSCs could promote and optimize collagen deposition in vitro and in vivo and further promote wound healing via the PI3K/Akt signaling pathway. CONCLUSIONS: This study demonstrates that ADSC-derived exosomes can promote fibroblast proliferation and migration and optimize collagen deposition via the PI3K/Akt signaling pathway to further accelerate wound healing. Our results suggest that ADSCs likely facilitate wound healing via the release of exosomes, and the PI3K/Akt pathway may play a role in this process. Our data also suggest that the clinical application of ADSC-derived exosomes may shed new light on the use of cell-free therapy to accelerate full-thickness skin wound healing and attenuate scar formation.

Acute downregulation of miR-199a attenuates sepsis-induced acute lung injury by targeting SIRT1.

MicroRNA-199a (miR-199a) is a novel gene regulator with an important role in inflammation and lung injury. However, its role in the pathogenesis of sepsis-induced acute respiratory distress syndrome (ARDS) is currently unknown. Our study explored the role of miR-199a in sepsis-induced ARDS and its mechanism of action. First, we found that LPS could upregulate miR-199a in alveolar macrophages. Downregulation of miR-199a inhibited the upregulation of inflammatory cytokines in alveolar macrophages and induced the remission of histopathologic changes, the reduction of proinflammatory cytokines, and the upregulation of apoptosis protein expression in an ARDS lung, showing a protective role for miR-199a. We further identified sirtuin 1 (SIRT1) as a direct target of miR-199a in alveolar macrophages, and the expression of SIRT1 was negatively correlated with the level of miR-199a. The protective role of miR-199a downregulation in LPS-stimulated alveolar macrophages and sepsis-induced ARDS could be attenuated by SIRT1 inhibitor. Taken together, these results indicate that downregulation of miR-199a might protect lung tissue against sepsis-induced ARDS by upregulation of SIRT1 through the suppression of excessive inflammatory responses and the inhibition of cellular apoptosis in lung tissue, suggesting its potential therapeutic effects on sepsis-induced ARDS.