Chronic nonhealing diabetic wound therapy and complete skin regeneration remains a critical clinical challenge. The controlled release of bioactive factors from a multifunctional hydrogel was a ...promising strategy to repair chronic wounds.
Herein, for the first time, we developed an injectable, self-healing and antibacterial polypeptide-based FHE hydrogel (F127/OHA-EPL) with stimuli-responsive adipose-derived mesenchymal stem cells exosomes (AMSCs-exo) release for synergistically enhancing chronic wound healing and complete skin regeneration. The materials characterization, antibacterial activity, stimulated cellular behavior and
full-thickness diabetic wound healing ability of the hydrogels were performed and analyzed.
The FHE hydrogel possessed multifunctional properties including fast self-healing process, shear-thinning injectable ability, efficient antibacterial activity, and long term pH-responsive bioactive exosomes release behavior.
, the FHE@exosomes (FHE@exo) hydrogel significantly promoted the proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs).
, the FHE@exo hydrogel significantly enhanced the healing efficiency of diabetic full-thickness cutaneous wounds, characterized with enhanced wound closure rates, fast angiogenesis, re-epithelization and collagen deposition within the wound site. Moreover, the FHE@exo hydrogel displayed better healing outcomes than those of exosomes or FHE hydrogel alone, suggesting that the sustained release of exosomes and FHE hydrogel can synergistically facilitate diabetic wound healing. Skin appendages and less scar tissue also appeared in FHE@exo hydrogel treated wounds, indicating its potent ability to achieve complete skin regeneration.
This work offers a new approach for repairing chronic wounds completely through a multifunctional hydrogel with controlled exosomes release.
Damaged deoxyribonucleic acid (DNA) is a primary pathologic factor for osteoarthritis (OA); however, the mechanism by which DNA damage drives OA is unclear. Previous research demonstrated that the ...cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) participates in DNA damage response. As a result, the current study aimed at exploring the role STING, which is the major effector in the cGAS-STING signaling casacde, in OA progress in vitro, as well as in vivo. In this study, the expression of STING was evaluated in the human and mouse OA tissues, and in chondrocytes exposed to interleukin-1 beta (IL-1β). The influences of STING on the metabolism of the extracellular matrix (ECM), apoptosis, and senescence, were assessed in STING overexpressing and knocking-down chondrocytes. Moreover, the NF-κB-signaling casacde and its role in the regulatory effects of STING on ECM metabolism, apoptosis, and senescence were explored. The STING knockdown lentivirus was intra-articularly injected to evaluate its therapeutic impact on OA in mice in vivo. The results showed that the expression of STING was remarkably elevated in the human and mouse OA tissues and in chondrocytes exposed to IL-1β. Overexpression of STING promoted the expression of MMP13, as well as ADAMTS5, but suppressed the expression of Aggrecan, as well as Collagen II; it also enhanced apoptosis and senescence in chondrocytes exposed to and those untreated with IL-1β. The mechanistic study showed that STING activated NF-κB signaling cascade, whereas the blockage of NF-κB signaling attenuated STING-induced apoptosis and senescence, and ameliorated STING-induced ECM metabolism imbalance. In in vivo study, it was demonstrated that STING knockdown alleviated destabilization of the medial meniscus-induced OA development in mice. In conclusion, STING promotes OA by activating the NF-κB signaling cascade, whereas suppression of STING may provide a novel approach for OA therapy.
The blockage of autophagic flux in chondrocytes has been considered as a major reason for the excessive cellular apoptosis and senescence in osteoarthritis (OA) development; however, the molecular ...mechanism and therapeutic strategy for interrupted autophagic flux is still not clear. Most recently, the transcription factor EB (TFEB) is identified as a master regulator for autophagic flux via initiating the expression of multiple autophagy-related genes and lysosomal biogenesis. This research was performed to confirm whether TFEB expression and activity are impacted in OA development and to confirm the effect of genetic up-regulation of TFEB on autophagic flux and cellular protection in the in vitro and in vivo models of OA. We demonstrated that the expression and nuclear localization of TFEB is decreased in human and mouse OA cartilage as well as in tert-Butyl hydroperoxide (TBHP)-treated chondrocytes. Applying lentivirus to transfect chondrocytes, we found that TFEB overexpression rescues the TBHP-induced the autophagic flux damage, lysosome dysfunction and protects chondrocyte against TBHP induced apoptosis and senescence; these protections of TFEB are diminished by chloroquine-medicated autophagy inhibition. Our destabilized medial meniscus (DMM) mouse OA model shows that TFEB overexpression ameliorates the surgery-induced cartilage degradation, restrains the apoptosis and senescence of chondrocyte, and enhances the autophagic flux. In summary, our study indicates that the activity of TFEB in chondrocyte is involved in OA development, also TFEB overexpression may be a promising strategy for OA treatment.
High tibial osteotomy (HTO) has been widely used for clinical treatment of osteoarthritis of the medial compartment of the knee, and both opening-wedge and closing-wedge HTO are the most commonly ...used methods. However, it remains unclear which technique has better clinical and radiological outcomes in practice. To systematically evaluate this issue, we conducted a comprehensive meta-analysis by pooling all available data for the opening-wedge HTO and closing-wedge HTO techniques from the electronic databases including PubMed, Embase, Wed of Science and Cochrane Library. A total of 22 studies encompassing 2582 cases were finally enrolled in the meta-analysis. There was no significant difference regarding surgery time, duration of hospitalization, knee pain VAS, Lysholm score and HSS knee score (clinical outcomes) between the opening-wedge and closing-wedge HTO groups (P > 0.05). However, the opening-wedge HTO group showed wider range of motion than the closing-wedge HTO group (P = 0.003). Moreover, as for Hip-Knee-Ankle angle and mean angle of correction, no significant difference was observed between the opening-wedge and closing-wedge HTO groups (P > 0.05), while the opening-wedge HTO group showed greater posterior tibial slope angle (P < 0.001) and lesser patellar height than the closing-wedge HTO group (P < 0.001). On light of the above analysis, we believe that individualized surgical approach should be introduced based on the clinical characteristics of each patient.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this study is to investigate the connection of pre-competition anxiety with gut microbiota and metabolites in wrestlers with different sports performances.
One week prior to a national ...competition, 12 wrestlers completed anxiety questionnaires. Faecal and urine samples were collected for the analysis of gut microbiota and metabolites through the high-throughput sequencing of the 16 S rRNA gene in conjunction with untargeted metabolomics technology. The subjects were divided into two groups, namely, achievement (CP) and no-achievement (CnP) wrestlers, on the basis of whether or not their performances placed them in the top 16 at the competition. The relationship amongst the variations in gut microbiota, metabolites, and anxiety indicators was analyzed.
(1) The CP group exhibited significantly higher levels of "state self-confidence," "self-confidence," and "somatic state anxiety" than the CnP group. Conversely, the CP group displayed lower levels of "individual failure anxiety" and "sports competition anxiety" than the CnP group. (2) The gut microbiota in the CP group was more diverse and abundant than that in the CnP group. Pre-competition anxiety was linked to Oscillospiraceae UCG_005, Paraprevotella, Ruminococcaceae and TM7x. (3) The functions of differential metabolites in faeces and urine of the CP/CnP group were mainly enriched in caffeine metabolism, lipopolysaccharide biosynthesis and VEGF and mTOR signaling pathways. Common differential metabolites in feces and urine were significantly associated with multiple anxiety indicators.
Wrestlers with different sports performance have different pre-competition anxiety states, gut microbiota distribution and abundance and differential metabolites in faeces and urine. A certain correlation exists between these psychological and physiological indicators.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells. Recent studies have revealed a close relationship between exosomes and ...bone homeostasis. It is suggested that bone cells can spontaneously secret exosomes containing proteins, lipids and nucleic acids, which then to regulate osteoclastogenesis and osteogenesis. However, the network of regulatory activities of exosomes in bone homeostasis as well as their therapeutic potential in bone injury remain largely unknown. This review will detail and discuss the characteristics of exosomes, the regulatory activities of exosomes in bone homeostasis as well as the clinical potential of exosomes in bone injury.
Intervertebral disc degeneration (IDD) is a complicated pathological condition blamed for low back pain. Mitochondrion is of vital importance for cellular homeostasis, and mitochondrial dysfunction ...is considered to be one of the major causes of cellular damage. Mitophagy is a cellular process to eliminate impaired mitochondria and showed protective effects in various diseases; however, its role in IDD is still not clear. Here, we explore the role of Parkin-mediated mitophagy in IDD. In this study, we found that Parkin was upregulated in degenerative nucleus pulposus (NP) tissues in vivo as well as in TNF-α stimulated NP cells in vitro. Knockdown of Parkin by siRNA showed that Parkin is crucial for apoptosis and mitochondrion homeostasis in NP cells. Further study showed that upregulation of Parkin by salidroside may eliminate impaired mitochondria and promote the survival of NP cells through activation of mitophagy in vitro. In in vivo study, we found that salidroside could inhibit the apoptosis of NP cells and ameliorate the progression of IDD. These results suggested that Parkin is involved in the pathogenesis of IDD and may be a potential therapeutic target for IDD.
Random-pattern skin flaps are important method for skin reconstruction after defect; however, the distal end of flaps is not easily viable due to inadequate nutrient supply. Erastin is a ...well-established ferroptosis inducer, but our study found that low-dose of erastin (2 μM) may reduce nutrient deficiency induced cell death in human umbilical vein endothelial cells (HUVECs). RNA-seq analysis suggested that its role was related to autophagy regulation. Follow-up studies have shown that the use of autophagy inhibitors or the knockdown of TFEB in HUVECs can both reduce the anti-apoptotic effect of erastin in HUVECs. Mechanism study demonstrated that erastin can suppress mTORC1 and promote TFEB activity in HUVECs, suggesting that the effect of erastin on the survival of HUVECs under nutrient deprivation conditions is regulated by mTORC1/TFEB. Subsequently, we evaluated the effect of erastin on the survival of random-pattern skin flaps in mice in vivo. On the postoperative day 7, we observed a significant increase in flap survival area, blood perfusion, and microvascular density after erastin treatment; also, erastin treatment showed enhanced autophagy within the ischemic region. In summary, our study demonstrates that low-dose of erastin may suppress cell death in endothelial cells under nutrient deficiency condition, and its effects may relate to the mTORC1-TFEB medicated autophagy regulation, erastin treatment may be a potential therapy for random-pattern skin flaps.
Random-pattern skin flaps are commonly used and valuable tools in reconstructive surgery, however, post-operative random skin flap necrosis remains a major and common complication. Previous studies ...have suggested that activating autophagy, a major pathway for degradation of intracellular waste, may improve flap survival. In this study, we investigated whether trehalose, a novel and potent autophagy activator, improves random skin flap viability. Our results demonstrated that trehalose significantly improves viability, augments blood flow, and decreases tissue edema. Furthermore, we found that trehalose leads to increased angiogenesis, decreased apoptosis, and reduced oxidative stress. Using immunohistochestry and western blot, we demonstrated that trehalose augments autophagy, and that inhibition of autophagy augmentation using 3MA significantly blunted the aforementioned benefits of trehalose therapy. Mechanistically, we showed that trehalose's autophagy augmentation is mediated by activation and nuclear translocation of TFEB, which may be due to inhibition of Akt and activation of the AMPK-SKP2-CARM1 signaling pathway. Altogether, our results established that trehalose is a potent agent capable for significantly increasing random-pattern skin flap survival by augmenting autophagy and subsequently promoting angiogenesis, reducing oxidative stress, and inhibiting cell death.
PDF
