Background/Aims: Since renal fibrosis always predisposes end-stage renal disease, elucidation of the molecular mechanisms that underlie the progression of renal fibrosis may substantially improve the ...understanding and treatment for renal failure. Previous studies have highlighted an important counteraction between transforming growth factor β 1 (TGFβ1) and bone morphogenic protein 7 (BMP7) in the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells during chronic renal injury. Macrophages are also believed to play a critical role in renal fibrosis. However, the relationship between macrophages and EMT is unknown. Methods: Here, we used a mouse unilateral ureteral obstruction (UUO) model to address to these questions, and analyzed macrophage and its subpopulations purified by flow cytometry. Results: We found that the recruited macrophages are polarized to a M2 subtype after renal injury. M2 macrophages released high levels TGFβ1 to suppress BMP7 to enhance EMT-induced renal fibrosis. Depletion of M2 macrophages, but not of M1 macrophages, specifically inhibited EMT, and subsequently the renal fibrosis. Adoptive transplantation of M2 macrophages deteriorated renal fibrosis. Conclusion: Thus, our study highlights M2 macrophages as a critical target for treating renal fibrosis.
Short-term load is a variable affected by many factors. It is difficult to forecast accurately with a single model. Taking advantage of the autoregressive integrated moving average (ARIMA) to ...forecast the linear basic part of load and of the support vector machines (SVMs) to forecast the non-linear sensitive part of load, a method based on hybrid model of ARIMA and SVMs is presented in this paper. It firstly uses ARIMA to forecast the daily load, and then uses SVMs, which is known for the great power to learn and generalize, to correct the deviation of former forecasting. Applying this hybrid model to a large sample prediction, the results show that it achieves the forecasting accuracy and has very good prospective in applications. So it can be used as a new load forecasting method.
Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic ...wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing. We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing. PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing.
Osteoblast differentiation is a vital process for fracture healing, and exosomes are nanosized membrane vesicles that can deliver therapeutic drugs easily and safely. Macrophages participate in the ...regulation of various biological processes in vivo, and macrophage-derived exosomes (MD-Exos) have recently been a topic of increasing research interest. However, few study has explored the link between MD-Exos and osteoblast differentiation. Herein, we sought to identify miRNAs differentially expressed between M1 and M2 macrophage-derived exosomes, and to evaluate their roles in the context of osteoblast differentiation.
We found that microRNA-5106 (miR-5106) was significantly overexpressed in M2 macrophage-derived exosomes (M2D-Exos), while its expression was decreased in M1 macrophage-derived exosomes (M1D-Exos), and we found that this exosomal miRNA can induce bone mesenchymal stem cell (BMSC) osteogenic differentiation via directly targeting the Salt-inducible kinase 2 and 3 (SIK2 and SIK3) genes. In addition, the local injection of both a miR-5106 agonist or M2D-Exos to fracture sites was sufficient to accelerate healing in vivo.
Our study demonstrates that miR-5106 is highly enriched in M2D-Exos, and that it can be transferred to BMSCs wherein it targets SIK2 and SIK3 genes to promote osteoblast differentiation.
Conventional seamless phase 2/3 design with fixed sample size determination (SSD) has gained its popularity in oncology drug development due to attractive features such as significantly shortening ...the development timeline, minimizing sample size, as well as early decision making. However, this design is not immune to inaccurate treatment effect assumption when only limited efficacy data are available at study design stage. We propose an innovative seamless phase 2/3 study design with flexible SSD for oncology trials, in which the trial is designed under a distribution of treatment effect instead of one single assumption due to huge uncertainty of treatment effect at design stage and the sample size for end of phase 3 analysis is not predetermined at design stage, but rather dynamically determined based on observed treatment effect at phase 2 portion. Some practical sample size determination rules for end of phase 3 analysis will be discussed. The proposed design can lead to reduced sample size or/and improved power compared with conventional seamless phase 2/3 design with fixed SSD. This innovative study design can be especially useful for programs with aggressive development strategy to expedite the process in delivering efficacious treatment to patients.
Radiation therapy is one of the main treatment methods for patients with thoracic malignant tumors, which can effectively improve the survival rate of the patients. However, radiation therapy can ...also cause damage to normal tissues while treating tumors, leading to radiation-induced lung injury such as radiation pneumonia and pulmonary fibrosis. Radiation-induced lung injury is a complex pathophysiological process involving many factors, and its prevention and treatment is one of the difficult problems in the field of radiation medicine. Therefore, the search for sensitive predictors of radiation-induced lung injury can guide clinical radiotherapy and reduce the incidence of radiation-induced lung injury. With the in-depth study of intestinal flora, it can drive immune cells or metabolites to reach lung tissue through the circulatory system to play a role, and participate in the occurrence, development and treatment of lung diseases. At present, there are few studies on intestinal flora and radiation-induced
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•Functionalized Ti3C2/Au NPs may swiftly kill S. aureus and prevent biofilm development.•Ti3C2/Au NPs may eliminate germs in subcutaneous tissue under irradiation, as demonstrated by ...the wound healing models and the subcutaneous abscess.•Immunofluorescence research revealed that Ti3C2/Au NPs may facilitate the conversion of M1 macrophages to M2 macrophages as well as boost angiogenesis to speed up the healing of infected wounds.
Infection by pathogenic bacteria presents a serious public health issue due to high morbidity and death rates. To aid infective wound closure and healing, a variety of anti-bacterial biomaterials optimized for multiple functions, including drug delivery, biosensing, or tissue engineering, have been designed and manufactured.
Ti3C2 and gold nanoparticles (Au NPs) were chosen as the building blocks for self-assembling biomaterials. The materials were characterized, and then the anti-biofilm and antibacterial properties of Ti3C2/Au NPs against Staphylococcus aureus (S. aureus) were examined.
Functionalized Ti3C2/Au NPs demonstrated to kill S. aureus and prevent biofilm development. Ti3C2/Au NPs with a photothermal property may eliminate germs in subcutaneous tissue under photo-irradiation, as demonstrated in the wound healing models and the subcutaneous abscess models. Meanwhile, histological evaluation revealed that Ti3C2/Au NPs may facilitate the conversion of macrophages from the M1 to M2 phenotype, and enhance angiogenesis to providing possible mechanisms by which this dressing fasten the healing of infected wounds.
The Ti3C2/Au NPs self-delivery system suggested in this work may thus provide novel materials and techniques for anti-infectious wound treatments.
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•We developed SPEEK@PDA-LAP to regulate macrophage-mediated bone homeostasis.•SPEEK@PDA-LAP alleviated intracellular ROS accumulation and further inhibited the NLRP3 ...inflammasome-mediated pyroptosis in macrophages.•The inhibition effect of ROS/NLRP3/IL-1β-mediated pyroptosis contributes to the restoration of the balance between osteogenesis and osteoclastogenesis in vitro and in vivo.
The treatment of osteoporotic implant failures tends to be challenging due to an imbalance in bone homeostasis. Recently, the accumulation of intracellular reactive oxygen species (ROS) and activation of the inflammasome containing nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) protein have been shown to indirectly affect osteogenesis and osteoclastogenesis. Owing to the release of multi-metal ions from laponite (LAP), we fabricated a multifunctional LAP coating on a three-dimensional microporous sulfonated polyetheretherketone (SPEEK) surface via polydopamine (PDA) modification (SPEEK@PDA-LAP). The balance between osteogenesis and osteoclastogenesis was examined using macrophages in an osteo-immune microenvironment. Employing in vitro assays, we showed that the SPEEK@PDA-LAP alleviated intracellular ROS accumulation and inhibited the activation of NLRP3 inflammasome-mediated pyroptosis in macrophages, creating an osteoimmunomodulatory microenvironment to stimulate osteogenesis and inhibit osteoclastogenesis. The micro-computed tomography and histological results of in vivo experiments indicated that SPEEK@PDA-LAP implants reversed the balance between osteogenesis and osteoclastogenesis to promote the formation of new bone around the implant even under osteoporotic conditions. The results indicate that inhibiting the NLRP3 inflammasome and regulating intracellular ROS in macrophages can be an effective therapy for osteoporosis. These results highlight the potential of functional PEEK materials for bone regeneration in patients with osteoporosis.
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