Silica-coated liquid metal nanoparticles with different stiffness for cellular uptake-enhanced tumor photothermal therapy.

Cells can sense the mechanical stimulation of nanoparticles (NPs) and then regulate the cellular uptake process. The enhanced endocytosis efficiency can improve the concentration of NPs in tumor cells significantly, which is the key prerequisite for achieving efficient biological performance. However, the preparation methods of NPs with flexible and tunable stiffness are relatively limited, and the impact of stiffness property on their interaction with tumor cells remains unclear. In this study, soft liquid metal (LM) core was coated with hard silica layer, the obtained core-shell NPs with a wide range of Young's modulus (130.5 ± 25.6 MPa - 1729.2 ± 146.7 MPa) were prepared by adjusting the amount of silica. It was found that the NPs with higher stiffness exhibited superior cellular uptake efficiency and lysosomal escape ability compared to the NPs with lower stiffness. The silica layer not only affected the stiffness, but also improved the photothermal stability of the LM NPs. Both in vitro and in vivo results demonstrated that the NPs with higher stiffness displayed significantly enhanced tumor hyperthermia capability. This work may provide a paradigm for the preparation of NPs with varying stiffness and offer insights into the role of the mechanical property of NPs in their delivery.

Lactylation-related gene signature for prognostic prediction and immune infiltration analysis in breast cancer.

Background: Lactylation is implicated in various aspects of tumor biology, but its relation to breast cancer remains poorly understood. This study aimed to explore the roles of the lactylation-related genes in breast cancer and its association with the tumor microenvironment. Methods: The expression and mutation patterns of lactylation-related genes were analyzed using the breast cancer data from The Cancer Genome Atlas (TCGA) database and GSE20685 datasets. Unsupervised clustering was used to identify two lactylation clusters. A lactylation-related gene signature was developed and validated using the training and validation cohorts. Immune cell infiltration and drug response were assessed. Results: We analyzed the mRNA expression, copy number variations, somatic mutations, and correlation networks of 22 lactylation-related genes in breast cancer tissues. We identified two distinct lactylation clusters with different survival outcomes and immune microenvironments. We further classified the patients into two gene subtypes based on lactylation clusters and identified a 7-gene signature for breast cancer survival prognosis. The prognostic score based on this signature demonstrated prognostic value and predicted the therapeutic response. Conclusion: Lactylation-related genes play a critical role in breast cancer by influencing tumor growth, immune microenvironment, and drug response. This lactylation-related gene signature may serve as a prognostic marker and a potential therapeutic target for breast cancer.

Dual siRNA-Loaded Cell Membrane Functionalized Matrix Facilitates Bone Regeneration with Angiogenesis and Neurogenesis.

Vascularization and innervation play irreplaceable roles in bone regeneration and bone defect repair. However, the reconstruction of blood vessels and neural networks is often neglected in material design. This study aims to design a genetically functionalized matrix (GFM) and enable it to regulate angiogenesis and neurogenesis to accelerate the process of bone defect repair. The dual small interfering RNA (siRNA)-polyvinylimide (PEI) (siRP) complexes that locally knocked down soluble vascular endothelial growth factor receptor 1 (sFlt-1) and p75 neurotrophic factor receptor (p75NTR ) are prepared. The hybrid cell membrane (MM) loaded siRP is synthesized as siRNA@MMs to coat on polylactone (PCL) electrospun fibers for mimicking the natural bone matrix. The results indicates that siRNA@MMs could regulate the expression of vascular-related and neuro-related cytokines secreted by mesenchymal stem cells (MSCs). GFMs promote the expression of osteogenic differentiation through paracrine function in vitro. GFMs attenuates inflammation and promotes osseointegration by regulating the coupling of vascularization and innervation in vivo. This study uses the natural hybrid cell membrane to carry genetic material and assist in the vascularization and innervation function of two siRNA. The results present the significance of neuro-vascularized organoid bone and may provide a promising choice for the design of bone tissue engineering scaffold.

Improving bridge effect to overcome interspecific hybrid sterility by pyramiding hybrid sterile loci from Oryza glaberrima.

In order to evaluate the genetic effect caused by hybrid sterile loci, NILs with O. glaberrima fragment at six hybrid sterile loci under O. sativa genetic background (single-locus-NILs) were developed; two lines harboring two hybrid sterile loci, one line harboring three hybrid sterile loci were further developed. A total of nine NILs were used to test cross with O. sativa recurrent parent, and O. glaberrima accessions respectively. The results showed that the sterility of pollen grains in F1 hybrids deepened with the increase of the number of hybrid sterile loci, when the nine lines test crossed with O. sativa recurrent parent. The F1 hybrids were almost completely sterile when three hybrid sterile loci were heterozygeous. On the other hand, the single-locus-NILs had limited bridge effect on improving pollen grain fertility of interspecific hybrids. Compared single-locus-NILs, the multiple-loci-NILs showed increasing effect on pollen fertility when test crossing with O. glaberrima accessions. Further backcrossing can improve the fertility of pollen grain and spikelet of interspecific hybrids. The optimal solution to improve the fertility of interspecific hybrid can be utilization of pyramiding bridge parent plus backcrossing. This report has potential for understanding the nature of interspecific hybrid sterility, and overcoming the interspecific hybrid F1 pollen grain sterility between O. sativa and O. glaberrima.

Suspension state affects the stemness of breast cancer cells by regulating the glycogen synthase kinase-3ß.

Circulating tumor cells (CTCs) are considered an important factor involved in tumor metastasis and can overcome mechanical interactions to gain the ability to distant metastasis. The previous study had shown that the suspension state could regulate the stemness of breast cancer cells (BCCs). However, the specific molecular mechanisms involved have not yet been explored clearly. In this study, MCF-7 and MDA-MBA-231 BCCs were cultured in suspension and adherent. The effect of suspension state on BCCs was further elucidated by observing suspension cell clusters, sorting CD44+/CD24- cell subpopulation and detecting self-renewal ability. Furthermore, it was found that glycogen synthase kinase-3ß (GSK-3ß) was significantly down-regulated in MCF-7 suspension cells along with the activation of the Wnt/ß-catenin signaling, but the converse was true for MDA-MB-231 cells. Subsequently, GSK-3ß was differentially expressed in MCF-7 suspension cells. The activation of the Wnt/ß-catenin signaling, epithelial-mesenchymal transition (EMT) and stemness were all inhibited when GSK-3 was overexpressed in suspension MCF-7 cells. While GSK-3ß was down-regulated, it further promoted the Wnt/ß-catenin signaling, mesenchymal characteristic and stemness of MCF-7 cells. This study demonstrated that suspension state could activate the Wnt/ß-catenin signaling by inhibiting GSK-3ß to promote the stemness of epithelial BCCs, providing a therapeutic strategy for targeted CTCs.

Hierarchically Released Liquid Metal Nanoparticles for Mild Photothermal Therapy/Chemotherapy of Breast Cancer Bone Metastases via Remodeling Tumor Stromal Microenvironment.

Currently, the treatment strategy for bone metastasis is mainly to inhibit the growth of tumor cells and the activity of osteoclasts, while ignoring the influence of the tumor stromal microenvironment (TSM) on the progression of bone metastasis. Herein, a dual-target liquid metal (LM)-based drug delivery system (DDS) with favorable photothermal performance is designed to spatially program the delivery of multiple therapeutic agents to enhance the treatment of bone metastasis through TSM remodeling. Briefly, mesoporous silicon-coated LM is integrated into zeolitic imidazolate framework-8 (ZIF-8) with both bone-seeking and tumor-targeting capacities. Curcumin (Cur), a tumor microenvironment modulator, is encapsulated into ZIF-8, and doxorubicin (DOX) is enclosed inside mesoporous silicon. Specific accumulation of the LM-based DDS in bone metastases first relieves the tumor stroma by releasing Cur in response to the acidic tumor microenvironment and then releases DOX deep into the tumor under near-infrared light irradiation. The combined strategy of the LM-based DDS and mild photothermal therapy has been shown to effectively restrain cross-talk between osteoclasts and tumor cells by inhibiting the secretion of transforming growth factor-ß, degrading extracellular matrix components, and increasing infiltration of CD4+ and CD8+ T cells, which provides a promising strategy for the treatment of bone metastases.

Three QTL from Oryza meridionalis Could Improve Panicle Architecture in Asian Cultivated Rice.

Rice panicle architecture is directly associated with grain yield and is also the key target in high-yield rice breeding program. In this study, three BC6F2 segregation populations derived from the crosses between two accessions of Oryza meridionalis and a O. sativa spp. japonica cultivar Dianjingyou 1, were employed to map QTL for panicle architecture. Three QTL, EP4.2, DEP7 and DEP8 were identified and validated using substitution mapping strategy on chromosome 4, 9 and 8, respectively. The three QTL showed pleiotropic phenotype on panicle length (PL), grain number per panicle (GNPP), number of primary branches (NPB), number of secondary branches (NSB), and grain width. DEP7 and DEP8 showed yield-enhancing potential by increasing GNPP, NPB and NSB, while EP4.2 exhibited wide grain, short stalk and panicle which can improve plant and panicle architecture, too. Moreover, epistatic interaction for PL was detected between EP4.2 and DEP7, and epistatic analysis between DEP7 and DEP8 for GNPP and NPB also revealed significant two QTL interactions. The result would help us understand the molecular basis of panicle architecture and lay the foundation for using these three QTL in rice breeding.

Dynamic-stiffening collagen-coated substrate enhances osteogenic differentiation of mesenchymal stem cells through integrin α2ß1.

Matrix stiffness dynamically increases during the bone formation process. Enhancement of the osteogenic differentiation of mesenchymal stem cells (MSCs) by the dynamic stiffening of the substrate has been reported in previous research. However, the mechanism by which the dynamic stiffening of the matrix effects the osteogenic differentiation of MSCs remains quite unknown. A previously reported dynamic hydrogel system with dynamic matrix stiffening was used in this study to investigate the mechanical transduction mechanism of MSCs. The integrin α2ß1 and phosphorylation focal adhesion kinase levels were evaluated. The results indicated that dynamic stiffening of the matrix mediated the activation of integrin α2ß1, and further influenced the focal adhesion kinase (FAK) phosphorylation level of MSCs. In addition, integrin α2 is a probable integrin subunit that causes integrin ß1 activation during the matrix dynamic stiffening process. The integrin ß1 is the main integrin subunit regulating the osteogenic differentiation of MSCs induced by FAK phosphorylation. Overall, the results suggested that the dynamic stiffness facilitated the osteogenic differentiation process of the MSCs by regulating the integrin-α2ß1-mediated mechanical transduction pathway, which implied that integrin α2ß1 played a crucial role in the physical biological coupling in the dynamic matrix microenvironment.

Hybrid Cell Membrane-Functionalized Matrixes for Modulating Inflammatory Microenvironment and Improving Bone Defect Repair.

Cell membranes from different sources retain the integrity of the original membrane structure and special membrane protein functions. However, the diversity function of membrane surface proteins is underutilized in bone defect repair. The current study creatively prepared a hybrid membrane (HM) (diameter, 92.25 ± 16.47 nm) and coated it on a poly-ε-caprolactone (PCL) (diameter, 313.79 ± 4.69 nm) electrospinning membrane for cell membrane-functionalized matrixes (MFMs) (diameter, 368.76 ± 5.90 nm) preparation. The effects of the HM and MFMs on inflammatory regulation and bone formation are further explored in vitro and in vivo. The results showed that MFMs can regulate macrophage into anti-inflammatory phenotype and promote alkaline phosphatase secretion and mineralization deposition of mesenchymal stem cells (MSCs) in vitro. The foreign body response is alleviated and bone regeneration is facilitated in rat calvarial critical-size defect in vivo. The study provides an innovative approach to applicate the cell membrane functions from different sources for immunomodulatory and osteogenic differentiation and provides a promising choice for designing bone repair materials.

A biomechanical view of epigenetic tumor regulation.

The occurrence and development of tumors depend on a complex regulation by not only biochemical cues, but also biomechanical factors in tumor microenvironment. With the development of epigenetic theory, the regulation of biomechanical stimulation on tumor progress genetically is not enough to fully illustrate the mechanism of tumorigenesis. However, biomechanical regulation on tumor progress epigenetically is still in its infancy. Therefore, it is particularly important to integrate the existing relevant researches and develop the potential exploration. This work sorted out the existing researches on the regulation of tumor by biomechanical factors through epigenetic means, which contains summarizing the tumor epigenetic regulatory mode by biomechanical factors, exhibiting the influence of epigenetic regulation under mechanical stimulation, illustrating its existing applications, and prospecting the potential. This review aims to display the relevant knowledge through integrating the existing studies on epigenetic regulation in tumorigenesis under mechanical stimulation so as to provide theoretical basis and new ideas for potential follow-up research and clinical applications. Mechanical factors under physiological conditions stimulate the tumor progress through epigenetic ways, and new strategies are expected to be found with the development of epidrugs and related delivery systems.

Icariin Induces Triple-Negative Breast Cancer Cell Apoptosis and Suppresses Invasion by Inhibiting the JNK/c-Jun Signaling Pathway.

Background: Breast cancer is a common cancer worldwide. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by a poor prognosis. Icariin (ICA) is a flavonoid glycoside purified from the natural product Epimedium, which is reported to exert an inhibitory effect on a variety of cancers. However, molecular mechanisms behind ICA suppressed TNBC remain elusive. Methods: The curative effects of ICA on TNBC cells and potential targets were predicted by network pharmacology and molecular biology methods screening, and the mechanism of inhibition was explained through in vitro experiments such as cell function determination, Western blot analysis, molecular docking verification, etc. Results: This study showed that ICA inhibits TNBC cell functions such as proliferation, migration, and invasion in a dose-dependent manner. ICA could induce redox-induced apoptosis in TNBC cell, as shown by ROS upregulation. As a result of network pharmacology, ICA was predicted to be able to inhibit the MAPK signaling pathway. ICA treatment inhibited the expression of JNK and c-Jun and downregulated the antiapoptotic gene cIAP-2. Our results suggested that ICA could induce apoptosis by inducing an excessive accumulation of ROS in cells and suppress TNBC cell invasion via the JNK/c-Jun signaling pathway. Conclusion: We demonstrated that ICA can effectively inhibit cell proliferation and induced apoptosis of TNBC cells. In addition, ICA could inhibit TNBC cell invasion through the JNK/c-Jun signaling pathway. The above suggests that ICA may become a potential drug for TNBC.

Palbociclib plus endocrine therapy in hormone receptor-positive and HER2 negative metastatic breast cancer: a multicenter real-world study in the northwest of China.

BACKGROUND: Real-world data of Palbociclib are insufficient in China. This study aimed to investigate the treatment pattern and real-world outcomes in hormone receptor positive and human epidermal growth factor 2 receptor negative (HR+/HER2-) metastatic breast cancer (MBC) patients treated with Palbociclib in the northwest of China. METHODS: HR+/HER2- MBC patients who received Palbociclib in 8 centers from July 2017 to September 2019 were retrospectively included in this study. Real-world objective response rate (ORR), progression-free survival (PFS) and safety profiles were analyzed. The survival curves were plotted by the Kaplan-Meier method to analyze PFS, which was verified by the log-rank test. RESULTS: In total, 211 women were eligible for the analysis. A total of 85 patients (40.3%), 78 (37.0%), and 48 (22.7%) received Palbociclib in the first-, second-, third- or later-line setting, respectively. 46 patients achieved partial response and 145 patients experienced stable disease, with an ORR of 21.8% and a disease control rate of 90.5%. Following a median follow-up period of 14.2 months, the median PFS was 12.2 months (95% confidence interval, 10.1-14.3 m), and the median overall survival was not reached. Early Palbociclib initiation, sensitivity or acquired resistance to endocrine therapy, estrogen receptor and progesterone receptor double positivity, less than 3 metastatic sites, without visceral metastasis, bone metastasis only, without prior chemotherapy or endocrine therapy were associated with a prolonged PFS in MBC (All P < 0.05). The most common grade 3 or 4 adverse events (AE) was neutropenia (36.5%), and the most common nonhematologic AE was fatigue (10.9%). No patient experienced AE leading to treatment discontinuation. CONCLUSION: Palbociclib plus endocrine therapy exhibited favorable effectiveness and manageable toxicities in the real-world setting, supporting their use in Chinese patients with HR+/HER2 - MBC.

Suspension state and shear stress enhance breast tumor cells EMT through YAP by microRNA-29b.

Except for biochemical effects, suspension state (Sus) is proved to induce epithelial-mesenchymal transition (EMT) of circulating tumor cells (CTCs) mechanically. However, the difference between the effects of the mechanical microenvironment in capillaries (simplified as shear stress (SS) and Sus) and single Sus on EMT is unclear, nor the underlying mechanism. Here, breast tumor cells (BTCs) were loaded with Sus and SS to mimic the situation of CTCs stimulated by these two kinds of mechanics. It was demonstrated that the EMT of BTCs was enhanced by Sus and SS and the mechanotransductor yes-associated protein (YAP) was partially cytoplasmic stored with microRNA (miR)-29b decreased, which was detected by miR sequencing. Though it couldn't possess a feedback regulation, YAP promoted miR-29b expression and posttranscriptionally regulated BTCs EMT through miR-29b, where transforming growth factor ß involved. Analysis of clinical database showed that high miR-29b expression was beneficial to high survival rate stabilizing its role of tumor suppressor. This study discovers the mechanism that Sus and SS promote BTCs EMT by YAP through miR-29b posttranscriptionally and highlight the potential of YAP and miR-29b in tumor therapy. The combination of suspension state and shear stress promotes transforming growth factor ß involved epithelial-mesenchymal transition by yes-associated protein through microRNA-29b.

In Situ Regulation and Mechanisms of 3D Matrix Stiffness on the Activation and Reversion of Hepatic Stellate Cells.

Activated hepatic stellate cells (HSCs) is a key event in the progression of liver fibrosis. HSCs transdifferentiate into myofibroblasts and secrete large amounts of extracellular matrix, resulting in increased liver stiffness. It is difficult for platforms constructed in vitro to simulate the structure, composition, and stiffness of the 3D microenvironment of HSCs in vivo. Here, 3D scaffolds with different stiffness are constructed by decellularizing rat livers at different stages of fibrosis. The effects of matrix stiffness on the proliferation, activation, and reversion of HSCs are studied. The results demonstrate these scaffolds have good cytocompatibility. It is also found that the high stiffness can significantly promote the activation of HSCs, and this process is accompanied by the activation of integrin ß1 as well as the nucleation and activation of Yes-associated protein (YAP). Moreover, the low stiffness of the scaffold can promote the reversion of activated HSCs, which is associated with cell apoptosis and accompanied by the inactivation of integrin ß1 and YAP. These results suggest that YAP may be a potential therapeutic target for the treatment of liver fibrosis and the theoretical feasibility of inducing activated HSCs reversion to the resting state by regulating matrix stiffness of liver.

Combining dual-targeted liquid metal nanoparticles with autophagy activation and mild photothermal therapy to treat metastatic breast cancer and inhibit bone destruction.

Although mild photothermal therapy (mild-PTT) avoids treatment bottleneck of the traditional PTT, the application of mild-PTT in deep and internal tumors is severely restricted due to thermal resistance, limited irradiation area and penetration depth. In addition, bone resorption caused by tumor colonization in distal bone tissue exacerbates tumor progression. Here, a strategy was developed for the treatment of bone metastasis and alleviation of bone resorption, which was based on liquid metal (LM) nanoparticle to resist thermal resistance induced by mild-PTT via autophagy activation. Briefly, LM and autophagy activator (Curcumin, Cur) were loaded into zeolitic imidazolate framework-8 (ZIF-8), which was then functionalized with hyaluronic acid/alendronate (CLALN). CLALN exhibited good photothermal performance, drug release ability under acidic environment, specifical recognition and aggregation at bone metastasis sites. CLALN combined with mild-PPT dramatically inhibited tumor progress by inducing the impaired autophagy and reduced the expression of programmed cell death ligand 1 (PD-L1) protein triggered by mild-PTT, resisting thermal resistance and alleviating the immunosuppression. Besides, CLALN combined with mild-PPT effectively alleviated osteolysis compared with only CLALN or mild-PPT. Our experiments demonstrated that this multi-functional LM-based nanoparticle combined with autophagy activation provided a promising therapeutic strategy for bone metastasis treatment. STATEMENT OF SIGNIFICANCE: Due to the limited light penetration, photothermal therapy (PTT) has limited inhibitory effect on tumor cells colonized in the bone. In addition, nonspecific heat diffusion of PTT may accidentally burn normal tissues and damage peripheral blood vessels, which can block the accumulation of drugs in deep tumors. Here, a multifunctional liquid metal based mild-PTT delivery system is designed to inhibit tumor growth and bone resorption by modulating the bone microenvironment and activating autophagy "on demand". It can overcome the treatment bottleneck of traditional PTT and improve the treatment effect of mild-PTT by resisting photothermal resistance and immune suppression. In addition, it also exhibits favorable heat/acid-responsive drug release performance and can specifically target tumor cells at the site of bone metastases.

Zonally Stratified Decalcified Bone Scaffold with Different Stiffness Modified by Fibrinogen for Osteochondral Regeneration of Knee Joint Defect.

Articular cartilage is generally known to be a complex tissue with multiple layers. Each layer has different composition, structure, and mechanical properties, making regeneration after knee joint defects a troubling clinical problem. A novel integrated stratified decalcified bone matrix (SDBM) scaffold with different stiffness to mimic the mechanical properties of articular cartilage is presented herein. This SDBM scaffold was modified using fibrinogen (Fg) (Fg + SDBM) to enhance its vascularization ability and improve its repair efficiency for osteochondral defects of knee joints. A Fg + SDBM scaffold with different elastic modulus in each layer (high-stiffness DBM (HDBM) layer, 174.208 ± 44.330 MPa (Fg + HDBM); medium-stiffness DBM (MDBM) layer, 21.214 ± 6.922 MPa (Fg + MDBM); and low-stiffness DBM (LDBM) layer, 0.678 ± 0.269 MPa (Fg + LDBM)) was constructed by controlling the stratified decalcification time with layered embedding paraffin (0, 3, and 5 days). The low- and medium-stiffness layers of the Fg + SDBM scaffold remarkably promoted the cartilage differentiation of bone marrow mesenchymal stem cells in vitro. Subcutaneous transplantation and rabbit knee joint osteochondral defect repair experiments revealed that the low- and medium-stiffness layers of the Fg + SDBM scaffold exhibited wonderful cartilage capacity, whereas the high-stiffness layer of Fg + SDBM scaffold exhibited good osteogenesis ability. Furthermore, this scaffold could promote blood vessel formation in subchondral bone area. This study presents a feasible strategy for osteochondral regeneration of defective knee joints, which is of great clinical value for tissue repair.

Prognostic and clinicopathological value of Slug protein expression in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Many studies have reported the relationship between prognosis and Slug protein expression in breast cancer patients, but the results are discrepant. Therefore, there is a need for meta-analyses with high statistical power to investigate and further explore their relationship. METHODS: We used PubMed, Embase, the Cochrane Library, Scopus, MEDLINE, and the Web of Science to find studies on breast cancer and Slug. Overall survival (OS) and disease-free survival (DFS) were the study's primary endpoints. We pooled hazard ratios (HRs) and odds ratios (ORs) to assess the association between Slug protein expression and prognostic and clinicopathological parameters. This study was performed using STATA version 14.0 for data analysis. (Stata Corporation, TX, USA). RESULTS: We conducted a literature search by searching six online databases. Ultimately, we obtained eight studies including 1458 patients through strict exclusion criteria. The results showed that increased Slug protein expression resulted in poorer OS (HR = 2.21; 95% CI = 1.47-3.33; P < 0.001) and DFS (HR = 2.03; 95% CI = 1.26-3.28; P = 0.004) in breast cancer patients. In addition, the results suggested that breast cancer patients with increased Slug protein expression had a higher TNM stage (I-II vs III-IV; OR = 0.42; 95% CI = 0.25-0.70; P = 0.001), a greater tendency to have axillary lymph node metastases (N+ vs N0; OR = 2.16; 95% CI = 1.31-3.56; P = 0.003) and were more prone to estrogen receptor deficiency (positive vs negative; OR = 0.67; 95% CI = 0.45-0.99; P = 0.042). However, Slug protein expression was not associated with age, histological grade, tumor size, progesterone receptor status, or human epidermal growth factor receptor 2 status in breast cancer patients. CONCLUSION: This meta-analysis showed that elevated Slug protein expression may be related to poor outcomes in patients with breast cancer. Therefore, Slug is not only an indicator of patient survival but may also become a new target for breast cancer therapy.

Study on the mechanism of low shear stress restoring the viability of damaged breast tumor cells.

Blood vessel is one of the 'pathways' for cancer to metastasize, in which cells are exposed to the fluid shear stress. Although most cells are damaged by fluid shear stress, a small number of tumor cells survive and metastasize when they are exposed to low shear stress (LSS) of tiny capillary. It is important to study the survival state of damaged cells during LSS. In this study, high shear stress (HSS) was applied to simulate the blood circulation and damage cells. The viability and mitochondrial function of cells were detected after HSS and LSS loading, respectively. Further, the expression of mitochondrial related proteins and genes were detected by western blot and real-time quantitative polymerase chain reaction, respectively. The role of cytochrome c (Cyt C) was also verified in this process. The experimental results showed that the viability of HSS damaged cells was increased significantly when they were exposed to LSS subsequently. The function of mitochondria was improved via reducing the release of Cyt C by LSS during this process. This study is expected to provide potential target for suppressing hematogenous metastasis.

Maresin 1 enhances osteogenic potential of mesenchymal stem cells by modulating macrophage peroxisome proliferator-activated receptor-γ-mediated inflammation resolution.

Inflammation resolution plays a significant role in attenuating bone injury aggravated by acute inflammation and maintaining bone homeostasis. Maresin 1 (MaR1), a specialized pro-resolving mediators (SPMs), is biosynthesised in macrophages (Mφs) that regulates acute inflammation. Strategies to accelerate the resolution of inflammation in bone repair include not only promoting vanish of acute inflammation, also improving osteogenic microenvironment. Here, previously prepared difunctional demineralized bone matrix (DBM) scaffold was used to study thoroughly the "cross-talk" between Mφs lipid metabolism and mesenchymal stem cells (MSCs) behaviors in vitro. The pro-resolving mechanism in Mφs treated with MaR1 was elaborated. Furthermore, the biological behaviors of MSCs in co-culture system were evaluated. The results indicated that MaR1 had an enhanced capability and performance in peroxisome proliferator-activated receptor-γ (PPAR-γ) activation, M2-type Mφs polarization, and lipid droplets (LDs) biogenesis in Mφs in vitro. The nuclear receptor PPAR-γ enhanced the anti-inflammatory proteins expression and the polarization of Mφs toward M2 subtype, thereby favoring the proliferation, migration, and osteogenesis of MSCs. Overall, the results verified that MaR1 facilitated MSCs behaviors by regulating PPAR-γ-mediated inflammatory response, which implied that PPAR-γ exhibited a significant role in the dialogue between MSCs behaviors and Mφs lipid metabolism.