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Hypoxia-Induced Glioma-Derived Exosomal miRNA-199a-3p Promotes Ischemic Injury of Peritumoral Neurons by Inhibiting the mTOR Pathway. Zhao Jian-Lan,Tan Bo,Chen Gong,Che Xiao-Ming,Du Zhuo-Ying,Yuan Qiang,Yu Jian,Sun Yi-Rui,Li Xiao-Mu,Hu Jin,Xie Rong Oxidative medicine and cellular longevity The underlying molecular mechanisms that the hypoxic microenvironment could aggravate neuronal injury are still not clear. In this study, we hypothesized that the exosomes, exosomal miRNAs, and the mTOR signaling pathway might be involved in hypoxic peritumoral neuronal injury in glioma. Multimodal radiological images, HE, and HIF-1 staining of high-grade glioma (HGG) samples revealed that the peritumoral hypoxic area overlapped with the cytotoxic edema region and directly contacted with normal neurons. In either direct or indirect coculture system, hypoxia could promote normal mouse hippocampal neuronal cell (HT22) injury, and the growth of HT22 cells was suppressed by C6 glioma cells under hypoxic condition. For administrating hypoxia-induced glioma-derived exosomes (HIGDE) that could aggravate oxygen-glucose deprivation (OGD)/reperfusion neuronal injury, we identified that exosomes may be the communication medium between glioma cells and peritumoral neurons, and we furtherly found that exosomal miR-199a-3p mediated the OGD/reperfusion neuronal injury process by suppressing the mTOR signaling pathway. Moreover, the upregulation of miRNA-199a-3p in exosomes from glioma cells was induced by hypoxia-related HIF-1 activation. To sum up, hypoxia-induced glioma-derived exosomal miRNA-199a-3p can be upregulated by the activation of HIF-1 and is able to increase the ischemic injury of peritumoral neurons by inhibiting the mTOR pathway. 10.1155/2020/5609637
Liuwei Dihuang pill suppresses metastasis by regulating the wnt pathway and disrupting -catenin/T cell factor interactions in a murine model of triple-negative breast cancer. Zheng Lixiang,Zheng Qing,Yu Zhipeng,Wang Jian,Ren Xiaoying,Gong Yan,Yang Xue,Huang Ping,Weng Meizhi,Liu Hongning,Liu Haizhou Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan OBJECTIVE:To investigate if the Liuwei Dihuang pill (LWDHP) can inhibit metastasis to the liver and lungs in mice bearing triple-negative breast cancer (TNBC), and the molecular mechanism underpinning this action. METHODS:Ninety-nine TNBC bearing-mice were distributed randomly to five groups: control (Con), paclitaxel (PTX), low-dose LWDHP (LLP, 2.3 g·kg-1·d-1), middle-dose LWDHP (MLP, 4.6 g·kg-1·d-1) and high-dose LWDHP (HLP, 9.2 g·kg-1·d-1). The LWDHP were administered (p.o.) to the agonal stage. The morphology of BC cells was observed by hematoxylin & eosin staining. Expression of axin-2, β-catenin, T cell factor (TCF), cyclin- D1 and vascular endothelial growth factor (VEGF) was detected by western blotting or immunofluorescence. β-catenin/TCF-1 interaction was measured using a co-immunoprecipitation assay. RESULTS:After LWDHP treatment, metastasis of BC cells to the lungs and liver was inhibited, expression of axin-2 was increased, expression of TCF-1, β-catenin, cyclin-D1 and VEGF was decreased, and β-catenin/TCF-1 interaction was disrupted. CONCLUSION:The LWDHP could inhibit metastasis of BC cells to the liver and lungs. The molecular mechanism underlying this action may be regulation of protein expression and β-catenin/TCF-1 interactions in the Wnt pathway.
Exploits Wnt Signaling Pathway to Promote Its Intracellular Replication in Macrophages. Volpini Ximena,Ambrosio Laura F,Fozzatti Laura,Insfran Constanza,Stempin Cinthia C,Cervi Laura,Motran Claudia Cristina Frontiers in immunology During the acute phase of infection, macrophages can act as host cells for the parasites as well as effector cells in the early anti-parasitic immune response. Thus, the targeting of specific signaling pathways could modulate macrophages response to restrict parasite replication and instruct an appropriate adaptive response. Recently, it has become evident that Wnt signaling has immunomodulatory functions during inflammation and infection. Here, we tested the hypothesis that during infection, the activation of Wnt signaling pathway in macrophages plays a role in modulating the inflammatory/tolerogenic response and therefore regulating the control of parasite replication. In this report, we show that early after infection of bone marrow-derived macrophages (BMM), β-catenin was activated and Wnt3a, Wnt5a, and some Frizzled receptors as well as Wnt/β-catenin pathway's target genes were upregulated, with Wnt proteins signaling sustaining the activation of Wnt/β-catenin pathway and then activating the Wnt/Ca pathway. Wnt signaling pathway activation was critical to sustain the parasite's replication in BMM; since the treatments with specific inhibitors of β-catenin transcriptional activation or Wnt proteins secretion limited the parasite replication. Mechanistically, inhibition of Wnt signaling pathway armed BMM to fight against by inducing the production of pro-inflammatory cytokines and indoleamine 2,3-dioxygenase activity and by downregulating arginase activity. Likewise, pharmacological inhibition of the Wnts' interaction with its receptors controlled the parasite replication and improved the survival of lethally infected mice. It is well established that infection activates a plethora of signaling pathways that ultimately regulate immune mediators to determine the modulation of a defined set of effector functions in macrophages. In this study, we have revealed a new signaling pathway that is activated by the interaction between protozoan parasites and host innate immunity, establishing a new conceptual framework for the development of new therapies. 10.3389/fimmu.2018.00859
Astaxanthin induces angiogenesis through Wnt/β-catenin signaling pathway. Xu Yangyang,Zhang Jie,Jiang Wanglin,Zhang Shuping Phytomedicine : international journal of phytotherapy and phytopharmacology OBJECTIVE:In the present study, we sought to elucidate whether astaxanthin contributes to induce angiogenesis and its mechanisms. MATERIALS AND METHODS:To this end, we examined the role of astaxanthin on human brain microvascular endothelial cell line (HBMEC) and rat aortic smooth muscle cell (RASMC) proliferation, invasion and tube formation in vitro. For study of mechanism, the Wnt/β-catenin signaling pathway inhibitor IWR-1-endo was used. HMBECs and RASMCs proliferation were tested by cell counting. Scratch adhesion test was used to assess the ability of invasion. A matrigel tube formation assay was performed to test capillary tube formation ability. The Wnt/β-catenin pathway activation in HMBECs and RASMCs were tested by Western blot. RESULTS:Our data suggested that astaxanthin induces angiogenesis by increasing proliferation, invasion and tube formation in vitro. Wnt and β-catenin expression were increased by astaxanthin and counteracted by IWR-1-endo in HMBECs and RASMCs. Tube formation was increased by astaxanthin and counteracted by IWR-1-endo. CONCLUSIONS:It may be suggested that astaxanthin induces angiogenesis in vitro via a programmed Wnt/β-catenin signaling pathway. 10.1016/j.phymed.2015.05.054
Exosomes secreted from mesenchymal stem cells mediate the regeneration of endothelial cells treated with rapamycin by delivering pro-angiogenic microRNAs. Wang Weizong,Zhao Yixin,Li Huilin,Zhang Yujiao,Jia Xiaomeng,Wang Cong,Zhu Pengju,Wang Jiangrong,Hou Yinglong Experimental cell research Delayed endothelial healing after drug eluting stent (DES) implantation is a critical clinical problem in treatment of coronary artery diseases. Exosomes exhibit proangiogenic potential in a variety of ischemic diseases. However, the association of exosomes with endothelial regeneration after DES implantation has been rarely reported. In this study, we aimed to investigate the therapeutic effects of mesenchymal stem cell (MSC)-derived exosomes on endothelial cells treated with rapamycin and explore the potential mechanisms of MSC-derived exosomes in promoting endothelial regeneration. Exosomes were isolated from MSCs by ultracentrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot assay. The in vitro effects of MSC-derived exosomes on the proliferation and migration of endothelial cells treated with rapamycin were evaluated by integrated experiment, cell counting kit-8, scratch, tube formation, and transwell assays. And the apoptosis of rapamycin-induced endothelial cells loaded with MSC-derived exosomes was detected using TUNEL and Annexin-V FITC and PI double-staining assays. The microRNA (miRNA) cargo of MSC-derived exosomes was identified by high-throughput RNA sequencing. Pro-angiogenic miRNAs and key pathways were further characterized. Our results indicated that MSC-derived exosomes could be ingested into umbilical vein endothelial cells (HUVECs) and significantly enhanced cell proliferation rate, migratory and tube-forming capabilities in vitro. MSC-derived exosomes also inhibited the apoptosis of HUVECs induced by rapamycin. A distinct class of exosomal miRNAs was further identified, including six miRNAs tightly related to neovasculogenesis. Silencing the expression of exosomal miRNA-21-5p and let-7c-5p attenuated the pro-proliferative and pro-migratory capacity of MSC-derived exosomes. Moreover, functional enrichment analysis indicated that metabolic pathways might contribute to reendothelialization. This study highlights a proregenerative effect of MSC-derived exosomes in vitro, which may be partly explained by the delivery of pro-angiogenic miRNAs to endothelial cells. 10.1016/j.yexcr.2020.112449
Exosomes Derived from Bone Mesenchymal Stem Cells with the Stimulation of FeO Nanoparticles and Static Magnetic Field Enhance Wound Healing Through Upregulated miR-21-5p. International journal of nanomedicine BACKGROUND:Both magnetic nanoparticles (MNPs) and exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been reported to improve wound healing. In this study, novel exosomes (mag-BMSC-Exos) would be fabricated from BMSCs with the stimulation of MNPs and a static magnetic field (SMF) to further enhance wound repair. METHODS:Mag-BMSC-Exos, namely, exosomes derived from BMSCs preconditioned with FeO nanoparticles and a SMF, together with BMSC-Exos were both first isolated by ultracentrifugation, respectively. Afterwards, we conducted in vitro experiments, including scratch wound assays, transwell assays, and tube formation assays, and established an in vivo wound healing model. The miRNA expression profiles were compared between BMSC-Exos and mag-BMSC-Exos to detect the potential mechanism of improving wound healing. At last, the function of exosomal miR-21-5p during wound healing was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro. RESULTS:The optimal working magnetic condition was 50 µg/mL FeO nanoparticles combined with 100 mT SMF. In vitro, mag-BMSC-Exo administration promoted proliferation, migration and angiogenesis to a greater extent than BMSC-Exo administration. Local transplantation of mag-BMSC-Exos into rat skin wounds resulted in accelerated wound closure, narrower scar widths and enhanced angiogenesis compared with BMSC-Exo transplantation. Notably, miR-21-5p was found to be highly enriched in mag-BMSC-Exos and served as a critical mediator in mag-BMSC-Exo-induced regulatory effects through inhibition of SPRY2 and activation of the PI3K/AKT and ERK1/2 signaling pathways. CONCLUSION:Mag-BMSC-Exos can further enhance wound healing than BMSC-Exos by improving angiogenesis and fibroblast function, and miR-21-5p upregulation in mag-BMSC-Exos might be the potential mechanism. This work offers an effective and promising protocol to improve wound healing in clinic. 10.2147/IJN.S275650
Human umbilical cord mesenchymal stem cells implantation accelerates cutaneous wound healing in diabetic rats via the Wnt signaling pathway. Han Yanfu,Sun Tianjun,Han Yanqing,Lin Lingling,Liu Chang,Liu Jing,Yan Guangzhi,Tao Ran European journal of medical research OBJECTIVE:Difficulty in wound healing is one common complication of diabetes mellitus. The study explored whether the therapeutic effect of human umbilical cord mesenchymal stem cells (hUCMSCs) on diabetic ulcer wound was enhanced by the activation of the Wnt signaling pathway. METHODS:Rat diabetic model was established by intraperitoneal injection of Streptozotocin (STZ). hUCMSCs were purified and seeded on the collagen-chitosan laser drilling acellular dermal matrix (CCLDADM) scaffold, which was subsequently implanted into the cutaneous wound of normal and diabetic rats, followed by daily injection of Wnt signaling pathway agonist (Wnt3a) or antagonist (sFRP3) at the edge of the scaffold. Wound healing was checked on days 7, 14, and 21, and the fibrous tissue deposition, capillaries, and epidermal regeneration at the wound were examined by hematoxylin-eosin staining. The hUCMSCs-CCLDADM scaffold was cultured in vitro and treated with Wnt3a or sFRP3, followed by evaluation of cell proliferation, cell proliferation rate, survival status, and altered protein levels in the Wnt signaling pathway using BrdU staining, CCK-8 assay, live/dead staining, and Western blotting, respectively. RESULTS:On days 7 and 14 postoperatively, the speed of wound healing was significantly lower in diabetic rats than that in normal control rats. This phenomenon was significantly improved by the activation of the Wnt signaling pathway that also elevated the fibrous protein deposition and the abundance of capillary in the granulation tissue. Conversely, blockade of Wnt signaling slowed the healing of skin wound in diabetic rats. The activation of Wnt signaling pathway promoted the proliferation and differentiation and decreased the apoptosis of hUCMSCs, thereby elevating the number of living hUCMSCs on the CCLDADM scaffold, while the suppression exerted a contrary effect. CONCLUSION:The activation of the Wnt signaling pathway promotes the healing of diabetic skin wound by the regulation of proliferation and differentiation of hUCMSCs on the CCLDADM scaffold. 10.1186/s40001-019-0366-9
Wnt signaling in the vessel wall. Badimon Lina,Borrell-Pages Maria Current opinion in hematology PURPOSE OF REVIEW:Wnt signaling plays a crucial role during embryogenesis. In an adult, Wnt is mainly associated to cellular proliferation and differentiation mechanisms. Recent data suggest that Wnt signaling is involved in the pathophysiology of atherosclerosis. However, the roles of Wnt signaling pathways in the vessel wall are poorly understood. This review outlines recent discoveries in understanding the role of Wnt pathways in healthy and atherosclerotic vessels. RECENT FINDINGS:In the last years, the involvement of both canonical and noncanonical Wnt pathways in the development of atherosclerotic lesions has been recognized. Indeed, several Wnt pathway components have been shown to participate in the early, intermediate, and late stages of atherosclerosis development. Specifically, the role of the Wnt coreceptors low-density lipoprotein receptor-related protein 5 and low-density lipoprotein receptor-related protein 6 seems to be crucial for atherosclerotic plaque progression. SUMMARY:Many of the clinical trials developed in the last decade to reduce atherosclerosis and cardiovascular diseases have been futile or have failed possibly because of a poor understanding of new mechanisms that lead to diseases. The understanding of the signaling pathways involved in human atherosclerosis development should help in the development of future therapies. 10.1097/MOH.0000000000000336
The role of Wnt signaling in skin fibrosis. Griffin Michelle F,Huber Julika,Evan Fahy J,Quarto Natalina,Longaker Michael T Medicinal research reviews Skin fibrosis is the excessive deposition of extracellular matrix in the dermis. Cutaneous fibrosis can occur following tissue injury, including burns, trauma, and surgery, resulting in scars that are disfiguring, limit movement and cause significant psychological distress for patients. Many molecular pathways have been implicated in the development of skin fibrosis, yet effective treatments to prevent or reverse scarring are unknown. The Wnt signaling pathways are known to play an important role in skin homeostasis, skin injury, and in the development of fibrotic skin diseases. This review provides a detailed overview of the role of the canonical Wnt signaling pathways in regulating skin scarring. We also discuss how Wnt signaling interacts with other known fibrotic molecular pathways to cause skin fibrosis. We further provide a summary of the different Wnt inhibitor types available for treating skin scarring. Understanding the role of the Wnt pathway in cutaneous fibrosis will accelerate the development of effective Wnt modulators for the treatment of skin fibrosis. 10.1002/med.21853
The Wnt Signaling Pathway in Diabetic Nephropathy. Wang Haiying,Zhang Ran,Wu Xinjie,Chen Yafen,Ji Wei,Wang Jingsuo,Zhang Yawen,Xia Yong,Tang Yiqun,Yuan Jinxiang Frontiers in cell and developmental biology Diabetic nephropathy (DN) is a serious kidney-related complication of both type 1 and type 2 diabetes mellitus (T1DM, T2DM) and the second major cause of end-stage kidney disease. DN can lead to hypertension, edema, and proteinuria. In some cases, DN can even progress to kidney failure, a life-threatening condition. The precise etiology and pathogenesis of DN remain unknown, although multiple factors are believed to be involved. The main pathological manifestations of DN include mesangial expansion, thickening of the glomerular basement membrane, and podocyte injury. Eventually, these pathological manifestations will lead to glomerulosclerosis, thus affecting renal function. There is an urgent need to develop new strategies for the prevention and treatment of DN. Existing evidence shows that the Wnt signaling cascade plays a key role in regulating the development of DN. Previous studies focused on the role of the Wnt canonical signaling pathway in DN. Subsequently, accumulated evidence on the mechanism of the Wnt non-canonical signaling indicated that Wnt/Ca and Wnt/PCP also have essential roles in the progression of DN. In this review, we summarize the specific mechanisms of Wnt signaling in the occurrence and development of DN in podocyte injury, mesangial cell injury, and renal fibrosis. Also, to elucidate the significance of the Wnt canonical pathway in the process of DN, we uncovered evidence supporting that both Wnt/PCP and Wnt/Ca signaling are critical for DN development. 10.3389/fcell.2021.701547
Wnt pathway modulators in cancer therapeutics: An update on completed and ongoing clinical trials. Neiheisel Ann,Kaur Manpreet,Ma Nancy,Havard Patty,Shenoy Anitha K International journal of cancer Wnt signaling plays an essential role in the initiation and progression of various types of cancer. Besides, the Wnt pathway components have been established as reliable biomarkers and potential targets for cancer therapy. Wnt signaling is categorized into canonical and noncanonical pathways. The canonical pathway is involved in cell survival, proliferation, differentiation and migration, while the noncanonical pathway regulates cell polarity and migration. Apart from its biological role in development and homeostasis, the Wnt pathway has been implicated in several pathological disorders, including cancer. As a result, inhibiting this pathway has been a focus of cancer research with multiple targetable candidates in development. In this review, our focus will be to summarize information about ongoing and completed clinical trials targeting various Wnt pathway components, along with describing current and emerging Wnt targeted therapies. In addition, we will discuss potential opportunities and associated challenges of inhibiting Wnt signaling for cancer therapy. 10.1002/ijc.33811
Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling. Barcelos Lucíola S,Duplaa Cécile,Kränkel Nicolle,Graiani Gallia,Invernici Gloria,Katare Rajesh,Siragusa Mauro,Meloni Marco,Campesi Ilaria,Monica Manuela,Simm Andreas,Campagnolo Paola,Mangialardi Giuseppe,Stevanato Lara,Alessandri Giulio,Emanueli Costanza,Madeddu Paolo Circulation research We evaluated the healing potential of human fetal aorta-derived CD133(+) progenitor cells and their conditioned medium (CD133(+) CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2x10(4) CD133(+) or CD133(-) cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133(+) cells expressed high levels of wingless (Wnt) genes, which were downregulated following differentiation into CD133(-) cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133(+) cells accelerated wound closure as compared with CD133(-) or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133(+) cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133(+) CCM accelerated wound closure and reparative angiogenesis, with this action abrogated by co-administering the Wnt antagonist sFRP-1 or neutralizing antibodies against VEGF-A or IL-8. In vitro, these effects were recapitulated following exposure of high-glucose-primed human umbilical vein endothelial cells to CD133(+) CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133(+) CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133(+) cells stimulate wound healing by paracrine mechanisms that activate Wnt signaling pathway in recipients. These preclinical findings open new perspectives for the cure of diabetic ulcers. 10.1161/CIRCRESAHA.108.192138
Regulatory Mechanisms of the Wnt/β-Catenin Pathway in Diabetic Cutaneous Ulcers. Zhang Han,Nie Xuqiang,Shi Xiujun,Zhao Jiufeng,Chen Yu,Yao Qiuyang,Sun Chengxin,Yang Jianwen Frontiers in pharmacology Skin ulcers are a serious complication of diabetes. Diabetic patients suffer from vascular lesions and complications such as peripheral neuritis, peripheral vascular lesions, and collagen abnormalities, which result in skin wounds that are refractory and often develop into chronic ulcers. The healing of skin ulcers requires an inflammatory reaction, wound proliferation, remodeling regulation, and control of stem cells. Studies investigating diabetic cutaneous ulcers have focused on cellular and molecular levels. Diabetes can cause nerve and blood vessel damage, and persistent high blood sugar levels can cause systemic multisite nerve damage based on peripheral neuropathy. The long-term hyperglycemia state enables the polyol glucose metabolism pathway to be activated, increasing the accumulation of toxic substances in the vascular injured nerve tissue cells. Sustained hyperglycemia leads to dysfunction of epithelial cells, leading to a decrease in pro-angiogenic signaling and nitric oxide production. In addition, due to impaired leukocyte function in hyperglycemia, immune function is impaired and the immune response at relevant sites is insufficient, making diabetic foot more difficult to heal. The Wnt/β-catenin pathway is a highly conserved signal transduction pathway involved in a variety of biological processes, such as cell proliferation, apoptosis, and differentiation. It is considered an important pathway involved in the healing of skin wounds. This article summarizes the mechanism of action of the Wnt/β-catenin pathway involved in the inflammatory responses to diabetic ulcers, wound proliferation, wound remodeling, and stem cells. The interactions between the Wnt signal pathway and other metabolic pathways are also discussed. 10.3389/fphar.2018.01114