scholarly journals mmu-miR-145a-5p Accelerates Diabetic Wound Healing by Promoting Macrophage Polarization Toward the M2 Phenotype

2021 ◽  
Vol 8 ◽  
Author(s):  
Yanhui Hao ◽  
Leilei Yang ◽  
Ying Liu ◽  
Yumeng Ye ◽  
Jiayu Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Macrophage Polarization ◽  
Differentially Expressed ◽  
Tissue Formation ◽  
Diabetic Mice ◽  
M1 Macrophage ◽  
Differentially Expressed Mirnas ◽  
Diabetic Wounds ◽  
M2 Phenotype

Diabetic wounds are recalcitrant to healing. One of the important characteristics of diabetic trauma is impaired macrophage polarization with an excessive inflammatory response. Many studies have described the important regulatory roles of microRNAs (miRNAs) in macrophage differentiation and polarization. However, the differentially expressed miRNAs involved in wound healing and their effects on diabetic wounds remain to be further explored. In this study, we first identified differentially expressed miRNAs in the inflammation, tissue formation and reconstruction phases in wound healing using Illumina sequencing and RT-qPCR techniques. Thereafter, the expression of musculus (mmu)-miR-145a-5p (“miR-145a-5p” for short) in excisional wounds of diabetic mice was identified. Finally, expression of miR-145a-5p was measured to determine its effects on macrophage polarization in murine RAW 264.7 macrophage cells and wound healing in diabetic mice. We identified differentially expressed miRNAs at different stages of wound healing, ten of which were further confirmed by RT-qPCR. Expression of miR-145a-5p in diabetic wounds was downregulated during the tissue formation stage. Furthermore, we observed that miR-145a-5p blocked M1 macrophage polarization while promoting M2 phenotype activation in vitro. Administration of miR-145a-5p mimics during initiation of the repair phase significantly accelerated wound healing in db/db diabetic mice. In conclusion, our findings suggest that rectifying macrophage function using miR-145a-5p overexpression accelerates diabetic chronic wound healing.

scholarly journals Nanofiber-mediated sequential photothermal antibacteria and macrophage polarization for healing MRSA-infected diabetic wounds

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhou Xu ◽  
Bin Deng ◽  
Xuewen Wang ◽  
Jie Yu ◽  
Zhuobin Xu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wound Healing ◽  
Macrophage Polarization ◽  
In Vivo Studies ◽  
Promote Cell Proliferation ◽  
Diabetic Wound Healing ◽  
Mrsa Infection ◽  
Diabetic Wounds

Abstract Background Diabetic wound healing remains a challenge because of its susceptibility to drug-resistant bacterial infection and its persistent proinflammatory state. Switching from proinflammatory M1 macrophages (Mφs) to proregenerative M2 dominant Mφs in a timely manner accelerates wound healing by coordinating inflammatory, proliferative, and angiogenic processes. Methods We propose a sequential photothermal antibacterial and subsequent M2 Mφ polarization strategy based on nanofibers (NFs) consisting of polydopamine (PDA) coating on curcumin (Cur) nanocrystals to treat Methicillin-resistant Staphylococcus aureus (MRSA)-infected diabetic wounds. Results The PDA/Cur NFs showed excellent photothermal conversion and antibacterial effects due to the PDA shell under laser irradiation, consequently resulting in the release of the inner Cur with the ability to promote cell proliferation and reinforce the M2 Mφ phenotype in vitro. In vivo studies on MRSA-infected diabetic wounds showed that PDA/Cur NFs not only inhibited MRSA infection but also accelerated the wound regeneration process. Furthermore, the NFs displayed the ability to promote the M2 Mφ phenotype with enhanced collagen deposition, angiogenesis, and cell proliferation. Conclusion Overall, the NFs displayed great potential as promising therapeutics for healing infected diabetic wounds through a sequential photothermal antibacterial and M2 Mφ polarization strategy. Graphical abstract

scholarly journals Topical insulin application accelerates diabetic wound healing by promoting anti-inflammatory macrophage polarization

2020 ◽  
Vol 133 (19) ◽  
pp. jcs235838
Author(s):  
Peilang Yang ◽  
Xiqiao Wang ◽  
Di Wang ◽  
Yan Shi ◽  
Meng Zhang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Macrophage Polarization ◽  
Healing Process ◽  
Polarization State ◽  
Wound Healing Process ◽  
Diabetic Wound ◽  
Insulin Degrading Enzyme ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

ABSTRACTBesides regulating glucose levels, insulin has been reported to participate actively in many other functions, including modulating inflammatory reactions. In this study we investigated how topical insulin application would affect the diabetic wound healing process. We found that the excessive expression of insulin-degrading enzyme led to insufficient insulin levels in diabetic skin during wound healing, which ultimately reduced the recovery rate of diabetic wounds. We confirmed that topical insulin application could reverse the impaired inflammation reaction in the diabetic wound environment and promote healing of diabetic wounds. Our study revealed that insulin promoted apoptosis of neutrophils and subsequently triggered polarization of macrophages. Both in vivo and in vitro studies verified that insulin re-established phagocytosis function and promoted the process of phagocytosis-induced apoptosis in neutrophils. Furthermore, we found that insulin treatment also promoted efferocytosis of the apoptosed neutrophils by macrophages, and thus induced macrophages to change their polarization state from M1 to M2. In conclusion, our studies proved that the exogenous application of insulin could improve diabetic wound healing via the restoration of the inflammatory response.

scholarly journals A Marine-Derived Anti-Inflammatory Scaffold for Accelerating Skin Repair in Diabetic Mice

Marine Drugs ◽  
2021 ◽  
Vol 19 (9) ◽  
pp. 496
Author(s):  
Xiaoli Huang ◽  
Na Guan ◽  
Qiu Li
Keyword(s):  
Electrospun Fiber ◽  
Skin Wound ◽  
Tissue Formation ◽  
Diabetic Mice ◽  
Skin Repair ◽  
Thickness Skin ◽  
Healing Efficiency ◽  
Diabetic Wounds

Reconstructing the typical analogue of extracellular matrix (ECM) in engineered biomaterials is essential for promoting tissue repair. Here, we report an ECM-mimetic scaffold that successfully accelerated wound healing through enhancing vascularization and regulating inflammation. We prepared an electrospun fiber comprising a brown alga-derived polysaccharide (BAP) and polyvinyl alcohol (PVA). The two polymers in concert exerted the function upon the application of PVA/BAP2 fiber in vivo; it started to reduce the inflammation and promote angiogenesis at the wound site. Our serial in vitro and in vivo tests validated the efficacy of PVA/BAP2 fiber. Particularly, PVA/BAP2 fiber accelerated the repair of a full-thickness skin wound in diabetic mice and induced optimal neo-tissue formation. Generally, our results suggest that, by mimicking the function of ECM, this fiber as an engineered biomaterial can effectively promote the healing efficiency of diabetic wounds. Our investigation may inspire the development of new, effective, and safer marine-derived scaffold for tissue regeneration.

scholarly journals HypoxamiR-210 accelerates wound healing in diabetic mice by improving cellular metabolism

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Sampath Narayanan ◽  
Sofie Eliasson Angelstig ◽  
Cheng Xu ◽  
Jacob Grünler ◽  
Allan Zhao ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cellular Metabolism ◽  
High Energy ◽  
Cellular Migration ◽  
Diabetic Mice ◽  
Adaptive Responses ◽  
Negative Effects ◽  
Hypoxic Environment ◽  
Diabetic Wounds

AbstractWound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment. In diabetes, hyperglycemia impairs the adaptive responses to hypoxia with profound negative effects on different cellular compartments of wound healing. miR-210 is a hypoxia-induced microRNA that regulates cellular metabolism and processes important for wound healing. Here, we show that hyperglycemia blunted the hypoxia-dependent induction of miR-210 both in vitro and in human and mouse diabetic wounds. The impaired regulation of miR-210 in diabetic wounds is pathogenic, since local miR-210 administration accelerated wound healing specifically in diabetic but not in non-diabetic mice. miR-210 reconstitution restores the metabolic balance in diabetic wounds by reducing oxygen consumption rate and ROS production and by activating glycolysis with positive consequences on cellular migration. In conclusion, miR-210 accelerates wound healing specifically in diabetes through improvement of the cellular metabolism.

scholarly journals A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guodong Li ◽  
Chung-Nga Ko ◽  
Dan Li ◽  
Chao Yang ◽  
Wanhe Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Von Hippel Lindau ◽  
Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

Fabrication of gelatin/sodium alginate-poly (3-hydroxybutyric acid) bilayer electrospun biosheet as wound healing material in nursing care on pediatric fracture surgery

2020 ◽  
pp. 152808372097634
Author(s):  
Daiqi Jiang ◽  
Zaiju Tong ◽  
Lingjun Peng ◽  
Lingzhi Zhang ◽  
Qianzi Ruan ◽  
...  
Keyword(s):  
Wound Healing ◽  
Sodium Alginate ◽  
Wound Closure ◽  
Skin Wound ◽  
Tissue Formation ◽  
Hydroxybutyric Acid ◽  
Physiochemical Properties ◽  
Pediatric Fracture ◽  
Fracture Surgery

Novel the bilayered electrospun biosheet with rapid cell mimiciking and proliferative efficacy will be suitable for wound healing application. The optimized concentration of gelatin (G) and sodium alginate (A) biosheet with nanofibrous Poly (3-hydroxybutyric acid) (P) as a bilayered elctrospun matrix through electrospinning. The engineered GAP bilayered biosheet involves tissue formation at extra cellular matrix (ECM) which further characterized its function in vitro and invivo. Here we fabricated GAP which exhibit better physiochemical properties, biological and mechanical properties with superior prosomes it enhance air passable at skin wounds. The Bilayered biosheet matrix possess better biocompatibility, cell adherence, fructuous and cell to cell interactions evaluated using cell lines. Furthermore, GAP bilayered matrix regulates growth factors to attain maximum wound closure efficiency during invivo. Thus, the fabricated GAP electrospun biosheet would be a possible wound dressing for skin wound applications.

scholarly journals Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Keizo Kohno ◽  
Satomi Koya-Miyata ◽  
Akira Harashima ◽  
Takahiko Tsukuda ◽  
Masataka Katakami ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Macrophage Polarization ◽  
Phenotypic Switching ◽  
Apoptotic Cells ◽  
Phenotypic Switch ◽  
Inflammatory Phase ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

871 In vitro immunoregulatory effect from cervical cancer derived mesenchymal stromal cells over molecules expression in monocyte derived macrophage polarization

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A923-A923
Author(s):  
Víctor Cortés-Morales ◽  
Juan Montesinos ◽  
Luis Chávez-Sánchez ◽  
Sandra Espíndola-Garibay ◽  
Alberto Monroy-García ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Stem Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Macrophage Polarization ◽  
Induction Medium ◽  
M2 Macrophage ◽  
List Type ◽  
M2 Phenotype

BackgroundMacrophages are immunological cells that sense microenvironmental signals that may result in the polarized expression of either proinflammatory (M1) or anti-inflammatory (M2) phenotype.1 Macrophages M2 are present in tumoral microenvironment and their presence in patients with cervical cancer (CeCa) is related with less survival.2Mesenchymal Stromal Cells (MSCs) are also present in tumor microenvironment of cervical cancer (CeCa-MSC), which have shown immunoregulatory effects over CD8 T cells, decreasing their cytotoxic effect against tumoral cells.3 Interestingly, MSCs from bone marrow (BM-MSC) decrease M1 and increase M2 macrophage polarization in an in vitro coculture system.4 Macrophages and MSCs are present in microenvironment of cervical cancer, however it is unknown if MSCs play a role in macrophage polarization. In the present study, we have evaluated the immunoregulatory capacity of CeCa-MSCs to induce macrophage polarization.MethodsCD14 monocytes were isolated from peripheral blood and cultivated in the absence or presence of MSCs from BM, normal cervix (NCx) and CeCa. Two culture conditions were included, in the presence of induction medium to favors M1 (GM-CSF, LPS and IFNg) or M2 (M-CSF, IL-4 and IL-13) macrophage polarization. M1 (HLA-DR, CD80, CD86 and IFNg) or M2 (CD14, CD163, CD206, IDO and IL-10) macrophage molecular markers were evaluated by flow cytometry. Finally, we evaluated concentration of IL-10 and TNFa in conditioned medium form all coculture conditions.ResultsWe observed that CeCa-MSCs and BM-MSCs in presence of M1 induction medium, decreased M1 macrophage markers (HLA-II, CD80, CD86 and IFNg), and increase the expression of CD14 (M2 macrophage marker). Interestingly, in presence of M2 induction medium, BM-MSCs and CaCe-MSCs but not CxN-MSC increased CD163, CD206, IDO and IL-10 (M2 macrophage markers). We observed a decreased concentration of TNFa in the supernatant medium from all cocultures with MSCs, but only in presence of CeCa-MSCs, increased IL-10 concentration was detected in such cocultures.ConclusionsIn contrast to NCx-MSCs, CeCa-MSCs similarly to BM-MSCs have in vitro capacity to decrease M1 and increase M2 macrophage phenotype.AcknowledgementsAcknowledgments The authors are indebted to gratefully acknowledge to CONACYT (Grant No. 272793) and IMSS (Grant no. 1731) for support to Juan J. Montesinos research.ReferencesMartinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014;6-13.Petrillo M, Zannoni GF, Martinelli E, et al. Polarization of tumor-associated macrophages toward M2 phenotype correlates with poor response to chemoradiation and reduced survival in patients with locally advanced cervical cancer. PLoS One 2015;10: e0136654.Montesinos JJ, Mora-García Mde L, et al. In vitro evidence of the presence of mesenchymal stromal cells in cervical cancer and their role in protecting cancer cells from cytotoxic T cell activity. Stem Cells Dev 2013;22:2508-2519.Vasandan AB, Jahnavi S, Shashank C. Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE 2-dependent mechanism. Sci Rep 2016;6:38308.

scholarly journals Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jie Yu ◽  
Peiwei Chai ◽  
Minyue Xie ◽  
Shengfang Ge ◽  
Jing Ruan ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Regulation Of Gene Expression ◽  
Metabolic Stress ◽  
Ocular Melanoma ◽  
Rna Modifications ◽  
M1 Macrophage ◽  
Melanoma Therapy

Abstract Background Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear. Results Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma. Conclusion We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.

scholarly journals Keratin Scaffolds Containing Casomorphin Stimulate Macrophage Infiltration and Accelerate Full-Thickness Cutaneous Wound Healing in Diabetic Mice

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2554
Author(s):  
Marek Konop ◽  
Anna K. Laskowska ◽  
Mateusz Rybka ◽  
Ewa Kłodzińska ◽  
Dorota Sulejczak ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Dressing ◽  
Healing Process ◽  
Skin Wound ◽  
Wound Healing Process ◽  
Diabetic Mice ◽  
Full Thickness ◽  
Skin Wound Healing ◽  
Impaired Wound Healing

Impaired wound healing is a major medical challenge, especially in diabetics. Over the centuries, the main goal of tissue engineering and regenerative medicine has been to invent biomaterials that accelerate the wound healing process. In this context, keratin-derived biomaterial is a promising candidate due to its biocompatibility and biodegradability. In this study, we evaluated an insoluble fraction of keratin containing casomorphin as a wound dressing in a full-thickness surgical skin wound model in mice (n = 20) with iatrogenically induced diabetes. Casomorphin, an opioid peptide with analgesic properties, was incorporated into keratin and shown to be slowly released from the dressing. An in vitro study showed that keratin-casomorphin dressing is biocompatible, non-toxic, and supports cell growth. In vivo experiments demonstrated that keratin-casomorphin dressing significantly (p < 0.05) accelerates the whole process of skin wound healing to the its final stage. Wounds covered with keratin-casomorphin dressing underwent reepithelization faster, ending up with a thicker epidermis than control wounds, as confirmed by histopathological and immunohistochemical examinations. This investigated dressing stimulated macrophages infiltration, which favors tissue remodeling and regeneration, unlike in the control wounds in which neutrophils predominated. Additionally, in dressed wounds, the number of microhemorrhages was significantly decreased (p < 0.05) as compared with control wounds. The dressing was naturally incorporated into regenerating tissue during the wound healing process. Applied keratin dressing favored reconstruction of more regular skin structure and assured better cosmetic outcome in terms of scar formation and appearance. Our results have shown that insoluble keratin wound dressing containing casomorphin supports skin wound healing in diabetic mice.

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