Benefits of pentoxifylline for skin flap tissue repair in rats

Pedretti, Stephanie Luzia da Costa; Rena, Cícero de Lima; Orellano, Laura Alejandra Ariza; Lazari, Marcela Guimarães de; Campos, Paula Peixoto; Nunes, Tarcizo Afonso

doi:10.1590/acb351105

Cited by 6 publications

(8 citation statements)

References 27 publications

(101 reference statements)

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“…Therefore, enhancing the blood supply to the flap, relieving oxidative stress damage, and inhibiting apoptosis are crucial for improving flap viability [ 4 , 5 ]. The loss of vitality of the skin flap, ranging from 9 to 65%, has a serious influence on the patient's quality of life [ 6 ]. Proangiogenic molecules (vascular endothelial growth factors, VEGF) and drugs (valproic acid and pravastatin) have been considered promising approaches to enhancing flap survival by promoting angiogenesis and inhibiting apoptosis [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress-induced endothelial cells-derived exosomes accelerate skin flap survival through Lnc NEAT1-mediated promotion of endothelial progenitor cell function

et al. 2022

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Background Flap transplantation is commonly used in reconstructive surgery. A prerequisite for skin flap survival is sufficient blood supply. However, such approaches remain unclear. This study aimed to explore the underlying mechanisms of exosomes derived from human umbilical vascular endothelial cells (HUVECs) exposed to oxidative stress on endothelial progenitor cells (EPCs) and their subsequent influence on the survival of skin flaps. Methods HUVECs were treated with various concentrations of H2O2 to establish an oxidative stress model. To investigate the effects of H2O2-HUVEC-Exos and HUVEC-Exos, Cell Counting Kit-8, tube formation, invasion assays, and quantitative real-time polymerase chain reaction (qRT-PCR) were performed in EPCs. Microarray analysis was used to reveal the differentially expressed long non-coding RNAs (lncRNAs) in the H2O2-HUVEC-Exos and HUVEC-Exos. In addition, gene silencing and western blotting were employed to determine the mechanism behind lncRNA nuclear enrichment enriched transcript 1 (Lnc NEAT1) in EPCs. Further, a rat skin flap model was used to determine the role of the exosomes in skin flap survival in vivo. Results HUVECs were stimulated with 100 μmol/L H2O2 for 12 h to establish an oxidative stress model. H2O2-HUVEC-Exos promoted the proliferation, tube formation, and invasion of EPCs and remarkably increased skin flap survival compared to the HUVEC-Exos and control groups. Sequencing of exosome RNAs revealed that the Lnc NEAT1 level was dramatically increased in the H2O2-HUVEC-Exos, leading to activation of the Wnt/β-catenin signaling pathway. Comparatively, knockdown of Lnc NEAT1 in HUVEC-Exos and H2O2-HUVEC-Exos significantly inhibits the angiogenic capacity of EPCs, reduced the survival area of skin flap and downregulated the expression levels of Wnt/β-catenin signaling pathway proteins, whereas Wnt agonist partly reversed the negative effect of NEAT1 downregulation on EPCs through the Wnt/β-catenin signaling pathway. Conclusions Exosomes derived from HUVECs stimulated by oxidative stress significantly promoted the pro-angiogenic ability of EPCs through the Wnt/β-catenin signaling pathway mediated by Lnc NEAT1 and hence enhanced random flap survival in vivo. Therefore, the application of H2O2-HUVEC-Exos may serve as an alternative therapy for improving random skin flap survival.

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Section: Introductionmentioning

confidence: 99%

Oxidative stress-induced endothelial cells-derived exosomes accelerate skin flap survival through Lnc NEAT1-mediated promotion of endothelial progenitor cell function

et al. 2022

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“…All of the included studies were laboratory studies that examined the ability of pentoxifylline to generate an effect on angiogenesis in various models. Fifteen studies were in vivo only [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], three studies were in vitro only [ 41 , 42 , 43 ], and four studies had both in vivo and in vitro models [ 44 , 45 , 46 , 47 ]. The in vitro studies used human cells [ 42 , 44 , 45 , 46 , 47 ] and mouse cell lines [ 41 , 43 , 44 , 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…The in vitro studies used human cells [ 42 , 44 , 45 , 46 , 47 ] and mouse cell lines [ 41 , 43 , 44 , 45 ]. The in vivo studies were mainly conducted using mouse [ 29 , 31 , 34 , 37 , 38 , 45 , 47 ] and rat [ 30 , 32 , 33 , 35 , 39 , 40 , 44 ] models, but zebrafish embryos [ 36 ], rabbit [ 26 , 27 ], and monkey [ 26 , 27 , 28 ] models were used as well. Study characteristics and their key findings are summarized in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

“…In addition, one study examined the role of angiogenesis in the context of radiation-induced osteoradionecrosis [ 40 ]. Seven studies reported other pathological states, such as hepatopulmonary syndrome [ 30 ], peritoneal adhesions [ 31 , 33 , 38 ], endometriosis [ 32 ], bone defects [ 35 ], and healing post-skin flap operation [ 39 ]. One study examined the embryonic development of zebrafish when exposed to pentoxifylline [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

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Parsimonious Effect of Pentoxifylline on Angiogenesis: A Novel Pentoxifylline-Biased Adenosine G Protein-Coupled Receptor Signaling Platform

Khoury

Trus

Chen

et al. 2023

Cells

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Angiogenesis is the physiological process of developing new blood vessels to facilitate the delivery of oxygen and nutrients to meet the functional demands of growing tissues. It also plays a vital role in the development of neoplastic disorders. Pentoxifylline (PTX) is a vasoactive synthetic methyl xanthine derivative used for decades to manage chronic occlusive vascular disorders. Recently, it has been proposed that PTX might have an inhibitory effect on the angiogenesis process. Here, we reviewed the modulatory effects of PTX on angiogenesis and its potential benefits in the clinical setting. Twenty-two studies met the inclusion and exclusion criteria. While sixteen studies demonstrated that pentoxifylline had an antiangiogenic effect, four suggested it had a proangiogenic effect, and two other studies showed it did not affect angiogenesis. All studies were either in vivo animal studies or in vitro animal and human cell models. Our findings suggest that pentoxifylline may affect the angiogenic process in experimental models. However, there is insufficient evidence to establish its role as an anti-angiogenesis agent in the clinical setting. These gaps in our knowledge regarding how pentoxifylline is implicated in host-biased metabolically taxing angiogenic switch may be via its adenosine A2BAR G protein-coupled receptor (GPCR) mechanism. GPCR receptors reinforce the importance of research to understand the mechanistic action of these drugs on the body as promising metabolic candidates. The specific mechanisms and details of the effects of pentoxifylline on host metabolism and energy homeostasis remain to be elucidated.

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“…The efficacy of Ptx was observed when using the dose of 4.5 mg/kg, which is a safe dose since its lethal dose 50 (LD50) is 195 mg/kg/i.p. in mice ( Pedretti et al, 2020 ), and 50 mg/kg/i.p. of Ptx does not induce liver or kidney damage in mice ( Inacio et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Brief research report: Repurposing pentoxifylline to treat intense acute swimming–Induced delayed-onset muscle soreness in mice: Targeting peripheral and spinal cord nociceptive mechanisms

et al. 2023

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In this study, we pursue determining the effect of pentoxifylline (Ptx) in delayed-onset muscle soreness (DOMS) triggered by exposing untrained mice to intense acute swimming exercise (120 min), which, to our knowledge, has not been investigated. Ptx treatment (1.5, 4.5, and 13.5 mg/kg; i.p., 30 min before and 12 h after the session) reduced intense acute swimming–induced mechanical hyperalgesia in a dose-dependent manner. The selected dose of Ptx (4.5 mg/kg) inhibited recruitment of neutrophils to the muscle tissue, oxidative stress, and both pro- and anti-inflammatory cytokine production in the soleus muscle and spinal cord. Furthermore, Ptx treatment also reduced spinal cord glial cell activation. In conclusion, Ptx reduces pain by targeting peripheral and spinal cord mechanisms of DOMS.

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Benefits of pentoxifylline for skin flap tissue repair in rats

Cited by 6 publications

References 27 publications

Oxidative stress-induced endothelial cells-derived exosomes accelerate skin flap survival through Lnc NEAT1-mediated promotion of endothelial progenitor cell function

Oxidative stress-induced endothelial cells-derived exosomes accelerate skin flap survival through Lnc NEAT1-mediated promotion of endothelial progenitor cell function

Parsimonious Effect of Pentoxifylline on Angiogenesis: A Novel Pentoxifylline-Biased Adenosine G Protein-Coupled Receptor Signaling Platform

Brief research report: Repurposing pentoxifylline to treat intense acute swimming–Induced delayed-onset muscle soreness in mice: Targeting peripheral and spinal cord nociceptive mechanisms

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