Combination therapy with melatonin, stem cells and extracellular vesicles is effective in limiting renal ischemia–reperfusion injury in a rat model

Zahran, Rasha; Ghozy, Asmaa; El-Kholy, Sanad S.; El‐Taweel, F. M. A.; El-Magd, Mohammed A.

doi:10.1111/iju.14345

Cited by 34 publications

(30 citation statements)

References 31 publications

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“…These data are also consistent with other observations showing that exosomes of bone marrow MSCs pre-conditioned with melatonin have benefits in MSCs via paracrine which improved therapeutic efficacy on I/R induced acute renal failure ( Alzahrani, 2019 ; Zahran et al, 2020 ). However, the exact relevance of melatonin as to its activities, such as those conveyed by exosomes, remains unknown ( He et al, 2016 ).…”

Section: Effect Of Melatonin On Exosome Biogenesis and Releasesupporting

confidence: 92%

An Examination of the Putative Role of Melatonin in Exosome Biogenesis

Amini

Rezabakhsh

Heidarzadeh

et al. 2021

Front. Cell Dev. Biol.

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During the last two decades, melatonin has been found to have pleiotropic effects via different mechanisms on its target cells. Data are abundant for some aspects of the signaling pathways within cells while other casual mechanisms have not been adequately addressed. From an evolutionary perspective, eukaryotic cells are equipped with a set of interrelated endomembrane systems consisting of intracellular organelles and secretory vesicles. Of these, exosomes are touted as cargo-laden secretory vesicles that originate from the endosomal multivesicular machinery which participate in a mutual cross-talk at different cellular interfaces. It has been documented that cells transfer various biomolecules and genetic elements through exosomes to sites remote from the original cell in a paracrine manner. Findings related to the molecular mechanisms between melatonin and exosomal biogenesis and cargo sorting are the subject of the current review. The clarification of the interplay between melatonin and exosome biogenesis and cargo sorting at the molecular level will help to define a cell’s secretion capacity. This review precisely addresses the role and potential significance of melatonin in determining the efflux capacity of cells via the exosomal pathway. Certain cells, for example, stem cells actively increase exosome efflux in response to melatonin treatment which accelerates tissue regeneration after transplantation into the injured sites.

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Section: Effect Of Melatonin On Exosome Biogenesis and Releasesupporting

confidence: 92%

An Examination of the Putative Role of Melatonin in Exosome Biogenesis

Amini

Rezabakhsh

Heidarzadeh

et al. 2021

Front. Cell Dev. Biol.

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“…In addition to its immunomodulatory effects, MT also serves as a cell protector, which protects MSCs from oxidation, inflammation, apoptosis when they are applied as a combination therapy ( 38 ). Besides, MT is consumed by human as a dietary complement without side-effects ( 39 ).…”

Section: Introductionmentioning

confidence: 99%

Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy

et al. 2021

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BackgroundChronic rejection characterized by chronic allograft vasculopathy (CAV) remains a major obstacle to long-term graft survival. Due to multiple complicated mechanisms involved, a novel therapy for CAV remains exploration. Although mesenchymal stromal cells (MSCs) have been ubiquitously applied to various refractory immune-related diseases, rare research makes a thorough inquiry in CAV. Meanwhile, melatonin (MT), a wide spectrum of immunomodulator, plays a non-negligible role in transplantation immunity. Here, we have investigated the synergistic effects of MT in combination with MSCs in attenuation of CAV.MethodsC57BL/6 (B6) mouse recipients receiving BALB/c mouse donor aorta transplantation have been treated with MT and/or adipose-derived MSCs. Graft pathological changes, intragraft immunocyte infiltration, splenic immune cell populations, circulating donor-specific antibodies levels, cytokine profiles were detected on post-operative day 40. The proliferation capacity of CD4+ and CD8+ T cells, populations of Th1, Th17, and Tregs were also assessed in vitro.ResultsGrafts in untreated recipients developed a typical pathological feature of CAV characterized by intimal thickening 40 days after transplantation. Compared to untreated and monotherapy groups, MT in combination with MSCs effectively ameliorated pathological changes of aorta grafts indicated by markedly decreased levels of intimal hyperplasia and the infiltration of CD4+ cells, CD8+ cells, and macrophages, but elevated infiltration of Foxp3+ cells. MT either alone or in combination with MSCs effectively inhibited the proliferation of T cells, decreased populations of Th1 and Th17 cells, but increased the proportion of Tregs in vitro. MT synergized with MSCs displayed much fewer splenic populations of CD4+ and CD8+ T cells, Th1 cells, Th17 cells, CD4+ central memory T cells (Tcm), as well as effector memory T cells (Tem) in aorta transplant recipients. In addition, the percentage of splenic Tregs was substantially increased in the combination therapy group. Furthermore, MT combined with MSCs markedly reduced serum levels of circulating allospecific IgG and IgM, as well as decreased the levels of pro-inflammatory IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, and MCP-1, but increased the level of IL-10 in the recipients.ConclusionsThese data suggest that MT has synergy with MSCs to markedly attenuate CAV and provide a novel therapeutic strategy to improve the long-term allograft acceptance in transplant recipients.

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“…Besides caspases, other proteins in response to apoptotic stimuli are also targeted as an indicator, such as Bid, Fas-associated protein with death domain (FADD), Bcl-2 and Bax, cytochrome c, high-mobility group box 1 (HMGβ1), nuclear factor kappa B (NFκB), poly [ADP-Ribose] polymerase 1 (PARP) and other apoptosis-related proteins (Nicholson et al, 1995;Gyulkhandanyan et al, 2012;Del Re et al, 2019;Yang L.L. et al, 2019;Zahran et al, 2020). In pyroptosis, it has been reported that caspase-1 could mediate the cleavage of the cytosolic protein gasdermin D (GSDMD), resulting in promotion of the formation of GSDMD membrane pores and cell lysis, which sheds much-needed light on the necrotic execution mechanism of pyroptosis (de Vasconcelos et al, 2019).…”

Section: Caspase Activationmentioning

confidence: 99%

Guidelines for Regulated Cell Death Assays: A Systematic Summary, A Categorical Comparison, A Prospective

Lin

et al. 2021

Front. Cell Dev. Biol.

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Over the past few years, the field of regulated cell death continues to expand and novel mechanisms that orchestrate multiple regulated cell death pathways are being unveiled. Meanwhile, researchers are focused on targeting these regulated pathways which are closely associated with various diseases for diagnosis, treatment, and prognosis. However, the complexity of the mechanisms and the difficulties of distinguishing among various regulated types of cell death make it harder to carry out the work and delay its progression. Here, we provide a systematic guideline for the fundamental detection and distinction of the major regulated cell death pathways following morphological, biochemical, and functional perspectives. Moreover, a comprehensive evaluation of different assay methods is critically reviewed, helping researchers to make a reliable selection from among the cell death assays. Also, we highlight the recent events that have demonstrated some novel regulated cell death processes, including newly reported biomarkers (e.g., non-coding RNA, exosomes, and proteins) and detection techniques.

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Combination therapy with melatonin, stem cells and extracellular vesicles is effective in limiting renal ischemia–reperfusion injury in a rat model

Cited by 34 publications

References 31 publications

An Examination of the Putative Role of Melatonin in Exosome Biogenesis

An Examination of the Putative Role of Melatonin in Exosome Biogenesis

Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy

Guidelines for Regulated Cell Death Assays: A Systematic Summary, A Categorical Comparison, A Prospective

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