Protective effect of melatonin‐supported adipose‐derived mesenchymal stem cells against small bowel ischemia‐reperfusion injury in rat

Chang, Chia-Lo; Sung, Pei‐Hsun; Sun, Cheuk‐Kwan; Chen, Chih‐Hung; Chiang, Hsin‐Ju; Huang, Tung‐Liang; Chen, Yi‐Ling; Zhen, Yen-Yi; Chai, Han‐Tan; Chung, Sheng-Ying; Tong, Meng-Shen; Chang, Hsueh‐Wen; Chen, Hong‐Hwa; Yip, Hon‐Kan

doi:10.1111/jpi.12251

Cited by 74 publications

(141 citation statements)

References 35 publications

(100 reference statements)

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“…High levels of melatonin compared to other cellular compartments have been identified in mitochondria [24,25,26,27,28]. A variety of in vitro and in vivo studies have proven that melatonin targets mitochondria to reduce oxidative stress [29,30,31,32,33,34,35,36]. This results in decreased apoptosis, improved metabolic status, and an elevated survival rate of cultured cells, unicellular organisms, animals, and plants, which suffer with oxidative stress [37,38,39,40,41,42,43,44,45].…”

Section: Introductionmentioning

confidence: 99%

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

Tan

Manchester

Qin

et al. 2016

IJMS

295

256

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Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria.

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Section: Introductionmentioning

confidence: 99%

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

Tan

Manchester

Qin

et al. 2016

IJMS

295

256

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“…Our recent studies have also shown that Ex4 possesses anti‐apoptotic, antioxidative, and antifibrotic capacity in the setting of ischemia–reperfusion organ injury . On the other hand, melatonin, an indole mainly secreted from the pineal gland and a strong and durable free radical scavenger, has been demonstrated to play an essential role in maintaining cell membrane stability and ensuring cell survival in toxic environment mainly through a reduction in the susceptibility to oxidative stress and free radical damage as well as a suppression of inflammatory reaction . Combination therapy with two or more drugs often offer great benefit for patients with different disease entities, such as hypertension, diabetes mellitus, heart failure, and HIV infection (i.e., cocktail therapy) are the commonest therapeutics in our daily clinical practice.…”

Section: Introductionmentioning

confidence: 99%

The cardioprotective effect of melatonin and exendin‐4 treatment in a rat model of cardiorenal syndrome

Chua

Lee

Chiang

et al. 2016

Journal of Pineal Research

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We investigated the cardioprotective effect of melatonin (Mel) and exendin-4 (Ex4) treatment in a rat model of cardiorenal syndrome (CRS). Adult male SD rats (n=48) were randomly and equally divided into sham control (SC), dilated cardiomyopathy (DCM) (doxorubicin 7 mg/kg i.p. every five days/4 doses), CRS (defined as DCM+CKD) only, CRS-Mel (20 mg/kg/d), CRS-Ex4 (10 μg/kg/d), and CRS-Mel-Ex4 groups. In vitro results showed protein expressions of oxidative stress (NOX-1/NOX-2/oxidized protein), DNA/mitochondrial damage (γ-H2AX/cytosolic cytochrome c), apoptosis (cleaved caspase-3/PARP), and senescence (β-galactosidase cells) biomarkers were upregulated, whereas mitochondrial ATP level was decreased in doxorubicin/p-cresol-treated H9c2 cells that were revised by Mel and Ex4 treatments (all P<.001). By day 60, LVEF was highest in the SC and lowest in the CRS, significantly lower in the DCM than in other treatment groups, lower in the CRS-Mel and CRS-Ex4 than in the CRS-Mel-Ex4, and lower in the CRS-Mel than in the CRS-Ex4, whereas LV chamber size and histopathology score showed a pattern opposite to that of LVEF among all groups (all P<.001). Plasma creatinine level was highest in the CRS and lowest in the SC and progressively decreased from the CRS-Mel, CRS-Ex4, CRS-Mel-Ex4 to DCM (P<.0001). Protein expressions of inflammation (TNF-α/NF-κB/MMP-2/MMP-9/IL-1β), apoptosis/DNA damage (Bax/c-caspase-3/c-PARP/γ-H2AX), fibrosis (Smad3/TGF-β), oxidative stress (NOX-1/NOX-2/NOX-4/oxidized protein), cardiac hypertrophy/pressure overload (BNP/β-MHC), and cardiac integrity (Cx43/α-MHC) biomarkers in LV myocardium showed an opposite pattern compared to that of LVEF among all groups (all P<.001). Fibrotic area, DNA damage (γ-H2AX /53BP1 CD90 /XRCC1 CD90 ), and inflammation (CD14 /CD68 ) biomarkers in LV myocardium displayed a pattern opposite to that of LVEF among all groups (all P<.001). Combined melatonin and exendin-4 treatment suppressed CRS-induced deterioration of LVEF and LV remodeling.

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“…Adipose-derived mesenchymal stromal cells (ASCs), however, show greater proliferative potential than BMSCs and other mesenchymal stromal cell lines, and their ease of accessibility and limitless supply via liposuction of subcutaneous adipose tissue make them an ideal candidate for widespread therapeutic use [11-13]. ASCs have also been suggested as an alternative stem cell source for the treatment of intestinal ischemia in a rat model of intestinal I/R [14]. In this study, rat derived ASCs decreased inflammation and preserved intestinal histological architecture, but the cellular effects on survival and mesenteric perfusion were not defined.…”

Section: Introductionmentioning

confidence: 99%

Human Adipose Stromal Cells Increase Survival and Mesenteric Perfusion Following Intestinal Ischemia and Reperfusion Injury

Jensen

Doster

Hunsberger

et al. 2016

Shock

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Background Intestinal ischemia can quickly escalate to bowel necrosis and perforation. Transplantation of stem cells presents a novel treatment modality for this problem. We hypothesized that: (1) Human adipose derived stromal cells (hASCs) would increase survival and mesenteric perfusion to a greater degree compared to differentiated cellular controls following ischemic intestinal injury, (2) improved outcomes with hASC therapy would be associated with preservation of intestinal histological and tight junction architecture, and lower levels of systemic inflammation following intestinal injury. Methods hASCs and keratinocytes (differentiated cellular control) were cultured on polystyrene flasks at 37C in 5% CO2 in air. Adult male C57Bl6J mice were anesthetized and a midline laparotomy performed. The intestines were eviscerated, the small bowel mesenteric root identified, and intestinal ischemia was established by temporarily occluding the superior mesenteric artery for 60 minutes with a non-crushing vascular clamp. Following ischemia, the clamp was removed and the intestines were returned to the abdominal cavity. Prior to abdominal closure, two million hASCs or keratinocytes in 250 uL of PBS (carrier for cells and control solution) were infused into the peritoneum. Animals were allowed to recover for 12 or 24 hours (perfusion, histology, cytokine, and immunofluoresence studies), or 7 days (survival studies). Intestinal perfusion was assessed by laser Doppler imaging. Intestinal tissue segments were stained with H&E, as well as antibodies for the tight junction protein claudin-1. Separate aliquots of intestine, liver and lung tissue were homogenized and assessed for inflammatory cytokines via multiplex beaded assay. Results Animals administered hASCs following intestinal ischemia and reperfusion injury (I/R) had significantly greater 7 day survival and better post-ischemic recovery of mesenteric perfusion compared to vehicle or keratinocyte therapy. hASCs also abated intestinal mucosal destruction, facilitated preservation of intestinal tight junctions, and decreased the systemic inflammatory response to injury. Conclusion Human adipose derived stromal cells improved survival and mesenteric perfusion and attenuated the mucosal damage associated with intestinal ischemia and reperfusion injury. hASCs should be considered as a plausible cell source for novel cellular treatment plans following intestinal ischemia.

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Protective effect of melatonin‐supported adipose‐derived mesenchymal stem cells against small bowel ischemia‐reperfusion injury in rat

Cited by 74 publications

References 35 publications

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics

The cardioprotective effect of melatonin and exendin‐4 treatment in a rat model of cardiorenal syndrome

Human Adipose Stromal Cells Increase Survival and Mesenteric Perfusion Following Intestinal Ischemia and Reperfusion Injury

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