Cardiomyocyte-derived adiponectin is biologically active in protecting against myocardial ischemia-reperfusion injury

Adiponectin (APN) has traditionally been viewed as an adipocyte-specific endocrine molecule with cardioprotective effects. Recent studies suggest that APN is also expressed in cardiomyocytes. However, biological significances of this locally produced APN remain completely unknown. The aim of this study was to investigate the pathological and pharmacological significance of cardiac-derived APN in cardiomyocyte pathology. Adult cardiomyocytes from wild-type littermates (WT) or gene-deficient mice were pretreated with vehicle (V) or rosiglitazone (RSG) for 6 h followed by simulated ischemia-reperfusion (SI/R, 3 h/12 h). Compared with WT cardiomyocytes, myocytes from APN knockout (APN-KO) mice sustained greater SI/R injury, evidenced by greater oxidative/nitrative stress, caspase-3 activity, and lactate dehydrogenase (LDH) release ( P < 0.05). Myocytes from adiponectin receptor 1 knockdown (AdipoR1-KD) or AdipoR1-KD/AdipoR2-KO mice had slightly increased SI/R injury, but the difference was not statistically significant. RSG significantly ( P < 0.01) increased APN mRNA and protein expression, upregulated AdipoR1/AdipoR2 expression, reduced SI/R-induced apoptosis, and decreased LDH release in WT cardiomyocytes. However, the anti-oxidative/anti-nitrative and cell protective effects of RSG were completely lost in APN-KO cardiomyocytes ( P > 0.05 vs. vehicle group), although a comparable degree of AdipoR1/AdipoR2 upregulation was observed. The upregulatory effect of RSG on APN mRNA and protein expression was significantly potentiated in AdipoR1-KD/AdipoR2-KO cardiomyocytes. However, the cellular protective effects of RSG were significantly blunted, although not completely lost, in these cells. These results demonstrated that cardiomyocyte APN is biologically active in protecting cells against SI/R injury. Moreover, this locally produced APN achieves its protective effect primarily through paracrine/autocrine activation of APN receptors.

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Roles of the Exogenous H2S-Mediated SR-A Signaling Pathway in Renal Ischemia/ Reperfusion Injury in Regulating Endoplasmic Reticulum Stress-Induced Autophagy in a Rat Model

Cellular Physiology and Biochemistry ◽

10.1159/000475915 ◽

2017 ◽

Vol 41 (6) ◽

pp. 2461-2474 ◽

Cited By ~ 13

Author(s):

Qing Ling ◽

Xiao Yu ◽

Tao Wang ◽

Shao-Gang Wang ◽

Zhang-Qun Ye ◽

...

Keyword(s):

Protein Expression ◽

Er Stress ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Urine Volume ◽

Urinary Protein ◽

Apoptosis Index ◽

Mrna And Protein Expression

Objective: This study aims to explore the effects of the exogenous hydrogen sulfide (H2S)-mediated scavenger receptor A (SR-A) signaling pathway on renal ischemia/reperfusion injury (IRI) by regulating endoplasmic reticulum (ER) stress-induced autophagy in rats. Methods: A total of 48 normal Sprague-Dawley (SD) rats and SR-A knockout rats were selected and divided into six groups (n = 8): wild-type (WT) + sham, WT + ischemia-reperfusion (I/R), WT + I/R + NaHS, SR-A-/- + sham, SR-A-/- + I/R and SR-A-/- + I/R + NaHS. The concentrations of urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), malondialdehyde (MDA) and H2S in renal tissue were detected. qRT-PCR and Western blotting were used to detect the mRNA and protein levels of IL-6, TGF-β, SR-A, LC3I, LC3II, P62, PERK, ATF6 and IRE1 pathway-related genes. A TUNEL assay was used to detect cell apoptosis. Electron microscopy was applied to observe the structure of renal autophagosomes. Results: Compared with the WT + sham group, in the rates of the WT + I/R group, the urine volume, urinary protein, BUN, SCR and MDA concentrations, the mRNA and protein expression of IL-6, TGF-β, LC3II/I, and ER stress pathway-related genes, the cell apoptosis index, and the number of autophagosomes were significantly increased 24 h after I/R, while P62 and SR-A protein expression and SOD and H2S concentrations were significantly decreased (all P < 0.05). The levels of renal injury, autophagy and ER stress pathway-related genes were decreased in the WT + I/R + NaHS group but were increased in the SR-A-/- + I/R group relative to the WT + I/R group. No significant differences were observed in the urine volume; the concentrations of urinary protein, BUN, SCR and MDA; the SOD activity; the mRNA and protein expression of IL-6, TGF-β, SR-A, GRP78, SR-A, GPR94, ATF4, IRE1, XBP1, ATF6, and eIF2α; the cell apoptosis index; or the number of autophagosomes in rats of the SR-A-/- + I/R and SR-A-/- + I/R + NaHS groups (all P > 0.05). Conclusion: These results demonstrate that the exogenous H2S-mediated SR-A signaling pathway reduces renal IRI injury by up-regulating ER stress-induced autophagy in rats.

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Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00377.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. H801-H806 ◽

Cited By ~ 209

Author(s):

Saurabh Jha ◽

John W. Calvert ◽

Mark R. Duranski ◽

Arun Ramachandran ◽

David J. Lefer

Keyword(s):

Hydrogen Sulfide ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Physiological Activity ◽

Vehicle Group ◽

Lipid Hydroperoxides ◽

Protective Effects ◽

Hepatic Ischemia ◽

Murine Liver ◽

Hepatic Ischemia Reperfusion

Hydrogen sulfide (H2S) is an endogenously produced gaseous signaling molecule with diverse physiological activity. The potential protective effects of H2S have not been evaluated in the liver. The purpose of the current study was to investigate if H2S could afford hepatoprotection in a murine model of hepatic ischemia-reperfusion (I/R) injury. Hepatic injury was achieved by subjecting mice to 60 min of ischemia followed by 5 h of reperfusion. H2S donor (IK1001) or vehicle were administered 5 min before reperfusion. H2S attenuated the elevation in serum alanine aminotransferase (ALT) by 68.6% and aspartate aminotransferase (AST) by 70.8% compared with vehicle group. H2S-mediated cytoprotection was associated with an improved balance between reduced glutathione (GSH) vs. oxidized glutathione (GSSG), an attenuated formation of lipid hydroperoxides, and an increased expression of thioredoxin-1 (Trx-1). Furthermore, H2S inhibited the progression of apoptosis after I/R injury by increasing the protein expression of heat shock protein (HSP-90) and Bcl-2. These results indicate that H2S protects the murine liver against I/R injury through an upregulation of intracellular antioxidant and antiapoptotic signaling pathways.

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Protective Effects of Pretreatment with Oleanolic Acid in Rats in the Acute Phase of Hepatic Ischemia-Reperfusion Injury: Role of the PI3K/Akt Pathway

Mediators of Inflammation ◽

10.1155/2014/451826 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 19

Author(s):

Bo Gui ◽

Fuzhou Hua ◽

Jie Chen ◽

Zeping Xu ◽

Hongbin Sun ◽

...

Keyword(s):

Protein Expression ◽

Oleanolic Acid ◽

Acute Phase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Protective Effects ◽

Sprague Dawley ◽

Hepatic Ischemia ◽

Time Points ◽

Hepatic Ischemia Reperfusion

Oleanolic acid (OA) has been used to treat liver disorders, but whether it can attenuate hepatic ischemia-reperfusion- (IR-) associated liver dysfunction remains unexplored. In the present study, 160 male Sprague-Dawley rats were equally divided into five groups: group SH received neither hepatic IR nor drugs; group IR received hepatic IR without drugs; group CM and group OA received 0.5% sodium carboxymethylcellulose and 100 mg/kg OA, intragastrically, once a day for seven days before the hepatic IR, respectively; on the basis of treatment in group OA, group OA+wortmannin further received 15 μg/kg of PI3K inhibitor wortmannin, intraperitoneally, 30 min before the hepatic IR. Then each group was equally divided into four subgroups according to four time points (preoperation, 0 h, 3 h, and 6 h after reperfusion). Serum ALT activity, IL-1βconcentration, and hepatic phosphorylation of PI3K, Akt, and GSK-3βprotein expression were serially studied. We found that OA pretreatment improved histological status and decreased serum ALT and IL-1βlevels. It also increased p-PI3K, p-Akt, and p-GSK-3βprotein expression at all the four time points. Prophylactic wortmannin partially reversed OA’s protective effects. The data indicate that OA pretreatment protects liver from IR injury during the acute phase partially through PI3K/Akt-mediated inactivation of GSK-3β.

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Network Pharmacology Reveals the Mechanism of Activity of Tongqiao Huoxue Decoction Extract Against Middle Cerebral Artery Occlusion-Induced Cerebral Ischemia-Reperfusion Injury

Frontiers in Pharmacology ◽

10.3389/fphar.2020.572624 ◽

2021 ◽

Vol 11 ◽

Author(s):

Si-peng Wu ◽

Ning Wang ◽

Li Zhao

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Cerebral Ischemia ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Functional Enrichment ◽

Vehicle Group ◽

Network Pharmacology ◽

Protective Effects ◽

Cerebral Ischemia Reperfusion

Several clinical therapies such as tissue repair by replacing injured tissues with functional ones have been reported; however, there is great potential for exploring traditional herbal-induced regeneration with good safety. Tongqiao Huoxue Decoction (TQHXD), a well-known classical traditional Chinese medicinal formula, has been widely used for clinical treatment of stroke. However, biological activity and mechanisms of action of its constituents toward conferring protection against cerebral ischemia-reperfusion (I/R) injury remain unclear. In this present study, we evaluated TQHXD quality using HPLC; then, it was screened for its potential active ingredients using a series of indices, such as their drug-likeness and oral bioavailability. Subsequently, we analyzed the potential mechanisms of TQHXD anti-I/R using gene ontology functional enrichment analyses. The network pharmacological approach enabled us to screen 265 common targets associated with I/R, indicating that TQHXD had remarkable protective effects on infarction volume, neurological function scores, and blood-brain barrier (BBB) injury. In addition, TQHXD significantly promoted the recovery of regional cerebral blood flow (rCBF) 7 days after reperfusion compared to rats in the vehicle group. Immunofluorescence results revealed a significantly higher CD34 expression in TQHXD-treated rats 7 days after reperfusion. TQHXD is not merely effective but eventually develops a secretory profile composed of VEGF and cerebral blood flow, a typical signature termed the angiogenesis-associated phenotype. Mechanistically, our data revealed that TQHXD (6 g/kg) treatment resulted in a marked increase in expression of p-focal adhesion kinase (FAK) and p-Paxillin proteins. However, Ki8751-mediated inhibition of VEGFR2 activity repealed its angiogenesis and protective effects and decreased both p-FAK and p-Paxillin protein levels. Taken together, these findings affirmed the potential of TQHXD as a drug for the management of stroke, which might be exerted by increasing the angiogenesis via the VEGF pathway. Therefore, these results provide proof-of-concept evidence that angiogenesis is a major contributor to TQHXD-treated I/R and that TQHXD is a promising traditional ethnic medicine for the management of this condition.

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Protective effects of Chinese herbal medicine Naoshuantong on neurovascular unit in rats with cerebral ischemia/reperfusion injury

Journal of Chinese Integrative Medicine ◽

10.3736/jcim20121010 ◽

2012 ◽

pp. 1135-1139 ◽

Cited By ~ 2

Author(s):

QH Shi

Keyword(s):

Cerebral Ischemia ◽

Herbal Medicine ◽

Chinese Herbal Medicine ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Neurovascular Unit ◽

Protective Effects ◽

Chinese Herbal ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury

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Acteoside Presents Protective Effects on Cerebral Ischemia/reperfusion Injury Through Targeting CCL2, CXCL10, and ICAM1

Cell Biochemistry and Biophysics ◽

10.1007/s12013-020-00965-8 ◽

2021 ◽

Author(s):

Weijiang Wu ◽

Gang Wu ◽

Deyan Cao

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Protective Effects ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury

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Dietary resveratrol attenuation of intestinal inflammation and oxidative damage is linked to the alteration of gut microbiota and butyrate in piglets challenged with deoxynivalenol

Journal of Animal Science and Biotechnology ◽

10.1186/s40104-021-00596-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yueqin Qiu ◽

Jun Yang ◽

Li Wang ◽

Xuefen Yang ◽

Kaiguo Gao ◽

...

Keyword(s):

Gut Microbiota ◽

Oxidative Damage ◽

Protein Expression ◽

Intestinal Inflammation ◽

Control Diet ◽

Intestinal Barrier Function ◽

Protective Effects ◽

Gut Health ◽

Antioxidant Genes ◽

Mrna And Protein Expression

Abstract Background Deoxynivalenol (DON) is a widespread mycotoxin that induces intestinal inflammation and oxidative stress in humans and animals. Resveratrol (RES) effectively exerts anti-inflammatory and antioxidant effects. However, the protective effects of RES on alleviating DON toxicity in piglets and the underlying mechanism remain unclear. Therefore, this study aimed to investigate the effect of RES on growth performance, gut health and the gut microbiota in DON-challenged piglets. A total of 64 weaned piglets [Duroc × (Landrace × Yorkshire), 21-d-old, 6.97 ± 0.10 kg body weight (BW)] were randomly allocated to 4 treatment groups (8 replicate pens per treatment, each pen containing 2 males; n = 16 per treatment) for 28 d. The piglets were fed a control diet (CON) or the CON diet supplemented with 300 mg RES/kg diet (RES group), 3.8 mg DON/kg diet (DON) or both (DON+RES) in a 2 × 2 factorial design. Results DON-challenged piglets fed the RES-supplemented diet had significantly decreased D-lactate concentrations and tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) mRNA and protein expression, and increased zonula occludens-1 (ZO-1) mRNA and protein expression compared with those of DON-challenged piglets fed the unsupplemented diet (P < 0.05). Compared with unsupplemented DON-challenged piglets, infected piglets fed a diet with RES showed significantly decreased malondialdehyde (MDA) levelsand increased mRNA expression of antioxidant enzymes and antioxidant genes (i.e., GCLC, GCLM, HO-1, SOD1 and NQO-1) and glutamate-cysteine-ligase modulatory subunit (GCLM) protein expression (P < 0.05). Moreover, RES supplementation significantly abrogated the increase in the proportion of TUNEL-positive cells and the protein expression of caspase3 in DON-challenged piglets (P < 0.05). Finally, RES supplementation significantly increased the abundance of Roseburia and butyrate concentrations, while decreasing the abundances of Bacteroides and unidentified-Enterobacteriaceae in DON-challenged piglets compared with DON-challenged piglets alone (P < 0.05). Conclusions RES supplementation improved gut health in DON-challenged piglets by strengthening intestinal barrier function, alleviating intestinal inflammation and oxidative damage, and positively modulating the gut microbiota. The protective effects of RES on gut health may be linked to increased Roseburia and butyrate concentrations, and decreased levels of Bacteroides and unidentified-Enterobacteriaceae.

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Propofol attenuates lung ischemia/reperfusion injury though the involvement of the MALAT1/microRNA-144/GSK3β axis

Molecular Medicine ◽

10.1186/s10020-021-00332-0 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Jian-Ping Zhang ◽

Wei-Jing Zhang ◽

Miao Yang ◽

Hua Fang

Keyword(s):

Cell Apoptosis ◽

Ischemia Reperfusion Injury ◽

Glycogen Synthase ◽

Ischemia Reperfusion ◽

Inflammatory Factors ◽

Therapeutic Effects ◽

Protective Effects ◽

Loss Of Function

Abstract Background Propofol, an intravenous anesthetic, was proven to protect against lung ischemia/reperfusion (I/R) injury. However, the detailed mechanism of Propofol in lung I/R injury is still elusive. This study was designed to explore the therapeutic effects of Propofol, both in vivo and in vitro, on lung I/R injury and the underlying mechanisms related to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-144 (miR-144)/glycogen synthase kinase-3β (GSK3β). Methods C57BL/6 mice were used to establish a lung I/R injury model while pulmonary microvascular endothelial cells (PMVECs) were constructed as hypoxia/reperfusion (H/R) cellular model, both of which were performed with Propofol treatment. Gain- or loss-of-function approaches were subsequently employed, followed by observation of cell apoptosis in lung tissues and evaluation of proliferative and apoptotic capabilities in H/R cells. Meanwhile, the inflammatory factors, autophagosomes, and autophagy-related proteins were measured. Results Our experimental data revealed that Propofol treatment could decrease the elevated expression of MALAT1 following I/R injury or H/R induction, indicating its protection against lung I/R injury. Additionally, overexpressing MALAT1 or GSK3β promoted the activation of autophagosomes, proinflammatory factor release, and cell apoptosis, suggesting that overexpressing MALAT1 or GSK3β may reverse the protective effects of Propofol against lung I/R injury. MALAT1 was identified to negatively regulate miR-144 to upregulate the GSK3β expression. Conclusion Overall, our study demonstrated that Propofol played a protective role in lung I/R injury by suppressing autophagy and decreasing release of inflammatory factors, with the possible involvement of the MALAT1/miR-144/GSK3β axis.

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Kaempferol Ameliorates Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Ferroptosis by Activating Nrf2/SLC7A11/GPX4 Axis

Biomolecules ◽

10.3390/biom11070923 ◽

2021 ◽

Vol 11 (7) ◽

pp. 923

Author(s):

Yuan Yuan ◽

Yanyu Zhai ◽

Jingjiong Chen ◽

Xiaofeng Xu ◽

Hongmei Wang

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Antioxidant Capacity ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation ◽

Related Factor ◽

Protective Effects

Kaempferol has been shown to protect cells against cerebral ischemia/reperfusion injury through inhibition of apoptosis. In the present study, we sought to investigate whether ferroptosis is involved in the oxygen-glucose deprivation/reperfusion (OGD/R)-induced neuronal injury and the effects of kaempferol on ferroptosis in OGD/R-treated neurons. Western blot, immunofluorescence, and transmission electron microscopy were used to analyze ferroptosis, whereas cell death was detected using lactate dehydrogenase (LDH) release. We found that OGD/R attenuated SLC7A11 and glutathione peroxidase 4 (GPX4) levels as well as decreased endogenous antioxidants including nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and superoxide dismutase (SOD) in neurons. Notably, OGD/R enhanced the accumulation of lipid peroxidation, leading to the induction of ferroptosis in neurons. However, kaempferol activated nuclear factor-E2-related factor 2 (Nrf2)/SLC7A11/GPX4 signaling, augmented antioxidant capacity, and suppressed the accumulation of lipid peroxidation in OGD/R-treated neurons. Furthermore, kaempferol significantly reversed OGD/R-induced ferroptosis. Nevertheless, inhibition of Nrf2 by ML385 blocked the protective effects of kaempferol on antioxidant capacity, lipid peroxidation, and ferroptosis in OGD/R-treated neurons. These results suggest that ferroptosis may be a significant cause of cell death associated with OGD/R. Kaempferol provides protection from OGD/R-induced ferroptosis partly by activating Nrf2/SLC7A11/GPX4 signaling pathway.

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