Reperfusion Model Research Articles

The combination of astragaloside IV and Panax notoginseng saponins attenuates cerebral ischaemia-reperfusion injury in rats through ferroptosis and inflammation inhibition via activating Nrf2.

This study aimed to observe the effect of the combination of astragaloside IV (AST IV) and Panax notoginseng saponins (PNS) on cerebral ischaemia-reperfusion injury (CIRI) and explore the specific mechanism of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated combination of AST IV and PNS against CIRI based on ferroptosis and inflammatory response. The therapeutic effect and mechanism of AST IV and PNS were evaluated by constructing a Sprague-Dawley rat middle cerebral artery ischaemia-occlusion-reperfusion model. The specific mechanism of the combination of AST IV and PNS against CIRI was revealed through the combined intervention of the Nrf2-specific inhibitor brusatol. After AST IV and PNS treatment, the cerebral infarction area of the rats was reduced; behavioural performance was improved; Fe2+, malondialdehyde, lipid peroxidation, interleukin-6, interleukin-1β, tumour necrosis factor-α and myeloperoxidase levels were reduced; and glutathione and glutathione peroxidase 4 levels were increased. In addition, the expression of Nrf2 was significantly increased, the combined treatment was more effective than the single treatment, and the Nrf2 inhibitor brusatol could reverse the effects of the combined intervention of AST IV and PNS. The findings of this study suggest that combining AST IV and PNS attenuates CIRI by activating Nrf2 to inhibit ferroptosis and inflammatory responses.

Evaluation of vascular repair by tissue-engineered human acellular vessels or expanded polytetrafluoroethylene grafts in a porcine model of limb ischemia and reperfusion.

This study evaluated performance of a tissue-engineered human acellular vessel (HAV) in a porcine model of acute vascular injury and ischemia. The HAV is an engineered blood vessel consisted of human vascular extracellular matrix proteins. Limb reperfusion and vascular outcomes of the HAV were compared with those from synthetic expanded polytetrafluoroethylene (ePTFE) grafts. Thirty-six pigs were randomly assigned to four treatment groups, receiving either the HAV or a PTFE graft following a hind limb ischemia period of either 0 or 6 hours. All grafts were 3-cm-long interposition 6-mm diameter grafts implanted within the right iliac artery. Animals were not immunosuppressed and followed for up to 28 days after surgery. Assessments performed preoperatively and postoperatively included evaluation of graft patency, hind limb function, and biochemical markers of tissue ischemia or reperfusion injury. Histological analysis was performed on explants to assess host cell responses. Postoperative gait assessment and biochemical analysis confirmed that ischemia and reperfusion injury were caused by 6-hour ischemia, regardless of vascular graft type. Hind limb function and tissue damage biomarkers improved in all groups postoperatively. Final patency rates at postoperative day 28 were higher for HAV than for ePTFE graft in both the 0-hour (HAV, 85.7%; ePTFE, 66.7%) and 6-hour (HAV, 100%; ePTFE, 75%) ischemia groups, but these differences were not statistically significant. Histological analyses identified some intimal hyperplasia and host reactivity to the xenogeneic HAV and also to the synthetic ePTFE graft. Positive host integration and vascular cell infiltration were identified in HAV but not ePTFE explants. Based on the functional performance and the histologic profile of explanted HAVs, this study supports further investigation to evaluate long-term performance of the HAV when used to repair traumatic vascular injuries.

Applicability of the histidine-tryptophan-ketoglutarate solution as a machine perfusion solution for marginal liver grafts.

There are very few reports comparing the use of the University of Wisconsin solution and histidine-tryptophan-ketoglutarate solution as machine perfusion solutions for marginal liver grafts. We aimed to clarify whether the use of the histidine-tryptophan-ketoglutarate solution in hypothermic machine perfusion improves the split-liver graft function in a large animal model. Porcine split-liver grafts were created by 75% liver resection. Hypothermic machine perfusion experimental groups were divided as follows: Group 1, perfusate, University of Wisconsin gluconate solution (UW group; n=5), and Group 2, perfusate, histidine-tryptophan-ketoglutarate solution (HTK group; n=4). After 4h of preservation, the liver function was evaluated using an isolated liver reperfusion model for 2h. In the HTK group, the portal vein and hepatic artery resistance during hypothermic machine perfusion and the portal vein resistance during isolated liver reperfusion were lower than those in the UW group. In addition, the total Suzuki score for hepatic ischemia-reperfusion injury in the HTK group was significantly better than that in the UW group. The number of anti-ETS-related genes staining-positive sinusoid epithelial cell nuclei in the HTK group was higher than that in the UW group (not significant). The histidine-tryptophan-ketoglutarate solution can be perfused with lower vascular resistance than the University of Wisconsin solution, reducing shear stress and preventing sinusoid epithelial cell injury in marginal grafts used as split-liver grafts.

Loureirin C inhibits ferroptosis after cerebral ischemia reperfusion through regulation of the Nrf2 pathway in mice

BackgroundIschemic stroke (IS) is considered as a serious cerebral vascular disease. Ferroptosis is a novel type of regulated cell death (RCD), that closely related to the occurrence and progress of IS. Loureirin C, a type of dihydrochalcone compound derived from the Chinese Dragon's blood (CDB). The effective components extracted from CDB have shown neuroprotective effects in ischemia reperfusion models. However, the role of Loureirin C in mice after IS is not well understood. Thus, it is worth to identify the effect and mechanism of Loureirin C on IS. PurposeThe present research aims to prove the existence of ferroptosis in IS and explore whether Loureirin C can inhibit ferroptosis by regulating nuclear factor E2 related factor 2 (Nrf2) pathway in mice and exert neuroprotective effects on IS models. MethodsMiddle cerebral artery occlusion and reperfusion (MCAO/R) model was established to evaluate the occurrence of ferroptosis and the potential Loureirin C brain-protective effect in vivo. The analysis of free iron, glutamate content, reactive oxygen species (ROS) and lipid peroxidation levels, along with transmission electron microscope (TEM) was applied to prove the existence of ferroptosis. The function of Loureirin C on Nrf2 nuclear translocation was verified by immunofluorescence staining. In vitro, primary neurons and SH-SY5Y cells were processed with Loureirin C after oxygen and glucose deprivation-reperfusion (OGD/R). ELISA kits, western blotting, co-immunoprecipitation (Co-IP) analysis, immunofluorescence, and quantitative real-time PCR were devoted to proving the neuroprotective effects of Loureirin C on IS via regulating ferroptosis and Nrf2 pathways. ResultsThe results showed that Loureirin C not only dramatically alleviated brain injury and inhibited neurons ferroptosis in mice after MCAO/R, but also dose-dependently reduce ROS accumulation in ferroptosis after OGD/R. Further, Loureirin C inhibits ferroptosis by activating Nrf2 pathway, and promoting nuclear translocation of Nrf2. Besides, Loureirin C increases heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1) and glutathione peroxidase 4 (GPX4) content after IS. Intriguingly, the anti-ferroptosis effect of Loureirin C is weakened by Nrf2 knockdown. ConclusionOur discoveries first revealed that the inhibitory action of Loureirin C on ferroptosis may greatly depend on its adjusting effect on the Nrf2 pathway, suggesting that Loureirin C could act as a novel anti-ferroptosis candidate and play a therapeutic role in IS. These novel discoveries on the role of Loureirin C on IS models reveal an innovative method that may contribute to neuroprotection for the prevention of IS.

γ-Mangostin alleviates myocardial ischemia-reperfusion injury by up-regulating SIRT3

Purpose: To determine the effect of γ-mangostin on myocardial ischemia (MI) -induced injury of myocardial cells, and the possible involvement of SIRT3 in myocardial cell apoptosis in Sprague-Dawley rats after ischemia-reperfusion (I/R).
 Methods: Ischemic reperfusion (I/R) model of rat was established, followed by TTC staining. The serum levels of CK-MB and LDH were also assessed. In addition, inflammatory response and oxidative stress were evaluated by quantitative PCR and enzyme linked immunosorbent assay (ELISA), while cell apoptosis was assessed using TdT-mediated dUTP nick end labeling (TUNEL) assay and western blot. The mechanism of action of γ-mangostin by which it mediated improvement in cardiac injury was investigated by ELISA and western blot.
 Results: γ-Mangostin attenuated myocardial injury and reduced myocardial inflammation in I/R rats (p < 0.05). In addition, it alleviated oxidative stress in I/R rat myocardial tissues and suppressed apoptosis. Furthermore, γ-mangostin improved myocardial injury probably by targeting SIRT3 (p < 0.05).
 Conclusion: γ-Mangostin has potentials for use as a therapeutic agent for the treatment of myocardial I/R injury. However, there is a need for clinical trials on the compound.

Therapeutic Treatment with Pycnogenol® Attenuates Ischemic Brain Injury in Gerbils Focusing on Cognitive Impairment, Neuronal Death, BBB Leakage and Neuroinflammation in the Hippocampus

A gerbil model of ischemia and reperfusion (IR) injury in the forebrain has been developed for studies on mechanisms, prevention and therapeutic strategies of IR injury in the forebrain. Pycnogenol® (PYC), a standardized extract of French maritime pine tree (Pinus pinaster Aiton) has been exploited as an additive for dietary supplement. In the present study, we investigated the neuroprotective effects of post-treatment with PYC and its therapeutic mechanisms in gerbils. The gerbils were given sham and IR operation and intraperitoneally injected with vehicle and Pycnogenol® (25, 50 and 100 mg/kg, respectively) immediately, at 24 hours and 48 hours after sham and IR operation. Through 8-arm radial maze test and passive avoidance test, each spatial memory and short-term memory function was assessed. To examine the neuroprotection of Pycnogenol®, we conducted cresyl violet staining, immunohistochemistry for neuronal nuclei, and Fluoro-Jade B histofluorescence. Moreover, we carried out immunohistochemistry for immunoglobulin G (IgG) to investigate blood-brain barrier (BBB) leakage and interleukin-1β (IL-1β) to examine change in pro-inflammatory cytokine. We found that IR-induced memory deficits were significantly ameliorated when 100 mg/kg Pycnogenol® was treated. In addition, treatment with 100 mg/kg Pycnogenol®, not 25 mg/kg nor 50 mg/kg, conferred neuroprotective effect against IR injury. For its mechanisms, we found that 100 mg/kg Pycnogenol® significantly reduced BBB leakage and inhibited the expression of IL-1β. Therapeutic treatment (post-treatment) with Pycnogenol® after IR effectively attenuated ischemic brain injury in gerbils. Based on these results, we suggest that PYC can be employed as an important material for ischemic drugs.

P‑hydroxybenzyl alcohol ameliorates neuronal cerebral ischemia‑reperfusion injury by activating mitochondrial autophagy through SIRT1.

Mitochondrial autophagy serves a key role in clearing damaged mitochondria. P‑hydroxybenzyl alcohol (pHBA) can improve neuronal injury induced by cerebral ischemia‑reperfusion (I/R). However, the mechanism of pHBA improving I/R damage through the mitochondrial pathway remains unclear. A rat model of middle cerebral artery occlusion and reperfusion (MCAO/R) was used in the present study. The rats were treated with sirtuin 1 (SIRT1) inhibitor EX527 and pHBA for 7 days, followed by reperfusion. At 24h after reperfusion, the infarct size was calculated and the severity of nerve damage was evaluated. Hematoxylin and eosin and Nissl staining revealed cellular changes in the ischemic penumbra. Changes in mitochondrial structure were observed using electron microscopy. Mitochondrial function was evaluated by detecting mitochondrial membrane potential (MMP), mitochondrial permeability transition pore (mPTP) and ATP levels using commercially available kits. In addition, the ischemic penumbra tissues were used for immunofluorescence staining for p62 and LC3 proteins. The expression of SIRT1 and mitochondrial autophagy‑related proteins, PTEN‑induced kinase 1 (PINK1) and Parkin, were detected by western blotting. Finally, apoptosis was analyzed by TUNEL staining and the expression of apoptosis‑related proteins (Bax, Bcl‑2 and Caspase‑3) by western blotting. The results suggested that postoperative pHBA treatment may reduce the size of cerebral infarction and damage to the nervous system, and may improve cell damage in the ischemic penumbra of MCAO/R rats. Compared with rats in the untreated MCAO/R group, the mitochondrial structure of the pHBA‑treated group was improved, the levels of MMP and ATP were increased, and the degree of opening of mPTP was decreased. Simultaneously, immunofluorescence and western blotting results showed that compared with the MCAO/R group, the number of LC3‑ and TUNEL‑positive cells increased, the number of p62‑positive cells decreased, SIRT1 and autophagy protein (PINK1, Parkin and LC3 II/I) expression levels increased and p62 expression decreased in the pHBA group. However, these improvements were blocked by treatment with EX527. In summary, results from the present study suggested that pHBA may improve neuronal injury in the ischemic penumbra of MCAO/R rats through SIRT1‑activated mitochondrial autophagy and mitochondrial‑mediated neuronal apoptosis.

Prothymosin α Plays Role as a Brain Guardian through Ecto-F1 ATPase-P2Y12 Complex and TLR4/MD2.

Prothymosin alpha (ProTα) was discovered to be a necrosis inhibitor from the conditioned medium of a primary culture of rat cortical neurons under starved conditions. This protein carries out a neuronal cell-death-mode switch from necrosis to apoptosis, which is, in turn, suppressed by a variety of neurotrophic factors (NTFs). This type of NTF-assisted survival action of ProTα is reproduced in cerebral and retinal ischemia-reperfusion models. Further studies that used a retinal ischemia-reperfusion model revealed that ProTα protects retinal cells via ecto-F1 ATPase coupled with the Gi-coupled P2Y12 receptor and Toll-like receptor 4 (TLR4)/MD2 coupled with a Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). In cerebral ischemia-reperfusion models, ProTα has additional survival mechanisms via an inhibition of matrix metalloproteases in microglia and vascular endothelial cells. Heterozygous or conditional ProTα knockout mice show phenotypes of anxiety, memory learning impairment, and a loss of neurogenesis. There are many reports that ProTα has multiple intracellular functions for cell survival and proliferation through a variety of protein-protein interactions. Overall, it is suggested that ProTα plays a key role as a brain guardian against ischemia stress through a cell-death-mode switch assisted by NTFs and a role of neurogenesis.

Abstract TMP115: Inhibition Of S-nitrosoglutathione Reductase Mitigates The Acute Injury In A Mouse Model Of Stroke

Background: This project aims to evaluate the potential beneficial effects of a selective S-nitrosoglutathione reductase (GSNOR) inhibitor on post-acute stroke outcomes. Nitric oxide (NO) metabolome plays a critical role in stroke towards maintaining the crucial levels of deleterious peroxynitrite (ONOOO - ) vs. beneficial S-nitrosoglutahione (GSNO). The homeostasis of endogenously-produced-GSNO following stroke is altered due to aberrantly increased activity of GSNO-degrading enzyme GSNOR. GSNO’s role in the context of stroke is recognized as anti-inflammatory, neuroprotective and neurorestorative. Therefore, we investigated the efficacy of a new and orally bioavailable GSNOR inhibitor N91115 (cavosonstat) in a mouse model of transient cerebral ischemia and reperfusion (IR). Methods: To determine the neuroprotective efficacy of GSNOR, a wild-type mouse model of middle cerebral artery occlusion (60 min) and reperfusion was used. N91115 (1 mg/kg body weight) was administered orally initially at 2 h after the reperfusion and the same treatment dose was repeated once a day for 3 consecutive days. The animals were evaluated for brain infarctions, neurological deficits, nitroxidative stress and the activity/expression of GSNOR. The study was validated in a GSNOR knock-out (KO) mouse model of IR. Results: The post-injury treatment with N91115 reduced brain infarctions and edema and improved survival and functional outcomes. The treatment also decreased the IR-induced GSNOR activity and the levels of injurious peroxynitrite. The significance of GSNOR inhibition-based mechanisms in neuroprotection was supported by a GSNOR KO mice study, showing significantly reduced brain infarctions and decreased neurological deficits following stroke. Conclusion: The study shows the neuroprotective and functional recovery potential of orally administered N91115 through the inhibition of GSNOR. Based on the safety profile in humans, favorable pharmacokinetics and neuroprotective efficacy in an animal model of stroke, N91115 seems to be an ideal small molecule drug to be investigated in stroke patients.

Alginate sulfate-nanoparticles loaded with hepatocyte growth factor and insulin-like growth factor-1 improve left ventricular repair in a porcine model of myocardial ischemia reperfusion injury

Nanomedicine offers great potential for the treatment of cardiovascular disease and particulate systems have the capacity to markedly improve bioavailability of therapeutics. The delivery of pro-angiogenic hepatocyte growth factor (HGF) and pro-survival and pro-myogenic insulin-like growth factor (IGF-1) encapsulated in Alginate-Sulfate nanoparticles (AlgS-NP) might improve left ventricular (LV) functional recovery after myocardial infarction (MI). In a porcine ischemia–reperfusion model, MI is induced by 75 min balloon occlusion of the mid-left anterior descending coronary artery followed by reperfusion. After 1 week, pigs (n = 12) with marked LV-dysfunction (LV ejection fraction, LVEF < 45%) are randomized to fusion imaging-guided intramyocardial injections of 8 mg AlgS-NP prepared with 200 µg HGF and IGF-1 (HGF/IGF1-NP) or PBS (Control). Intramyocardial injection is safe and pharmacokinetic studies of Cy5-labeled NP confirm superior cardiac retention compared to intracoronary infusion. Seven weeks after intramyocardial-injection of HGF/IGF1-NP, infarct size, measured using magnetic resonance imaging, is significantly smaller than in controls and is associated with increased coronary flow reserve. Importantly, HGF/IGF1-NP-treated pigs show significantly increased LVEF accompanied by improved myocardial remodeling. These findings demonstrate the feasibility and efficacy of using AlgS-NP as a delivery system for growth factors and offer the prospect of innovative treatment for refractory ischemic cardiomyopathy.

Immune Checkpoint Molecule TIGIT Regulates Kidney T Cell Functions and Contributes to AKI.

T cells mediate pathogenic and reparative processes during AKI, but the exact mechanisms regulating kidney T cell functions are unclear. This study identified upregulation of the novel immune checkpoint molecule, TIGIT, on mouse and human kidney T cells after AKI. TIGIT-expressing kidney T cells produced proinflammatory cytokines and had effector (EM) and central memory (CM) phenotypes. TIGIT-deficient mice had protection from both ischemic and nephrotoxic AKI. Single-cell RNA sequencing led to the discovery of possible downstream targets of TIGIT. TIGIT mediates AKI pathophysiology, is a promising novel target for AKI therapy, and is being increasingly studied in human cancer therapy trials. T cells play pathogenic and reparative roles during AKI. However, mechanisms regulating T cell responses are relatively unknown. We investigated the roles of the novel immune checkpoint molecule T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in kidney T cells and AKI outcomes. TIGIT expression and functional effects were evaluated in mouse kidney T cells using RNA sequencing (RNA-Seq) and flow cytometry. TIGIT effect on AKI outcomes was studied with TIGIT knockout (TIGIT-KO) mice in ischemia reperfusion (IR) and cisplatin AKI models. Human kidney T cells from nephrectomy samples and single cell RNA sequencing (scRNA-Seq) data from the Kidney Precision Medicine Project were used to assess TIGIT's role in humans. RNA-Seq and flow cytometry analysis of mouse kidney CD4+ T cells revealed increased expression of TIGIT after IR injury. Ischemic injury also increased TIGIT expression in human kidney T cells, and TIGIT expression was restricted to T/natural killer cell subsets in patients with AKI. TIGIT-expressing kidney T cells in wild type (WT) mice had an effector/central memory phenotype and proinflammatory profile at baseline and post-IR. Kidney regulatory T cells were predominantly TIGIT+ and significantly reduced post-IR. TIGIT-KO mice had significantly reduced kidney injury after IR and nephrotoxic injury compared with WT mice. scRNA-Seq analysis showed enrichment of genes related to oxidative phosphorylation and mTORC1 signaling in Th17 cells from TIGIT-KO mice. TIGIT expression increases in mouse and human kidney T cells during AKI, worsens AKI outcomes, and is a novel therapeutic target for AKI.

Triptolide promotes nerve repair after cerebral ischemia reperfusion injury by regulating the NogoA/NgR/ROCK pathway.

Activation of the NogoA/NgR/ROCK pathway limits nerve repair after brain ischemia-reperfusion (I/R) injury. Triptolide displays anti-inflammatory, anti-oxidant, and immunosuppressive effects and is derived from the traditional Chinese medicine Tripterygium wilfordii Hook F. This agent can also penetrate the blood-brain barrier, where it has a neuroprotective effect and ameliorates cerebral I/R injury via an as yet unknown mechanism(s). Here, an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) was employed to assess triptolide's therapeutic impact on brain I/R injury and the possible mechanism of action. The results indicate that triptolide treatment can decrease cerebral infarction and nerve injury after cerebral I/R injury. Importantly, in vivo and in vitro experiments revealed that treatment with triptolide decreased NogoA, NgR, p75NTR and ROCK2 expression, and upregulated the expression of GAP43 and PSD-95, thus suggesting improved synaptic function. These results indicate that triptolide can promote nerve repair following brain I/R injury by inhibiting NogoA/NgR/ROCK signalling.

Puerarin alleviated oxidative stress and ferroptosis during renal fibrosis induced by ischemia/reperfusion injury via TLR4/Nox4 pathway in rats.

To investigate the role of puerarin on renal fibrosis and the underlying mechanism in renal ischemia and reperfusion (I/R) model. Rats were intraperitoneally injected with puerarin (50 or 100 mg/kg) per day for one week before renal I/R. The level of renal collagen deposition and interstitial fibrosis were observed by hematoxylin and eosin and Sirius Red staining, and the expression of α-smooth muscle actin (α-SMA) was examined by immunohistochemical staining. The ferroptosis related factors and TLR4/Nox4-pathway-associated proteins were detected by Western blotting. Puerarin was observed to alleviate renal collagen deposition, interstitial fibrosis and the α-SMA expression induced by I/R. Superoxide dismutase (SOD) activities and glutathione (GSH) level were decreased in I/R and hypoxia/reoxygenation (H/R), whereas malondialdehyde (MDA) and Fe2+ level increased. However, puerarin reversed SOD, MDA, GSH and Fe2+ level changes induced by I/R and H/R. Besides, Western blot indicated that puerarin inhibited the expression of ferroptosis related factors in a dose-dependent manner, which further demonstrated that puerarin had the effect to attenuate ferroptosis. Moreover, the increased expression of TLR/Nox4-pathway-associated proteins were observed in I/R and H/R group, but puerarin alleviated the elevated TLR/Nox4 expression. Our results suggested that puerarin inhibited oxidative stress and ferroptosis induced by I/R and, thus, delayed the progression of renal fibrosis, providing a new target for the treatment of renal fibrosis.

A Single Dose of Intravenous Human Amniotic Membrane-Derived Mesenchymal Stem Cells Limits Transmural Infarction, Reduces Fibrosis Size, and Improves Left Ventricular Systolic Function In The Myocardial Ischemic/ Reperfusion Model of Rats

A Single Dose of Intravenous Human Amniotic Membrane-Derived Mesenchymal Stem Cells Limits Transmural Infarction, Reduces Fibrosis Size, and Improves Left Ventricular Systolic Function In The Myocardial Ischemic/ Reperfusion Model of Rats

The significance of glycocalyx in surgery.

Surgical treatment is associated with an unwanted response of the organism to the so-called surgical trauma. This response is called surgical stress. Ischaemia-reperfusion injury is one of essential causes of tissue damage. It comprises functional and structural changes in tissue that occur after the restoration of circulation, after an episode of ischaemia. Necrosis of irreversibly changed cells and endothelial and mitochondrial-induced tissue swelling occur. Physiology, pathophysiology of endothelial glycocalyx: Endothelial glycocalyx is a 0.2 to 5 micrometres thin heteropolysaccharide layer that covers the endothelium on its intraluminal side. Backbone molecules of the glycocalyx include proteoglycans, glycoproteins, and glycosaminoglycans. Damage of the endothelial glycocalyx was described in trauma patients, in patients with septic shock, in ischemia and reperfusion injury, and during extensive surgical procedures. Approaches to prevent endothelial glycocalyx damage: Remote ischemic preconditioning was tested as a method of ischemia and reperfusion injury prevention during and after surgery. Nevertheless, the expected effect was not confirmed in performed meta-analyses. Endothelial glycocalyx damage can be prevented pharmacologically with a broad spectrum of substances, such as antithrombin III, doxycycline, hydrocortisone, etanercept, or nitric oxide donors. Hydrogen inhalation or albumin affects glycocalyx positively. Sulodexide provides a positive effect on the protection and reparation of endothelial glycocalyx. This proteoglycan with antithrombotic, fibrinolytic, hypofibrinogenemic, and lipolytic function is used for the treatment of venous diseases, ischaemic heart disease, and peripheral arterial disease. A positive effect of sulodexide on renal dysfunction was documented in a model of ischaemia and reperfusion injury. Equally, a positive effect of sulodexide was described on endothelium repair after its mechanical damage. Further research needs to be performed to evaluate the effect of endothelium-protectives on glycocalyx damage prevention and repair in ischaemia and reperfusion models involving large laboratory animals or in clinical trials in patients undergoing surgical revascularisation procedures.

Geraniol-Mediated Suppression of Endoplasmic Reticulum Stress Protects against Cerebral Ischemia-Reperfusion Injury via the PERK-ATF4-CHOP Pathway.

Endoplasmic reticulum (ER) stress plays an important role in cerebral ischemia-reperfusion injury (CIRI). Geraniol has antioxidant, antibacterial, and anti-inflammatory activities. Studies have shown that geraniol has a protective effect against CIRI in rats, but the exact mechanism is unclear. Purpose: The aim of this study was to investigate the protective mechanism of geraniol against CIRI. We established a middle cerebral artery occlusion reperfusion model in rats and a PC12 cell oxygen-glucose deprivation/reoxygenation (OGD/R) model to observe the neuroprotective effects of geraniol. Neurological scoring, 2,3,5-triphenyltetrazolium chloride staining, and hematoxylin and eosin staining were used to evaluate the neuroprotective effects of geraniol against CIRI. ER-stress-related and apoptosis-related protein expression was detected via Western blotting and immunofluorescence. Apoptosis was also detected via TUNEL assays and flow cytometry. The fluorescent detection of intracellular calcium was achieved using fluorescent calcium-binding dyes, and transmission electron microscopy was used to assess the neuronal ultrastructure. Geraniol effectively attenuated cerebral infarction and pathological injury after CIRI, had a protective effect against CIRI, significantly reduced the expression of the ER-stress-related proteins P-PERK, ATF4, CHOP, and GRP78 and the pro-apoptotic protein BAX, increased the expression of the anti-apoptotic protein BCL-2, and reduced the occurrence of apoptosis. In the OGD/R model in PC12 cells, the protective effect of geraniol was the same as that in vivo. Our results suggest that geraniol has a protective effect against ischemic stroke by a mechanism possibly related to ER stress via the PERK-ATF4-CHOP pathway.

Intraluminal oxygen mitigates acute mesenteric ischaemia: a systematic review of methods and outcomes in animal studies.

Acute Mesenteric Ischaemic (AMI) is a rare condition with significant morbidity and mortality. Many causes of AMI exist, which usually begin with mucosal injury. Onset is insiduous and there is frequent diagnostic delay. Current treatments can only control established injury and prevent propagation, hence new interventions are needed. The prevention and treatment of AMI by intraluminal delivery of oxygen has yet to be investigated in the clinical setting. This article aims to systemically review experimental studies investigating this novel therapy. Following the PRISMA guidelines, searches of PubMed and Ovid MEDLINE databases were performed up to June 2022. Two independent investigators extracted the data. There were 20 experimental studies, 16 of which used an occlusive ischaemia reperfusion model. Six different formulations were used to deliver intraluminal oxygen, with perflurocarbon being the most common. Studies consistently showed local and systemic benefits. Intraluminal oxygen therapy improved histological severity of mucosal injury in all studies when oxygen was delivered during the ischaemia phase, but could cause harm if given during the reperfusion phase. Improvement was also demonstrated in endpoints assessing intestinal function, biomarkers of intestinal damage, measures of systemic physiological derangement and mortality. Intraluminal oxygenation appears to be an effective treatment for AMI. There remain significant questions regarding optimal timing and delivery formulation before clinical translation of this treatment strategy.

Dexmedetomidine treatment prevents cerebral ischemic reperfusion injury through HIF-1α/Beclin1-mediated autophagy

ABSTRACT Objective Cerebral ischemic reperfusion injury (CIRI) is a common cerebrovascular disorder with high disability and morbidity that threatens human health. Former investigations found that dexmedetomidine (DEX) has a protective effect against CIRI, but regulatory mechanism is unclear. Methods The current study utilized C57BL/6 mice to establish a focal cerebral ischemic reperfusion model. Cerebral infarct volume was defined by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. BV2 cells and primary neurons were utilized for molecular mechanism studies after treatment with DEX or autophagy inhibitor 3-Methyladenine (3-Ma). Results Data revealed that DEX pretreatment protected nerves against CIRI. In vitro studies also found that DEX pretreatment enhanced microglial M2 polarization and protected against neuronal apoptosis by autophagy activation. Downregulation of hypoxia inducible factor (HIF)-1α or Beclin-1 inhibited the promotional effects of DEX on microglial M2 polarization and inhibited the protective effects of DEX against neuronal apoptosis. Conclusion The present study found that DEX treatment protects against CIRI by modulating microglial polarization via HIF-1α/Beclin1-mediated autophagy.

A Study on the Protective Effect of sRAGE-MSCs in a Rodent Reperfusion Model of Myocardial Infarction

Acute myocardial infarction (AMI) is one of the major leading causes of death in humans globally. Recently, increased levels of recruited macrophages and AGE-albumin were observed in the hearts of humans and animals with acute myocardial infarction. Thus, the purposes of this study were to investigate whether the elevated levels of AGE-albumin from activated macrophage cells are implicated in ischemia-induced cardiomyocyte death and to develop therapeutic strategies for AMI based on its underlying molecular mechanisms with respect to AGEs. The present study demonstrated that activated macrophages and AGE-albumin were observed in heart tissues obtained from humans and rats with AMI incidences. In the cellular model of AMI, it was found that increased expression of AGE-albumin was shown to be co-localized with macrophages, and the presence of AGE-albumin led to increased expression of RAGE through the mitogen-activated protein kinase pathway. After revealing cardiomyocyte apoptosis induced by toxicity of the AGE-RAGE system, sRAGE-secreting MSCs were generated using the CRISPR/Cas9 platform to investigate the therapeutic effects of sRAGE-MSCs in an AMI rat model. Gene-edited sRAGE-MSCs showed greater therapeutic effects against AMI pathogenesis in rat models compared to mock MSCs, and promising results of the functional improvement of stem cells could result in significant improvements in the clinical management of cardiovascular diseases.

LncRNA SNHG7 Knockdown Aggravates Hepatic Ischemia-Reperfusion Injury and Promotes Apoptosis in Hemorrhagic Shock Pregnant Rats by Modulating miR-34a-5p/YWHAG Axis.

Hemorrhagic shock is a frequent threat to pregnant women, and blood transfusions can contribute to organ damage, including hepatic ischemia-reperfusion (HIR) injury. LncRNA SNHG7 (SNHG7) has been reported to exert an essential role in various diseases, while the effect of SNHG7 on HIR injury induced by hemorrhagic shock and reperfusion in pregnant rats is still unclear. In our study, we examined the function and mechanism of SNHG7 in the progression of HIR injury in pregnant rats. The results showed that SNHG7 expression was low in the hepatic tissues of pregnant rats after the hemorrhagic shock and reperfusion modeling. Knockdown of SNHG7 further aggravated hepatic injury, apoptosis, and oxidative stress induced by hemorrhagic shock and reperfusion during pregnancy. Additionally, SNHG7 was bound directly to miR-34a-5p, and miR-34a-5p inhibitors partially reversed the effect of SNHG7 silencing on models of hemorrhagic shock and reperfusion. Furthermore, YWHAG is a direct target of miR-34a-5p and is negatively regulated by miR-34a-5p mimics. Overexpression of YWHAG effectively eliminated the effect of SNHG7 knockdown on pregnant rats. In summary, this investigation proved that SNHG7 knockdown exacerbated HIR injury after hemorrhagic shock in pregnant rats, and reperfusion might by mediating miR-34a-5p/YWHAG axis, indicating that SNHG7 can serve as a target gene for the treatment of HIR injury caused by hemorrhagic shock and reperfusion during pregnancy.