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Abstract Acute myocardial infarction (AMI) and related cardiovascular disease complications are the leading causes of mortality worldwide. Brown adipose tissue (BAT) is thermogenic and characterized by the uncoupling protein expression. Recent studies have found that in cardiovascular diseases, activated BAT can effectively improve the prognosis of AMI and concurrent heart failure through intercellular communication. However, a clear and systematic understanding of the myocardial protective mechanism of BAT after AMI is lacking, especially in the endocrine function of BAT. This review describes the effects of BAT on various cells in the heart after AMI. BAT plays a protective role on cardiac cells and fibroblasts during ischemia/reperfusion (I/R), myocardial remodeling, and myocardial fibrosis. This review also discusses the changes caused by BAT activation in different stages of heart failure. Finally, this review summarizes the treatment methods that target BAT to improve AMI. Further in-depth researches are still needed to clarify the underlying mechanism of the connection between BAT and different cells in cardiac tissue in order to identify potential therapeutic targets.

Acute myocardial infarction (AMI) and related cardiovascular disease complications are the leading causes of mortality worldwide. Brown adipose tissue (BAT) is thermogenic and characterized by the uncoupling protein expression. Recent studies have found that in cardiovascular diseases, activated BAT can effectively improve the prognosis of AMI and concurrent heart failure through intercellular communication. However, a clear and systematic understanding of the myocardial protective mechanism of BAT after AMI is lacking, especially in the endocrine function of BAT. This review describes the effects of BAT on various cells in the heart after AMI. BAT plays a protective role on cardiac cells and fibroblasts during ischemia/reperfusion (I/R), myocardial remodeling, and myocardial fibrosis. This review also discusses the changes caused by BAT activation in different stages of heart failure. Finally, this review summarizes the treatment methods that target BAT to improve AMI. Further in-depth researches are still needed to clarify the underlying mechanism of the connection between BAT and different cells in cardiac tissue in order to identify potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background and Aims The spleen serves as an important relay organ that releases cardioprotective factor(s) upon vagal activation during remote ischaemic conditioning (RIC) in rats and pigs. The translation of these findings to humans was attempted. Methods Remote ischaemic conditioning or electrical auricular tragus stimulation (ATS) were performed in 10 healthy young volunteers, 10 volunteers with splenectomy, and 20 matched controls. Venous blood samples were taken before and after RIC/ATS or placebo, and a plasma dialysate was infused into isolated perfused rat hearts subjected to global ischaemia/reperfusion. Results Neither left nor right RIC or ATS altered heart rate and heart rate variability in the study cohorts. With the plasma dialysate prepared before RIC or ATS, respectively, infarct size (% ventricular mass) in the recipient rat heart was 36 ± 6% (left RIC), 34 ± 3% (right RIC) or 31 ± 5% (left ATS), 35 ± 5% (right ATS), and decreased with the plasma dialysate from healthy volunteers after RIC or ATS to 20 ± 4% (left RIC), 23 ± 6% (right RIC) or to 19 ± 4% (left ATS), 26 ± 9% (right ATS); infarct size was still reduced with plasma dialysate 4 days after ATS and 9 days after RIC. In a subgroup of six healthy volunteers, such infarct size reduction was abrogated by intravenous atropine. Infarct size reduction by RIC or ATS was also abrogated in 10 volunteers with splenectomy, but not in their 20 matched controls. Conclusions In humans, vagal innervation and the spleen as a relay organ are decisive for the cardioprotective signal transduction of RIC and ATS. [ABSTRACT FROM AUTHOR]

Heart failure, a leading driver of global mortality, remains a topic of intense contemporary research interest due to the prevailing unmet need in cardiometabolic therapeutics. Numerous mechanisms with the potential to influence the onset and development of heart failure remain incompletely understood. Firstly, myocardial autophagy, which involves lysosomal degradation of damaged cellular components, confers context-dependent beneficial and detrimental effects. Secondly, sterile inflammation may arise following cardiac stress and exacerbate the progression of heart failure. Inflammation changes in a temporal manner and its onset must be adequately resolved to limit progression of heart failure. Mitochondria are an important factor in contributing to sterile inflammation by releasing damage associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA). Accordingly, this is one reason why the selective autophagy of mitochondria to maintain optimal function is important in determining cardiac function. In this review, we examine the increasing evidence suggesting crosstalk between autophagy and sterile inflammation together with their role in the development of heart failure. In particular, this is exemplified in the preclinical models of ischaemia/reperfusion injury and pressure overload induced heart failure. We also highlight potential therapeutic approaches focusing on autophagy and addressing sterile inflammation, aiming to enhance outcomes in heart failure.

Aims The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-α) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-α production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI. Methods and results HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNF-α, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-α levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNF-α levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. Conclusion HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNF-α–induced mitochondrial injury in experimental diabetes. [ABSTRACT FROM AUTHOR]

Background: Liver ischaemia/reperfusion (I/R) injury, which is an inevitable clinical problem of liver resection, liver transplantation and haemorrhagic shock. Fibroblast growth factor 21 (FGF21) was intimately coupled with multiple metabolic processes and proved to protect against apoptosis and inflammatory response in hepatocytes during hepatic I/R injury. However, the regulatory mechanisms of FGF21 in hepatic I/R injury remains unknown. Therefore, we hypothesize that FGF21 protects hepatic tissues from I/R injury. Methods: Blood samples were available from haemangiomas patients undergoing he-patectomy and murine liver I/R model and used to further evaluate the serum levels of FGF21 both in humans and mice. We further explored the regulatory mechanisms of FGF21 in murine liver I/R model by using FGF21-knockout mice (FGF21-KO mice) and FGF21-overexpression transgenic mice (FGF21-OE mice) fed a high-fat or ketogenic diet. Results: Our results show that the circulating levels of FGF21 were robustly decreased after liver I/R in both humans and mice. Silencing FGF21 expression with FGF21-KO mice aggravates liver injury at 6h after 75min of partial liver ischaemia, while FGF21-OE mice display alleviated hepatic I/R injury and inflammatory response. Compared with chow diet mice, exogenous FGF21 decreases the levels of aminotransferase, histological changes, apoptosis and inflammatory response in hepatic I/R injury treatment mice with a high-fat diet. Meanwhile, ketogenic diet mice are not sensitive to hepatic I/R injury. Conclusions: The circulating contents of FGF21 are decreased during liver warm I/R injury and exogenous FGF21 exerts hepatoprotective effects on hepatic I/R injury. Thus, FGF21 regulates hepatic I/R injury and may be a key therapeutic target. [ABSTRACT FROM AUTHOR]

Background & aimsThe stimulator of interferon genes (STING)/TANK-binding kinase 1 (TBK1) pathway is vital in mediating innate immune and inflammatory responses during oxidative/endoplasmic reticulum (ER) stress. However, it remains unknown whether macrophage thioredoxin-interacting protein (TXNIP) may regulate TBK1 function and cell death pathways during oxidative/ER stress.MethodsA mouse model of hepatic ischaemia/reperfusion injury (IRI), the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific TXNIP knockout (TXNIPM-KO) and TXNIP-proficient (TXNIPFL/FL) mice.ResultsThe TXNIPM-KO mice were resistant to ischaemia/reperfusion (IR) stress-induced liver damage with reduced serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the TXNIPFL/FL controls. IR stress increased TXNIP, p-STING, and p-TBK1 expression in ischaemic livers. However, TXNIPM-KO inhibited STING, TBK1, interferon regulatory factor 3 (IRF3), and NF-κB activation with interferon-β (IFN-β) expression. Interestingly, TXNIPM-KO augmented nuclear factor (erythroid-derived 2)-like 2 (NRF2) activity, increased antioxidant gene expression, and reduced macrophage reactive oxygen species (ROS) production and hepatic apoptosis/necroptosis in IR-stressed livers. Mechanistically, macrophage TXNIP deficiency promoted cylindromatosis (CYLD), which colocalised and interacted with NADPH oxidase 4 (NOX4) to enhance NRF2 activity by deubiquitinating NOX4. Disruption of macrophage NRF2 or its target gene 2',5' oligoadenylate synthetase-like 1 (OASL1) enhanced Ras GTPase-activating protein-binding protein 1 (G3BP1) and TBK1-mediated inflammatory response. Notably, macrophage OASL1 deficiency induced hepatocyte apoptotic peptidase activating factor 1 (APAF1), cytochrome c, and caspase-9 activation, leading to increased caspase-3-initiated apoptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated necroptosis.ConclusionsMacrophage TXNIP deficiency enhances CYLD activity and activates the NRF2-OASL1 signalling, controlling IR stress-induced liver injury. The target gene OASL1 regulated by NRF2 is crucial for modulating STING-mediated TBK1 activation and Apaf1/cytochrome c/caspase-9-triggered apoptotic/necroptotic cell death pathway. Our findings underscore a novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases.Lay summaryLiver inflammation and injury induced by ischaemia and reperfusion (the absence of blood flow to the liver tissue followed by the resupply of blood) is a significant cause of hepatic dysfunction and failure following liver transplantation, resection, and haemorrhagic shock. Herein, we uncover an underlying mechanism that contributes to liver inflammation and cell death in this setting and could be a therapeutic target in stress-induced liver inflammatory injury.

Conditions associated with chronic hypoxia increase morbidity and mortality attributable to cardiovascular complications. Myocardial hypoxia is a common feature in several diseases including: stroke, infarction, anaemia, chronic lung diseases, obstructive sleep apnoea and cyanotic congenital heart defects. The present study was planned to investigate the cardiovascular effects of chronic intermittent hypoxia and its association with increased myocardial oxidative stress. In addition, to evaluate the protective effect of chromium supplementation, aiming at achieving an alternative that may enable to devise a therapy for hypoxic patients. Male rats were allocated into three groups: control group (normoxic), untreated hypoxic group (exposed to hypoxia 8 h/day, 5 days/week for 6 weeks) and hypoxic group supplemented with chromium picolinate (90 µg/kg/day by gavage). Rats were subjected to measurement of body weight, haematocrit value, mean arterial blood pressure, heart rate and ECG recording. Cardiac activities of isolated hearts were studied on Langendorff preparation under basal conditions and in response to ischaemia/reperfusion. Thereafter, cardiac weights were determined and cardiac tissue catalase activity as well as malondialdhyde level were assessed. Significant results were obtained upon exposure to hypoxia including; low body weight, increased haematocrit, elevated blood pressure, left ventricular hypertrophy and impaired cardiac activities, basally and in response to ischaemia/reperfusion challenges, associated with increased oxidative stress in cardiac tissue. At the same time, chromium supplementation increased body weight, lowered blood pressure, reduced ventricular hypertrophy and significantly improved the cardiac performance. Chromium supplementation confers protection against hypoxia-induced cardiovascular dysfunction by improvement of the antioxidant capacity. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Myocardial protection and specifically cardioplegia have been extensively investigated in the beginnings of cardiac surgery. After cardiopulmonary bypass had become routine, more and more cardiac operations were possible, requiring reliable and reproducible protection for times of blood flow interruptions to the most energy-demanding organ of the body. The concepts of hypothermia and cardioplegia evolved as tools to extend cardiac ischaemia tolerance to a degree considered safe for the required operation. A plethora of different solutions and delivery techniques were developed achieving remarkable outcomes with cross-clamp times of up to 120 min and more. With the beginning of the new millennium, interest in myocardial protection research declined and, as a consequence, conventional cardiac surgery is currently performed using myocardial protection strategies that have not changed in decades. However, the context, in which cardiac surgery is currently performed, has changed during this time. Patients are now older and suffer from more comorbidities and, thus, other organs move more and more into the centre of risk assessment. Yet, systemic effects of cardioplegic solutions have never been in the focus of attention. They say hindsight is always 20–20. We therefore review the biochemical principles of ischaemia, reperfusion and cardioplegic extension of ischaemia tolerance and address the concepts of myocardial protection with 'hindsight from the 2020s'. In light of rising patient risk profiles, minimizing surgical trauma and improving perioperative morbidity management becomes key today. For cardioplegia, this means accounting not only for cardiac, but also for systemic effects of cardioplegic solutions. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Despite the success of coronary artery bypass graft (CABG) surgery using autologous saphenous vein grafts (SVGs), nearly 50% of patients experience vein graft disease within 10 years of surgery. One contributing factor to early vein graft disease is endothelial damage during short-term storage of SVGs in inappropriate solutions. Our aim was to evaluate the effects of a novel endothelial damage inhibitor (EDI) on SVGs from patients undergoing elective CABG surgery and on venous endothelial cells (VECs) derived from these SVGs. METHODS SVGs from 11 patients participating in an ongoing clinical registry (NCT02922088) were included in this study, and incubated with both full electrolyte solution (FES) or EDI for 1 h and then examined histologically. In 8 of 11 patients, VECs were isolated from untreated grafts, incubated with both FES and EDI for 2 h under hypothermic stress conditions and then analysed for activation of an inflammatory phenotype, cell damage and cytotoxicity, as well as endothelial integrity and barrier function. RESULTS The EDI was superior to FES in protecting the endothelium in SVGs (74 ± 8% versus 56 ± 8%, P  < 0.001). Besides confirming that the EDI prevents apoptosis in SVG-derived VECs, we also showed that the EDI temporarily reduces adherens junctions in VECs while protecting focal adhesions compared to FES. CONCLUSIONS The EDI protects the connectivity and function of the SVG endothelium. Our data suggest that the EDI can preserve focal adhesions in VECs during short-term storage after graft harvesting. This might explain the superiority of the EDI in maintaining most of the endothelium in venous CABG surgery conduits. [ABSTRACT FROM AUTHOR]

Background: Hypothermia is an effective method of reducing brain injury caused by a variety of neurological insults. It is aimed to elucidate whether a change in the expression of PERK‐mediated pathway proteins is an indicator of the neuroprotective effect of mild hypothermia after cerebral ischaemia/reperfusion. Methods: One hundred and ninety‐two male C57BL/6 mice were randomly divided into three groups: a sham group, a cerebral normothermic ischaemia/reperfusion (I/R) group and a cerebral hypothermic I/R group. A cerebral ischaemia model was established by ligating the bilateral common carotid artery for 15 min. Mice in the hypothermia group stayed in a cage that was set at 33°C, sprayed with a spray of 70% ethanol, and blown with two high‐speed fans. The state of neurons was assessed on micropreparations stained with haematoxylin–eosin and TUNEL. The expressions of GRP78, p‐perk, p‐eif2α, ATF4 and CHOP were measured by western blot analysis 6, 12, 24 and 72 h after reperfusion. Results: The number of surviving cells was significantly higher in the hypothermia group than in the group without hypothermia (p <.05). The GRP78 expression in the hypothermia group was statistically higher (p <.05) than in the ischaemia/reperfusion group. Optical densities of p‐perk, p‐eif2α and ATF4 in hippocampus CA1 neurons ischaemia were statistically significantly lower in the hypothermia group than in the ischaemia/reperfusion group (p <.05). The CHOP expression in the hypothermia group was statistically lower (p <.05) than in the ischaemia/reperfusion group. Conclusion: Mild hypothermia for 6 h promoted moderate neuroprotection by mediating the expression of GRP78, p‐PERK, p‐eIF2α, ATF4 and CHOP. [ABSTRACT FROM AUTHOR]

Retinal ischaemia/reperfusion (I/R) injury is a common cause of retinal ganglion cell (RGC) apoptosis and axonal degeneration, resulting in irreversible visual impairment. However, there are no available neuroprotective and neurorestorative therapies for retinal I/R injury, and more effective therapeutic approaches are needed. The role of the myelin sheath of the optic nerve after retinal I/R remains unknown. Here, we report that demyelination of the optic nerve is an early pathological feature of retinal I/R and identify sphingosine‐1‐phosphate receptor 2 (S1PR2) as a therapeutic target for alleviating demyelination in a model of retinal I/R caused by rapid changes in intraocular pressure. Targeting the myelin sheath via S1PR2 protected RGCs and visual function. In our experiment, we observed early damage to the myelin sheath and persistent demyelination accompanied by S1PR2 overexpression after injury. Blockade of S1PR2 by the pharmacological inhibitor JTE‐013 reversed demyelination, increased the number of oligodendrocytes, and inhibited microglial activation, contributing to the survival of RGCs and alleviating axonal damage. Finally, we evaluated the postoperative recovery of visual function by recording visual evoked potentials and assessing the quantitative optomotor response. In conclusion, this study is the first to reveal that alleviating demyelination by inhibiting S1PR2 overexpression may be a therapeutic strategy for retinal I/R‐related visual impairment. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Ischaemia and reperfusion-induced microvascular dysfunction is a serious problem encountered during a variety surgical procedures, leading to systemic inflammation and affecting remote organs, specially the lungs. 17β-Oestradiol reduces pulmonary repercussions from various acute lung injury forms. Here, we focused on the 17β-oestradiol therapeutic effects after aortic ischaemia and reperfusion (I/R) by evaluating lung inflammation. METHODS Twenty-four Wistar rats were submitted to I/R by insufflation of a 2-F catheter in thoracic aorta for 20 min. Reperfusion took 4 h and 17β-oestradiol (280 µg/kg, i.v.) was administered after 1 h of reperfusion. Sham-operated rats were controls. Bronchoalveolar lavage was performed and lung samples were prepared for histopathological analysis and tissue culture (explant). Interleukin (IL)-1β, IL-10 and tumour necrosis factor-α were quantified. RESULTS After I/R, higher number of leukocytes in bronchoalveolar lavage were reduced by 17β-oestradiol. The treatment also decreased leukocytes in lung tissue. I/R increased lung myeloperoxidase expression, with reduction by 17β-oestradiol. Serum cytokine-induced neutrophil chemoattractant 1 and IL-1β increased after I/R and 17β-oestradiol decreased cytokine-induced neutrophil chemoattractant 1. I/R increased IL-1β and IL-10 in lung explants, reduced by 17β-oestradiol. CONCLUSIONS Our results showed that 17β-oestradiol treatment performed in the period of reperfusion, modulated the systemic response and the lung repercussions of I/R by thoracic aortic occlusion. Thus, we can suggest that 17β-oestradiol might be a supplementary approach leading the lung deterioration after aortic clamping in surgical procedures. [ABSTRACT FROM AUTHOR]

Background Oxidative damage is critical in the pathogenesis of ovarian ischaemia/reperfusion (I/R) injury, and statins have been reported to exert antioxidant activity. However, the role of VCAM-1 and xanthine oxidase (XO)/uric acid (UA) in ovarian I/R injury is not known. Also, whether or not atorvastatin exerts antioxidant activity like other statins is unclear.Objectives This study investigated the involvement of VCAM-1 and XO/UA in ovarian I/R injury and the likely protective role of atorvastatin.Methods Forty female Wistar rats were randomized into sham-operated, ischaemia, ischaemia/reperfusion (I/R), ischaemia and atorvastatin, and I/R and atorvastatin.Results In comparison with the sham-operated group, atorvastatin blunted ischaemia and I/R-induced distortion of ovarian histoarchitecture and follicular degeneration. Also, atorvastatin alleviated ischaemia and I/R-induced rise in XO, UA, and malondialdehyde, which was accompanied by inhibition of ischaemia and I/R-induced reductions in reduced glutathione level, enzymatic antioxidant activities and increase in myeloperoxidase activity and TNF-α and IL-6 levels by atorvastatin treatment. Additionally, atorvastatin blocked ischaemia and I/R-induced increase in VCAM-1 expression, caspase 3 activity, 8-hydroxydeoxyguanosine level and ovarian DNA fragmentation index.Conclusion For the first time, this study revealed that atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative injury, inflammation, and apoptosis induced by ovarian ischaemia/reperfusion injury.

Objectives: This study aimed to evaluate the cardioprotective effects and mechanism of scutellarin (Scu) on heart ischaemia/reperfusion (I/R) injury by using an isolated Langendorff rat heart model. Methods: Myocardial function was evaluated via measurements of cardiac haemodynamic parameters. Myocardial infarct size was macroscopically estimated by using TTC staining. The release of creatine kinase (CK) and lactate dehydrogenase (LDH) was used to evaluate cardiac injury. GSH/GSSG, SOD, and MDA were determined as being indicators of oxidative stress. CRP, IL-6, and TNF-α were also analysed to assess inflammation in the heart tissues. Cardiomyocyte apoptosis was quantified by using a TUNEL kit. PPARγ, Nrf2, and NF-κB were assayed via Western blotting. Results: The results indicated that I/R induced significant cardiac dysfunction, myocardial infarct, and apoptosis, as well as decreasing the GSH/GSSG ratio, SOD activity, Nrf2 protein expression, and PPARγ protein expression, but increased levels of TNF-α, MDA, CRP, IL-6, and NF-κB. Conclusion: These data suggest that Scu attenuates cardiac I/R. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in the apoptotic process during cardiac ischaemia/reperfusion (I/R) injury. This study aimed to investigate whether post-treatment with dexmedetomidine (DEX) could protect against I/R-induced cardiac apoptosis in vivo and in vitro via regulating HIF-1α signalling pathway. Rat myocardial I/R was induced by occluding the left anterior descending artery for 30 minutes followed by 6-hours reperfusion, and cardiomyocyte hypoxia/reoxygenation (H/R) was induced by oxygen-glucose deprivation for 6 hours followed by 3-hours reoxygenation. Dexmedetomidine administration at the beginning of reperfusion or reoxygenation attenuated I/R-induced myocardial injury or H/R-induced cell death, alleviated mitochondrial dysfunction, reduced the number of apoptotic cardiomyocytes, inhibited the activation of HIF-1α and modulated the expressions of apoptosis-related proteins including BCL-2, BAX, BNIP3, cleaved caspase-3 and cleaved PARP. Conversely, the HIF-1α prolyl hydroxylase-2 inhibitor IOX2 partly blocked DEX-mediated cardioprotection both in vivo and in vitro. Mechanistically, DEX down-regulated HIF-1α expression at the post-transcriptional level and inhibited the transcriptional activation of the target gene BNIP3. Post-treatment with DEX protects against cardiac I/R injury in vivo and H/R injury in vitro. These effects are, at least in part, mediated via the inhibition of cell apoptosis by targeting HIF-1α signalling.

Objectives: This study aimed to evaluate the cardioprotective effects and mechanism of scutellarin (Scu) on heart ischaemia/reperfusion (I/R) injury by using an isolated Langendorff rat heart model. Methods: Myocardial function was evaluated via measurements of cardiac haemodynamic parameters. Myocardial infarct size was macroscopically estimated by using TTC staining. The release of creatine kinase (CK) and lactate dehydrogenase (LDH) was used to evaluate cardiac injury. GSH/GSSG, SOD, and MDA were determined as being indicators of oxidative stress. CRP, IL-6, and TNF-α were also analysed to assess inflammation in the heart tissues. Cardiomyocyte apoptosis was quantified by using a TUNEL kit. PPARγ, Nrf2, and NF-κB were assayed via Western blotting. Results: The results indicated that I/R induced significant cardiac dysfunction, myocardial infarct, and apoptosis, as well as decreasing the GSH/GSSG ratio, SOD activity, Nrf2 protein expression, and PPARγ protein expression, but increased levels of TNF-α, MDA, CRP, IL-6, and NF-κB. Conclusion: These data suggest that Scu attenuates cardiac I/R. [ABSTRACT FROM AUTHOR]

Oxidative damage is critical in the pathogenesis of ovarian ischaemia/reperfusion (I/R) injury, and statins have been reported to exert antioxidant activity. However, the role of VCAM-1 and xanthine oxidase (XO)/uric acid (UA) in ovarian I/R injury is not known. Also, whether or not atorvastatin exerts antioxidant activity like other statins is unclear. This study investigated the involvement of VCAM-1 and XO/UA in ovarian I/R injury and the likely protective role of atorvastatin. Forty female Wistar rats were randomized into sham-operated, ischaemia, ischaemia/reperfusion (I/R), ischaemia and atorvastatin, and I/R and atorvastatin. In comparison with the sham-operated group, atorvastatin blunted ischaemia and I/R-induced distortion of ovarian histoarchitecture and follicular degeneration. Also, atorvastatin alleviated ischaemia and I/R-induced rise in XO, UA, and malondialdehyde, which was accompanied by inhibition of ischaemia and I/R-induced reductions in reduced glutathione level, enzymatic antioxidant activities and increase in myeloperoxidase activity and TNF-α and IL-6 levels by atorvastatin treatment. Additionally, atorvastatin blocked ischaemia and I/R-induced increase in VCAM-1 expression, caspase 3 activity, 8-hydroxydeoxyguanosine level and ovarian DNA fragmentation index. For the first time, this study revealed that atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative injury, inflammation, and apoptosis induced by ovarian ischaemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

Background: Activation of caspase 3 has been implicated in the pathogenesis of I/R injury in various organs, but there is a paucity of data on its role in IIRI. Also, no reports were found on the beneficial role of methanolic Moringa oleifera leaf extract (MMOLE) in IIRI. This study investigated the involvement of caspase 3 in IIRI, and the impact of MMOLE in IIRI. Methods: Male Wistar rats were randomized into five groups; the sham-operated group that was sham-operated and received 0.5 ml of distilled water for 7 days prior to sham surgery, and the IIRI, febuxostat (FEB) +IIRI, low dose MMOLE (LDMO)+IIRI, and high dose MMOLE (HDMO)+IIRI groups that underwent I/R and also received 0.5 ml of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of MMOLE, and 400 mg/kg of MMOLE respectively for 7 days prior to I/R. Markers of hepatic function, oxidative stress, and inflammation as well as enteric bacterial translocation and histoarchitecture integrity of intestinal and hepatic tissues were evaluated. The bioactive components of MMOLE were also determined by GC-MS. Results: As revealed by GC-MS, the active bioactive components of MMOLE were thiosemicarbazone, hydrazine, 1,3-dioxolane, octanoic acid, 1,3-benzenediamine, 9-octadecenoic acid, oleic acid, nonadecanoic acid, 3-undecanone, phosphonic acid, and cyclopentanecarboxylic acid. MMOLE alleviated IIRI-induced rise in intestinal and hepatic injury markers, malondialdehyde, TNF-α, IL-6, and myeloperoxidase activities. MMOLE improved IIRI-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase and glutathione peroxidase activities. These were associated with suppression of IIRI-induced caspase 3 activity and bacterial translocation. Histopathological evaluation revealed that MMOLE attenuated IIRI-induced alterations in intestinal and hepatic histoarchitecture integrity. MMOLE also militated against increased absolute and relative intestinal and hepatic weight, intestinal and hepatic injuries, epithelial mucosal barrier dysfunction, and enteric bacterial translocation associated with IIRI by downregulating oxidative stress-mediated activation of caspase 3. Conclusion: IIRI is associated with a rise in caspase 3 activity. Also, MMOLE confers protection against IIRI, possibly due to its constituent bioactive molecules, especially hydrazine, 9-octadecenoic acid, 1,3-dioxolane, oleic acid, and nonadecanoic acid. [ABSTRACT FROM AUTHOR]

Background: Activation of caspase 3 has been implicated in the pathogenesis of I/R injury in various organs, but there is a paucity of data on its role in IIRI. Also, no reports were found on the beneficial role of methanolic Moringa oleifera leaf extract (MMOLE) in IIRI. This study investigated the involvement of caspase 3 in IIRI, and the impact of MMOLE in IIRI.Methods: Male Wistar rats were randomized into five groups; the sham-operated group that was sham-operated and received 0.5 ml of distilled water for 7 days prior to sham surgery, and the IIRI, febuxostat (FEB) +IIRI, low dose MMOLE (LDMO)+IIRI, and high dose MMOLE (HDMO)+IIRI groups that underwent I/R and also received 0.5 ml of distilled water, 10 mg/kg of febuxostat, 200 mg/kg of MMOLE, and 400 mg/kg of MMOLE respectively for 7 days prior to I/R. Markers of hepatic function, oxidative stress, and inflammation as well as enteric bacterial translocation and histoarchitecture integrity of intestinal and hepatic tissues were evaluated. The bioactive components of MMOLE were also determined by GC-MS.Results: As revealed by GC-MS, the active bioactive components of MMOLE were thiosemicarbazone, hydrazine, 1,3-dioxolane, octanoic acid, 1,3-benzenediamine, 9-octadecenoic acid, oleic acid, nonadecanoic acid, 3-undecanone, phosphonic acid, and cyclopentanecarboxylic acid. MMOLE alleviated IIRI-induced rise in intestinal and hepatic injury markers, malondialdehyde, TNF-α, IL-6, and myeloperoxidase activities. MMOLE improved IIRI-induced suppression of reduced glutathione, thiol and non-thiol proteins, and superoxide dismutase, catalase and glutathione peroxidase activities. These were associated with suppression of IIRI-induced caspase 3 activity and bacterial translocation. Histopathological evaluation revealed that MMOLE attenuated IIRI-induced alterations in intestinal and hepatic histoarchitecture integrity. MMOLE also militated against increased absolute and relative intestinal and hepatic weight, intestinal and hepatic injuries, epithelial mucosal barrier dysfunction, and enteric bacterial translocation associated with IIRI by downregulating oxidative stress-mediated activation of caspase 3.Conclusion: IIRI is associated with a rise in caspase 3 activity. Also, MMOLE confers protection against IIRI, possibly due to its constituent bioactive molecules, especially hydrazine, 9-octadecenoic acid, 1,3-dioxolane, oleic acid, and nonadecanoic acid.

This study investigated the effect of dexmedetomidine on the oxidant–antioxidant (thiol/disulphide) balance. A total of 24 rats were divided into four groups. The renal arteries in groups IR (ischaemia/reperfusion) and IR + D (ischaemia/reperfusion + dexmedetomidine) were clamped for 45 min and reperfused for 180 min. Groups D (Dexmedetomidine) and IR + D were administered 100 μg/kg dexmedetomidine. Oxidant–antioxidant (thiol/disulphide) levels were measured. Kidney tissue was examined histopathologically. No statistically difference was found between the groups in terms of thiol–disulphide averages, while IMA, TOS and thiol–disulphide results showed a minimal decrease in Group IR + D compared to Group IR (p > 0.05). Tubular lesions and necrosis were found in 26–50% of tubules in Group IR. Tubular damage and necrosis in Group IR + D declined to 5–25%. No statistically difference was found in the study where OSI index, thiol/disulphide balance and IMA were measured together as biochemical values. [ABSTRACT FROM AUTHOR]

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models. Despite this, preclinical models are limited in their ability to fully reproduce the complexity of MI in humans. The preclinical model must be carefully selected to maximise the translational potential of experimental findings. This review describes current experimental models of MI and considers how they have been used to understand drug mechanisms of action and support translational medicine development. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc [ABSTRACT FROM AUTHOR]

Abstract Background Ischaemic stroke has become the main cause of death and severe neurological disorders, for which effective restorative treatments are currently limited. While stem cell transplantation offers therapeutic potential through neural regeneration, this approach is associated with the challenges of limited applicable sources. Hair follicle stem cells (HFSCs) are multipotential cells that can differentiate into ectodermal and mesodermal lineages and proliferate for long periods. The therapeutic potentials of HFSCs have not been investigated in ischaemic stroke models, and therefore, in this study, we aimed to determine whether they could survive and migrate to ischaemic areas after a stroke attack. Methods A rat model of middle cerebral artery ischaemia/reperfusion was established and intravenously administered HFSCs. The potential of HFSCs to migrate and differentiate into neuron-like cells as well as their ability to reduce the infarct size was evaluated. Rat brain tissue samples were collected 2 weeks after cell transplantation and analysed via TTC staining, immunofluorescence and immunohistochemistry methods. The data were statistically analysed and presented as the means ± standard deviations. Results Intravenously administrated rat HFSCs were able to migrate to the penumbra where they expressed neuron-specific markers, reduced the infarct volume and promoted neurological recovery. Conclusion HFSC transplantation has therapeutic potential for ischaemic stroke and is, therefore, worthy of further investigation toward possible clinical development for treating stroke patients.

Deep hypothermic circulatory arrest (DHCA) can cause acute lung injury (ALI), and its pathogenesis mimics ischaemia/reperfusion (I/R) injury. Autophagy is also involved in lung I/R injury. The present study aimed to elucidate whether DHCA induces natural autophagy activation and its role in DHCA‐mediated lung injury. Here, rats were randomly assigned to the Sham or DHCA group. The sham group (n = 5) only received anaesthesia and air intubation. DHCA group rats underwent cardiopulmonary bypass (CPB) followed by the DHCA procedure. The rats were then sacrificed at 3, 6 and 24 h after the DHCA procedure (n = 5) to measure lung injury and autophagy activity. Chloroquine (CQ) was delivered to evaluate autophagic flux. DHCA caused lung injury, which was prominent 3–6 h after DHCA, as confirmed by histological examination and inflammatory cytokine quantification. Lung injury subsided at 24 h. Autophagy was suppressed 3 h but was exaggerated at 6 h. At both time points, autophagic flux appeared uninterrupted. To further assess the role of autophagy in DHCA‐mediated lung injury, the autophagy inducer rapamycin and its inhibitor 3‐methyladenine (3‐MA) were applied, and lung injury was reassessed. When rapamycin was administered at an early time point, lung injury worsened, whereas administration of 3‐MA at a late time point ameliorated lung injury, indicating that autophagy contributed to lung injury after DHCA. Our study presents a time course of lung injury following DHCA. Autophagy showed adaptive yet protective suppression 3 h after DHCA, as induction of autophagy caused worsening of lung tissue. In contrast, autophagy was exaggerated 6 h after DHCA, and autophagy inhibition attenuated DHCA‐mediated lung injury. [ABSTRACT FROM AUTHOR]

Ischaemia/reperfusion injury (IRI) is an inevitable and damaging consequence of the process of kidney transplantation, ultimately leading to delayed graft function and increased risk of graft loss. A key driver of this adverse reaction in kidneys is activation of the complement system, an important part of the innate immune system. This activation causes deposition of complement C3 on renal tubules as well as infiltration of immune cells and ultimately damage to the tubules resulting in reduced kidney function. Collectin-11 (CL-11) is a pattern recognition molecule of the lectin pathway of complement. CL-11 binds to a ligand that is exposed on the renal tubules by the stress caused by IRI, and through attached proteases, CL-11 activates complement and this contributes to the consequences outlined above. Recent work in our lab has shown that this damage-associated ligand contains a fucose residue that aids CL-11 binding and promotes complement activation. In this review, we will discuss the clinical context of renal transplantation, the relevance of the complement system in IRI, and outline the evidence for the role of CL-11 binding to a fucosylated ligand in IRI as well as its downstream effects. Finally, we will detail the simple but elegant theory that increasing the level of free fucose in the kidney acts as a decoy molecule, greatly reducing the clinical consequences of IRI mediated by CL-11. [ABSTRACT FROM AUTHOR]

Although the liver is the only organ with regenerative capacity, various injury factors induce irreversible liver dysfunction and end‐stage liver disease. Liver resection and liver transplantation (LT) are effective treatments for individuals with liver failure, liver cirrhosis and liver cancers. The remnant or transplanted liver tissues will undergo hepatic ischaemia/reperfusion (IR), which leads to oxidative stress, inflammation, immune injury and liver damage. Moreover, systemic ischaemia induced by trauma, stroke, myocardial ischaemia, haemorrhagic shock and other injury factors also induces liver ischaemia/reperfusion injury (IRI) in individuals. Hepatic IRI can be divided into warm IRI, which is induced by liver surgery and systemic ischaemia, and cold IRI, which is induced by LT. Multiple studies have shown that melatonin (MT) acts as an endogenous free radical scavenger with antioxidant capacity and is also able to attenuate hepatic IRI via its anti‐inflammatory and antiapoptotic capacities. In this review, we discuss the potential mechanisms and current strategies of MT administration in liver surgery for protecting against warm or cold hepatic IRI. We highlight strategies to improve the efficacy and safety of MT for attenuating hepatic IRI in different conditions. After the potential mechanisms underlying the interactions between MT and other important cellular processes during hepatic IR are clarified, more opportunities will be available to use MT to treat liver diseases in the future. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischaemia/reperfusion (I/R) results in myocardial injury via excessive autophagy. Huoxue Jiedu Formula (HJF) has been widely applied in China for the treatment of ischaemic heart disease. However, the mechanisms of HJF are still poorly understood. Thus, the present experiment was designed to observe the effects of HJF on myocardial I/R injury and explore the possible mechanism.Methods: Myocardial injury in rats subjected to myocardial I/R was reflected by nitrotetrazolium blue chloride staining, thioflavin S staining, serum creatine kinase-MB (CK-MB) and cardiac troponin T (cTnT). Autophagy was determined by electron microscopy, laser confocal microscopy, Q-PCR and western blot. The possible pathway was predicted by network pharmacology and validated in vivo and in vitro.Results: Pretreatment of HJF decreased the no-reflow area, infarcted area, serum CK-MB levels and serum cTnT levels in I/R rat model. In addition, pretreatment of HJF decreased autophagy in heart tissues (decrease in Beclin-1 and LC3-II, and increase in Bcl-2, p62 and ratio of LC3-I/LC3-II). In the vivo study, pretreatment of HJF significantly decreased hypoxia/reoxygenation (H/R)-induced autophagy in H9C2 cells. Network pharmacology was applied to predict the possible mechanism by which HJF affects cardiac autophagy, and the PI3K/AKT/mTOR signalling pathway was the most significantly enriched pathway. And experimental studies demonstrated that pretreatment of HJF increased the phosphorylation of AKT and mTOR, and the effects of HJF on autophagy would be offset by PI3K inhibitor LY294002.Conclusion: Pretreatment of HJF ameliorates myocardial I/R injury by decreasing autophagy through activating PI3K/AKT/mTOR pathway.

Background and objectiveAnaesthetic preconditioning (APC) protects against myocardial ischaemia/reperfusion injury. Nuclear factor-kappaB (NF-kappaB) has been implicated in APC-induced myocardial protection in vitro. Our study tested the hypothesis that in-vivo APC with sevoflurane is triggered by NF-kappaB through downregulation of inflammatory mediators and upregulation of antiapoptosis factors to prevent myocardial injury during ischaemia/reperfusion.MethodsIn this in-vivo study, rats were anaesthetized and maintained with sodium pentobarbital throughout the experiment. Rats were exposed to 30 min of 2.5% sevoflurane followed by 15 min washout (APC group) or no inhalation anaesthetics (ischaemia/reperfusion group) before ischaemia/reperfusion. In the sevoflurane group, rats were exposed to 30 min sevoflurane followed by a 165 min washout period. The NF-kappaB inhibitor parthenolide (PTN) was used before or after exposure to sevoflurane (PTN+APC group and APC+PTN group). Left ventricular samples were obtained to measure infarct size, pro-inflammation and apoptosis. A P value less than 0.05 was considered significant.ResultsAPC reduced infarct size (34 +/- 6%) compared with ischaemia/reperfusion (53 +/- 6%, P

Despite advancements in management of acute myocardial infarction, this disease remains one of the leading causes of death. Timely reestablishment of epicardial coronary blood flow is the cornerstone of therapy; however, substantial amount of damage can occur as a consequence of cardiac ischaemia/reperfusion (I/R) injury. It has been previously proposed that the pathway leading to major cell death, apoptosis, is responsible for cardiac I/R injury. Nevertheless, there is compelling evidence to suggest that necroptosis, a programmed necrosis, contributes remarkably to both myocardial injury and microcirculatory dysfunction following cardiac I/R injury. Receptor‐interacting protein kinase 1 (RIPK1), RIPK3, and mixed‐lineage kinase domain‐like pseudokinase (MLKL) are shown as the major mediators of necroptosis. In addition to the traditional perception that RIPK1/RIPK3/MLKL‐dependent plasma membrane rupture is fundamental to this process, several RIPK3‐related pathways such as endoplasmic reticulum stress and mitochondrial fragmentation have also been implicated in cardiac I/R injury. In this review, reports from both in vitro and in vivo studies regarding the roles of necroptosis and RIPK3‐regulated necrosis in cardiac I/R injury have been collectively summarized and discussed. Furthermore, reports on potential interventions targeting these processes to attenuate cardiac I/R insults to the heart have been presented in this review. Future investigations adding to the knowledge obtained from these previous studies are needed in the pursuit of discovering the most effective pharmacological agent to improve cardiac I/R outcomes. [ABSTRACT FROM AUTHOR]

miRNA‐mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR‐383‐dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR‐383 overexpression or miR‐383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR‐383. Pyroptosis‐related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis‐related mediators including NLRP3, cleaved caspase‐1, cleaved IL‐1β and IL‐18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI‐caused elevation of miR‐383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR‐383 target. miR‐383 knockdown ameliorated but miR‐383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti‐pyroptotic effect from miR‐383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR‐383/RP105/AKT‐dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR‐383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI. [ABSTRACT FROM AUTHOR]

Testicular torsion is a serious urological disease leading to testicular damage. This study aimed to assess the effect of minocycline on testicular ischaemia/reperfusion (I/R) injury caused by testicular torsion/detorsion. Male adult Wistar rats (n = 32) were assigned into four groups of sham, I/R, I/R + minocycline and minocycline. I/R injury was induced by two sets of surgical operations, including the rotation of the left testis (720°, counterclockwise), followed by detorsion after 4 hr. The administration of minocycline was carried out 30 min before detorsion and then continued for 8 weeks. At the end of the 8th week, rats were killed and sampling was done. Johnson's score, the height of seminiferous tubule epithelium, the mean seminiferous tubule diameter, as well as biochemical parameters, SOD, GPx and CAT, were significantly enhanced in the I/R + minocycline group compared with the I/R group. The administration of minocycline led to a marked decrease in expression levels of Caspase‐3, Bax, IL‐1β and TNF‐α genes, and a remarkable increase in expression levels of Bcl‐2, 3β‐HSD and 17β‐HSD3 genes compared with the I/R group. Administration of minocycline could also reduce the rate of germ cell apoptosis (TUNEL staining). Hence, minocycline was useful in the management of testicular torsion/detorsion. [ABSTRACT FROM AUTHOR]

Background: Ischaemic stroke has become the main cause of death and severe neurological disorders, for which effective restorative treatments are currently limited. While stem cell transplantation offers therapeutic potential through neural regeneration, this approach is associated with the challenges of limited applicable sources. Hair follicle stem cells (HFSCs) are multipotential cells that can differentiate into ectodermal and mesodermal lineages and proliferate for long periods. The therapeutic potentials of HFSCs have not been investigated in ischaemic stroke models, and therefore, in this study, we aimed to determine whether they could survive and migrate to ischaemic areas after a stroke attack. Methods: A rat model of middle cerebral artery ischaemia/reperfusion was established and intravenously administered HFSCs. The potential of HFSCs to migrate and differentiate into neuron-like cells as well as their ability to reduce the infarct size was evaluated. Rat brain tissue samples were collected 2 weeks after cell transplantation and analysed via TTC staining, immunofluorescence and immunohistochemistry methods. The data were statistically analysed and presented as the means ± standard deviations. Results: Intravenously administrated rat HFSCs were able to migrate to the penumbra where they expressed neuron-specific markers, reduced the infarct volume and promoted neurological recovery. Conclusion: HFSC transplantation has therapeutic potential for ischaemic stroke and is, therefore, worthy of further investigation toward possible clinical development for treating stroke patients. [ABSTRACT FROM AUTHOR]

Aims Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood–brain barrier (BBB) is crucially involved in ischaemia/reperfusion (I/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke. Methods and results SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6−/−) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6−/− animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6−/− mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia/reoxygenation (H/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I/R. Further, SIRT6 -silenced HBMVECs exposed to H/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome. Conclusion Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Circular RNA YAP1 (circYAP1) was reported to participate in progression of gastric cancer. However, the role of circYAP1 in acute kidney injury (AKI) remains obscure. We attempted to examine the effects of circYAP1 on ischaemia/reperfusion‐stimulated renal injury. AKI model was established by treating HK‐2 cells in ischaemia/reperfusion (I/R) environment. CircYAP1 expression in blood of AKI patients and I/R‐treated HK‐2 cells was evaluated via RT‐qPCR. CCK‐8, flow cytometry, ELISA and ROS assay were executed to test the impact of circYAP1 on cell viability, apoptosis, inflammatory cytokines and ROS generation. Bioinformatic analysis was executed to explore miRNA targets. The relativity between circYAP1 and miR‐21‐5p was verified by RT‐qPCR and luciferase assay. The functions of miR‐21‐5p in I/R‐triggered injury were reassessed. PI3K/AKT/mTOR pathway was detected by Western blot. Down‐regulated circYAP1 was observed in AKI blood samples and I/R‐treated HK‐2 cells. CircYAP1 overexpression expedited cell growth and weakened secretion of inflammatory factors and ROS generation in I/R‐disposed cells. Besides, we found circYAP1 could sponge to miR‐21‐5p. Interestingly, miR‐21‐5p overexpression overturned the repressive effects of circYAP1 on cell injury. Moreover, PI3K/AKT/mTOR pathway was activated by circYAP1 via inhibiting miR‐21‐5p. We demonstrated that circYAP1 activated PI3K/AKT/mTOR pathway and secured HK‐2 cells from I/R injury via sponging miR‐21‐5p. [ABSTRACT FROM AUTHOR]

This document is a reply to a letter from Dr. Condello regarding a review on myocardial protection. The authors of the review agree with Dr. Condello's comments on technical aspects such as post-conditioning, the impact of aortic regurgitation on cardioplegia delivery, and differences in delivery routes. They also acknowledge that there are other factors to consider, such as the timing and temperature of cardioplegia delivery. However, the authors emphasize that none of these individual factors have been shown to make a significant difference in myocardial protection. They believe that the quality of myocardial protection is more related to the surgeon's attention to avoiding damage rather than one specific aspect. The authors appreciate the discussion and consider it valuable for surgeons to adapt their myocardial protection strategies as needed. [Extracted from the article]

An increase in phosphorylated tau (p-tau) is associated with Alzheimer's disease (AD), and brain hypoxia. Investigation of the association of residue-specific tau hyperphosphorylation and changes in cognition, leads to greater understanding of its potential role in the pathology of memory impairment. The aims of this study are to investigate the involvement of the main metabolic kinases, Liver Kinase B1 (LKB1) and Adenosine Monophosphate Kinase Protein Kinase (AMPK), in tau phosphorylation-derived memory impairment, and to study the potential contribution of the other tau kinases and phosphatases including Glycogen Synthase Kinase (GSK-3β), Protein kinase A (PKA) and Protein Phosphatase 2A (PP2A). Spatial memory and learning were tested in a rat global brain ischemic model of reversible cardiac arrest (CA). The phosphorylation levels of LKB1, AMPK, GSK-3β, PP2A, PKA and tau-specific phosphorylation were assessed in rats, subjected to ischaemia/reperfusion and in clinically diagnosed AD and normal human brains. LKB1 and AMPK phosphorylation increased 4 weeks after CA as did AMPK related p-tau (Ser262). The animals showed unchanged levels of GSK-3β specific p-tau (Ser202/Thr205), phospho-PP2A (Tyr307), total GSK-3β, PP2A, phospho-cAMP response element-binding protein (CREB) which is an indicator of PKA activity, and no memory deficits. AD brains had hyperphosphorylated tau in all the residues of Ser262, Ser202 and Thr205, with increased phosphorylation of both AMPK (Thr172) and GSK-3β (Ser9), and reduced PP2A levels. Our data suggests a crucial role for a combined activation of tau kinases and phosphatases in adversely affecting memory and that hyperphosphorylation of tau in more than one specific site may be required to create memory deficits.

Background: Vascular endothelial cell dysfunction, characterized by cell apoptosis and migration, plays a crucial role in ischaemia/reperfusion (I/R) injury, a common aspect of cardiovascular diseases. Recent studies have suggested that non-coding RNAs, such as circular RNAs (circRNA), play a role in cell dysfunction in I/R injury, although the detailed mechanism is unclear. Methods: Human umbilical vein endothelial cells (HUVECs) were used for in vitro I/R model. Protein expression was detected by western blotting (WB) and immunocytochemistry. The CRISPR/Cas9 system, WB, cell viability assays, Hoechst staining and a 3D migration model were used to explore functional changes. RNA expression was evaluated using quantitative real-time PCR and a FISH assay combined with lentivirus transfection regulating circRNAs and miRNAs. A mouse myocardial I/R model using C57 mice was established to confirm the in vitro findings. Results: In HUVECs, I/R induced a significant time-dependent decrease in HECTD1 associated with an approximately 45% decrease in cell viability and increases in cell apoptosis and migration, which were attenuated by HECTD1 overexpression. I/R-induced upregulation of endoplasmic reticulum stress was also attenuated HECTD1 overexpression. Moreover, miR-143 mimics inhibited HECTD1 expression, which was restored by circDLGAP4 overexpression, providing insight as to the molecular mechanism of I/R-induced HECTD1 in endothelial cell dysfunction. Conclusion: Our results suggest a critical role for circDLGAP4 and HECTD1 in endothelial cell dysfunction induced by I/R, providing novel insight into potential therapeutic targets for the treatment of myocardial ischaemia. [ABSTRACT FROM AUTHOR]

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in cardiovascular disease by modulating apoptosis and oxidative stress. We hypothesized that LOX-1 may be involved in pathophysiology of stroke by mediating ischaemia/reperfusion (I/R)-dependent cell death. Transient middle cerebral artery occlusion (tMCAO) was performed in wild-type (WT) mice, endothelial-specific LOX-1 transgenic mice (eLOX-1TG) and WT animals treated with LOX-1 silencing RNA (siRNA). In WT mice exposed to tMCAO, LOX-1 expression and function were increased in the MCA. Compared to WT animals, eLOX-1TG mice displayed increased stroke volumes and worsened outcome after I/R. Conversely, LOX-1-silencing decreased both stroke volume and neurological impairment. Similarly, in HBMVECs, hypoxia/reoxygenation increased LOX-1 expression, while LOX-1 overexpressing cells showed increased death following hypoxia reoxygenation. Increased caspase-3 activation was observed following LOX-1 overexpression both in vivo and in vitro, thus representing a likely mediator. Finally, monocytes from ischaemic stroke patients exhibited increased LOX-1 expression which also correlated with disease severity. Our data unequivocally demonstrate a key role for LOX-1 in determining outcome following I/R brain damage. Our findings could be corroborated in human brain endothelial cells and monocytes from patients, underscoring their translational relevance and suggesting siRNA-mediated LOX-1 knockdown as a novel therapeutic strategy for stroke patients. [ABSTRACT FROM AUTHOR]

Sildenafil is a phosphodiesterase type 5 inhibitor which confers cardioprotection against myocardial ischaemia/reperfusion (I/R) injury. The aim of this study was to determine if Trx1 participates in cardioprotection exerted by sildenafil in an acute model of I/R, and to evaluate mitochondrial bioenergetics and cellular redox status. Langendorff-perfused hearts from wild type (WT) mice and a dominant negative (DN-Trx1) mutant of Trx1 were assigned to placebo or sildenafil (0.7 mg/kg i.p.) and subjected to 30 min of ischaemia followed by 120 min of reperfusion. WT + S showed a significant reduction of infarct size (51.2 ± 3.0% vs. 30 ± 3.0%, p <.001), an effect not observed in DN-Trx. After I/R, sildenafil preserved state 3 oxygen consumption from WT, but had a milder effect in DN-Trx1 only partially protecting state 3 values. Treatment restored respiratory control (RC) after I/R, which resulted 8% (WT) and 24% (DN-Trx1) lower than in basal conditions. After I/R, a significant increase in H2O2 production was observed both for WT and DN-Trx (WT: 1.17 ± 0.13 nmol/mg protein and DN-Trx: 1.38 ± 0.12 nmol/min mg protein). With sildenafil, values were 21% lower only in WT I/R. Treatment decreased GSSG levels both in WT and DN-Trx1. In addition, GSSG/GSH2 ratio was partially restored by sildenafil. Also, an increase in p-eNOS/eNOS even before the myocardial ischaemia was observed with sildenafil, both in WT (14%, p >.05) and in DN-Trx (35%, p <.05). Active Trx1 is required for the onset of the cardioprotective effects of sildenafil on I/R injury, together with the preservation of cellular redox balance and mitochondrial function. [ABSTRACT FROM AUTHOR]

Ischemic heart disease is a leading cause of death on a global scale, placing major socio-economic burdens on health systems worldwide. Myocardial ischaemia and reperfusion (I/R)-induced tissue injury is associated with alteration in activity of inflammatory system and nitric oxide pathway. Sumatriptan, which is mainly used to relieve migraine headache, has recently been shown to exert anti-inflammatory properties. In this study, we aimed to assess the possible cardioprotective effect of sumatriptan in a rat model of I/R injury. Male Wistar rats were subjected to 30-min ligation of left anterior descending coronary artery and 120-min reperfusion. Animals were randomly divided into five groups: (1) Sham (2) I/R (3) I/R treated with sumatriptan (0.3 mg/kg i.p.) 20 min after induction of I/R rats, (4) GR127935 (a selective antagonist of 5-HT1B/D serotonin receptors; 0.3 mg/kg) 20 min after induction of I/R, and (5) GR127935 (0.3 mg/kg) 15 min before administration of sumatriptan. Post-infarct treatment with sumatriptan increased left ventricular function, which was damaged in I/R animal's heart. Sumatriptan (0.3 mg/kg) decreased lipid peroxidation, CK-MB and lactate dehydrogenase levels; tumor necrosis factor concentration; and Nf-ҡB' protein production. Treatment with sumatriptan significantly increased the endothelial nitric oxide synthase (eNOS) expression consequences nitric oxide metabolites' level in I/R rats. Also, injection of sumatriptan remarkably decreased myocardial tissue injury assessed by histopathological study. These findings suggest that sumatriptan may attenuate I/R injury via modulating the inflammatory responses and endothelial NOS activity. But therapeutic index of sumatriptan is narrow according to the result of this study. [ABSTRACT FROM AUTHOR]

Objectives. The hypothermic circulatory arrest (HCA) is still of paramount importance in aortic arch surgery, but the safe period of the arrest is limited. Remote ischaemic preconditioning (RIPC) prepares the cerebral tissue for ischaemic insult. Prolongation of the permissible period of HCA with RIPC may have a major impact on the outcome of aortic operations requiring cessation of blood flow by decreasing the rate of neurological deficits. Design. Twenty pigs were randomised into the RIPC group (n  =  10) and the control group (n  =  10). The RIPC group underwent four cycles of transient hind limb ischaemia. Both groups underwent cooling with cardiopulmonary bypass to 11 °C followed by a 45-minute HCA and re-warming to 36 °C. Cerebral blood flow was measured with a transit time ultrasonic flowmeter from the right common carotid artery, and the arteriovenous oxygen difference was calculated from sagittal sinus and arterial blood samples. Measurements were taken at several time points during cooling and warming. Temperature coefficient (Q10) was calculated to determine estimated permissible periods of HCA. Results. The Q10 was 2.27 (1.98-2.58) for the RIPC group and 1.87 (1.61-2.25) for the control group. The permissible period of HCA at 18 °C was 26 minutes (20-33) in the RIPC group and 17 minutes (13-25) in the control group (p = .063)(Data expressed in medians and interquartile ranges). Conclusions. RIPC tends to suppress cerebral metabolism during cooling with cardiopulmonary bypass and may prolong estimated permissible period of HCA. [ABSTRACT FROM AUTHOR]

Objectives. The hypothermic circulatory arrest (HCA) is still of paramount importance in aortic arch surgery, but the safe period of the arrest is limited. Remote ischaemic preconditioning (RIPC) prepares the cerebral tissue for ischaemic insult. Prolongation of the permissible period of HCA with RIPC may have a major impact on the outcome of aortic operations requiring cessation of blood flow by decreasing the rate of neurological deficits. Design. Twenty pigs were randomised into the RIPC group (n  =  10) and the control group (n  =  10). The RIPC group underwent four cycles of transient hind limb ischaemia. Both groups underwent cooling with cardiopulmonary bypass to 11 °C followed by a 45-minute HCA and re-warming to 36 °C. Cerebral blood flow was measured with a transit time ultrasonic flowmeter from the right common carotid artery, and the arteriovenous oxygen difference was calculated from sagittal sinus and arterial blood samples. Measurements were taken at several time points during cooling and warming. Temperature coefficient (Q10) was calculated to determine estimated permissible periods of HCA. Results. The Q10 was 2.27 (1.98-2.58) for the RIPC group and 1.87 (1.61-2.25) for the control group. The permissible period of HCA at 18 °C was 26 minutes (20-33) in the RIPC group and 17 minutes (13-25) in the control group (p = .063)(Data expressed in medians and interquartile ranges). Conclusions. RIPC tends to suppress cerebral metabolism during cooling with cardiopulmonary bypass and may prolong estimated permissible period of HCA. [ABSTRACT FROM AUTHOR]

Background: Ischemia heart disease is one of the major causes of death worldwide which often associated with tissue infarction and limit the recovery of function. Multiple factors involved in the I/R-induced cardiomyocyte dysfunction which were consistent with a role of oxidative stress and altered endothelium-dependent responses. However, the pathogenic mechanisms in I/R injury remain unclear. Materials and methods: The H9C2 cells were in the ischaemia/reperfusion (I/R) condition. After I/R, the cells were transfected with or without adenovirus-urothelial carcinoma associated 1(Ad-UCA1). Then qRT-PCR analysis was performed to quantify mRNA expression of different treatment groups. Cell apoptosis rate was assessed using flow cytometry and ER stress biomarker expression were measured by immunoblotting. Intracellular and mitochondrial ROS generation were assayed by fluorescence microscope after staining with the DCFDA or MitoSOX. Results: I/R conditions trigger lncRNAs UCA1 expression, cellular and mitochondria ROS production, resulting in cell apoptosis through the induction of oxidative and ER stress. Overexpression of UCA1 protects H9C2 cells from I/R-induced ER stress and cell apoptosis. Moreover, UCA1 might be a potential regulator in the protective effect of I/R‑induced oxidative stress and mitochondria dysfunction. Subsequently, ER stress inhibitor attenuated the effect of siUCA1 induced injury in H9C2 cells. Conclusion: The expression of UCA1 against I/R induced oxidative stress and mitochondria dysfunction via suppression of endoplasmic reticulum stress. UCA1 might be a biomarker to improved diagnosis of I/R injury. [ABSTRACT FROM AUTHOR]

Long non‐coding RNAs (lncRNAs) have been identified as playing critical roles in multiple diseases. However, little is known regarding their roles and mechanisms in post‐stroke angiogenesis. Our studies focused on deciphering the functional roles and the underlying mechanisms of the lncRNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) in the process of angiogenesis following oxygen‐glucose deprivation/reoxygenation (OGD/R). We characterized the up‐regulation of MALAT1 expression in the process of angiogenesis after hypoxic injury in vivo and in vitro. We further showed that compared with the empty vector, MALAT1 knockdown had significantly reduced the capacity for angiogenesis, which was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium (MTT), scratching, cell cycle and immunofluorescent staining. Thus, our findings suggest that MALAT1 may mediate proangiogenic function in OGD/R. To further explore the potential mechanisms, we used lentiviruses expressing shMALAT1 and empty vector; the results revealed that shMALAT1 reduced the expression of 15‐lipoxygenase 1 (15‐LOX1), vascular endothelial growth factor (VEGF) and the phosphorylation of signal transducers and activators of transcription 3 (pSTAT3). Taken together, our results are the first to propose that MALAT1 may regulate angiogenesis through the 15‐LOX1/STAT3 signalling pathway, and they may provide a critical target for the treatment of hypoxic injury and an avenue for therapeutic angiogenesis. [ABSTRACT FROM AUTHOR]

Background: We have previous evidence that in anesthetized dogs the inorganic sodium nitrite protects against the severe ventricular arrhythmias, resulting from coronary artery occlusion and reperfusion, when administered 24 h before. The present study aimed to examine, whether in this effect changes in mitochondrial morphology and function would play a role.Methods: Thirty dogs were infused intravenously either with saline (n = 15) or sodium nitrite (0.2 μmol/kg/min; n = 15) for 20 min, and 24 h later, 10 dogs from each group were subjected to a 25 min period of occlusion and then reperfusion of the left anterior descending coronary artery. The severity of ischaemia and ventricular arrhythmias were examined in situ. Left ventricular tissue samples were collected either before the occlusion (5 saline and 5 nitrite treated dogs) or, in dogs subjected to occlusion, 2 min after reperfusion. Changes in mitochondrial morphology, in complex I and complex II-dependent oxidative phosphorylation (OXPHOS), in ATP, superoxide, and peroxynitrite productions were determined.Results: The administration of sodium nitrite 24 h before ischemia/reperfusion significantly attenuated the severity of ischaemia, and markedly reduced the number and incidence of ventricular arrhythmias. Nitrite also attenuated the ischaemia and reperfusion (I/R)-induced structural alterations, such as reductions in mitochondrial area, perimeter, and Feret diameter, as well as the increase in mitochondrial roundness. The administration of nitrite, however, enhanced the I/R-induced reduction in the mitochondrial respiratory parameters; compared to the controls, 24 h after the infusion of nitrite, there were further significant decreases, e.g., in the complex I-dependent OXPHOS (by −20 vs. −53%), respiratory control ratio (by −14 vs. −61%) and in the P/E control coupling ratio (by 2 vs. −36%). Nitrite also significantly reduced the I/R-induced generation of superoxide, without substantially influencing the ATP production.Conclusions: The results suggest that sodium nitrite may have an effect on the mitochondria; it preserves the mitochondrial structure and modifies the mitochondrial function, when administered 24 h prior to I/R. We propose that nitrite affects primary the phosphorylation system (indicated by the decreased P/E ratio), and the reduction in superoxide production would result from the subsequent suppression of the ROS producing complexes; an effect which may certainly contribute to the antiarrhythmic effect of nitrite.

Among the different causes of gynecological acute pelvic pain, ovarian torsion represents a surgical emergency. It is a rare case in the pediatric/adolescent aged group that must be included in the differential diagnosis of any girl with abdominal pain or pelvic/abdominal mass. Current recommendations suggest that laparoscopic detorsion should be performed in order to preserve the integrity of the ovaries and fertility, although oophoropexy may be considered in case of severe necrosis. Nevertheless, maintaining the circulation of the ovary after detorsion deteriorates the tissue injury and leads to a pathologic process called ischaemia/reperfusion (I/R) injury, which is characterized by oxidative stress. During the detorsion process, an excess amount of molecular oxygen is supplied to the tissues, and reactive species of oxygen (ROS) such as superoxide radical (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH•), as well as reactive nitrogen species (RNS) are produced in excess. ROS, RNS and their toxic products cause DNA damage and lipid peroxidation in the cellular and mitochondrial membranes, leading to cell death. In spite of attention on this topic, currently there is no shared and clear evidence about the use of anti-inflammatory and antioxidant agents to prevent I/R damage after laparoscopic ovarian detorsion. Considering this element, future research should aim to develop shared protocols for the clinical use (route of application, dosage and time of application) of antioxidants after laparoscopic management of this condition.

Objectives In the presence of ischaemia/reperfusion (I/R) induced endothelial injury, volume administration may not correlate with increased microcirculation. The aim of this study was to evaluate intestinal microcirculation after standardised sequential volume loading in an animal model of I/R injury following supracoeliac aortic clamping. Methods This was a prospective exploratory pilot animal study. Intestinal I/R injury was induced in eight pigs during experimental thoraco-abdominal aortic repair. After 6 h of I/R, microcirculatory blood flow (mFlux, measured in the ileum using direct laser speckle contrast imaging) and macrohaemodynamic parameters (using trans-cardiopulmonary thermodilution) were measured and measurements were repeated after each of four sequential volume loading steps (VLS1 – 4). Each load was administered over 5 min followed by another 5 min for equilibration. Results All animals survived until after VLS4. After 6 h of I/R cardiac output (CO) (p <.001) and mFlux (p <.001) had both decreased. CO increased again after VLS1 (p <.001) and VLS2 (p =.036), whereas mFlux did not change. In contrast, mFlux further decreased after VLS3 (p <.01) and VLS4 (p <.001), whereas CO did not change anymore. Extravascular lung water continued to increase after VLS2 (p =.046) and VLS4 (p =.049). Conclusions I/R leads to impaired intestinal microcirculation, which was not restored by volume administration in spite of improved CO. In contrast, further volume administration exceeding preload reserves was associated with additional decreases in the intestinal microcirculation. The potentially negative effect of excessive volume resuscitation after I/R injury should encourage further translational research. [ABSTRACT FROM AUTHOR]

Aims Previous studies indicate that nitric oxide derived from endothelial nitric oxide synthase (eNOS) serves as both trigger and mediator in anaesthetic cardiac preconditioning. The mechanisms underlying regulation of eNOS by volatile anaesthetics have not been fully understood. Therefore, this study examined the role of vascular endothelial growth factor (VEGF) in isoflurane cardiac preconditioning. Methods and results Wistar rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Isoflurane given prior to ischaemia/reperfusion significantly decreased myocardial infarct size from 60 ± 1% in control to 40 ± 3% (n  = 8 rats/group, P  < 0.05). The beneficial effects of isoflurane were blocked by neutralizing antibody against VEGF (nVEGF). Coronary arterial endothelial cells (ECs) alone or together with cardiomyocytes (CMs) were subjected to hypoxia/reoxygenation injury. The expression of VEGF and eNOS was analysed by western blot, and nitric oxide was measured by ozone-based chemiluminescence. In co-cultured CMs and ECs, isoflurane administered before hypoxia/reoxygenation attenuated lactate dehydrogenase activity and increased the ratio of phosphorylated eNOS/eNOS and nitric oxide production. The protective effect of isoflurane on CMs was compromised by nVEGF and after VEGF in ECs was inhibited with hypoxia inducible factor-1α short hairpin RNA (shRNA). The negative effect of hypoxia inducible factor-1α shRNA was restored by recombinant VEGF. Conclusion Isoflurane cardiac preconditioning is associated with VEGF regulation of phosphorylation of eNOS and nitric oxide production. [ABSTRACT FROM AUTHOR]

Highlights • LPS preconditioning significantly attenuates brain injury and motor damage in mice induced by ischaemia/reperfusion. • LPS preconditioning reduced the inflammatory response of the spleen after ischaemia/reperfusion. • LPS preconditioning increased regulatory B cells in the spleen after ischaemia/reperfusion. Abstract Background The inflammatory reaction of the spleen is an important component in the pathophysiology of cerebral ischaemia (CI). Regulatory B cells (Bregs) derived from the spleen can inhibit the expansion of inflammation and reduce the damage caused by CI. Aim The aim of the present study was to explore changes in spleen function and Bregs production due to lipopolysaccharide preconditioning (LPS PC) in ischaemia/reperfusion (I/R) and to uncover potential protective effect of LPS PC on stroke. Methods Focal cerebral I/R mice were induced by middle cerebral artery occlusion (MCAO). Infarct size and inflammatory cell infiltration in brain tissue, athletic ability, and immune status were analysed by immunostaining, behavioural analyses, and flow cytometry, respectively. Results The volume of the cerebral infarct was significantly decreased in I/R mice with LPS PC (LPS + I/R) compared to I/R mice, and neuronal apoptosis was ameliorated by LPS PC. After preconditioning with LPS, locomotor activity, forelimb strength, motor endurance, motor coordination, and short-term memory were improved to varying degrees. Moreover, blood-brain barrier (BBB) dysfunction was reversed, and CD11b+, major histocompatibility complex-II positive (MHC-II+), and Gr-1+ cell infiltration in the brains of LPS + I/R mice was also significantly reduced. B cell-activating factor (BAFF), tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 in the brain and spleen in the LPS + I/R group decreased to different degrees, while the levels of transforming growth factor-β (TGF-β) and IL-10 increased. LPS PC alleviated atrophy of the spleen following I/R. In addition, the number of CD8+ T cells, macrophages, TNF+ cells, NF-κB+ cells, and neutrophils in the spleen was reduced, while the number of proliferating cells and CD19+-IL10+ Bregs was significantly increased. The number of follicular B (FO B) cells and marginal zone B (MZ B) cells in the spleens of LPS + I/R mice was also increased. Conclusions I/R mice preconditioned with LPS showed significantly reduced pathological damage, motor dysfunction, cognitive dysfunction, and inflammatory responses. LPS PC may initiate anti-inflammatory protective mechanism in the spleen after stroke, may increase the number of anti-inflammatory cells, such as Bregs, in the spleen, and may play a protective role in stroke. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (MI) is a leading cause of morbidity and mortality in the world. Traditional method to induce MI by left coronary artery (LCA) ligation is typically performed by an invasive approach that requires ventilation and thoracotomy, causing serious injuries in animals undergoing this surgery. We attempted to develop a minimally invasive method (MIM) to induce MI in mice. Under the guide of ultrasound, LCA ligation was performed in mice without ventilation and chest‐opening. Compared to sham mice, MIM induced MI in mice as determined by triphenyltetrazolium chloride staining and Masson staining. Mice with MIM surgery revealed the reductions of LVEF, LVFS, E/A and ascending aorta (AAO) blood flow, and the elevations of S‐T segment and serum cTn‐I levels at 24 post‐operative hours. The effects of MI induced by MIM were comparable to the effects of MI produced by traditional method in mice. Importantly, MIM increased the survival rates and caused less inflammation after the surgery of LCA ligation, compared to the surgery of traditional method. Further, MIM induced angiogenesis and apoptosis in ischaemic hearts from mice at postoperative 28 days as similarly as traditional method did. Finally, the MIM model was able to develop into the myocardial ischaemia/reperfusion model by using a balloon catheter with minor modifications. The MI model is able to be efficiently induced by a minimally invasive approach in mice without ventilation and chest‐opening. This new model is potentially to be used in studying ischaemia‐related heart diseases. [ABSTRACT FROM AUTHOR]