Restoration Of Blood Flow Research Articles

Abstract TP368: Targeted Lipid Nanoparticles to Modulate Blood-Brain Barrier Transcytosis in Acute Ischemic Stroke

Ischemic stroke affects more than 600,000 Americans annually. Thrombectomy, where occluded arteries are cannulated for mechanical clot removal, can restore blood flow and improve survival, but still leaves 1/3 of patients functionally dependent, largely due to secondary ischemia-reperfusion injury. Brain edema in the acute phase of ischemia-reperfusion primarily associates with early-stage neurovascular damage and plays a major role in poor outcomes of stroke. Early on after ischemia/reperfusion, edema is mediated by increased transcytosis in the blood brain barrier (BBB) endothelium. Suppression of transcytosis has not yet been tested as a treatment for stroke. Major facilitator superfamily domain containing 2a (Mfsd2a) is a transporter protein that regulates caveolar transcytosis and is downregulated in ischemic stroke. We have previously demonstrated that 1) lipid nanoparticles loaded with mRNA (mRNA/LNP) enable rapid and robust protein expression; 2) vascular cell adhesion molecule (VCAM) targeting selectively delivers nanoparticles to stroke-affected BBB endothelium; 3) mRNA/LNP targeted to VCAM enabled protein expression in BBB endothelium. Therefore, we hypothesize that using LNPs containing Mfsd2a mRNA and targeted to vascular cell adhesion molecule (VCAM) can modulate Mfsd2a expression in inflamed BBB and improve outcome in ischemic stroke. In this work, we screened 10 LNP formulations and identified the optimized formulation on bEND.3 brain endothelial cells for Mfsd2a expression. The induction of Mfsd2a expression significantly enhanced Cav-1 expression and reduced the number of apical caveolae-formations by electron microscopy. Next, we used the acute ischemic stroke animal model (transient middle cerebral artery occlusion for 45 minutes) to assess the therapeutic outcome of VCAM-targeted LNP loaded with Mfsd2a mRNA. Right after reperfusion, we intravenously injected LNP and two additional dose every 24 hours (8ug RNA per dose). On day 3, we assessed brain edema by measuring the extravasation of radiolabeled albumin into the brain parenchyma. The percent of the extravasated albumin was significantly reduced after LNP treatment. In addition, using transmission electron microscopy, we observed less number of caveolae in the treated mice, compared to vehicle control. In conclusion, we have showed that VCAM targeted LNPs are able to deliver Mfsd2a mRNA to the inflamed brain vasculature and reduce brain edema by suppression of transcytosis.

Photothrombolytics: A light-driven technology for the targeted lysis of thrombi

Occlusive blood clots remain a significant global health challenge and result in emergencies that are main causes of death and disability worldwide. Thrombolytic agents (including tissue plasminogen activator, tPA) are the only pharmacological means to dissolve blood clots. However, these drugs have modest efficacy and severe safety concerns persist. We have developed light-responsive tPA-loaded red blood cells (tPA-RBCsPhoto) to target thrombolytic activity at the site of a blood clot. Herein, we describe the use of light to control the release of tPA from engineered RBCs and the subsequent degradation of a blood clot ex vivo. Furthermore, we have employed this technology to restore blood flow to an occluded mouse artery in vivo using a targeted dose that is 25 times lower than conventional systemic tPA treatment.

Mesenchymal Stem Cells With Polydopamine-Coated NaGdF4 Nanoparticles with Ca2+ Chelation Ability for Ischemic Stroke Therapy.

Mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for ischemic stroke. However, the survival of transplanted MSCs is often compromised by the excessive levels of reactive oxygen species (ROS) and calcium ions (Ca2+) in the ischemic microenvironment following blood flow occlusion. In this study, a protective strategy is developed using functional nanomaterials to escort and shield MSCs. Specifically, NaGdF4@PDA-ALD nanoparticles (NPANs) are synthesized, featuring a NaGdF4 core coated with polydopamine (PDA) for ROS scavenging and further modified with alendronate sodium (ALD) for Ca2+ chelation. The internalization of NPANs by MSCs protected them from oxidative damage and calcium overload, thereby promoting their viability and functionality. Furthermore, NaGdF4 generated T1 signal enhancement, enabling in vivo tracking of MSCs via magnetic resonance imaging. The NPANs-treated MSCs demonstrated improved survival and migration to the ischemic region, promoting blood flow restoration and angiogenesis. These findings confirm the feasibility of employing functional nanoparticles to augment MSCs-based therapies, offering a promising strategy to improve their therapeutic efficacy in ischemic stroke treatment.

Extracorporeal shockwave therapy rescued mouse critical limb ischemia via upregulating GPR120 against inflammation and promoting angiogenesis for restoring the blood flow in ischemic zone-experimental study.

This study tested the hypothesis that extracorporeal shockwave therapy (ECSWT) effectively rescues critical limb ischemia (CLI) in mice through the upregulation of GPR120, which protects against inflammation and angiogenesis to restore blood flow in the ischemic area. Compared with the control, ECSWT-induced GPR120-mediated anti-inflammatory effects significantly suppressed the expression of inflammatory signaling biomarkers (TAK1/MAPK family/NF-κB/IL-1β/IL-6/TNF-α/MCP-1) in HUVECs, and these effects were abolished by silencing GPR120 or by the GPR120 antagonist AH7614 (all P < 0.001). C57BL/6 mice (n =40) were equally categorized into Groups 1 (sham-operated control), 2 (CLI), 3 (CLI+ECSWT), and 4 (CLI+ECSWT+AH7614). By Days 7, 14, and 28 just prior to harvesting the quadriceps muscle, the laser Doppler results showed that the ratio of ischemia to normal blood flow (INBF) in the CLI area was highest in Group 1, lowest in Group 2, and significantly greater in Group 3 than in Group 4 (all P < 0.0001). Endothelial cell markers (CD31/vWF) and GPR120+cells exhibited identical patterns of INBF among the groups, whereas angiogenesis biomarkers (CXCR4/SDF-1/VEGF/VEGFR2) were significantly and progressively upregulated from Groups 1 to 4 (all P < 0.0001). The protein levels of inflammation (MMP-9, IL-6, and TNF-α) and oxidative stress (NOX-1 and NOX-2) and the cellular levels of inflammation (CD68+)/DNA damage (γ-H2AX+) displayed opposite patterns, whereas the small vessel density in the CLI area displayed an identical pattern of INBF among the groups (all P < 0.0001). ECSWT rescued CLI by increasing GPR120-mediated suppression of inflammation and enhancing angiogenesis via activation of VEGFR2.

Recurrent thrombus formation in a carotid web: highlighting the importance of timely surgical intervention. Illustrative case.

Carotid webs are rare nonatherosclerotic disorders in the carotid artery and are increasingly recognized as factors of ischemic stroke in the young population. Asymptomatic webs can be treated with antithrombotic therapy, whereas symptomatic cases frequently require surgical interventions, including carotid endarterectomy (CEA). However, guidelines for the optimal timing of these treatments remain unestablished, especially compared to atherosclerotic stenotic lesions, due to the rarity of carotid webs. A 50-year-old female patient had a carotid web-induced left hemispheric ischemic stroke. Mechanical thrombectomy successfully restored blood flow, but a thrombus reformed in the carotid web within 1 month following the procedure. This caused early CEA, during which the carotid web and thrombus were removed. This case highlights rapid thrombus reformation, indicating that some carotid webs can be more unstable than previously thought. This case emphasizes the importance of timely surgical intervention in symptomatic carotid webs to prevent recurrent strokes. Additionally, antithrombotic therapy can manage asymptomatic webs, but surgical treatment may be required in unstable cases. Thus, further studies are warranted to establish standardized treatment guidelines for carotid webs. https://thejns.org/doi/10.3171/CASE24682.

Antithrombotic use in retinal artery occlusion: A narrative review.

Retinal artery occlusion (RAO) is a critical ophthalmic emergency with a high risk of significant visual impairment. While traditional treatment aims to promptly restore blood flow to the retina, recent research has investigated the potential benefits of anticoagulation therapy for managing this condition. This paper reviews current literature and clinical trials investigating the efficacy and safety of anticoagulant and antiplatelet therapies, such as systemic heparinization and direct oral anticoagulants and aspirin, in treating RAO. The mechanism of action involves preventing thrombus propagation and platelet aggregation to promote microvascular circulation, potentially mitigating ischemic damage and improving visual outcomes. However, controversies exist regarding the optimal timing, duration, and selection of antithrombotic agents due to the risk of hemorrhagic complications. Further large-scale prospective studies are warranted to establish evidence-based guidelines for incorporating antithrombotic into the standard management of RAO. This paper underscores the evolving landscape of antithrombotic therapy as a promising adjunctive treatment strategy in the management of retinal artery occlusion.

Traditional Chinese Medicine Borneol-Based Polymeric Micelles Intracerebral Drug Delivery System for Precisely Pathogenesis-Adaptive Treatment of Ischemic Stroke.

The scarcity of effective neuroprotective agents and the presence of blood-brain barrier (BBB)-mediated extremely inefficient intracerebral drug delivery are predominant obstacles to the treatment of cerebral ischemic stroke (CIS). Herein, ROS-responsive borneol-based amphiphilic polymeric NPs are constructed by using traditional Chinese medicine borneol as functional blocks that served as surface brain-targeting ligand, inner hydrophobic core for efficient drug loading of membrane-permeable calcium chelator BAPTA-AM, and neuroprotective structural component. In MCAO mice, the nanoformulation (polymer: 3.2 mg·kg-1, BAPTA-AM: 400 µg·kg-1) reversibly opened the BBB and achieved high brain biodistribution up to 12.7%ID/g of the total administered dose after 3 h post single injection, effectively restoring intracellular Ca2+ and redox homeostasis, improving cerebral histopathology, and inhibiting mitochondrial PI3K/Akt/Bcl-2/Bax/Cyto-C/Caspase-3,9 apoptosis pathway for rescuing dying neurons (reduced apoptosis cell from 59.5% to 7.9%). It also remodeled the inflammatory microenvironment in cerebral ischemic penumbra by inhibiting astrocyte over-activation, reprogramming microglia polarization toward an anti-inflammatory phenotype, and blocking NF-κB/TNF-α/IL-6 signaling pathways. These interventions eventually reduced the cerebral infarction area by 96.3%, significantly improved neurological function, and restored blood flow reperfusion from 66.2% to ≈100%, all while facilitating BBB repair and avoiding brain edema. This provides a potentially effective multiple-stage sequential treatment strategy for clinical CIS.

Direct Superficial Temporal Artery-Proximal Middle Bypass in Moyamoya Disease: Predicting Postoperative Symptomatic Contralateral Stroke Using Clinical Characteristics and Angiographic Collateralization Patterns.

Moyamoya disease (MMD) is a rare cerebrovascular disorder marked by internal carotid artery narrowing, collateral neovascularization, and symptomatic cerebral ischemia. Select patients can benefit from direct bypass (superficial temporal artery [STA]-proximal middle [MCA] bypass) by restoring blood flow to hypoperfused territories. Symptomatic contralateral stroke (CS) following STA-MCA bypass is a devastating, poorly understood complication. We investigate clinical and radiographic risk factors influencing CS incidence after bypass surgery. A retrospective review of patients with bilateral MMD undergoing STA-MCA bypass at our institution (2018-2022) included demographic details, comorbidities, average preoperative systolic blood pressure (SBP), postoperative SBP goals, and angiographic patterns. Preoperative diagnostic angiograms were analyzed for collateral vascular patterns. Postoperative clinical course was recorded. Statistical analyses employed parametric and nonparametric tests for small sample size. Six of 39 patients (15.4%) experienced CS postbypass. No baseline demographic differences were identified between patients with and without CS. CS patients had higher preoperative SBP (146.2 vs. 131.1, P<0.05), were more likely to have postoperative SBP goals below their average preoperative SBP (66.7% vs. 15.2%, P= 0.018) and had longer time from symptom onset to surgery (51.8 vs. 13 months, P= 0.039). There were no differences in specific angiographic patterns in either hemisphere for patients with CS versus those without CS though overall contralateral Suzuki grade was higher in patients with CS (P < 0.05). Patients with CS following bypass had significantly higher preoperative SBP, postoperative SBP goals below their average preoperative SBP, and longer time from symptom onset to surgery compared to patients without CS. Patient-specific postoperative SBP management and timely surgical revascularization are crucial for preventing CS in patients with MMD undergoing STA-MCA bypass.

Enhanced nasal-to-brain drug delivery by multivalent bioadhesive nanoparticle clusters for cerebral ischemic reperfusion injury protection.

Following cerebral ischemia, reperfusion injury can worsen ischemia-induced functional, metabolic disturbances, and pathological damage upon blood flow restoration, potentially leading to irreversible harm. Yet, there's a dearth of advanced, localized drug delivery systems ensuring active pharmaceutical ingredient (API) efficacy in cerebral protection during ischemia-reperfusion. This study introduces a multivalent bioadhesive nanoparticle-cluster, merging bioadhesive nanoparticles (BNPs) with dendritic polyamidoamine (PAMAM), enhancing nose-to-brain delivery and brain protection efficacy against cerebral ischemia-reperfusion injuries (CIRI). The BNPs-PAMAM cluster exhibits superior adhesion within the rat nasal cavity, prolonged retention, enabling sustained drug release, cerebral transportation, and accumulation, resulting in enhanced intracerebral pharmacokinetic profile. Intranasal administration circumvents systemic delivery challenges, ensuring CIRI protection drugs reach ischemic areas pre-reperfusion, overcoming thrombus-related delays. Administering BNPs-PAMAM loaded with dexmedetomidine (DEX) pre-reperfusion effectively prevents neuron apoptosis by α2-adrenoceptor activation, modulating the ischemic microenvironment, exerting triple neuroprotective effects against cerebral reperfusion injury. Importantly, only therapeutic DEX releases and accumulates in the nasal cavity, averting brain nanomaterial toxicity, promising for repeat administrations. This study presents a translational platform for nasal-to-brain drug delivery in CNS disease treatment. STATEMENT OF SIGNIFICANCE: Innovative Drug Delivery System: This study introduces a multivalent bioadhesive nanoparticle-cluster (BNPs-PAMAM) to enhance nasal-to-brain drug delivery for cerebral ischemia-reperfusion injury (CIRI) treatment. Enhanced Retention and Efficacy: The BNPs-PAMAM system significantly improves drug retention in the nasal cavity and ensures sustained release, thereby enhancing the therapeutic efficacy of the neuroprotective agent dexmedetomidine (DEX). Blood-Brain Barrier Circumvention: By leveraging intranasal administration, the system bypasses the blood-brain barrier, delivering DEX directly to ischemic brain regions before reperfusion and minimizing systemic side effects. Triple Neuroprotective Effects for CIRI protection: DEX delivered via BNPs-PAMAM effectively reduces oxidative stress and inflammation while enhancing mitochondrial autophagy, providing comprehensive protection against neuronal damage.

Endovascular treatment and selection criteria for acute mesenteric ischemia

To demonstrate the results of endovascular intervention in patients with acute arterial mesenteric ischemia, while observing the indications developed in the clinic. In total, endovascular approach in the treatment of acute mesenteric ischemia were used in 49 patients in the clinic. In compliance with the developed indications and criteria, endovascular intestinal revascularization was performed in 27 patients. Various endovascular intervention techniques were used (aspiration, balloon dilation, artery stenting and their combinations). Extracorporeal filtration techniques were used as a treatment for reperfusion syndrome after intestinal revascularization in 10 patients. Angiographic success in the form of complete restoration of the main blood flow in the basin of the superior mesenteric artery and its large branches was obtained in 85% of cases. Intestinal viability was preserved in 15 (56%) patients. After successful endovascular surgery, intestinal necrosis was diagnosed on laparoscopy in the remaining 12 (44%) patients, which required extensive (n=2) or non-extensive (n=10) resection. Postoperative mortality was 48% (13 patients). Endovascular surgery in acute mesenteric ischemia is an effective method of intestinal revascularization. To optimize the indications for these interventions, it is necessary to gain experience and conduct large-scale studies.

The role of the cyclooxygenase-2 pathway in tissue ischemia and revascularization following skeletal muscle injury induced by bothropic snake venom

Bothrops asper venom (Bav) contains metalloproteinases that disrupt the microvascular system, impairing muscle tissue regeneration after injury. This study investigated the impact of the cyclooxygenase-2 (COX-2) pathway on vascular injury and revascularization in muscle injuries induced by Bav. Mice were injected with Bav into the gastrocnemius muscle and treated with lumiracoxib, a selective COX-2 inhibitor, 30 min, 2 days, and 6 days post-Bav injection. Muscle tissue was analyzed at 24 h, 7 days, and 21 days post-injection. A decrease in COX-2 expression at 24 h post-Bav injection indicated significant necrosis and tissue loss. Both Bav injection and lumiracoxib treatment influenced the decrease of prostaglandin (PG)D2 and PGE2 production. Seven and 21 days post-Bav injections, COX-2 expression increased, along with PGDs levels unaffected by lumiracoxib, indicating that the other isoform COX-1 pathway could contribute to the release of PGs. Bav/lumiracoxib treated animals presented exacerbated limb ischemia, implying that COX-2-derived prostaglandins preserve vessel integrity. CD31, an angiogenesis marker, initially (24 h) decreased post-Bav injection but increased at 7 and 21 days in Bav/lumiracoxib mice, suggesting a down-modulatory role for COX-2-derived prostaglandins in early angiogenesis and tissue regeneration. Vascular endothelial growth factor (VEGF) production rose 7 days post-Bav injection, supporting its role in angiogenesis. Previous treatment with lumiracoxib promoted release of VEGF levels 21 days post-Bav injury showing that the inhibition of COX-2 pathway in the early stage of revascularization stimulates the neovascularization regulated by elevated release of VEGF. Similarly, metalloproteinases (MMPs), such as MMP-9, MMP-10, and MMP-13, crucial for vascular remodeling, were elevated 21 days after Bav/lumiracoxib treatment. In conclusion, the COX-2 pathway is essential to decrease the high grade of ischemia caused by acute injury induced by Bav. However, the decrease of activity in the COX-2 pathway in the first stages of revascularization contributes to the elevated production of key pro-angiogenic mediators that up-regulate the restoration of microvasculature and blood flow in muscle tissue injured by botropic venoms.

Overexpressed CD73 attenuates GSDMD-mediated astrocyte pyroptosis induced by cerebral ischemia-reperfusion injury through the A2B/NF-κB pathway.

Ischemic stroke, resulting from the blockage or narrowing of cerebral vessels, causes brain tissue damage due to ischemia and hypoxia. Although reperfusion therapy is essential to restore blood flow, it may also result in reperfusion injury, causing secondary damage through mechanisms like oxidative stress, inflammation, and excitotoxicity. These effects significantly impact astrocytes, neurons, and endothelial cells, aggravating brain injury and disrupting the blood-brain barrier. CD73, an ectoenzyme that regulates adenosine production through ATP hydrolysis, plays a critical role in purinergic signaling and neuroprotection. During ischemic stroke, CD73 expression is dynamically regulated in response to ischemia and inflammation. It catalyzes the conversion of AMP to adenosine, which activates adenosine receptors to exert neuroprotective effects. Targeting the CD73-adenosine pathway presents a potential therapeutic strategy for mitigating ischemic stroke damage. Pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasomes like NLRP3 and caspases, plays a significant role in cerebral ischemia-reperfusion injury. Astrocytes, the most abundant CNS cells, contribute to both neuroprotection and injury, with pyroptosis exacerbating inflammation and brain damage. Regulating astrocyte pyroptosis is a promising therapeutic target. Our study investigates CD73's role in regulating astrocyte pyroptosis during ischemia-reperfusion injury. Using CD73 knockout mice and overexpression models, along with in vitro oxygen-glucose deprivation/reperfusion experiments, we found that CD73 overexpression reduces GSDMD-mediated astrocyte pyroptosis via the A2B/NF-κB pathway. These findings offer a novel approach to reducing neuroinflammation, protecting astrocytes, and improving outcomes in ischemic stroke.

Skin Necrosis: Pathophysiology and innovations in tissue regeneration

Skin, the largest organ in the human body, serves as a crucial barrier against environmental threats. However, larger skin defects or compromised wound healing can result in persistent wounds, sometimes requiring skin substitutes. Skin tissue engineering aims to create materials that can replace skin functions temporarily or permanently. The skin comprises several tissue types, including epithelial, connective, muscular, nervous, and vascular tissues. Keratinocytes, for instance, undergo a specialized process to form the cornified layer, which differentiates from apoptosis, a type of programmed cell death. Pathogenic processes often involve necrosis, a form of tissue death caused by insufficient blood supply, infections, or trauma. There are various types of necrosis, including coagulation, liquefactive, gangrenous, caseous, fat, and fibrinoid necrosis, each defined by the tissue changes and underlying causes. Necrosis can result from external factors like mechanical trauma, thermal damage, or ischemia, and internal factors such as infection or certain diseases. Necrosis is linked to autoimmune conditions, vascular diseases, and toxic exposures. Risk factors include age, alcohol abuse, infections, and conditions like diabetes and HIV. Treatment for necrosis involves removing dead tissue (debridement), managing infections, and restoring blood flow, often requiring surgery or amputation. Additional treatments like antibiotics, hyperbaric oxygen therapy, and wound dressings support healing. Alternative approaches, including homeopathy and Ayurveda, focus on stimulating natural healing processes through herbs and detoxification.

Intestinal oxygen utilisation and cellular adaptation during intestinal ischaemia-reperfusion injury.

The gastrointestinal tract can be deranged by ailments including sepsis, trauma and haemorrhage. Ischaemic injury provokes a common constellation of microscopic and macroscopic changes that, together with the paradoxical exacerbation of cellular dysfunction and death following restoration of blood flow, are collectively known as ischaemia-reperfusion injury (IRI). Although much of the gastrointestinal tract is normally hypoxemic, intestinal IRI results when there is inadequate oxygen availability due to poor supply (pathological hypoxia) or abnormal tissue oxygen use and metabolism (dysoxia). Intestinal oxygen uptake usually remains constant over a wide range of blood flows and pressures, with cellular function being substantively compromised when ischaemia leads to a>50% decline in intestinal oxygen consumption. Restoration of perfusion and oxygenation provokes additional injury, resulting in mucosal damage and disruption of intestinal barrier function. The primary cellular mechanism for sensing hypoxia and for activating a cascade of cellular responses to mitigate the injury is a family of heterodimer proteins called hypoxia-inducible factors (HIFs). The HIF system is connected to numerous biochemical and immunologic pathways induced by IRI and the concentration of those proteins increases during hypoxia and dysoxia. Activation of the HIF system leads to augmented transcription of specific genes in various types of affected cells, but may also augment apoptotic and inflammatory processes, thus aggravating gut injury. KEY POINTS: During intestinal ischaemia, mitochondrial oxygen uptake is reduced when cellular oxygen partial pressure decreases to below the threshold required to maintain normal oxidative metabolism. Upon reperfusion, intestinal hypoxia may persist because microcirculatory flow remains impaired and/or because available oxygen is consumed by enzymes, intestinal cells and neutrophils.

Nd:Yag Laser Transluminal Embolysis: A Therapeutic Approach in Retinal Artery Occlusion.

Background: Central and branch retinal artery occlusion (CRAO and BRAO) are critical causes of acute vision loss, predominantly affecting older adults with systemic vascular pathology. These occlusions typically result from embolic events, leading to partial or complete retinal ischemia. Methods: This retrospective case series report details of our 10-year experience using the 1064 nm Nd:YAG laser for Transluminal Nd:YAG Embolysis (TYE) in order to lyse visible emboli within the retinal arteries. Results: We conducted a retrospective case series involving 18 patients treated by TYE for different retinal arteries occlusions between 2014 and 2024. TYE effectively restored blood flow in the occluded arteries, with variable but generally favorable visual outcomes. Our article highlights significant clinical and interventional aspects of three treated patients: a BRAO case with multiple transluminal emboli, a case of double BRAO and a CRAO case. We also report the successful use of TYE for intraluminal lysing of an embolus located outside the optic disc. The procedures were well-tolerated, with minor complications such as preretinal or vitreous hemorrhages resolving spontaneously. Conclusions: TYE is a minimally invasive therapeutic option for retinal artery occlusion with visible emboli, particularly when intervention occurs shortly after the onset of symptoms. Compared to observation, TYE can improve visual outcomes and reduce the risk of permanent vision loss, presenting a significant advancement in the management of this ophthalmic emergency. The worldwide experience with TYE is continuously increasing. Further research with larger cohorts is recommended to validate these results and refine the treatment protocol.

Histone Deacetylase Inhibitors as a Promising Treatment Against Myocardial Infarction: A Systematic Review.

Background/Objectives: Acute myocardial infarction (AMI) is a critical medical condition that requires immediate attention to minimise heart damage and improve survival rates. Early identification and prompt treatment are essential to save the patient's life. Currently, the treatment strategy focuses on restoring blood flow to the myocardium as quickly as possible. However, reperfusion activates several cellular cascades that contribute to organ dysfunction, resulting in the ischaemia/reperfusion (I/R) injury. The search for treatments against AMI and I/R injury is urgent due to the shortage of effective treatments at present. In this regard, histone deacetylase (HDAC) inhibitors emerge as a promising treatment against myocardial infarction. The objective of this systematic review is to analyse the effects of HDAC inhibitors on ventricular function, cardiac remodelling and infarct size, among other parameters, focusing on the signalling pathways that may mediate these cardiovascular effects and protect against AMI. Methods: Original experimental studies examining the effects of HDAC inhibitors on AMI were included in the review using the PubMed and Scopus databases. Non-experimental papers were excluded. The SYRCLE RoB tool was used to assess risk of bias and the results were summarised in a table and presented in sections according to the type of HDAC inhibitor used. Results: A total of 18 studies were included, 10 of them using trichostatin A (TSA) as an HDAC inhibitor and concluding that the treatment improved ventricular function, reduced infarct size, and inhibited myocardial hypertrophy and remodelling after AMI. Other HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA), mocetinostat, givinostat, entinostat, apicidin, and RGFP966, were also analysed, showing antioxidant and anti-inflammatory effects, an improvement in cardiac function and remodelling, and a decrease in apoptosis, among other effects. Conclusions: HDAC inhibitors constitute a significant promise for the treatment of AMI due to their diverse cardioprotective effects. However, high risk of selection, performance, and detection bias in the in vivo studies means that their application in the clinical setting is still a long way off and more research is needed to better understand their benefits and possible side effects.

Pathological roles of mitochondrial dysfunction in endothelial cells during the cerebral no-reflow phenomenon: A review.

Emergency intravascular interventional therapy is the most effective approach to rapidly restore blood flow and manage occlusion of major blood vessels during the initial phase of acute ischemic stroke. Nevertheless, several patients continue to experience ineffective reperfusion or cerebral no-reflow phenomenon, that is, hypoperfusion of cerebral blood supply after treatment. This is primarily attributed to downstream microcirculation disturbance. As integral components of the cerebral microvascular structure, endothelial cells (ECs) attach importance to regulating microcirculatory blood flow. Unlike neurons and microglia, ECs harbor a relatively low abundance of mitochondria, acting as key sensors of environmental and cellular stress in regulating the viability, structural integrity, and function of ECs rather than generating energy. Mitochondria dysfunction including increased mitochondrial reactive oxygen species levels and disturbed mitochondrial dynamics causes endothelial injury, further causing microcirculation disturbance involved in the cerebral no-reflow phenomenon. Therefore, this review aims to discuss the role of mitochondrial changes in regulating the role of ECs and cerebral microcirculation blood flow during I/R injury. The outcomes of the review will provide promising potential therapeutic targets for future prevention and effective improvement of the cerebral no-reflow phenomenon.

The cGAS-STING pathway in ischemia-reperfusion injury in acute cerebral infarction: a new therapeutic opportunities?

The innate immune response is the body's first line of defense against external pathogens and endogenous damage signals. The cGAS-STING pathway is a crucial component of the innate immune response, playing a key role in initiating antiviral and anti-infective immune responses by recognizing cytosolic DNA. Acute cerebral infarction is one of the leading causes of death and disability worldwide, with the primary treatment approach being the restoration of blood flow to ischemic brain tissue. However, reperfusion injury remains a significant challenge during treatment. The overactivation of the cGAS-STING pathway and its association with ischemia-reperfusion injury have been confirmed in numerous studies. This article will systematically elucidate the mechanisms of the cGAS-STING pathway, its role in ischemia-reperfusion injury in acute cerebral infarction, the current research status of cGAS-STING inhibitors, and the application of nanomaterials in this context, evaluating the therapeutic potential of this pathway.

Impact of direct mesenteric perfusion on malperfusion in acute type A aortic dissection repair.

Mesenteric malperfusion in acute aortic dissection remains a life-threatening complication with no standardized treatment strategy. This study aimed to describe and evaluate the outcomes of our integrated approach combining exploratory laparotomy, immediate mesenteric reperfusion, and central aortic repair. We retrospectively reviewed patients with acute aortic dissection with a preoperative diagnosis of mesenteric malperfusion who were treated between August 2011 and November 2022. Our surgical approach was to establish cardiopulmonary bypass, followed by exploratory laparotomy with mesenteric artery flow assessment using Doppler ultrasound and direct perfusion if needed, central aortic repair, and subsequent mesenteric artery reconstruction. The primary end-point was the 30-day operative mortality. Among 217 patients with acute aortic dissection, 12 (5.5%) had mesenteric malperfusion on preoperative computed tomography. Ten patients underwent exploratory laparotomy, where Doppler ultrasonography revealed reduced mesenteric blood flow in five patients (2.3% of the total 217 patients). These patients underwent direct perfusion of the mesenteric artery via a side branch of the cardiopulmonary bypass circuit. Doppler ultrasound confirmed the restoration of mesenteric blood flow in all perfused patients. No bowel resections were required. The operative mortality in patients with mesenteric malperfusion was 20%. The causes of death were stroke (n = 1) and acute myocardial infarction (n = 1). Our integrated surgical strategy combining central aortic repair with concurrent exploratory laparotomy and immediate mesenteric perfusion demonstrated technical feasibility in managing mesenteric malperfusion during aortic repair. Further prospective studies with larger cohorts are warranted to validate these findings.

Effects of Cerium Oxide on Kidney and Liver Tissue Damage in an Experimental Myocardial Ischemia-Reperfusion Model of Distant Organ Damage.

Background and Objectives: Ischemia-reperfusion (I/R) injury is a process in which impaired perfusion is restored by restoring blood flow and tissue recirculation. Nanomedicine uses cutting-edge technologies that emerge from interdisciplinary influences. In the literature, there are very few in vivo and in vitro studies on how cerium oxide (CeO2) affects systemic anti-inflammatory response and inflammation. Therefore, in our study, we aimed to investigate whether CeO2 administration has a protective effect against myocardial I/R injury in the liver and kidneys. Materials and Methods: Twenty-four rats were randomly divided into four groups after obtaining approval from an ethics committee. A control (group C), cerium oxide (group CO), IR (group IR), and Cerium oxide-IR (CO-IR group) groups were formed. Intraperitoneal CeO2 was administered at a dose of 0.5 mg/kg 30 min before left thoracotomy and left main coronary (LAD) ligation, and myocardial muscle ischemia was induced for 30 min. After LAD ligation was removed, reperfusion was performed for 120 min. All rats were euthanized using ketamine, and blood was collected. Liver and kidney tissue samples were evaluated histopathologically. Serum AST (aspartate aminotransferase), ALT (alanine aminotransaminase), GGT (gamma-glutamyl transferase), glucose, TOS (Total Oxidant Status), and TAS (Total Antioxidant Status) levels were also measured. Results: Necrotic cell and mononuclear cell infiltration in the liver parenchyma of rats in the IR group was observed to be significantly increased compared to the other groups. Hepatocyte degeneration was greater in the IR group compared to groups C and CO. Vascular vacuolization and hypertrophy, tubular degeneration, and necrosis were increased in the kidney tissue of the IR group compared to the other groups. Tubular dilatation was significantly higher in the IR group than in the C and CO groups. TOS was significantly higher in all groups than in the IR group (p < 0.0001, p < 0.0001, and p = 0.006, respectively). However, TAS level was lower in the IR group than in the other groups (p = 0.002, p = 0.020, and p = 0.031, respectively). Renal and liver histopathological findings decreased significantly in the CO-IR group compared to the IR group. A decrease in the TOS level and an increase in the TAS level were found compared to the IR group. The AST, ALT, GGT, and Glucose levels are shown. Conclusions: CeO2 administered before ischemia-reperfusion reduced oxidative stress and ameliorated IR-induced damage in distant organs. We suggest that CeO2 exerts protective effects in the myocardial IR model.