Ischemic Damage Research Articles

Dimethyl sulfoxide : A review of pharmacology and clinical effect on interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a refractory chronic cystitis of unknown origin. The intravesical instillation therapy of Dimethyl sulfoxide (DMSO) for IC/BPS was approved by the FDA in 1978, and there are reports showing its effectiveness. However, there are still many parts of the mechanism of action of DMSO that remain unclear.DMSO has high membranous permeability, and when instilled into the bladder, DMSO easily penetrates the mucosa and infiltrates the submucosal and muscular layers, and is absorbed into the bloodstream, where it is rapidly metabolized. DMSO does not cause irreversible damage to membranes during penetration and absorption, rather it has a protective effect on cells and organs.The main mechanism of action of DMSO for IC is thought to be its anti-inflammatory effect on Hunner lesions and protection against ischemic tissue damage, mediated by radical scavenging activity of both DMSO and its reduction metabolite, DMS. Furthermore, recent studies have demonstrated that intravesical instillation of DMSO is effective only for HIC.This review will highlight the known pharmacology and clinical effects of DMSO on the treatment of IC/BPS.

Insufficient arterial driving pressure turns hypoxic microvascular remodeling into a catastrophe

Abstract The tissue microvasculature is known to remodel in response to ischemia. However, the benefit or harm of this process is not completely understood and may limit also the potential of taking control of ischemic diseases that remain the leading cause of death worldwide. In a series of clinical and preclinical studies, we have thus dissected the biological relevance and the pathomechanistic role of hypoxic microvascular remodeling in critical limb threatening ischemia (CLTI). High-resolution contrast enhanced ultrasound was used in 50 patients with severe CLTI scheduled for immediate revascularization to study ischemic muscle microvascular blood flow. Immunohistological analyses were performed for amputation muscle samples from a set of 40 CLTI patients to analyze microvascular changes with respect to the level of myofiber atrophy. Furthermore, the amputation muscle samples were used to find 3 paired samples from 20 patients representing microvascular transformation along worsening of ischemic muscle damage, and used for RNA sequencing to analyze mechanisms of microvascular transformation. Additionally, animal models for acute ischemia in C57Bl-mice (n=42) and hypercholesterolemic LDLR-/-ApoB100/100 mice (n=61) and chronic CLTI-like ischemia model in cholesterol-fed NZW rabbits (n=24) with AdVEGF-A or AdLacZ control gene transfer were employed to study: 1) the natural course of microvascular changes leading to efficient muscle regeneration; 2) the effect of reduced arterial driving pressure on muscle regeneration; and 3) the effect of reduced arterial driving pressure and microvascular transformation on muscle regeneration, respectively. Decreased capillary transit time (P<0.01) and a gradual arterialization of capillaries along worsening of ischemic tissue damage (P<0.001) were observed in CLTI muscle. CLTI muscle RNA sequencing further suggested that the capillary arterialization process is an orchestration of different growth factors, cell types and even physical forces in the hypoxic muscle. Furthermore, animal models of acute and chronic limb ischemia display post-ischemic capillary enlargement (P<0.05) as a primary microvascular modification that facilitates collateral maturation but under decreased arterial driving pressure can turn from a good intention to aggravating ischemic damage. These results depict a critical role for the microvasculature in determining ischemic muscle outcome after an initial arterial occlusion in CLTI. Hypoxic microvascular remodeling, according to this data, initially has a good purpose but can also cause harm given enough time and the wrong environment. Moreover, these results offer understanding to the differential natural recoveries of experimental animals and human patients from an ischemic exposure – information that is essential for designing better treatments for ischemic diseases.

Myocardial inflammation in Fabry disease: correlations between myocardial histology, T2 mapping, and troponin

Abstract Background Myocardial inflammation likely plays a key role in cardiac Fabry disease (FD), supported by the frequent observation using cardiac MRI (CMR) of high T2 mapping values, mainly in areas of late gadolinium enhancement, LGE), typically representing oedema, and increased troponin (myocardial injury). Purpose To characterize inflammation in FD cardiomyopathy by comparing myocardial histology, T2 mapping and troponin. Methods Fifteen FD patients (67% females; 51 years old, range 39-62), undergoing 3 tests: biopsy (either RV endomyocardial biopsy, n=10, or myectomy, n=5); CMR (1.5T: cines, LGE, native T1/T2 mapping quantified in the sampling area); and troponin assessment (high sensitivity TnI). Mapping values were compared to local healthy volunteers. Left ventricle hypertrophy (LVH) was defined as either MWT ≥12mm or indexed LV mass above sex specific reference ranges. Tissue was stained using Haematoxylin-Eosin and Azan Mallory trichrome. Inflammatory cell staining used CD68 and CD3 antibodies. An abnormal inflammatory infiltrate was defined according to ESC criteria as ≥14 leukocytes/mm2 (up to 4monocytes/mm2, CD3+T-lymphocytes>7cells/mm2) and its distribution classified as focal (<30% of the specimen), multifocal (30-60%), diffuse (>60%). Results Median LV ejection fraction was 63% (58-67); indexed end diastolic volume 83ml/m2 (68-91). Seven patients had LVH. 8 patients had low native T1 and 6 had infero-lateral LGE. Median septal T2 value was 50ms (47-52) with 3 (all females) above local upper limit value (ULV). TnI was increased in 6 pts (40%; median value 54ng/L [38-128]). Histology showed mild inflammatory infiltrates in 8 pts (46%), none diffuse (focal 4, multifocal 4). Seven were mixed - T lymphocytes and macrophages, one was exclusively macrophages. Inflammatory foci were quiescent (n=5), or associated to myocytes injury not typical of ischemic damage and fibrosis (n=3). None had histologically visible myocardial oedema. Patients with inflammatory infiltrates had higher T2 values (52ms [50-54] vs 47ms [46-51]; p=0.043) but the same troponin (18ng/L [3-82] vs 14ms [3-24], p=0.215) (figure 1). The 3 patients with high T2 all had inflammatory cells associated to histologic myocyte injury (figure 2). Conclusion For the first time we correlate histology with T2 and myocardial injury in FD. In this small study, mild myocardial macrophage/lymphocyte infiltrates are common in FD and are associated to higher T2 values. Abnormal T2 septal elevation is less common (it is known common in the basal inferolateral wall however) and when present, infiltration with histological myocyte damage is found.

Changes in peripapillary microvasculature in patients with type 2 diabetes patients: effect of systemic hypertension

To determine the effect of hypertension (HTN) on the peripapillary microvasculature in type 2 diabetes mellitus (T2DM) patients without diabetic retinopathy (DR). The patients were classified into three groups: the control group (group 1), T2DM group (group 2), and both T2DM and HTN group (group 3). Peripapillary vessel density (VD) was compared using analysis of covariance and linear regression analysis was performed to identify the factors affecting the peripapillary VD. A total of 286 eyes were enrolled: 124 in group 1, 111 in group 2, and 51 in group 3. The peripapillary VDs for the full area were 18.3 ± 0.6, 17.8 ± 1.0, and 17.3 ± 1.2 mm−1 in group 1, group 2, and group 3, respectively, which were significantly different after adjustment for age and best-corrected visual acuity (P < 0.001). In post hoc analyses, group 1 versus group 2 (P < 0.001), group 1 versus group 3 (P < 0.001), and group 2 versus group 3 (P = 0.001) showed significant differences. In linear regression analysis, HTN (B = − 0.352, P = 0.043) and peripapillary retinal nerve fiber layer (pRNFL) thickness (B = 0.045, P < 0.001) were significantly associated with peripapillary VD in T2DM patients. Peripapillary VD in T2DM patients without clinical DR were lower compared to normal controls, and they were more decreased when HTN was comorbid. The combination of ischemic damage by high blood pressure and impairment of the neurovascular unit by hyperglycemia would result in more severe deterioration of peripapillary microvasculature, and this impairment could be also reflected by pRNFL thinning.

Mild traumatic brain injury induces pericyte detachment independent of stroke vulnerability

Mild traumatic brain injury (mTBI) is an independent risk factor for ischemic stroke and can result in poorer outcomes- an effect presumed to involve the cerebral vasculature. Here we tested the hypothesis that mTBI-induced pericyte detachment from the cerebrovascular endothelium is responsible for worsened stroke outcomes. We performed a mild closed-head injury and/or treated C57/bl6 mice with imatinib mesylate, a tyrosine kinase inhibitor that induces pericyte detachment. The time course of pericyte detachment was assessed 7, 14, and 28 days post injury (DPI). To test the role of pericytes in TBI-induced exacerbation of ischemic stroke outcomes, we induced mTBI and/or treated mice with imatinib for one week prior to transient middle cerebral artery occlusion. We found that injury promoted pericyte detachment from the vasculature commensurate with the levels of detachment seen in imatinib-only treated animals, and that the detachment persisted for at least 14DPI, but recovered to sham levels by 28DPI. Further, mTBI, but not imatinib-induced pericyte detachment, increased infarct volume. Thus, we conclude that the transient detachment of pericytes caused by mTBI may not be sufficient to exacerbate subsequent ischemic stroke damage. These data have important implications for understanding cerebrovascular dysfunction following mTBI and potential mechanisms of increased risk for future ischemic strokes.

Abstract 17326: Urine Exosomes Proteomics for Parenchymal Kidney Health in Heart Failure Patients With Mechanical Circulatory Support

Introduction: Kidney dysfunction frequently affects heart failure (HF) patients with left ventricular assist device (LVAD) support and is linked to unfavorable outcomes. However, the effects of LVAD support on parenchymal kidney health are uncertain. We performed a pilot study on urine exosome proteomics in LVAD recipients as they offer a non-invasive glimpse into kidney cellular states. Methods: We collected urine samples from 33 patients who underwent LVAD (HeartMate III) surgery between 01/2022-02/2023. Urine exosomes were isolated from the samples collected before the operation and on the 7th day after surgery. The exosome fraction underwent untargeted proteomics using LC-MS/MS and iBAQ quantification. Our investigation focused on identifying and studying kidney-enhanced proteins. Results: The exosomes isolated were verified by canonical exosome proteins (CD63, Hsp70) and TEM imaging (Fig.A,B), with 82.7% of exosomes between 51-120 nm (Fig.C). Over 7K strict genes were identified with an average of 1,150 proteins (Fig.D,E). In GO analysis, exosomes were the primary cellular compartment represented (Fig.F). A total of 176 kidney-enhanced proteins were present in &gt;50% of samples. Differential expression analysis revealed 8 proteins with increased expression on the 7 th day after surgery with FDR&lt;0.1(Fig.G). The 2 top proteins were glutathione peroxidase 3 (GPX3, log2 FC 3.4 [95%CI 2.1-4.8]), and fatty acid binding protein 3 (FABP3, log2 FC 2.9 [95%CI 1.7-4.2]). Enrichment analysis (Fig.H) demonstrated pathway changes consistent with inflammatory and ischemic kidney damage, metabolic dysfunction, and fibrotic transformation, consistent with kidney stress from advanced HF and cardiac surgery. Conclusions: We have demonstrated the feasibility of urine exosomes for non-invasive parenchymal kidney health assessment in LVAD patients. Further investigation in a larger cohort with additional sampling points may be warranted.

Abstract 19124: Systemic Sclerosis Masquerading as Heart Failure

Cardiac disease occurs in 80% of patients with systemic sclerosis (SS). Patients may present with various symptoms, including dyspnea, palpitations, chest pain, and heart failure. Of these, systolic heart failure has the rarest prevalence, estimated between 1-5% of patients. The mechanism behind myocardial damage is still unclear. Current literature supports a fibrotic process due to ischemic necrosis and reperfusion damage. There is a lack of representation of SS-related cardiac disease, but it is crucial to recognize it early for prompt intervention. A 62-year-old male with a history of diastolic dysfunction presented with acute hypoxic respiratory failure. A transthoracic echocardiogram demonstrated a new severely reduced systolic function at 20%. Angiogram demonstrated non-obstructive coronary artery disease. Further autoimmune workup revealed a significantly elevated ANA and highly positive RNA polymerase III antibody. The patient underwent a cardiac magnetic resonance imaging (MRI) scan, which showed evidence of inflammation with diffuse myocardial fibrosis concerning an infiltrative process. Subsequent cardiac positron emission tomography (PET) showed increased uptake in the basal portions of the septum and anterior wall for myocarditis. Given his autoimmune workup results and imaging, the patient was subsequently diagnosed with rapidly progressive cutaneous systemic sclerosis and associated non-ischemic cardiomyopathy. The patient was started on goal-directed medical therapy, including losartan, spironolactone, metoprolol, and empagliflozin. Additionally, he started on mycophenolate mofetil for immunosuppression. Roughly six months after discharge, his pulmonary function tests remain stable. His ejection fraction improved to 62%. Roughly one-third of systemic sclerosis-related deaths are due to cardiac involvement. Yet, most patients are asymptomatic during the early stages, with a variable phenotype later in disease progression. We report a case of a patient who developed systemic sclerosis-related myocarditis with an initial presentation of acute systolic heart failure. His cardiac dysfunction recovered from optimal goal-directed therapy and immunosuppression.

Restoration of the nervous system in acute ischemia-reperfusion of the rat brain by intravenous administration of mesenchymal stromal cells of different origin

Transplantation of mesenchymal stromal cells (MSCs) is a promising direction in the therapy of ischemic stroke, which promotes the regeneration of neurons in experimental and clinical studies. We evaluated the neuroprotective and angioprotective properties of intravenously transplanted allogeneic and xenogeneic MSCs obtained from human and rat adipose tissue, human umbilical cord Wharton jelly and its cells lysate compared with citicoline in a rat brain ischemia-reperfusion model. We studied the somatosensory cortex and CA1 zone of the hippocampus in rats using immunohistochemical analysis. It was found that the CA1 zone of the hippocampus was the most sensitive to ischemic damage. Analysis of brain sections 7 and 14 days after ischemia-reperfusion showed that all treatment options increased the staining intensity of NeuN-positive neurons, but did not reach the control value in sham-operated rats. To quantify the obtained results, we used the integrated fluorescence density indicator, which demonstrated a decrease in the fluorescence intensity of NeuN-positive neurons in 4.2 (7 days) and 3.2 times (14 days). All treatment variants significantly increased the intensity of fluorescence, but human umbilical cord Wharton’s jelly MSCs gave the best result. There was no difference in the fluorescence intensity of RECA-1-positive blood vessels. Thus, immunohistochemical analysis using a broad panel of antibodies against neurons and endothelial cells demonstrated that ischemia-reperfusion resulted in the death of NeuN-positive neurons in the CA1 zone of the hippocampus. Transplantation of stem cells of different origin, lysate of umbilical cord Wharton’s jelly MSCs and administration of citicoline had a neuroprotective effect on the CA1 zone of the hippocampus. However, the best result has been shown by the treatment with Wharton’s jelly MSCs.

Pathogenesis-adaptive polydopamine nanosystem for sequential therapy of ischemic stroke

Ischemic stroke is lethal cerebrovascular disease, and reperfusion as the main strategy of blood supply restoration can cause severe ischemic brain damage. Considered as the major obstacle in medication for stroke, neuroinflammation after reperfusion undergoes dynamic progression, making precision treatment for stroke a Herculean task. In this work, we report a pathogenesis-adaptive polydopamine nanosystem for sequential therapy of ischemic stroke. Intrinsic free radical scavenging and tailored mesostructure of the nanosystem can attenuate oxidative stress at the initial stage. Upon microglial overactivation at the later stage, minocycline-loaded nanosystem can timely reverse the pro-inflammatory transition in response to activated matrix metalloproteinase-2, providing on-demand regulation. Further in vivo stroke study demonstrates a higher survival rate and improved brain recovery of the sequential strategy, compared with mono-therapy and combined therapy. Complemented with satisfactory biosafety results, this adaptive nanosystem for sequential and on-demand regulation of post-stroke neuroinflammation is a promising approach to ischemic stroke therapy.

Heart graft preservation technics and limits: an update and perspectives.

Heart transplantation, the gold standard treatment for end-stage heart failure, is limited by heart graft shortage, justifying expansion of the donor pool. Currently, static cold storage (SCS) of hearts from donations after brainstem death remains the standard practice, but it is usually limited to 240 min. Prolonged cold ischemia and ischemia-reperfusion injury (IRI) have been recognized as major causes of post-transplant graft failure. Continuous ex situ perfusion is a new approach for donor organ management to expand the donor pool and/or increase the utilization rate. Continuous ex situ machine perfusion (MP) can satisfy the metabolic needs of the myocardium, minimizing irreversible ischemic cell damage and cell death. Several hypothermic or normothermic MP methods have been developed and studied, particularly in the preclinical setting, but whether MP is superior to SCS remains controversial. Other approaches seem to be interesting for extending the pool of heart graft donors, such as blocking the paths of apoptosis and necrosis, extracellular vesicle therapy, or donor heart-specific gene therapy. In this systematic review, we summarize the mechanisms involved in IRI during heart transplantation and existing targeting therapies. We also critically evaluate all available data on continuous ex situ perfusion devices for adult donor hearts, highlighting its therapeutic potential and current limitations and shortcomings.

ATF3 Ameliorates Ischemic Kidney Damage by Controlling the Cross-Talk Between Immune and Kidney Cells

ATF3 Ameliorates Ischemic Kidney Damage by Controlling the Cross-Talk Between Immune and Kidney Cells

Iliac Crest Skin Necrosis: A Case Report

Cases of dermal necrosis developing after injection of local anesthetics in the upper extremities or face have previously been reported in the literature. However, local anesthetic-induced dermal necrosis in the trunk, such as above the iliac crest, has rarely been reported. This article reports a case of skin necrosis that developed over the iliac crest after injection of a local anesthetic during a surgical procedure. This suggests that close monitoring of skin circulation is required after the administration of articaine–epinephrine in the trunk area to prevent ischemic damage such as dermal necrosis.

Plasma metabolomic profiling of patients with transient ischemic attack reveals positive role of neutrophils in ischemic tolerance

Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of patients with stroke. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of patients with TIA for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke. Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse middle cerebral artery occlusion (MCAO)-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of patients with TIA were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance. Plasma metabolomics analysis identified five differentially upregulated metabolites associated with potentially TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in patients with TIA that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted. TIA-induced potential ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils. National Natural Science Foundation of China (81974210), Science and Technology Planning Project of Guangdong Province, China (2020A0505100045), Natural Science Foundation of Guangdong Province (2019A1515010671), Science and Technology Program of Guangzhou, China (2023A03J0577), and Natural Science Foundation of Jiangxi, China（20224BAB216043).

Suspension Cell Culture of Polyscias fruticosa (L.) Harms in Bubble-Type Bioreactors-Growth Characteristics, Triterpene Glycosides Accumulation and Biological Activity.

Polyscias fruticosa (L.) Harms, or Ming aralia, is a medicinal plant of the Araliaceae family, which is highly valued for its antitoxic, anti-inflammatory, analgesic, antibacterial, anti-asthmatic, adaptogenic, and other properties. The plant can be potentially used to treat diabetes and its complications, ischemic brain damage, and Parkinson's disease. Triterpene glycosides of the oleanane type, such as 3-O-[β-D-glucopyranosyl-(1→4)-β-D-glucuronopyranosyl] oleanolic acid 28-O-β-D-glucopyranosyl ester (PFS), ladyginoside A, and polysciosides A-H, are mainly responsible for biological activities of this species. In this study, cultivation of the cell suspension of P. fruticosa in 20 L bubble-type bioreactors was attempted as a sustainable method for cell biomass production of this valuable species and an alternative to overexploitation of wild plant resources. Cell suspension cultivated in bioreactors under a semi-continuous regime demonstrated satisfactory growth with a specific growth rate of 0.11 day-1, productivity of 0.32 g (L · day)-1, and an economic coefficient of 0.16 but slightly lower maximum biomass accumulation (~6.8 g L-1) compared to flask culture (~8.2 g L-1). Triterpene glycosides PFS (0.91 mg gDW-1) and ladyginoside A (0.77 mg gDW-1) were detected in bioreactor-produced cell biomass in higher concentrations compared to cells grown in flasks (0.50 and 0.22 mg gDW-1, respectively). In antibacterial tests, the minimum inhibitory concentrations (MICs) of cell biomass extracts against the most common pathogens Staphylococcus aureus, methicillin-resistant strain MRSA, Pseudomonas aeruginosa, and Escherichia coli varied within 250-2000 µg mL-1 which was higher compared to extracts of greenhouse plant leaves (MIC = 4000 µg mL-1). Cell biomass extracts also exhibited antioxidant activity, as confirmed by DPPH and TEAC assays. Our results suggest that bioreactor cultivation of P. fruticosa suspension cell culture may be a perspective method for the sustainable biomass production of this species.

Role of speckle-tracking echocardiography in diagnosis and further prognosis of coronary heart disease

Echocardiography is one of the first-line methods of detection and evaluation of coronary artery disease, which helps clinicians in the diagnostic and prognostic evaluation of this disease. However, visual assessment of abnormal left ventricular myocardial wall motion is not always appropriate in detecting less severe or transient myocardial ischemia and in making an accurate differential diagnosis. Speckle-tracking echocardiography is a widely available non-invasive tool that can easily and quickly provide clarifying information and significantly extend the standard echocardiographic study, as the method allows you to identify subtle myocardial damage and local areas of ischemia that correspond to the pattern of coronary disease, and obtain an objective report in the form of simple visual scheme, very easy to use for differential diagnosis and treatment. Therefore, this method, which is increasingly used in various manifestations of coronary insufficiency and is convenient to use both at rest and with stress echocardiography, has proved efficient results in terms of predicting coronary heart disease, quantitative interpretation of emerging or persistent ischemia, assessment of the clinical course and outcome, and left ventricular remodeling. In this review, we have attempted to reflect the currently available findings that demonstrate the significance of speckle-tracking echocardiography for the evaluation and follow-up of coronary heart disease, including some congenital anomalies of the coronary arteries, and to touch on the main achievements and discoveries in the use of two-dimensional and three-dimensional deformation parameters and their potential application for a wider introduction into clinical practice.

Role of microRNA-34a in blood-brain barrier permeability and mitochondrial function in ischemic stroke.

Over the past decade, there has been an uptick in the number of studies conducting research on the role of microRNA (miRNA) molecules in stroke. Among these molecules, miR-34a has emerged as a significant player, as its levels have been observed to exhibit a substantial rise following ischemic events. Elevated levels of miR-34a have been found to have multiple effects, including the modulation of inflammatory molecules involved in the post-stroke recovery process, as well as negative effects on the blood-brain barrier (BBB) permeability. Interestingly, the increase of miR-34a appears to increase BBB permeability post stroke, through the negative effect on mitochondrial function. The strength of mitochondrial function is crucial for limiting para-cellular permeability and maintaining the structural integrity of the BBB. Furthermore, the activation of ischemic repair mechanisms and the reduction of ischemic event damage depend on healthy mitochondrial activity. This review aims to emphasize the involvement of miR-34a in ischemic stroke, specifically its interaction with mitochondrial genes in cerebrovascular endothelial cells, the effect on mitochondrial function, and lastly its regulatory role in BBB permeability. A comprehensive understanding of the role of miR-34a in maintaining BBB integrity and its contribution to the pathogenesis of stroke holds significant value in establishing a foundation for the development of future therapeutics and diagnostic markers.

Integrin α4 Positive Subpopulation in Adipose Derived Stem Cells Effectively Reduces Infarct Size through Enhanced Engraftment into Myocardial Infarction.

The efficacy of adipose-derived stem cells (ASCs) on myocardial infarction is limited due to poor survival and engraftment. Integrin-mediated cell adhesion is a prerequisite for its survival and homing. ASCs expressed insufficient integrin α4, limiting their homing capacity. This study aims to characterize integrin α4＋ ASC subpopulation and investigate their therapeutic efficacy in myocardial infarction. We used fluorescence-activated cell sorting to harvest integrin α4＋ ASCs subpopulation, which were characterized in vitro and transplanted into myocardial infarction model. Positron emission tomography imaging were performed to measure infarction size. Cardiac cine magnetic resonance imaging was used to evaluate heart contractile function. Compared with the unfractionated ASCs, integrin α4＋ ASCs subpopulation secreted a higher level of angiogenic growth factors, migrated more rapidly, and exhibited a stronger anti-apoptotic capacity. Vascular cell adhesion molecule-1 was obviously up-regulated at 3 days after myocardial infarction, which interacted with integrin α4 receptor on the surface of ASCs to enhance the survival and adhesion. Thus, we implanted unfractionated ASCs or integrin α4＋ ASCs subpopulation into the 3-day infarcted myocardium. Integrin α4＋ ASCs subpopulation exhibited more robust engraftment into the infarcted myocardium. Integrin α4＋ ASCs subpopulation more effectively decreased infarct size and strengthen cardiac function recovery than did the unfractionated ASCs. Integrin α4＋ ASCs subpopulation is superior to unfractionated ASCs in ameliorating ischemic myocardial damage in animal model. Mechanistically, their more robust engraftment into the infarct area, higher migratory capacity and their increased release of paracrine factors contribute to enhanced tissue repair.

Uric Acid: A Translational Journey in Cerebroprotection That Spanned Preclinical and Human Data.

Uric acid (UA) is a strong endogenous antioxidant that neutralizes the toxicity of peroxynitrite and other reactive species on the neurovascular unit generated during and after acute brain ischemia. The realization that a rapid reduction of UA levels during an acute ischemic stroke was associated with a worse stroke outcome paved the way to investigate the value of exogenous UA supplementation to counteract the progression of redox-mediated ischemic brain damage. The long translational journey for UA supplementation recently reached a critical milestone when the results of the multicenter NIH stroke preclinical assessment network (SPAN) were reported. In a novel preclinical paradigm, 6 treatment candidates including UA supplementation were selected and tested in 6 independent laboratories following predefined criteria and strict methodological rigor. UA supplementation was the only intervention in SPAN that exceeded the prespecified efficacy boundary with male and female animals, young mice, young rats, aging mice, obese mice, and spontaneously hypertensive rats. This unprecedented achievement will allow UA to undergo clinical testing in a pivotal clinical trial through a NIH StrokeNet thrombectomy endovascular platform created to assess new treatment strategies in patients treated with mechanical thrombectomy. UA is a particularly appealing adjuvant intervention for mechanical thrombectomy because it targets the microcirculatory hypoperfusion and oxidative stress that limits the efficacy of this therapy. This descriptive review aims to summarize the translational development of UA supplementation, highlighting those aspects that likely contributed to its success. It includes having a well-defined target and mechanism of action, and an approach that simultaneously integrated rigorous preclinical assessment, with epidemiologic and preliminary human intervention studies. Validation of the clinical value of UA supplementation in a pivotal trial would confirm the translational value of the SPAN paradigm in preclinical research.

Pharmacological intervention of curcumin via the NLRP3 inflammasome in ischemic stroke.

Ischemic-induced neuronal injury arises due to low oxygen/nutrient levels and an inflammatory response that exacerbates neuronal loss. NOD-like receptor family pyrin domain-containing 3 (NLRP3) is an important regulator of inflammation after ischemic stroke, with its inhibition being involved in nerve regeneration. Curcumin, a main active ingredient in Chinese herbs, plays a positive role in neuronal repair and neuroprotection by regulating the NLRP3 signaling pathway. Nevertheless, the signaling mechanisms relating to how curcumin regulates NLRP3 inflammasome in inflammation and neural restoration following ischemic stroke are unknown. In this report, we summarize the main biological functions of the NLRP3 inflammasome along with the neuroprotective effects and underlying mechanisms of curcumin via impairment of the NLRP3 pathway in ischemic brain injury. We also discuss the role of medicinal interventions that target the NLRP3 and potential pathways, as well as possible directions for curcumin therapy to penetrate the blood-brain barrier (BBB) and hinder inflammation in ischemic stroke. This report conclusively demonstrates that curcumin has neuroprotective properties that inhibit inflammation and prevent nerve cell loss, thereby delaying the progression of ischemic brain damage.

Granuloma, vasculitis, and demyelination in sarcoid neuropathy.

Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens. Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.