Infarction Registry Research Articles

Design of a Zn-based nanozyme injectable multifunctional hydrogel with ROS scavenging activity for myocardial infarction therapy

The existing strategies for myocardial infarction therapy mainly focus on reinstating myocardial blood supply, often disregarding the intrinsic and intricate microenvironment created by elevated levels of reactive oxygen species (ROS) that accompanies myocardial infarction. This microenvironment entails cardiomyocytes apoptosis, substantial vascular cell death, excessive inflammatory infiltration and fibrosis. In such situation, the present study introduces a zinc-based nanozyme injectable multifunctional hydrogel, crafted from ZIF-8, to counteract ROS effects after myocardial infarction. The hydrogel exhibits both superoxide dismutase (SOD)-like and catalase (CAT)-like enzymatic activities, proficiently eliminating surplus ROS in the infarcted region and interrupting ROS-driven inflammatory cascades. Furthermore, the hydrogel's exceptional immunomodulatory ability spurs a notable transformation of macrophages into the M2 phenotype, effectively neutralizing inflammatory factors and indirectly fostering vascularization in the infarcted region. For high ROS and demanding for zinc of the infarcted microenvironment, the gradual release of zinc ions as the hydrogel degrades further enhances the bioactive and catalytic performance of the nanozymes, synergistically promoting cardiac function post myocardial infarction. In conclusion, this system of deploying catalytic nanomaterials within bioactive matrices for ROS-related ailment therapy not only establishes a robust foundation for biomedical material development, but also promises a holistic approach towards addressing myocardial infarction complexities. Statement of significanceMyocardial infarction remains the leading cause of death worldwide. However, the existing strategies for myocardial infarction therapy mainly focus on reinstating myocardial blood supply. These therapies often ignore the intrinsic and intricate microenvironment created by elevated levels of reactive oxygen species (ROS). Hence, we designed an injectable Zn-Based nanozyme hydrogel with ROS scavenging activity for myocardial infarction therapy. ALG-(ZIF-8) can significantly reduce ROS in the infarcted area and alleviate the ensuing pathological process. ALG-(ZIF-8) gradually releases zinc ions to participate in the repair process and improves cardiac function. Overall, this multifunctional hydrogel equipped with ZIF-8 makes full use of the characteristics of clearing ROS and slowly releasing zinc ions, and we are the first to test the therapeutic efficacy of Zinc-MOFs crosslinked-alginate hydrogel for myocardial infarction.

Monomeric CXCL12-Engineered Adipose-Derived Stem Cells Transplantation for the Treatment of Ischemic Stroke.

Adipose-derived stem cells (ASCs) possess therapeutic potential for ischemic brain injury, and the chemokine CXCL12 has been shown to enhance their functional properties. However, the cumulative effects of ASCs when combined with various structures of CXCL12 on ischemic stroke and its underlying molecular mechanisms remain unclear. In this study, we genetically engineered mouse adipose-derived ASCs with CXCL12 variants and transplanted them to the infarct region in a mice transient middle cerebral artery occlusion (tMCAO) model of stroke. We subsequently compared the post-ischemic stroke efficacy of ASC-mCXCL12 with ASC-dCXCL12, ASC-wtCXCL12, and unmodified ASCs. Neurobehavior recovery was assessed using modified neurological severity scores, the hanging wire test, and the elevated body swing test. Changes at the tissue level were evaluated through cresyl violet and immunofluorescent staining, while molecular level alterations were examined via Western blot and real-time PCR. The results of the modified neurological severity score and cresyl violet staining indicated that both ASC-mCXCL12 and ASC-dCXCL12 treatment enhanced neurobehavioral recovery and mitigated brain atrophy at the third and fifth weeks post-tMCAO. Additionally, we observed that ASC-mCXCL12 and ASC-dCXCL12 promoted angiogenesis and neurogenesis, accompanied by an increased expression of bFGF and VEGF in the peri-infarct area of the brain. Notably, in the third week after tMCAO, the ASC-mCXCL12 exhibited superior outcomes compared to ASC-dCXCL12. However, when treated with the CXCR4 antagonist AMD3100, the beneficial effects of ASC-mCXCL12 were reversed. The AMD3100-treated group demonstrated worsened neurological function, aggravated edema volume, and brain atrophy. This outcome is likely attributed to the interaction of monomeric CXCL12 with CXCR4, which regulates the recruitment of bFGF and VEGF. This study introduces an innovative approach to enhance the therapeutic potential of ASCs in treating ischemic stroke by genetically engineering them with the monomeric structure of CXCL12.

Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia.

Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood-brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders.

Inpatient morbidity of the population of the Transcarpathian Region of acute myocardial infarction in the pre-war period and the first year of the war

Inpatient morbidity of the population of the Transcarpathian Region of acute myocardial infarction in the pre-war period and the first year of the war

Pathological Asymmetry-Guided Progressive Learning for Acute Ischemic Stroke Infarct Segmentation.

Quantitative infarct estimation is crucial for diagnosis, treatment and prognosis in acute ischemic stroke (AIS) patients. As the early changes of ischemic tissue are subtle and easily confounded by normal brain tissue, it remains a very challenging task. However, existing methods often ignore or confuse the contribution of different types of anatomical asymmetry caused by intrinsic and pathological changes to segmentation. Further, inefficient domain knowledge utilization leads to mis-segmentation for AIS infarcts. Inspired by this idea, we propose a pathological asymmetry-guided progressive learning (PAPL) method for AIS infarct segmentation. PAPL mimics the step-by-step learning patterns observed in humans, including three progressive stages: knowledge preparation stage, formal learning stage, and examination improvement stage. First, knowledge preparation stage accumulates the preparatory domain knowledge of the infarct segmentation task, helping to learn domain-specific knowledge representations to enhance the discriminative ability for pathological asymmetries by constructed contrastive learning task. Then, formal learning stage efficiently performs end-to-end training guided by learned knowledge representations, in which the designed feature compensation module (FCM) can leverage the anatomy similarity between adjacent slices from the volumetric medical image to help aggregate rich anatomical context information. Finally, examination improvement stage encourages improving the infarct prediction from the previous stage, where the proposed perception refinement strategy (RPRS) further exploits the bilateral difference comparison to correct the mis-segmentation infarct regions by adaptively regional shrink and expansion. Extensive experiments on public and in-house NCCT datasets demonstrated the superiority of the proposed PAPL, which is promising to help better stroke evaluation and treatment.

Topological Hydrogels for Long-Term Brain Signal Monitoring, Neuromodulation, and Stroke Treatment.

Stroke is the primary cause of disability without effective rehabilitation methods. Emerging brain-machine interfaces offer promise for regulating brain neural circuits and promoting the recovery of brain function disorders. Implantable probes play key roles in brain-machine interfaces, which are subject to two irreconcilable tradeoffs between conductivity and modulus match/transparency. In this work, mechanically interlocked polyrotaxane is incorporated into topological hydrogels to solve the two tradeoffs at the molecular level through the pulley effect of polyrotaxane. The unique performance of the topological hydrogels enables them to acquire brain neural information and conduct neuromodulation. The probe is capable of continuously recording local field potentials for eight weeks. Optogenetic neuromodulation in the primary motor cortex to regulate brain neural circuits and control limb behavior is realized using the probe. Most importantly, optogenetic neuromodulation is conducted using the probe, which effectively reduces the infarct regions of the brain tissue and promotes locomotor function recovery. This work exhibits a significant scientific advancement in the design concept of neural probes for developing brain-machine interfaces and seeking brain disease therapies.

Radiological features of internal carotid artery occlusion caused by pituitary apoplexy: illustrative case.

Pituitary apoplexy rarely causes internal carotid artery (ICA) occlusion and acute ischemic stroke. Some cases have been reported, but the neuroimaging findings, including cerebral angiography, have not been discussed. A 55-year-old male suffered the sudden onset of right cervical pain and left mild hemiparesis. Computed tomography indicated a pituitary mass, and magnetic resonance angiography showed a right ICA occlusion. The initial diagnosis was ICA occlusion caused by ICA dissection. His symptoms worsened and the region of cerebral infarction expanded, so the patient was transferred to our hospital. Magnetic resonance imaging and cerebral angiography showed the sudden stoppage of right ICA blood flow caused by local compression of the tumor near the distal dural ring. The diagnosis was acute ischemic stroke resulting from ICA pseudo-occlusion caused by pituitary apoplexy, and emergent endoscopic transsphenoidal resection was performed. Postoperatively, the right ICA was completely patent, and hemiparesis was improved with rehabilitation. ICA occlusion caused by pituitary apoplexy is very rare, but emergent treatment is necessary. However, the pathology is difficult to diagnose quickly. Neuroimaging findings showing that the ICA is easily stenosed or occluded if rapidly compressed by the tumor near the distal dural ring may be useful to rapidly diagnose and treat.

Parametrization of subsegmental infarcts using high spatial resolution 2DSTE and synthetic ultrasonic data

Abstract Introduction: The purpose of this study was to assess the performance of a set of parameters in characterizing simulated infarcts in left ventricular (LV) models with variations in size and transmural extent. Material and methods: The deformation of the LV models with different infarct sizes was simulated using the Finite Element Method. These simulations provided meshes that were used to generate synthetic ultrasonic data within the FIELD II package. The strain components (longitudinal and circumferential) were then estimated over small subsegments of the of segments 7 and 12 (according to 17-segment left ventricle segmentation standard proposed by the American Heart Association - AHA17), using a hierarchical block matching method. The strain maps obtained were utilized to calculate the Strain Drop Factor (SDF) maps, which represent the percentage ratio of strain observed in the subsegments of the studied model to that observed in the healthy model. Infarct segmentation was performed using these maps, and various parameters were derived, including Infarct Cross-Section Area (ICSA), relative ICSA, Transmurality Ratio (TR), Mean Infarct Transmurality (MIT), strain drop factor in the infarcted region (SDFi), and Strain Contrast (SC). Results: The estimates of ICSA, SC, MIT, and SDFI showed good repeatability and demonstrated the ability to provide a quantitative assessment of the size and transmural extent of the infarcts. Conclusions: The study findings suggest that the evaluated parameters, including ICSA, SC, MIT, and SDFI, can be reliably used to assess the size and transmural extent of infarcts. These parameters offer a quantitative approach for characterizing infarcts based on strain analysis and have the potential to contribute to the diagnosis and evaluation of myocardial infarctions.

Influence of microRNAs on iNOS expression in postmortem human infarction hearts

MicroRNAs (miRNAs) are important post-transcriptional regulators in several diseases, including cancer, immunologic and cardiovascular diseases. A growing list of miRNAs are dysregulated in cardiac arrhythmias, contractility diseases, myocardial infarction (MI), sudden cardiac death (SCD), chronic heart failure and hypertrophy. However, the exact regulatory pathways, through which miRNAs exert their effects are often unclear. In this study, we measured the expression patterns of miR-21, miR-939 and miR-30e in postmortem human MI. The aim of the study was to examine the influence of these miRNAs on cardiac inducible nitric oxide synthase (iNOS) mRNA levels. We measured iNOS mRNA and miRNA expression patterns by means of qPCR. Further we used correlation analyses to determine causality between miRNA expression and cardiac iNOS levels. iNOS mRNA, miR-21, miR-939 and miR-30e were significantly upregulated in infarcted and non-infarcted regions of postmortem human MI hearts in comparison to healthy controls. While miR-21 and miR-939 showed their strongest expression in infarcted regions, miR-30e peaked in the non-infarcted myocardium. Further, we found a significant correlation between miR-939 and iNOS expression levels in controls and infarcted regions. The results indicate, that miR-939 is a regulator of cardiac iNOS expression. However, a massive iNOS activation might exceed the capability of miR-939 to keep its expression in balance. miR-21 and miR-30e do not seem to influence cardiac iNOS levels in MI. Further studies are needed to evaluate downstream targets of these miRNAs and their signaling pathways to clarify their role in human MI.

CNSC-41. DOES ISCHEMIC STROKE DRIVE BRAIN TUMOR PROGRESSION?

Abstract Glioblastoma multiforme is the most common and lethal primary brain tumor, with a 5-year survival rate of less than 5%. Its complex pathophysiology, highlighted by massive inflammatory responses, enhances tumor progression and impedes therapeutic interventions, leading to its dismal prognosis. Inflammatory responses are also a cardinal feature of brain injury and remarkably, clinical evidence from large-scale patient cohort studies indicates a link between glioma and cerebral ischemic stroke, where approximately 10% of ischemic stroke patients develop glioma. This observation suggests that brain injury may be a risk factor for the development of brain tumors; however, whether and how stroke occurrence promotes brain tumor progression is unknown. To address this knowledge gap, we employed a photothrombotic stroke mouse model in conjunction with established glioma models. In these models, we observed a significant increase in tumor cell proliferation and infiltration towards the infarct region and blood-brain barrier disruption. Intriguingly, spatial transcriptomic analysis in stroke-glioma models highlighted altered pH regulation in the microenvironment at the leading edge of tumor cells near stroke lesions. Further analysis revealed that the astrocytic pH regulator, Slc4a4, is significantly downregulated in the infiltrating tumor cells near infarct lesions, and that Slc4a4 inhibits tumor progression in our glioma models. Based on patient cohort studies that link glioma occurrence with cerebral ischemia and our new mouse model results, our data demonstrates that exposure to cortical ischemia-induced-hypoxia during tumorigenesis, promotes malignant glioma progression by altering the brain microenvironment via pH modulation. These conceptually innovative studies will integrate our new stroke-glioma models and advanced methodologies to investigate the stroke-glioma interaction via hypoxia and pH modulation, potentially identifying new therapy targets.

Integrin alpha 11 is cardioprotective post myocardial infarction, regulating infarct formation and collagen organization

Abstract Background Post Myocardial Infarction (MI), fibrosis and in particular collagen production is an important response in order to replace apoptotic cells within the injured area and stabilize the heart wall1. Cardiac fibroblasts in and around the infarct region under mechanical and biochemical stress transform into myofibroblasts, secreting collagen to help stabilize the infarct segment2. In the short term this is an appropriate response to avoid rupture and death3. However, Long term collagen deposition will increase ventricular stiffness reducing compliance leading to further cardiac dysfunction and heart failure4. Mechanical activation of collagen production and fibrosis is understood to be a significant mediator of cardiac fibrosis, yet the mechanisms controlling mechanical activation of fibrosis are not well understood5,6. Purpose Here, we sort to investigate the role of Integrin α11 in cardiac remodelling post MI, a collagen binding integrin which preferentially binds to type I collagen and, is significantly upregulated post MI4,7. Methods Fibroblast Conditional α11 knockout (KO) and Wildtype Littermates (WT) underwent either SHAM or left anterior descending aorta (LAD) ligation surgery. Cardiac function was assessed with echocardiography and pressure volume loops. Ventricle samples were processed for FFPE histological/immunohistochemical analysis with hematoxylin/eosin, Collagen I & III antibodies. Finally, Second Harmonic generation microscopy was undertaken to identify collagen organisation with previously validated CurveAlign and CT-Fire algorithms. Results α11KO and WT mice demonstrated similar cardiac function. There was evidence of basal structural differences as Collagen I (P<0.05) and III (P<0.0001) deposition was reduced along with cardiac myocyte size (P<0.0001) in α11KO mice. In response to LAD ligation α11KO mice had significantly worse mortality (∼57% v’s ∼22%, P<0.05) which, correlated with an increased MI size (WT=∼39%, α11KO=∼64% P<0.05). Cardiac function 2 days following ligation measured by echo demonstrated that Fractional Area Change (FAC) (23%±2 v’s 16%±2 P<0.05) and Cardiac Output (8.5ml±1 v’s 5ml±0.7, P<0.05) were significantly worse in α11 KO compared to WT mice. The reduced function persisted 4 weeks post ligation as FAC was significantly worse in α11KO mice (∼9%±2%, P<0.0001) compared to WT (∼19%±1%). Moreover, α11KO mice that survived MI had significantly more collagen I (P<0.0001) content in the remote, peri-infarct and infarct zone’s than that of WT along with a lack of hypertrophic response. Finally, Collagen alignment measured using SHG images with CurveAlign demonstrated collagen fibres had significantly less structural alignment in α11KO mice (P<0.05). Conclusion We demonstrate a cardioprotective role for Integrin α11 post myocardial infarction. Where, the lack of α11 leads to worsened mortality, larger MI, worsened cardiac function and impaired collagen organisation in the infarct post MI.

Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis

Mesenchymal stem cells (MSCs) experience substantial viability issues in the stroke infarct region, limiting their therapeutic efficacy and clinical translation. High levels of deadly reactive oxygen radicals (ROS) and proinflammatory cytokines (PC) in the infarct milieu kill transplanted MSCs, whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs' viability. Based on the intrinsic hormesis effects in cellular biology, we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy. This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer. In this system, extracellular ROS-scavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a micro-livable niche at the level of a single MSC for transplantation. Meanwhile, the infarct's inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing. The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days. This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.

Abstract 16919: Analysis of Astrocyte Activation and Reduction of Motor Deficits Following hSOX2 Gene Therapy Delivered Using PAMAM Dendrimer Nanomolecules in Ischemic Stroke

PAMAM dendrimers are 3-dimensional nanomolecules which have the capability to deliverbiomolecules and gene therapy to the cells in vitro and in vivo . We have previously used the generation-4 surface-modified PAMAM dendrimers having 90% hydroxyl groups and 10% amine groups (G4-90/10) which are safe, cross the blood-brain barrier and deliver the biomolecules into the cells. In thecurrent study, we utilized G4-90/10 PAMAM dendrimers to deliver a gene therapy to the infarct in aischemic stroke brain in rats. Following an ischemic stroke, glial cells (such as astrocytes) are recruitedat the infarct region to perform maintenance functions, creating severe neuroinflammation. The goalof this study was to reprogram some of the astrocytes into neuronal lineage and repopulate the infarctregion. In addition, we also analyzed the temporal profile of astrocyte activation following ischemicstroke in the striatal and cortical regions to determine the time-point at which the maximum gliosisoccurs. This gives us a crucial timeline for treatment intervention to achieve astrocytereprogramming. We have used a transcription factor (hSOX2 gene), which was then delivered to thestroke brain in rats using the G4-90/10 dendrimers. Our results showed that the maximum glial cellactivation occurs in striatal and cortical regions on day 4 following ischemic stroke. Following genetherapy intervention, our initial analyses indicated that there was recovery from behavioral deficits inthe stroked rats compared to the vehicle-treated stroked rats and sham controls. Overall, these resultsshow that PAMAM dendrimers have significant potential delivering therapeutic molecules for treatingstroke and other neurological conditions. Support for this study was provided by the American Heart Association (18AIREA 33990094),Neuroscience program, the College of Medicine, department of Chemistry and Biochemistry, the JohnG. Kulhavi Professorship and the E. Malcolm Field and Gary Leo Dunbar Endowed Chair of Neuroscience at Central Michigan University.

Abstract 17096: Immune Modulation to Treat Ischemic Heart Failure

Introduction: Clinical use of induced pluripotent derived cardiomyocytes (iPSC-CMs) has been slow because their mechanism is not well defined. Our lab developed a cardiac patch composed of iPSC-CMs and human neonatal dermal fibroblast (NDF) seeded on a bioresorbable matrix. Implantation on the epicardium of the infarcted heart in immune competent animal models of ischemic CHF (mice, rats, swine) repaired the damaged heart, improved cardiac function/structure with increased viable myocardium, increased myocardial blood flow, improved left ventricular (LV) contractility, and reversal of maladaptive LV remodeling. Preliminary analysis indicates that the patch created a novel host derived immune response not observed in untreated animals. Hypothesis: The iPSC-CMs and NDFs coordinate an immunomodulatory response that results in reduction of inflammatory cytokine producing M1 macrophages with concomitant polarization to the M2 state. Methods: Spatial transcriptomics and histological analysis was utilized for investigation of patch driven immunomodulatory responses in WT BL6 mice. All animals underwent two procedures; 1) Infarct via left coronary ligation 2) Left lateral sternotomy with patch placement (N=5) (no patch for controls, N=3) 3 weeks post MI. Patch secretions underwent quantitative mass spectroscopy to identify drivers of immunomodulation. Results: Histology demonstrated reduction of left chamber dimension and presence of viable cardiomyocytes in the LV wall. IF demonstrated a novel immune response in the treated group absent in the controls. This response is isolated to the epicardial infarct-patch interface. Cellular deconvolution of the infarct region revealed macrophages and dendritic cells compose this response. Macrophage phenotype was assessed via expression of classical M1(CD68, NOS2, AXL) as well as M2 markers (RETNLA, MRC1, ADGRE1) which were found to be significantly elevated in treated groups. Proteomic analysis of the patch secretome indicates the patch has a role in coordinating this response by upregulation of Il-4/Il-13 signaling and wound healing that stimulates enrichment of pathways associated with reorganization of the ECM.

The NR2B-targeted intervention alleviates the neuronal injuries at the sub-acute stage of cerebral ischemia: an exploration of stage-dependent strategy against ischemic insults.

Stroke is reported to be the second leading cause of death worldwide, among which ischemic stroke has fourfold greater incidence than intracerebral hemorrhage. Excitotoxicity induced by NMDAR plays a central role in ischemic stroke-induced neuronal death. However, intervention targeted NMDARs against ischemic stroke has failed, which may result from the complex composition of NMDARs and the dynamic changes of their subunits. In this current study, the levels of NR1, NR2A and NR2B subunits of NMDARs were observed upon different time points during the reperfusion after 1h ischemia with the western blot assay. It was found that the changes of NR1 subunit were only detected after ischemia 1h/reperfusion 1day (1d). While, the changes of NR2A and NR2B subunits may last to ischemia 1h/reperfusion 7day(7d), indicating that NR2subunits may be a potential target for ischemia-reperfusion injuries at the sub-acute stage of ischemic stroke. Simultaneously, mitochondrial injuries in neurons were investigated with transmission electron microscopy (TEM), and mitochondrial dysfunction was evaluated with mitochondrial membrane proteins oxidative respiratory chain complex and OCR. When the antagonist of NMDARs was used before ischemic exposure, the neuronal mitochondrial dysfunction was alleviated, suggesting that these aberrant deviations of NMDARs from basal levels led to mitochondrial dysfunction. Furthermore, when the antagonist of NR2B was administrated intracerebroventricularly at the sub-acute cerebral ischemia, the volume of cerebral infarct region was decreased and the neural functions were improved. To sum up, the ratio of NR2B-containing NMDARs is vital for mitochondrial homeostasis and then neuronal survival. NR2B-targeted intervention should be chosen at the sub-acute stage of cerebral ischemia.

End to end vision transformer architecture for brain stroke assessment based on multi-slice classification and localization using computed tomography.

Brain stroke is a leading cause of disability and death worldwide, and early diagnosis and treatment are critical to improving patient outcomes. Current stroke diagnosis methods are subjective and prone to errors, as radiologists rely on manual selection of the most important CT slice. This highlights the need for more accurate and reliable automated brain stroke diagnosis and localization methods to improve patient outcomes. In this study, we aimed to enhance the vision transformer architecture for the multi-slice classification of CT scans of each patient into three categories, including Normal, Infarction, Hemorrhage, and patient-wise stroke localization, based on end-to-end vision transformer architecture. This framework can provide an automated, objective, and consistent approach to stroke diagnosis and localization, enabling personalized treatment plans based on the location and extent of the stroke. We modified the Vision Transformer (ViT) in combination with neural network layers for the multi-slice classification of brain CT scans of each patient into normal, infarction, and hemorrhage classes. For stroke localization, we used the ViT architecture and convolutional neural network layers to detect stroke and localize it by bounding boxes for infarction and hemorrhage regions in a patient-wise manner based on multi slices. Our proposed framework achieved an overall accuracy of 87.51% in classifying brain CT scan slices and showed high precision in localizing the stroke patient-wise. Our results demonstrate the potential of our method for accurate and reliable stroke diagnosis and localization. Our study enhanced ViT architecture for automated stroke diagnosis and localization using brain CT scans, which could have significant implications for stroke management and treatment. The use of deep learning algorithms can provide a more objective and consistent approach to stroke diagnosis and potentially enable personalized treatment plans based on the location and extent of the stroke. Further studies are needed to validate our method on larger and more diverse datasets and to explore its clinical utility in real-world settings.

Cardioprotective effects of plant-based silver nanoparticles: Describing a modern drug

Regarding applicative, facile, green chemical research, a bio-inspired approach is being reported for the synthesis of Ag nanoparticles by Rumex alpinus L as a natural reducing and stabilizing agent without using any toxic and harmful reagent. Our study examined the ability of Ag NPs to make the cardioprotective effects. The biosynthesized Ag NPs@Rumex alpinus L were characterized by advanced physicochemical techniques like ultraviolet–visible (UV–Vis), Fourier Transformed Infrared spectroscopy (FT-IR), and Scanning Electron Microscopy (SEM) study. It has been established that Rumex alpinus L-stabilized silver nanoparticles have a spherical shape with a mean diameter from 12 to 55 nm. In the in medicinal part of this research, four groups of Wister rats were used: a control group; a group treated only with isoproterenol, to induce myocardial infarction; and two groups pretreated with silver nanoparticles containing Rumex alpinus (15 or 45 mg/kg, respectively) for 14 days and challenged with isoproterenol on the 13th and 14th days. Several parameters were measured including cardiac markers, electrocardiogram (ECG), nuclear factor erythroid 2-related factor 2 (Nrf2), the expression of Kelch-like ECH-associated protein 1 (Keap1), and other downstream antioxidant enzymes, as well as the expression of phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and other downstream apoptotic and inflammatory mediators. Silver nanoparticles containing Rumex alpinus may possess a protective effect against myocardial infarction through moderating myocardial infarction-induced myocardial oxidative stress (GSH, SOD, GPx, GST, and Keap1/Nrf2 pathway), inflammation (IL-1β, IL-6, TNF-α, and NF-κB), apoptosis (caspase-3, caspase-9, Bcl2, and Bax), and autophagy (PI3K/Akt/mTOR pathway). Silver nanoparticles containing Rumex alpinus treatment activated the Keap1/Nrf2/heme oxygenase-1 (HO-1) pathway, increased antioxidant enzyme activities, modulated the PI3K/Akt/mTOR pathway, and ameliorated myocardial autophagy, inflammation, and apoptosis. Silver nanoparticles containing Rumex alpinus treatment reduced the size of the infarct region, attenuated the levels of cardiac indicators, and diminished myocardial necrosis and immune cell infiltration.

Acute minocycline treatment inhibits microglia activation, reduces infarct volume, and has domain-specific effects on post-ischemic stroke cognition in rats

Ischemic stroke affects millions of individuals worldwide and a high prevalence of survivors experience cognitive deficits. At present, the underlying mechanisms that drive post-stroke cognitive decline are not well understood. Microglia play a critical role in the post-stroke inflammatory response, but experimental studies show that an accumulation of chronically activated microglia can be harmful and associates with cognitive impairment. This study assessed the effect of acute post-stroke minocycline treatment on chronic microglia and astrocyte expression within the infarct and remote white matter regions, as well as its effect on various domains of cognitive function post-stroke. Nine-month-old male rats received an injection of endothelin-1 into the right dorsal striatum to induce transient focal ischemia, and then were treated with minocycline or saline for 4 days post-stroke. Rats were tested using a series of lever-pressing tasks and the Morris water maze to assess striatal-based learning, cognitive flexibility, and spatial learning and reference memory. We found that minocycline-treated rats had smaller stroke-induced infarcts and less microglia activation in the infarct area and remote white matter regions compared to saline-treated rats at 28 days post-stroke. The behavioural testing results differed according to the cognitive domain; whereas minocycline-treated rats trended towards improved striatal-based learning in a lever-pressing task, but cognitive flexibility was unaffected during the subsequent set-shifting task. Furthermore, minocycline treatment unexpectedly impaired spatial learning, yet it did not alter reference memory. Collectively, we show that post-stroke minocycline treatment can reduce chronic microglia activation even in remote brain regions, with domain-specific effects on cognitive function.

Enzyme-Responsive Nanoparticles for the Targeted Delivery of an MMP Inhibitor to Acute Myocardial Infarction.

Herein, we have developed a drug-loaded matrix metalloproteinase (MMP)-responsive micellar nanoparticle (NP) intended for minimally invasive intravenous injection during the acute phase of myocardial infarction (MI) and prolonged retention in the heart for small-molecule drug delivery. Peptide-polymer amphiphiles (PPAs) bearing a small-molecule MMP inhibitor (MMPi), PD166793, were synthesized via ring-opening metathesis polymerization (ROMP) and formulated into spherical micelles by transitioning to aqueous solution. The resulting micellar NPs underwent MMP-induced aggregation, demonstrating enzyme responsiveness. Using a rat MI model, we observed that these NPs were capable of successfully extravasating into the infarcted region of the heart where they were retained due to the active, enzyme-mediated targeting, remaining detectable after 1 week post administration without increasing macrophage recruitment. Furthermore, in vitro studies show that these NPs demonstrated successful drug release following MMP treatment and maintained drug bioactivity as evidenced by comparable MMP inhibition to free MMPi. This work establishes a targeted NP platform for delivering small-molecule therapeutics to the heart after MI, opening possibilities for myocardial infarction treatment.

Wnt signaling pathway inhibitor promotes mesenchymal stem cells differentiation into cardiac progenitor cells in vitro and improves cardiomyopathy in vivo.

Cardiovascular diseases particularly myocardial infarction (MI) are the leading cause of mortality and morbidity around the globe. As cardiac tissue possesses very limited regeneration potential, therefore use of a potent small molecule, inhibitor Wnt production-4 (IWP-4) for stem cell differentiation into cardiomyocytes could be a promising approach for cardiac regeneration. Wnt pathway inhibitors may help stem cells in their fate determination towards cardiomyogenic lineage and provide better homing and survival of cells in vivo. Mesenchymal stem cells (MSCs) derived from the human umbilical cord have the potential to regenerate cardiac tissue, as they are easy to isolate and possess multilineage differentiation capability. IWP-4 may promote the differentiation of MSCs into the cardiac lineage. To evaluate the cardiac differentiation ability of IWP-4 and its subsequent in vivo effects. Umbilical cord tissue of human origin was utilized to isolate the MSCs which were characterized by their morphology, immunophenotyping of surface markers specific to MSCs, as well as by tri-lineage differentiation capability. Cytotoxicity analysis was performed to identify the optimal concentration of IWP-4. MSCs were treated with 5 μM IWP-4 at two different time intervals. Differentiation of MSCs into cardiomyocytes was evaluated at DNA and protein levels. The MI rat model was developed. IWP-4 treated as well as untreated MSCs were implanted in the MI model, then the cardiac function was analyzed via echocardiography. MSCs were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) dye for tracking, while the regeneration of infarcted myocardium was examined by histology and immunohistochemistry. MSCs were isolated and characterized. Cytotoxicity analysis showed that IWP-4 was non-cytotoxic at 5 μM concentration. Cardiac specific gene and protein expression analyses exhibited more remarkable results in fourteen days treated group that was eventually selected for in vivo transplantation. Cardiac function was restored in the IWP-4 treated group in comparison to the MI group. Immunohistochemical analysis confirmed the homing of pre-differentiated MSCs that were labeled with DiI cell labeling dye. Histological analysis confirmed the significant reduction in fibrotic area, and improved left ventricular wall thickness in IWP-4 treated MSC group. Treatment of MSCs with IWP-4 inhibits Wnt pathway and promotes cardiac differentiation. These pre-conditioned MSCs transplanted in vivo improved cardiac function by cell homing, survival, and differentiation at the infarcted region, increased left ventricular wall thickness, and reduced infarct size.