Elucidating metabolite and pH variations in stroke through guanidino, amine and amide CEST MRI: A comparative multi-field study at 9.4T and 3T.

This study aims to investigate the variations in guanidino (Guan), amine and amide chemical exchange saturation transfer (CEST) contrasts in ischemic stroke using permanent middle cerebral artery occlusion (pMCAO) and transient MCAO (tMCAO) models at high (9.4T) and clinical (3T) MRI fields. CEST contrasts were extracted using the Polynomial and Lorentzian Line-shape Fitting (PLOF) method.

NCAM mimetic peptide P2 synergizes with bone marrow mesenchymal stem cells in promoting functional recovery after stroke.

The neural cell adhesion molecule (NCAM) promotes neural development and regeneration. Whether NCAM mimetic peptides could synergize with bone marrow mesenchymal stem cells (BMSCs) in stroke treatment deserves investigation. We found that the NCAM mimetic peptide P2 promoted BMSC proliferation, migration, and neurotrophic factor expression, protected neurons from oxygen-glucose deprivation through ERK and PI3K/AKT activation and anti-apoptotic mechanisms .

Tunable Nanoparticles with Aggregation-Induced Emission Heater for Precise Synergistic Photothermal and Thermodynamic Oral Cancer Therapy of Patient-Derived Tumor Xenograft.

The fluorophores in the second near-infrared (NIR-II) biological window (1000 - 1700 nm) show great application prospects in the fields of biology and optical communications. However, both excellent radiative transition and nonradiative transition cannot be achieved simultaneously for the majority of traditional fluorophores. Herein, tunable nanoparticles formulated with aggregation-induced emission (AIE) heater are developed rationally.

Cerebral small vessel disease: Pathological mechanisms and potential therapeutic targets.

Cerebral small vessel disease (CSVD) represents a diverse cluster of cerebrovascular diseases primarily affecting small arteries, capillaries, arterioles and venules. The diagnosis of CSVD relies on the identification of small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, and microbleeds using neuroimaging. CSVD is observed in 25% of strokes worldwide and is the most common pathology of cognitive decline and dementia in the elderly.

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice.

Background: Multiple sclerosis (MS) is a neurodegenerative disease, wherein aberrant immune cells target myelin-ensheathed nerves. Conventional magnetic resonance imaging (MRI) can be performed to monitor damage to the central nervous system that results from previous inflammation; however, these imaging biomarkers are not necessarily indicative of active, progressive stages of the disease. The immune cells responsible for MS are first activated and sensitized to myelin in lymph nodes (LNs).

Hyperosmolar blood-brain barrier opening using intra-arterial injection of hyperosmotic mannitol in mice under real-time MRI guidance.

The blood-brain barrier (BBB) is the main obstacle to the effective delivery of therapeutic agents to the brain, compromising treatment efficacy for a variety of neurological disorders. Intra-arterial (IA) injection of hyperosmotic mannitol has been used to permeabilize the BBB and improve parenchymal entry of therapeutic agents following IA delivery in preclinical and clinical studies. However, the reproducibility of IA BBB manipulation is low and therapeutic outcomes are variable.

Bone Marrow Mesenchymal Stem Cells Exert Protective Effects After Ischemic Stroke Through Upregulation of Glutathione.

Bone marrow mesenchymal stem cells (BMSCs) have been shown to promote stroke recovery, however, the underlying mechanisms are not well understood. In this study naïve rats were intravenously injected with syngeneic BMSCs to screen for potential differences in brain metabolite spectrum versus vehicle-treated controls by capillary electrophoresis-mass spectrometry. A total of 65 metabolites were significantly changed after BMSC treatment.

Mesenchymal Stem Cells Do Not Lose Direct Labels Including Iron Oxide Nanoparticles and DFO-Zr Chelates through Secretion of Extracellular Vesicles.

Rapidly ageing populations are beset by tissue wear and damage. Stem cell-based regenerative medicine is considered a solution. Years of research point to two important aspects: (1) the use of cellular imaging to achieve sufficient precision of therapeutic intervention, and the fact that (2) many therapeutic actions are executed through extracellular vesicles (EV), released by stem cells.

Reversible blood-brain barrier opening utilizing the membrane active peptide melittin in vitro and in vivo.

The blood-brain barrier (BBB) tightly controls entry of molecules and cells into the brain, restricting the delivery of therapeutics. Blood-brain barrier opening (BBBO) utilizes reversible disruption of cell-cell junctions between brain microvascular endothelial cells to enable transient entry into the brain. Here, we demonstrate that melittin, a membrane active peptide present in bee venom, supports transient BBBO.

Deuterium oxide as a contrast medium for real-time MRI-guided endovascular neurointervention.

Endovascular intervention plays an important role in the treatment of various diseases, in which MRI-guidance can potentially improve precision. However, the clinical applications of currently available contrast media, including Gadolinium-based contrast agents and superparamagnetic iron oxide particles (SPIO), are hindered by safety concerns. In the present study, we sought to develop DO as a novel contrast agent for guiding endovascular neurointervention.

Imaging of Allografted Glial-Restricted Progenitor Cell Survival and Hydrogel Scaffold Biodegradation.

Transplanted glial-restricted progenitor (GRP) cells have potential to focally replace defunct astrocytes and produce remyelinating oligodendrocytes to avert neuronal death and dysfunction. However, most central nervous system cell therapeutic paradigms are hampered by high initial cell death and a host anti-graft immune response. We show here that composite hyaluronic acid-based hydrogels of tunable mechanical strengths can significantly improve transplanted GRP survival and differentiation.

Traumatic brain injury does not disrupt costimulatory blockade-induced immunological tolerance to glial-restricted progenitor allografts.

Background: Cell transplantation-based treatments for neurological disease are promising, yet graft rejection remains a major barrier to successful regenerative therapies. Our group and others have shown that long-lasting tolerance of transplanted stem cells can be achieved in the brain with systemic application of monoclonal antibodies blocking co-stimulation signaling. However, it is unknown if subsequent injury and the blood-brain barrier breach could expose the transplanted cells to systemic immune system spurring fulminant rejection and fatal encephalitis.

White matter demyelination predates axonal injury after ischemic stroke in cynomolgus monkeys.

Unraveling the pathology of stroke is a prerequisite for designing therapeutic strategies. It was reported that myelin injury exceeded axonal loss in the peri-infarct region of rodent white matter stroke. An in-depth investigation of the post-stroke white matter damage in higher-order species might innovate stroke intervention.

Imaging as a tool to accelerate the translation of extracellular vesicle-based therapies for central nervous system diseases.

Extracellular vesicles (EVs) are natural and diverse lipid bilayer-enclosed particles originating from various cellular components and containing an abundance of cargoes. Due to their unique properties, EVs have gained considerable interest as therapeutic agents for a variety of diseases, including central nervous system (CNS) disorders. Their therapeutic value depends on cell origin but can be further enhanced by enrichment of cargo when used as drug carriers.

Photoacoustic Cavitation-Ignited Reactive Oxygen Species to Amplify Peroxynitrite Burst by Photosensitization-Free Polymeric Nanocapsules.

Photoacoustic (PA) technology can transform light energy into acoustic wave, which can be used for either imaging or therapy that depends on the power density of pulsed laser. Here, we report photosensitizer-free polymeric nanocapsules loaded with nitric oxide (NO) donors, namely NO-NCPs, formulated from NIR light-absorbable amphiphilic polymers and a NO-releasing donor, DETA NONOate. Controlled NO release and nanocapsule dissociation are achieved in acidic lysosomes of cancer cells.

Modeling human pediatric and adult gliomas in immunocompetent mice through costimulatory blockade.

Currently, human glioma tumors are mostly modeled in immunodeficient recipients; however, lack of interactions with adaptive immune system is a serious flaw, particularly in the era when immunotherapies dominate treatment strategies. Our group was the first to successfully establish the orthotopic transplantation of human glioblastoma (GBM) in immunocompetent mice by inducing immunological tolerance using a short-term, systemic costimulation blockade strategy (CTLA-4-Ig and MR1). In this study, we further validated the feasibility of this method by modeling pediatric diffuse intrinsic pontine glioma (DIPG) and two types of adult GBM (GBM1, GBM551), in mice with intact immune systems and immunodeficient mice.

Neuroinflammation After Stereotactic Radiosurgery-Induced Brain Tumor Disintegration Is Linked to Persistent Cognitive Decline in a Mouse Model of Metastatic Disease.

Purpose: Improved efficacy of anticancer therapy and a growing pool of survivors give rise to a question about their quality of life and return to premorbid status. Radiation is effective in brain metastasis eradication, although the optimal approach and long-term effects on brain function are largely unknown. We studied the effects of radiosurgery on brain function.

Imaging of Composite Hydrogel Scaffold Degradation Using CEST MRI and Two-Color NIR Imaging.

Hydrogel scaffolding of stem cells is a promising strategy to overcome initial cell loss and manipulate cell function post-transplantation. Matrix degradation is a requirement for downstream cell differentiation and functional tissue integration, which determines therapeutic outcome. Therefore, monitoring of hydrogel degradation is essential for scaffolded cell replacement therapies.

Optimization of osmotic blood-brain barrier opening to enable intravital microscopy studies on drug delivery in mouse cortex.

Intra-arterial (IA) infusion of mannitol induces osmotic blood-brain barrier opening (OBBBO) and that method has been used for decades to improve drug delivery to the brain. However, high variability of outcomes prevented vast clinical adoption. Studies on dynamic multi-scale imaging of OBBBO as well as extravasation of IA injected therapeutic agents are essential to develop strategies assuring precision and reproducibility of drug delivery.

Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts.

The immunological barrier currently precludes the clinical utilization of allogeneic stem cells. Although glial-restricted progenitors have become attractive candidates to treat a wide variety of neurological diseases, their survival in immunocompetent recipients is limited. In this study, we adopted a short-term, systemically applicable co-stimulation blockade-based strategy using CTLA4-Ig and anti-CD154 antibodies to modulate T-cell activation in the context of allogeneic glial-restricted progenitor transplantation.