Electrically conductive biomaterials and nanomaterials have demonstrated great potential in the development of functional mature cardiac tissues. In particular, gold emerged as promising candidates due to their biocompatibility ease fabrication for tissue engineering utilizing rat- or stem cell-derived cardiomyocytes (CMs). However, despite significant advancements, it is still not clear whether enhancement function primarily electroconductivity features nanoparticles structural changes...

Medin is a common amyloidogenic protein in humans that accumulates arteries with advanced age and has been implicated vascular degeneration. Medin's effect on endothelial function remains unknown. The aims are to assess medin's effects human arteriole identify potential mechanisms underlying medin-induced injury.

Long QT syndrome (LQTS) is a cardiovascular disease characterized by interval prolongation that can lead to sudden cardiac death. Many mutations with heterogeneous mechanisms have been identified in KCNH2, the gene encodes for hERG (Kv11.1), which onset of LQTS type 2 (LQTS2). In this work, we developed LQTS2-diseased tissue-on-a-chip model, using 3D coculture isogenic stem cell-derived cardiomyocytes (CMs) and fibroblasts (CFs) within an organotypic microfluidic chip technology. Primarily,...

Background The function of medin, one the most common human amyloid proteins that accumulates in vasculature with aging, remains unknown. We aim to probe medin's role cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients studying its effects on endothelial cell (EC) immune activation neuroinflammation. also tested whether monosialoganglioside-containing nanoliposomes could reverse adverse effects. Methods Results...

Severe traumatic brain injury (TBI) results in cognitive dysfunction part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic and cerebrovascular function assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion (n = 20) or sham 21). Cognitive was (3- 6-month novel object recognition [NOR], location [NOL], temporal order [TOR]). Six-month cerebral...

Introduction Medin, an aging-associated amyloidogenic protein, induces cerebrovascular dysfunction and inflammation. We investigated the relationship between medin Alzheimer's disease (AD) vascular dementia (VaD). Methods Cerebral arteriole was quantified from 91 brain donors with no (ND), AD, VaD, or combined AD VaD. Correlation analyses evaluated medin, plaques, tangles, white matter lesions (WML). Receiver operating characteristic regression assessed whether is predictive of VaD versus...

Background Light chain amyloidosis (AL) is associated with high mortality, especially in patients advanced cardiovascular involvement. It caused by toxicity of misfolded light proteins ( LC ) vascular, cardiac, and other tissues. There no treatment to reverse tissue toxicity. We tested the hypothesis that nanoliposomes composed monosialoganglioside, phosphatidylcholine, cholesterol (GM1 ganglioside–containing [ NLGM 1]) can protect against ‐induced human microvascular dysfunction assess...

We tested whether nanoliposomes containing phosphatidylcholine, cholesterol and phosphatidic acid (NLPA) prevent β-amyloid 1-42 (Aβ42) fibrillation Aβ42-induced human arteriole endothelial dysfunction. NLPA abolished Aβ42 fibril formation (thioflavin-T fluorescence/electron microscopy). In ex-vivo adipose leptomeningeal arterioles, impaired dilator response to acetylcholine that was reversed by NLPA; this protection L-NG-nitroarginine methyl ester. reduced umbilical vein cell NO production...

Clinical and preclinical studies have suggested a link between cardiovascular disease dementia disorders, but the role of collateral brain circulation in cognitive dysfunction remains unknown. We aimed to test hypothesis that leptomeningeal arteriole (LMA) function response metabolic stressors differ among subjects with dementia, mild impairment (MCI), normal cognition (CN). After rapid autopsy, LMAs were isolated from CN ( n = 10), MCI 12), or [ 42, Alzheimer’s (AD), vascular (VaD), other...

Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phosphatidylcholine, cholesterol, and monosialogangliosides (nanoliposomes) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that nanoliposomes will preserve human neuroblastoma (SH-SY5Y) brain microvascular viability following oxygen-glucose deprivation (OGD)-reoxygenation reduce injury mice middle cerebral artery occlusion.

Light chain (AL) amyloidosis is a disease associated with significant morbidity and mortality arising from multi-organ injury induced by amyloidogenic light proteins (LC). There no available treatment to reverse the toxicity of LC. We previously showed that chaperone glycoprotein clusterin (CLU) nanoliposomes (NL), separately, restore human microvascular endothelial function impaired In this work, we aim prepare PEGylated-nanoliposomal (NL-CLU) formulations could allow combined benefit...

ABSTRACT Background Medin is one of the most common amyloidogenic proteins and accumulates in vasculature with aging. Vascular medin accumulation associated Alzheimer’s disease, vascular dementia aortic aneurysms. impairs smooth muscle-dependent vasodilation isolated human brain cerebral arteries. The role muscle (VSMC) activation unknown. We aim to evaluate effects on VSMC activation. Methods VSMCs were exposed physiologic doses (0.5, 1 5 µM) without or small molecule nuclear factor-κB...

Background: Age is the most important risk factor for coronary artery disease (CAD), independent of traditional factors such as hypertension, diabetes (DM), hyperlipidemia and smoking, through poorly understood mechanisms. Medin, a cleavage product MFGE8 protein that forms common human amyloid, accumulates in vasculature with age, including arteries. Although medin amyloid has been implicated various diseases Alzheimer’s disease, vascular dementia aortic aneurysms, its role CAD remains...

Background: Stroke remains a leading cause of mortality and disability. The narrow temporal window limited availability of, eligibility for thrombolytic therapy or endovascular thrombectomy are major therapeutic limitations in treating stroke. Neuroprotective therapies that could be given early to replace augment these existing needed improve stroke outcomes. We showed monosialoganglioside (GM1) containing nanoliposomes composed phosphatidylcholine, cholesterol GM1 (70/25/5% molar ratios,...

Background: Medin is one of the most common amyloidogenic proteins and accumulates in vasculature with aging. Vascular medin accumulation associated Alzheimer's disease, vascular dementia aortic aneurysms. In vitro , has been shown to induce endothelial proinflammatory activation ex vivo human cerebral arterial tissue, induces both smooth muscle dysfunction. The role (VSMC) remains unknown. Aim: aim study determine using gene transcription assay whether VSMC phenotypic transformation....

Abstract Medin is a common vascular amyloidogenic peptide recently implicated in Alzheimer’s disease (AD) and dementia its pathology remains unknown. We aim to identify changes transcriptomic profiles pathways human brain microvascular endothelial cells (HBMVECs) exposed medin, compare that exposure β-amyloid (Aβ) evaluate protection by monosialoganglioside-containing nanoliposomes (NL). HBMVECs were for 20 h medin (5 µM) without or with Aβ(1-42) (2 NL (300 µg/mL), RNA-seq signaling pathway...

Background: The endothelium plays a major role in preventing thrombosis. Aging leads to hypercoagulable state with increased procoagulant factors without accompanying rise anticoagulant factors, shifting the balance prothrombotic profile. This increases risk for conditions such as stroke or myocardial infarction. mediator/s of this change remains unknown. Medin is 50 amino acid cleavage product MFGE8, accumulates vasculature aging and most common human amyloid. Vascular medin burden vascular...

Background Medin peptides form the most common human amyloid proteins that accumulate in vasculature with aging and are thus implicated as potential etiologic agents phenotypic changes associated vascular aging. We previously showed med impairs endothelium‐mediated dilator response microvessels induces pro‐inflammatory signaling. Impaired autophagy has been cellular endothelial dysfunction could be a mechanism by which links dysfunction. also monosialoganglioside nanoliposomes (NLGM1),...

Aims Medin is a common amyloidogenic protein in humans, especially older individuals. It has been implicated the development of arterial degenerative changes associated with vascular aging. The mechanisms underlying medin‐induced injury remain unknown. aims are to assess medin's effects on human peripheral and central arteriole endothelial function, nitrative stress inflammation identify potential injury. Methods Results Ex‐vivo adipose leptomeningeal arterioles were exposed (1 hour) medin...

Introduction: Epidemiologic data show strong link between cardiovascular risk factors and dementia-related illnesses (DRI) such as Alzheimer’s disease (AD) with evidence that the earliest changes in AD involve vascular dysfunction. The mechanisms behind impairment DRI remain poorly understood, lack of a human model to study them impedes progress towards cure. Aim: aim is determine effects acute exposure palmitic acid (PA), saturated fatty implicated atherosclerosis, on endothelium-dependent...

Alzheimer’s disease (AD) and aging-related dementia are associated with early vascular dysfunction (VD) increased cardiovascular metabolic risk factors (CVRFs). We showed that β-amyloid peptide (Aβ) induce human leptomeningeal arteriole (LMA) endothelial oxidative stress peripheral adipose arterioles (AA) may be useful surrogates to assess central cerebrovascular response. It is not known whether combined Aβ CVRFs cause synergistic VD. tested the hypothesis 1) (saturated fatty acid [palmitic...

Light chain (LC) amyloidosis (AL) is a systemic associated with significant morbidity and mortality. Current treatment involves depletion of LC producing cells but patients advanced disease are usually intolerant chemotherapy autologous stem cell transplantation, no available to directly address the tissue pathology LC. Microvascular injury may be important in it spathobiology. Our overall objective discover strategies ameliorate LC‐mediated at level endothelial death dysfunction. We tested...

Background: Vascular aging is characterized by endothelial dysfunction and proinflammatory & prothrombotic changes. It responsible for aging-associated pathologies including stroke, vascular dementia (VaD) Alzheimer’s disease (AD). The underlying mechanisms of are poorly understood. Medin an amyloidogenic protein that accumulates in vasculature, associated with VaD AD, a candidate mediator through unknown mechanisms. Our aim to test the hypothesis medin induces changes human brain...

Electrically conductive biomaterials and nanomaterials have demonstrated a great potential in the development of functional mature cardiac tissues. In particular, gold emerged as promising candidates due to their biocompatibility ease fabrication for tissue engineering, utilizing rat- or stem cell-derived cardiomyocytes (CMs). Among various cell types, human induced pluripotent (hiPSC-CMs) unique source engineering tissues, serving range applications from vitro disease modeling vivo heart...