Innovative Cyanine-Based Fluorescent Dye for Targeted Mitochondrial Imaging and Its Utility in Whole-Brain Visualization

Conducting in vivo brain imaging can be a challenging task due to the complexity of brain tissue and the strict requirements for safe and effective imaging agents. However, a new fluorescent dye called Cy5-PEG2 has been developed that selectively accumulates in mitochondria, enabling the visualization of these essential organelles in various cell lines. This dye is versatile and can be used for the real-time monitoring of mitochondrial dynamics in living cells. Moreover, it can cross the blood-brain barrier, making it a promising tool for noninvasive in vivo brain imaging. Based on the assessment of glial cell responses in the hippocampus and neocortex regions using GFAP and Iba1 biomarkers, Cy5-PEG2 seems to have minimal adverse effects on brain immune response or neuronal health. Therefore, this mitochondria-targeting fluorescent dye has the potential to advance our understanding of mitochondrial dynamics and function within the broader context of whole-brain physiology and disease progression. However, further research is needed to evaluate the safety and efficacy of Cy5-PEG2

Induction of Neuroinflammation and Brain Oxidative Stress by Brain-Derived Extracellular Vesicles from Hypertensive Rats

Neuroinflammation and brain oxidative stress are recognized as significant contributors to hypertension including salt sensitive hypertension. Extracellular vesicles (EVs) play an essential role in intercellular communication in various situations, including physiological and pathological ones. Based on this evidence, we hypothesized that EVs derived from the brains of hypertensive rats with salt sensitivity could trigger neuroinflammation and oxidative stress during hypertension development. To test this hypothesis, we compared the impact of EVs isolated from the brains of hypertensive Dahl Salt-Sensitive rats (DSS) and normotensive Sprague Dawley (SD) rats on inflammatory factors and mitochondrial reactive oxygen species (mtROS) production in primary neuronal cultures and brain cardiovascular relevant regions, including the hypothalamic paraventricular nucleus (PVN) and lamina terminalis (LT). We found that brain-derived DSS-EVs significantly increased the mRNA levels of proinflammatory cytokines (PICs) and chemokines, including TNFα, IL1β, CCL2, CCL5, and CCL12, as well as the transcriptional factor NF-κB in neuronal cultures. DSS-EVs also induced oxidative stress in neuronal cultures, as evidenced by elevated NADPH oxidase subunit CYBA coding gene mRNA levels and persistent mtROS elevation. When DSS-EVs were injected into the brains of normal SD rats, the mRNA levels of PICs, chemokines, and the chronic neuronal activity marker FOSL1 were significantly increased in the PVN and LT. Furthermore, DSS-EVs caused mtROS elevation in brain PVN and LT, particularly in neurons. Our study reveals a novel role for brain-derived EVs from hypertensive rats in triggering neuroinflammation, upregulating chemokine expression, and inducing excessive ROS production. These findings provide insight into the complex interactions between EVs and hypertension-associated processes, offering potential therapeutic targets for hypertension-linked neurological complications

Design, synthesis and cardioprotective effect of a new class of dual-acting agents: Phenolic tetrahydro-Β-carboline RGD peptidomimetic conjugates.

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Engineering Exosomes to Specifically Target the Mitochondria of Brain Cells

Mitochondrial dysfunction is associated with various health conditions, including cardiovascular and neurodegenerative diseases. Mitochondrial-targeting therapy aims to restore or enhance mitochondrial function to treat or alleviate these conditions. Exosomes, small vesicles that cells secrete, containing a variety of biomolecules, are critical in cell-to-cell communication and have been studied as potential therapeutic agents. Exosome-based therapy has the potential to treat both cardiovascular and neurodegenerative diseases. Combining these two approaches involves using exosomes as carriers to transport mitochondrial-targeting agents to dysfunctional or damaged mitochondria within target cells. This article presents a new technique for engineering brain-derived exosomes that target mitochondria and has demonstrated promise in initial tests with primary neuron cells and healthy rats. This promising development represents a significant step forward in treating these debilitating conditions

Design, synthesis and cardioprotective effect of a new class of dual-acting agents: Phenolic tetrahydro-β-carboline RGD peptidomimetic conjugates

In this study, a new class of phenolic tetrahydro-β-carboline RGD peptidomimetic conjugates was designed and synthesized. The radical scavenging activities of these newly synthesized compounds 12a-c were evaluated in PC12 cell survival assays. The NO scavenging activities of these compounds were confirmed in the acetylcholine-induced vasorelaxation assay. Compounds 12a-c were efficacious in a rat arterial thrombosis model, and were active in ADP- or PAF-induced in vitro platelet aggregation assays, which suggests these compounds also possess anti-thrombotic activity. The beneficial effects of dual-acting agent 12c were demonstrated on the ischemia-reperfusion induced cardiac infarct size and oxidative change in an in vivo rat model. © 2007 Elsevier Ltd. All rights reserved

Targeted fluorescent probes for detection of oxidative stress in the mitochondria

Mitochondrial oxidative stress has been implicated in aging, neurodegenerative diseases, diabetes, stroke, ischemia/reperfusion injury, age-related macular degeneration (AMD) and cancer. Recently, we developed two new mitochondria-targeting fluorescent probes, MitoProbes I/II, which specifically localize in mitochondria and employed both in vivo and in vitro for detection of mitochondrial oxidative stress. Here, we report the design and synthesis of these agents, as well as their utility for real-time imaging of mitochondrial oxidative stress in cells

Determination of intracellular pH using sensitive, clickable fluorescent probes

We synthesized and evaluated a series of acidic fluorescent pH probes exhibiting robust pH dependence, high sensitivity and photostability, and excellent cell membrane permeability. Titration analyses indicated that probe 3 could increase its fluorescence intensity 800-fold between pH 8.0 and 4.1. Additionally, its pK a value is optimal for intracellular probing of acidic organelles. Fluorescent imaging of HepG2 and Hela cells further revealed that probe 3 demonstrates outstanding capacity for monitoring of intracellular [H +] levels. The easily accessible terminal alkyne/azido function groups of these probes offer the possibility of rapidly constructing sensor molecule libraries using \u27click\u27 chemistry. © 2011 Elsevier Ltd. All rights reserved

Novel TEMPO-PEG-RGDs conjugates remediate tissue damage induced by acute limb ischemia/reperfusion

We have recently developed new Tempo-PEG-RGDs conjugates and have quantitatively examined their antithrombotic and antioxidant capabilities. These compounds were therapeutically beneficial when characterized in both in vitro platelet aggregation assays and a rat model of arterial thrombosis. Moreover, these compounds demonstrated significant protection from organ damage in a rat model of ischemia/reperfusion. Our data indicate that Tempo-PEG-RGDs represent a new class of adjuvants with therapeutic efficacy in acute and transient ischemic damage. © 2012 American Chemical Society

Pharmacological protection of mitochondrial function mitigates acute limb ischemia/reperfusion injury

© 2016 We describe several novel curcumin analogues that possess both anti-inflammatory antioxidant properties and thrombolytic activities. The therapeutic efficacy of these curcumin analogues was verified in a mouse ear edema model, a rat arterial thrombosis assay, a free radical scavenging assay performed in PC12 cells, and in both in vitro and in vivo ischemia/reperfusion models. Our findings suggest that their protective effects partially reside in maintenance of optimal mitochondrial function

Cardioprotection effects of LPTC-5 involve mitochondrial protection and dynamics

We recently designed and synthesized a series of novel levodopa–peptide–TEMPO conjugates (LPTCs). Among these compounds, LPTC-5 possesses both free-radical scavenging potential and mitochondrial fusion-promoting activity. The free-radical scavenging capacity of LPTC-5 was confirmed using a PC12 cell survival assay. LPTC-5 could restore the mitochondrial tubular network following genetically induced fragmentation. The therapeutic efficacy of LPTC-5 was then examined employing in vitro and in vivo ischemia/reperfusion (I/R) models. LPTC-5 protected cells from mitochondrial reactive oxygen species overproduction and inhibited cytochrome c release in a simulated I/R cellular model. Additionally, LPTC-5 attenuated organ damage in a cardiac I/R animal model. The data suggest that LPTC-5 exerts cardioprotection via modulation of mitochondrial fission/fusion dynamics, ultimately improving mitochondrial function and cardiac function