Central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), are important causes of death and long-term disability worldwide. MicroRNA (miRNA), small non-coding RNA molecules that negatively regulate gene expression, can serve as diagnostic biomarkers and are emerging as novel therapeutic targets for CNS injuries. MiRNA-based therapeutics include miRNA mimics and inhibitors (antagomiRs) to respectively decrease and increase the expression of target genes. In this review, we summarize current miRNA-based therapeutic applications in stroke, TBI and SCI. Administration methods, time windows and dosage for effective delivery of miRNA-based drugs into CNS are discussed. The underlying mechanisms of miRNA-based therapeutics are reviewed including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis and neurogenesis. Pharmacological agents that protect against CNS injuries by targeting specific miRNAs are presented along with the challenges and therapeutic potential of miRNA-based therapies.

MicroRNA-based therapeutics in central nervous system injuries.

Arctigenin (AR) and its glycoside, arctiin, are two major active ingredients of Arctium lappa L (A lappa), a popular medicinal herb and health supplement frequently used in Asia. In the past several decades, bioactive components from A lappa have attracted the attention of researchers due to their promising therapeutic effects. In the current article, we aimed to provide an overview of the pharmacology of AR and arctiin, focusing on their anti-inflammatory effects, pharmacokinetics properties and clinical efficacies. Compared to acrtiin, AR was reported as the most potent bioactive component of A lappa in the majority of studies. AR exhibits potent anti-inflammatory activities by inhibiting inducible nitric oxide synthase (iNOS) via modulation of several cytokines. Due to its potent anti-inflammatory effects, AR may serve as a potential therapeutic compound against both acute inflammation and various chronic diseases. However, pharmacokinetic studies demonstrated the extensive glucuronidation and hydrolysis of AR in liver, intestine and plasma, which might hinder its in vivo and clinical efficacy after oral administration. Based on the reviewed pharmacological and pharmacokinetic characteristics of AR, further pharmacokinetic and pharmacodynamic studies of AR via alternative administration routes are suggested to promote its ability to serve as a therapeutic agent as well as an ideal bioactive marker for A lappa.

/pdf/overview-of-the-anti-inflammatory-effects-pharmacokinetic-4bv22dmm6u.pdf

Overview of the anti-inflammatory effects, pharmacokinetic properties and clinical efficacies of arctigenin and arctiin from Arctium lappa L.

Mesenchymal stem cell-derived extracellular vesicle-based therapies protect against coupled degeneration of the central nervous and vascular systems in stroke.

Traumatic brain injury leads to major brain anatomopathological damages underlined by neuroinflammation, oxidative stress and progressive neurodegeneration, ultimately leading to motor and cognitive deterioration The multiple pathological events resulting from traumatic brain injury can be addressed not by a single therapeutic approach, but rather by a synergistic biotherapy capable of activating a complementary set of signaling pathways and providing synergistic neuroprotective, anti-inflammatory, antioxidative, and neurorestorative activities Human platelet lysate might fulfill these requirements as it is comprised of a plethora of biomolecules readily accessible as a traumatic brain injury biotherapy In the present study, we have tested the therapeutic potential of human platelet lysate using in vitro and in vivo models of traumatic brain injury We first prepared and characterized platelet lysate from clinical-grade human platelet concentrates Platelets were pelletized, lysed by three freeze-thaw cycles, and centrifuged The supernatant was purified by 56 °C-30 minutes heat-treatment and spun to obtain the heat-treated platelet pellet lysate that was characterized by ELISA and proteomic analyses Two mouse models were used to investigate platelet lysate neuroprotective potential The injury was induced by an in-house manual controlled scratching of the animals' cortex or by controlled cortical impact injury The platelet lysate treatment was performed by topical application of 60 µL in the lesioned area, followed by daily 60 µL intranasal administration from day 1 to 6 post-injury Platelet lysate proteomics identified over 1000 proteins including growth factors, neurotrophins, and antioxidants ELISA detected several neurotrophic and angiogenic factors at ca 1-50 ng/mL levels We demonstrate, using the two mouse models of traumatic brain injury that topical application and intranasal platelet lysate consistently improved mice motor function in the beam and rotarod tests, mitigated cortical neuroinflammation, and oxidative stress in the injury area, as revealed by downregulation of pro-inflammatory genes and the reduction in reactive oxygen species levels Moreover, platelet lysate treatment reduced the loss of cortical synaptic proteins Unbiased proteomic analyses revealed that HPPL reversed several pathways promoted by both CCI and CBS and related to transport, post-synaptic density, mitochondria or lipid metabolism The present data strongly support for the first time that human platelet lysate is a reliable and effective therapeutic source of neurorestorative factors Therefore, brain administration of platelet lysate is a therapeutical strategy that deserves serious and urgent consideration for universal brain trauma treatment

Human platelet lysate biotherapy for traumatic brain injury: preclinical assessment

Objectives Endothelial cell inflammation plays an important role in atherosclerosis. Low-intensity pulsed ultrasonography (LIPUS) exerts an anti-inflammatory function on endothelial cells, whereas the underlying mechanism has not been fully elucidated. Methods Bone marrow dendritic cells (BMDCs) derived from bone barrow cells were treated with LIPUS, and exosomes secreted into the supernatant were purified. The isolated exosomes were incubated with human umbilical vein endothelial cells (HUVECs) to investigate their effect on tumor necrosis factor (TNF)-α-induced endothelial inflammation. Ultrastructure was analyzed by transmission electron microscopy. Messenger RNA levels were determined by quantitative reverse transcription polymerase chain reaction, and protein levels were analyzed by western blot. Results The isolated exosomes presented a typical exosomal size of 30 to 100 nm in diameter and expressed exosome positive markers (Alix, CD63, and TSG101) but not the exosome negative marker (Calnexin). Exosomes derived from LIPUS-treated BMDCs were rich in miR-16 and miR-21, which could be engulfed by HUVECs. Pretreatment with exosomes impeded TNFα-induced HUVEC activation and downregulated TNFα-stimulated expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, thus preventing TNFα-induced activation of the nuclear factor-κB signaling pathway. Conclusion Exosomes derived from LIPUS-treated BMDC inhibit TNFα-induced endothelial inflammation by inhibiting the nuclear factor-κB signaling pathway.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/jum.14898

Exosomes Derived From Low-Intensity Pulsed Ultrasound-Treated Dendritic Cells Suppress Tumor Necrosis Factor-Induced Endothelial Inflammation.

Mechanical trauma injury is a severe insult to neural cells. Subsequent secondary injury involves the release of inflammatory factors that have dramatic consequences for undamaged cells, leading to normal cell death after the initial injury. The present study investigated the capacity for arctigenin (ARC) to prevent secondary effects and evaluated the mechanism underlying the action of microRNA (miRNA)-199a and miRNA-16 in a mechanical trauma injury (MTI) model using SH-SY5Y cells in vitro. SH-SY5Y cells are often applied to in vitro models of neuronal function and differentiation. Recently, miRNAs have been demonstrated to play a crucial role in NF-κB and cholinergic signaling, which can regulate inflammation. The cell model was established by scratch-induced injury of human SH-SY5Y cells, which mimics the characteristics of MTI. A cell counting kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunocytochemistry were used to measure cell viability. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the inflammatory cytokine and cholinesterase (CHE) content. The lactate dehydrogenase (LDH) content was measured to assess the degree of cell injury. The mRNA levels were measured by RT-PCR to analyze ARC's mechanism of action. miRNA inhibitors and mimics were used to inhibit and strengthen the expression of miRNAs. Protein expression was detected by western blotting analysis. ARC treatment reduced the TNF-α and IL-6 levels as well as the number of TUNEL+ apoptotic SH-SY5Y cells surrounding the scratch and increased the IL-10 level compared to the controls. ARC attenuated the increase of the cell damage degree and LDH content induced by scratching, indicating increased cell survival. Mechanistic studies showed that ARC upregulated the miRNA-16 and miRNA-199a levels to reduce upstream protein (IKKα and IKKβ) expression and inhibit NF-κB signaling pathway activity; moreover, the increased miRNA-199a suppresses cholinesterases to increase cholinergic signaling, resulting in decreased expression of proinflammatory cytokines. ARC treatment confers protection for SH-SY5Y cells through positive regulation of miRNA expression, thereby reducing the inflammatory response. In turn, these effects accelerate injury repair in the scratch-induced injury model. These results might provide insights into the pharmacological role of ARC in anti-inflammation and neuroprotection in neural cells.

Arctigenin Confers Neuroprotection Against Mechanical Trauma Injury in Human Neuroblastoma SH-SY5Y Cells by Regulating miRNA-16 and miRNA-199a Expression to Alleviate Inflammation.

MiR-143-3p facilitates motility and invasiveness of endometriotic stromal cells by targeting VASH1/TGF-β signaling.

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Arctigenin Confers Neuroprotection Against Mechanical Trauma Injury in Human Neuroblastoma SH-SY5Y Cells by Regulating miRNA-16 and miRNA-199a Expression to Alleviate Inflammation.

MiR-143-3p facilitates motility and invasiveness of endometriotic stromal cells by targeting VASH1/TGF-β signaling.