Erratum: Corrigendum: Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle

Abstract Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.

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Effects of prednisolone on the dystrophin-associated proteins in the blood–brain barrier and skeletal muscle of dystrophic mdx mice

Laboratory Investigation ◽

10.1038/labinvest.2013.46 ◽

2013 ◽

Vol 93 (5) ◽

pp. 592-610 ◽

Cited By ~ 17

Author(s):

Roberto Tamma ◽

Tiziana Annese ◽

Roberta F Capogrosso ◽

Anna Cozzoli ◽

Vincenzo Benagiano ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Mdx Mice ◽

Blood Brain ◽

Associated Proteins

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Skeletal muscle is an early site of Zika virus replication and injury impairing myogenesis

Journal of Virology ◽

10.1128/jvi.00904-21 ◽

2021 ◽

Author(s):

Daniel Gavino-Leopoldino ◽

Camila Menezes Figueiredo ◽

Mariana Oliveira Lopes da Silva ◽

Letícia Gonçalves Barcellos ◽

Rômulo Leão Silva Neris ◽

...

Keyword(s):

Skeletal Muscle ◽

Central Nervous System ◽

Nervous System ◽

Blood Brain Barrier ◽

Zika Virus ◽

Muscle Development ◽

Brain Barrier ◽

Zikv Infection ◽

Viral Spread ◽

Blood Brain

Zika virus (ZIKV) infection became a worldwide concern due to its correlation with the development of microcephaly and other neurological disorders. ZIKV neurotropism is well characterized, but the role of peripheral viral amplification to brain infection remains unknown. Here we found that ZIKV replicates in human primary skeletal muscle myoblasts, impairing its differentiation into myotubes but not interfering with the integrity of the already formed muscle fibers. Using mouse models, we showed ZIKV tropism to muscle tissue either during embryogenesis after maternal transmission or when infection occurred after birth. Interestingly, ZIKV replication in the mouse skeletal muscle started immediately after ZIKV inoculation, preceding viral RNA detection in the brain and causing no disruption to the integrity of the blood brain barrier, and remained active for more than two weeks, while replication in spleen and liver were not sustained over time. In addition, ZIKV infection of the skeletal muscle induces necrotic lesions, inflammation and fiber atrophy. We also found a reduction in the expression of regulatory myogenic factors that are essential for muscle repair after injury. Taken together our results indicate that the skeletal muscle is an early site of viral amplification and lesion that may result in late consequences in muscle development after ZIKV infection. Importance Zika Virus (ZIKV) neurotropism and its deleterious effects on central nervous system have been well characterized. But, investigations of the initial replication sites for the establishment of infection and viral spread to neural tissues remain under explored. The complete description of the range of ZIKV induced lesions and others factors that can influence the severity of the disease are necessary to prevent ZIKV deleterious effects. ZIKV has been shown to access the central nervous system without significantly affecting blood-brain barrier permeability. Here we demonstrated that skeletal muscle is an earlier site of ZIKV replication, contributing to the increase of peripheral ZIKV load. ZIKV replication in muscle promotes necrotic lesions, inflammation and also impairs myogenesis. Overall, our findings showed that skeletal muscle is involved in pathogenesis and opens new fields in the investigation of the long-term consequence of early infection.

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Gliotransmitters and cytokines in the control of blood-brain barrier permeability

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0092 ◽

2018 ◽

Vol 29 (5) ◽

pp. 567-591 ◽

Cited By ~ 11

Author(s):

Elena D. Osipova ◽

Oxana V. Semyachkina-Glushkovskaya ◽

Andrey V. Morgun ◽

Natalia V. Pisareva ◽

Natalia A. Malinovskaya ◽

...

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Neurovascular Unit ◽

Glutamate Transporters ◽

Brain Barrier ◽

Functional Coupling ◽

Blood Brain ◽

Substantial Progress ◽

Bbb Permeability ◽

Brain Microvessel

AbstractThe contribution of astrocytes and microglia to the regulation of neuroplasticity or neurovascular unit (NVU) is based on the coordinated secretion of gliotransmitters and cytokines and the release and uptake of metabolites. Blood-brain barrier (BBB) integrity and angiogenesis are influenced by perivascular cells contacting with the abluminal side of brain microvessel endothelial cells (pericytes, astrocytes) or by immune cells existing (microglia) or invading the NVU (macrophages) under pathologic conditions. The release of gliotransmitters or cytokines by activated astroglial and microglial cells is provided by distinct mechanisms, affects intercellular communication, and results in the establishment of microenvironment controlling BBB permeability and neuroinflammation. Glial glutamate transporters and connexin and pannexin hemichannels working in the tight functional coupling with the purinergic system serve as promising molecular targets for manipulating the intercellular communications that control BBB permeability in brain pathologies associated with excessive angiogenesis, cerebrovascular remodeling, and BBB-mediated neuroinflammation. Substantial progress in deciphering the molecular mechanisms underlying the (patho)physiology of perivascular glia provides promising approaches to novel clinically relevant therapies for brain disorders. The present review summarizes the current understandings on the secretory machinery expressed in glial cells (glutamate transporters, connexin and pannexin hemichannels, exocytosis mechanisms, membrane-derived microvesicles, and inflammasomes) and the role of secreted gliotransmitters and cytokines in the regulation of NVU and BBB permeability in (patho)physiologic conditions.

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Synthesis, Physicochemical, Computational and Biological Evaluation of Phenylurea Derivatives as CNS agents

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524921666210908145356 ◽

2021 ◽

Vol 21 ◽

Author(s):

Sandeep Singh ◽

Shweta Verma

Keyword(s):

Skeletal Muscle ◽

Blood Brain Barrier ◽

Muscle Relaxant ◽

Biological Evaluation ◽

Brain Barrier ◽

Log P ◽

Skeletal Muscle Relaxant ◽

Blood Brain ◽

Chloro Group ◽

Muscle Relaxant Activity

Background: A series of phenylurea derivatives were designed and synthesized, The target compounds were subjected to pharmacological studies. Various other parameters such as physicochemical properties, computational studies, and % similarity were also calculated. Materials and Methods: The synthesis of the target compounds has been carried out by reaction of Phenylurea with chloroacetyl chloride to afford 1-(2-chloroacetyl)-3-phenylurea, which further reacted with substituted anilines. All the reactions were monitored by TLC. All the target compounds were purified by recrystallization and characterized by spectroscopic methods. Physicochemical parameters and Log P values of the synthesized derivatives were also calculated. It identified compounds that have the prospect to cross the blood-brain barrier (BBB) and are CNS active. Skeletal muscle relaxant activity was also carried out using the Rotarod method. Results: The data of Log P indicated that the synthesized compounds have the potential to cross the BBB, so they are CNS active. Pharmacological activities of the derivatives showed that the compounds containing chloro group have moderate skeletal muscle relaxant activity. The test compounds possess significant differences between the control group and the treated group. Conclusion: The synthesized derivatives containing chloro group were found to be more potent when compared to standard drug Diazepam. Various others parameters studied revealed that the drug has the potency to cross the blood-brain barrier.

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