Circulating Extracellular Vesicles Containing Xenobiotic Metabolizing CYP Enzymes and Their Potential Roles in Extrahepatic Cells Via Cell–Cell Interactions

Gerth, Kelli; Kumar, Santosh; Mahon, Madeline; Haque, Sanjana; Verma, Neha; Kumar, Santosh

doi:10.3390/ijms20246178

Cited by 33 publications

(32 citation statements)

References 120 publications

(177 reference statements)

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“…Epoxyeicosatrienoic acids (EETs), the cytochrome P450 (CYP) epoxygenases-derived metabolites of arachidonic acid, exert a critical role in vascular functions by regulating the membrane hyperpolarization of smooth muscle cells (22). A recent study revealed that EETs induced the expression of VEGF and promoted angiogenesis in endothelial cells (ECs) (23).…”

Section: Introductionmentioning

confidence: 99%

Targeting CYP2J2 to Enhance the Anti-Glioma Efficacy of Cannabinoid Receptor 2 Stimulation by Inhibiting the Pro-Angiogenesis Function of M2 Microglia

et al. 2020

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Enhancing the therapeutic efficacy of anti-tumor drugs is essential for cancer management. Although cannabinoid receptor 2 (CB2R) stimulation exerts anti-tumor action in glioma cells by regulating cellular proliferation, differentiation, or apoptosis, selective CB2R agonist alone does not achieve a satisfactory therapeutic outcome. Herein, we aimed to evaluate the possible strategy for enhancing the anti-glioma efficacy of JWH133, a selective CB2R agonist. In this study, immunofluorescence and qRT-PCR were used to investigate microglia polarization. Tumor growth was monitored via bioluminescent imaging using the IVIS Spectrum System. The angiogenesis of human brain microvascular endothelial cells (HBMECs) was detected by the tube formation assay. qRT-PCR was used to investigate cytochrome P450 2J2 (CYP2J2) and 11,12-epoxyeicosatrienoic acid (11,12-EET) expression. Our results showed that administration of JWH133 significantly promoted microglial M2 polarization both in vitro and in vivo. The medium supernatant of M2 microglia induced by JWH133 treatment facilitated angiogenesis of HBMECs. CYP2J2 expression and 11,12-EET release in the supernatant of JWH133-induced M2 microglia were significantly upregulated. Treatment with 11,12-EET prompted HBMEC angiogenesis and glioma growth. CYP2J2 knockdown restrained the release of 11,12-EET and significantly enhanced the anti-tumor effect of JWH133 on glioma. This study showed that targeting CYP2J2 might be a beneficial strategy to enhance the anti-glioma efficacy of JWH133 by inhibiting the pro-angiogenesis function of M2 microglia.

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Section: Introductionmentioning

confidence: 99%

Targeting CYP2J2 to Enhance the Anti-Glioma Efficacy of Cannabinoid Receptor 2 Stimulation by Inhibiting the Pro-Angiogenesis Function of M2 Microglia

et al. 2020

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“…In addition, they likely play an important mechanistic role in communication between the liver and the immune system. They have been studied both in patients and in animal models of liver injury (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50). Belonging to the group of extracellular vehicles comprising also microvesicles and apoptotic bodies ( 40), exosomes represent vesicles, which are commonly derived from cell membranes of various organs including the liver (39).…”

Section: Blood Exosomesmentioning

confidence: 99%

Mechanism of idiosyncratic drug induced liver injury (DILI): unresolved basic issues

Teschke¹,

Uetrecht²

2021

Ann Transl Med

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Clinical features of idiosyncratic drug induced liver injury (DILI) are well described in cases that have been assessed for causality using the Roussel Uclaf Causality Assessment Method (RUCAM), but our understanding of the mechanistic steps leading to injury is fragmentary. The difficulties describing mechanistic events can be traced back to the lack of an animal model of experimental idiosyncratic DILI that can mimic the genetic requirements of human idiosyncratic DILI. However, immune tolerance plays a dominant role in the immune response of the liver, and impairment of immune tolerance with immune checkpoint inhibitors increases DILI in both humans and animals. This may provide one method to study the individual steps involved. In general. the human DILI liver is a secret keeper providing little insight into what occurs in the diseased organ. Sufficient evidence exists that most idiosyncratic cases are mediated by the adaptive immune system, which depends on stimulation of the innate immune system, but the triggering factors are unknown. It is attractive to hypothesize that the gut microbiome plays a role; however, it is very difficult to study. Similarly, exosomes are likely to play an important role in communication between hepatic cells and the immune system, but there is a lack of data on blood exosomes in affected patients. Reactive metabolites are likely to play an important role. This is supported by the current analysis, which revealed an association between metabolism by cytochrome P450 and drugs most commonly involved in causing idiosyncratic DILI with causality verified by RUCAM. Circumstantial evidence suggests that reactive oxygen species (ROS) generated by cytochrome P450 could be responsible for the initial steps of injury, but details are unknown. In conclusion, most of the mechanistic steps leading to idiosyncratic DILI remain unclear.

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“…They can be found primarily in the liver but also in various other organs, such as the gut, brain, kidneys, and lungs [100,101]. Notably, CYPs also circulate in the bloodstream in CYP-containing extracellular vesicles [102].…”

Section: Metabolic Functionality and Response Assessmentmentioning

confidence: 99%

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

et al. 2020

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Organs-on-a-Chip (OOAC) is a disruptive technology with widely recognized potential to change the efficiency, effectiveness, and costs of the drug discovery process; to advance insights into human biology; to enable clinical research where human trials are not feasible. However, further development is needed for the successful adoption and acceptance of this technology. Areas for improvement include technological maturity, more robust validation of translational and predictive in vivo-like biology, and requirements of tighter quality standards for commercial viability. In this review, we reported on the consensus around existing challenges and necessary performance benchmarks that are required toward the broader adoption of OOACs in the next five years, and we defined a potential roadmap for future translational development of OOAC technology. We provided a clear snapshot of the current developmental stage of OOAC commercialization, including existing platforms, ancillary technologies, and tools required for the use of OOAC devices, and analyze their technology readiness levels. Using data gathered from OOAC developers and end-users, we identified prevalent challenges faced by the community, strategic trends and requirements driving OOAC technology development, and existing technological bottlenecks that could be outsourced or leveraged by active collaborations with academia.

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Circulating Extracellular Vesicles Containing Xenobiotic Metabolizing CYP Enzymes and Their Potential Roles in Extrahepatic Cells Via Cell–Cell Interactions

Cited by 33 publications

References 120 publications

Targeting CYP2J2 to Enhance the Anti-Glioma Efficacy of Cannabinoid Receptor 2 Stimulation by Inhibiting the Pro-Angiogenesis Function of M2 Microglia

Targeting CYP2J2 to Enhance the Anti-Glioma Efficacy of Cannabinoid Receptor 2 Stimulation by Inhibiting the Pro-Angiogenesis Function of M2 Microglia

Mechanism of idiosyncratic drug induced liver injury (DILI): unresolved basic issues

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

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