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Chrysophanol inhibits NALP3 inflammasome activation and ameliorates cerebral ischemia/reperfusion in mice.

Zhang N, Zhang X, Liu X, Wang H, Xue J, Yu J, Kang N, Wang X - Mediators Inflamm. (2014)

Bottom Line: Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity.The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored.Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.

ABSTRACT
The most effective way to contain cerebral ischemic injury is reperfusion; however, reperfusion itself may result in tissue injury, for which inflammatory damage is one of the main causative factors. NALP3 inflammasome is a multiprotein complex. It consists of NALP3, ASC, and caspase-1, whose function is to switch on the inflammatory process. Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity. In this study, the effects of chrysophanol in cerebral ischemia/reperfusion and the potential mechanisms were investigated. Male CD1 mice were subject to transient middle cerebral artery occlusion (tMCAO). The NALP3 inflammasome activation status and its dynamic expression during the natural inflammatory response induced by tMCAO were first profiled. The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored. Physical parameters including neurological deficit, infarct size, brain edema, and BBB permeability were measured at 24 h after tMCAO. Confocal microscopy, Western blotting, immunohistochemistry, and qRT-PCR techniques were utilized to analyze the expression of NALP3 inflammasome and IL-1 β . Our results indicated that the brain tissue damage during cerebral ischemia/reperfusion is accompanied by NALP3 inflammasome activation. Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke.

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Related in: MedlinePlus

Model of danger signals activation of the NALP3 inflammasome. Tissue injury leads to the formation and release of danger signals such as ATP or uric acid crystals that are recognized by the innate immune system. A number of these signals mediate a potassium efflux or other secondary intracellular danger signals that are required for NALP3 inflammasome activation [51, 52]. NALP3 inflammasome then oligomerizes to recruit the adaptor ASC and caspase-1 [53]. Activation of caspase-1 results in the processing and maturation of pro IL-1β into its biologically active form, active IL-1β [12, 54]. Active IL-1β will then trigger the IL-1β receptor, leading to the activation of multiple cytokines involved in the inflammation cascade [55].
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fig1: Model of danger signals activation of the NALP3 inflammasome. Tissue injury leads to the formation and release of danger signals such as ATP or uric acid crystals that are recognized by the innate immune system. A number of these signals mediate a potassium efflux or other secondary intracellular danger signals that are required for NALP3 inflammasome activation [51, 52]. NALP3 inflammasome then oligomerizes to recruit the adaptor ASC and caspase-1 [53]. Activation of caspase-1 results in the processing and maturation of pro IL-1β into its biologically active form, active IL-1β [12, 54]. Active IL-1β will then trigger the IL-1β receptor, leading to the activation of multiple cytokines involved in the inflammation cascade [55].

Mentions: Recent evidence suggested that the downstream processing of IL-1β is regulated by some cytosolic factors such as inflammasomes, a family of protein complexes that were recently identified as the cellular machinery responsible for recognizing pathogen-associated molecular patterns and reacting to these through activation of inflammatory processes [4]. Among different types of inflammasomes is the NALP3 inflammasome, which has been well characterized in a variety of mammalian cells. It is characterized as a proteolytic complex mainly composed of the NACHT domain-, leucine-rich repeat-, and pyrin domain (PYD)-containing protein 3 (NALP3), the adaptor protein apoptosis-associated speck-like protein (ASC), and caspase-1 [5]. The NALP3 inflammasome can be activated by bacterial toxins [6] or pathogen-associated molecular patterns, such as muramyldipeptide, and other stimuli. NALP3 can also detect and respond to endogenous stress-associated danger signals, such as ATP [7], ROS [8], monosodium urate crystals [9], low intracellular potassium concentrations, sodium overload [10], or β-amyloid by activating caspase-1, and active caspase-1 subsequently matures the proinflammatory IL-1β family cytokines by cleaving their proforms into biologically active cytokines in turn [11, 12]. Active IL-1β then triggers the IL-1β receptors on surrounding tissues [13, 14], leading to the activation of multiple cytokines involved in the inflammation cascade, including IL-8, TNF, and IL-17 [15, 16] (Figure 1). However, the role of NALP3 inflammasome in cerebral I/R inflammatory disorders has not been well explored [17, 18].


Chrysophanol inhibits NALP3 inflammasome activation and ameliorates cerebral ischemia/reperfusion in mice.

Zhang N, Zhang X, Liu X, Wang H, Xue J, Yu J, Kang N, Wang X - Mediators Inflamm. (2014)

Model of danger signals activation of the NALP3 inflammasome. Tissue injury leads to the formation and release of danger signals such as ATP or uric acid crystals that are recognized by the innate immune system. A number of these signals mediate a potassium efflux or other secondary intracellular danger signals that are required for NALP3 inflammasome activation [51, 52]. NALP3 inflammasome then oligomerizes to recruit the adaptor ASC and caspase-1 [53]. Activation of caspase-1 results in the processing and maturation of pro IL-1β into its biologically active form, active IL-1β [12, 54]. Active IL-1β will then trigger the IL-1β receptor, leading to the activation of multiple cytokines involved in the inflammation cascade [55].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4020303&req=5

fig1: Model of danger signals activation of the NALP3 inflammasome. Tissue injury leads to the formation and release of danger signals such as ATP or uric acid crystals that are recognized by the innate immune system. A number of these signals mediate a potassium efflux or other secondary intracellular danger signals that are required for NALP3 inflammasome activation [51, 52]. NALP3 inflammasome then oligomerizes to recruit the adaptor ASC and caspase-1 [53]. Activation of caspase-1 results in the processing and maturation of pro IL-1β into its biologically active form, active IL-1β [12, 54]. Active IL-1β will then trigger the IL-1β receptor, leading to the activation of multiple cytokines involved in the inflammation cascade [55].
Mentions: Recent evidence suggested that the downstream processing of IL-1β is regulated by some cytosolic factors such as inflammasomes, a family of protein complexes that were recently identified as the cellular machinery responsible for recognizing pathogen-associated molecular patterns and reacting to these through activation of inflammatory processes [4]. Among different types of inflammasomes is the NALP3 inflammasome, which has been well characterized in a variety of mammalian cells. It is characterized as a proteolytic complex mainly composed of the NACHT domain-, leucine-rich repeat-, and pyrin domain (PYD)-containing protein 3 (NALP3), the adaptor protein apoptosis-associated speck-like protein (ASC), and caspase-1 [5]. The NALP3 inflammasome can be activated by bacterial toxins [6] or pathogen-associated molecular patterns, such as muramyldipeptide, and other stimuli. NALP3 can also detect and respond to endogenous stress-associated danger signals, such as ATP [7], ROS [8], monosodium urate crystals [9], low intracellular potassium concentrations, sodium overload [10], or β-amyloid by activating caspase-1, and active caspase-1 subsequently matures the proinflammatory IL-1β family cytokines by cleaving their proforms into biologically active cytokines in turn [11, 12]. Active IL-1β then triggers the IL-1β receptors on surrounding tissues [13, 14], leading to the activation of multiple cytokines involved in the inflammation cascade, including IL-8, TNF, and IL-17 [15, 16] (Figure 1). However, the role of NALP3 inflammasome in cerebral I/R inflammatory disorders has not been well explored [17, 18].

Bottom Line: Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity.The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored.Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.

ABSTRACT
The most effective way to contain cerebral ischemic injury is reperfusion; however, reperfusion itself may result in tissue injury, for which inflammatory damage is one of the main causative factors. NALP3 inflammasome is a multiprotein complex. It consists of NALP3, ASC, and caspase-1, whose function is to switch on the inflammatory process. Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity. In this study, the effects of chrysophanol in cerebral ischemia/reperfusion and the potential mechanisms were investigated. Male CD1 mice were subject to transient middle cerebral artery occlusion (tMCAO). The NALP3 inflammasome activation status and its dynamic expression during the natural inflammatory response induced by tMCAO were first profiled. The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored. Physical parameters including neurological deficit, infarct size, brain edema, and BBB permeability were measured at 24 h after tMCAO. Confocal microscopy, Western blotting, immunohistochemistry, and qRT-PCR techniques were utilized to analyze the expression of NALP3 inflammasome and IL-1 β . Our results indicated that the brain tissue damage during cerebral ischemia/reperfusion is accompanied by NALP3 inflammasome activation. Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke.

Show MeSH
Related in: MedlinePlus