Flavonoids with Preclinical Antidepressant-Like Effects
Scott Mendelson in Herbal Treatment of Major Depression, 2019
Flavonoids have also been found to inhibit, directly or indirectly, activation of the NLRP3 inflammasome. The inflammasome is a multi-protein complex that regulates major components of the inflammatory response, including caspase-1 activation and IL-1β secretion. Inflammasome activation is mediated by NLR proteins that respond to a variety of stimuli, including infection, oxidative damage, and physical injury, but also psychological stress. Among the NLRs, NLRP3 senses the widest array of stimuli. The flavonoid apigenin has been found to inhibit lipopolysaccharide-induced synthesis of the inflammatory cytokine IL-1β by inhibiting caspase-1 activation through the disruption of the NLRP3 inflammasome assembly.102 Luteoloside also decreases expression of NLRP3 inflammasome resulting in decreases in proteolytic activation of caspase-1. Inactivation of caspase-1 in turn results in inhibition of IL-1β production.103
Inflammatory bowel disease
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
The synthesis and secretion of pro-inflammatory cytokines are governed by germline-encoded receptors such as the TLRs and nucleotide-binding-domain and LRR-containing (NLR) proteins that can be activated by microbe- associated molecular patterns (MAMPs). For example, the production of active (mature) IL-1β and IL-18 occurs through a two-step process initiated by the transcriptional induction of a procytokine (e.g., a TLR stimulus) followed by caspase 1–mediated cleavage. In this process, NLRP3, also known as cryopyrin, associates with the NLR adaptor protein, apoptotic speck protein containing a CARD domain (ASC/PYCARD), to recruit procaspase 1. This complex is referred to as the inflammasome, and leads to the processing of procaspase 1 into active caspase 1. Caspase 1 is responsible for the subsequent cleavage of the IL-1β/IL-18 precursors into their functional forms. In addition to NLRP3, other NLRs, including NLRP1, NLRC4, and NAIP, also function in caspase-1 activation and IL-1β production through the formation of other inflammasomes in response to distinct sets of stimuli. Mice lacking NLRP3, ASC, or caspase 1 produce reduced levels of IL-1β and TNF-α and are protected from inflammation in acute, but not necessarily chronic, experimental colitis, suggesting that the NLRP inflammasome has a more critical role during the early phase of colitis.
Antiproliferative Potential of Medicinal Plants—an Evaluation by in Vivo, in Vitro, and in Silico Approaches
V. R. Mohan, A. Doss, P. S. Tresina in Ethnomedicinal Plants with Therapeutic Properties, 2019
Caspases, or cysteine–aspartic acid proteases, are a family of cysteine proteases that play an essential role in apoptosis, necrosis, and inflammation. Caspases are widely expressed in an inactive pro-enzyme form in most cells and once activated can often activate pro-enzyme form in most cells and once activated can often activate other pro-caspases, allowing initiation of a protease cascade. Some pro-caspases can also aggregate and auto-activate. This proteolytic cascade, in which one caspase can activate other caspases, amplifies the apoptotic signaling pathway and thus leads to rapid cell death. Once caspases are initially activated, there seems to be an irreversible commitment toward cell death. Ten major caspases have been identified and broadly categorized into initiators (caspase-2, -8, -9, -10), effectors or executioners (caspase-3, -6, -7), and inflammatory caspases (caspase-1, -4, -5) (Cohen, 1997). Effects of ethyl acetate fraction of the extract on the activity of lung caspase-9 and caspase-3 were studied by the researchers and the results indicated that 50 µg/mL of ethyl acetate showed significant increase of caspase-9 and caspase-3 activity when compared with the control group. The maximum activity was found at 100 µg/mL and least at 12.5 µg/mL. The caspase-3 activity was increased from 1.37 to 2.8 at concentration from 25 to 100 µg/mL of ethyl-acetate-fraction-treated conditions. Camptothecin at concentration of 1 µg/mL could activate the caspase -3 significantly to 2.96 and activate caspase-9 at the 2.5. Caspase-9 was activated at final stage of apoptosis conditions. The activity of caspase-9 and caspase-3 was significantly elevated in a dose-dependent manner. It was observed that 92% increase in activity of caspase-9 and caspase-3 was in A549 lung cancer cells treated with extract (Unpublished data).
Kaempferol alleviates LPS-ATP mediated inflammatory injury in splenic lymphocytes via regulation of the pyroptosis pathway in mice
Published in Immunopharmacology and Immunotoxicology, 2019
Changliang He, Jia Yang, Xiaolin Jiang, Xiaoxia Liang, Lizi Yin, Zhongqiong Yin, Yi Geng, Zhijun Zhong, Xu Song, Yuanfeng Zou, Lixia Li, Wei Zhang, Cheng Lv
Inflammation is a self-protective mechanism that defends the host organism from pathogens and signals to mobilize defensive resources. The initial immune response is generated by cell membrane and cytoplasmic pattern recognition receptors (PRRs) that can discern exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs). Once triggered by PAMPs and DAMPs, membrane Toll-like receptor (TLR) and intracellular sensor NOD-like receptor 3 (NLRP3) signaling pathways start to operate. Then, NLRP3 recruits apoptosis-associated speck-like protein containing CARD (ASC) and procaspase-1 to assemble a supramolecular complex called inflammasome [1–4]. The process of assembly leads to the activation of caspase-1 via releasing its isoform p10, followed by the cleavage of gasdermin D (GSDMD) [5–7]. Caspase-1 enzymes are defined as one of the pro-inflammatory subfamilies of caspases which are expressed in both humans and mice, and contribute to an inflammatory cell death named pyroptosis. The subfamily of caspases also includes caspase-4 and -5 in humans, and caspase-11 in mice [8–10].
Factors associated with the activity and severity of bullous pemphigoid: a review
Published in Annals of Medicine, 2020
Yangchun Liu, Yiman Wang, Xinyi Chen, Hongzhong Jin, Li Li
The inflammasome is a multi-molecular complex which activates pro-inflammatory cytokines such as IL-1β and IL-18 via caspase-1 activation. Caspase-1 is the primary enzyme responsible for the activation of pro-inflammatory cytokines. Fang et al. found that mRNA expression of the components of the NLRP3 inflammasome (NLRP3, pro-caspase-1 and pro-IL-18) in the peripheral blood mononuclear cells (PBMCs) of BP patients were significantly higher than those of healthy people [18]. Fang et al. demonstrated that expression of the components of the NLRP3 inflammasome (caspase-1, IL-18 and apoptosis-associated speck-like protein caspase recruitment domain) were correlated positively with autoantibody titres against the NC16A domain of BP180. Hence, NLRP3-inflammasome components were closely related to disease activity. The important pro-inflammatory cytokines IL-1β and IL-18 can stimulate the release of other cytokines, such as IL-2, IL-6, IL-12, and IL-17A. Hence, the NLRP3–caspase-1–IL-18 axis in the PBMCs of BP patients is correlated positively with disease activity. NLRP3-inflammasome components contribute to BP pathogenesis, so targeting these components may provide a novel therapy for BP. Fang et al. also showed that levels of lactate dehydrogenase and high-mobility group-1 protein were increased in the blister fluid of BP patients, so they could also be considered as parameters for monitoring BP activity [18,36].
Bidirectional role of reactive oxygen species during inflammasome activation in acrolein-induced human EAhy926 cells pyroptosis
Published in Toxicology Mechanisms and Methods, 2021
Liping Jiang, Songsong Luo, Tianming Qiu, Qiannan Li, Chunteng Jiang, Xiance Sun, Guang Yang, Cong Zhang, Xiaofang Liu, Lijie Jiang
Recent studies have demonstrated that acrolein could result in cell death and apoptosis in a variety of cells, such as acrolein-induced cardiomyocyte apoptosis (Wang et al. 2011), rapamycin inhibited acrolein-induced apoptosis in male germ cells (He et al. 2014). Pyroptosis is inflammatory programmed cell death, accompanying by pore formation, cell swelling, and inflammasome activation. Recent studies showed that acrolein can cause an inflammatory response in different cells and tissues including endothelial cells (Sun et al. 2014). However, the underlying mechanism is unknown. Caspase-1 plays a fundamental role in several important inflammatory diseases act as the protease of the pro-inflammatory cytokines pro-IL-1β. Therefore, we hypothesized that pyroptosis may be one of the mechanisms by which acrolein induces inflammation. The measurement of LDH release, dead cell staining, and caspase-1 activation has been used to confirm pyroptosis (Wree et al. 2014; Yang et al. 2014). Our results revealed that acrolein induced cell death as indicated by dead cell staining and increased LDH. Based on Western blot analysis, the protein levels of NLRP3, caspase-1, and IL-1β were increased significantly after acrolein treatment. NLRP3 siRNA treatment resulted in a significant decrease in cleaved caspase-1 expression (Figure 3). All of these data illustrated that pyroptosis is triggered by acrolein in EAhy926 cells and NLRP3 inflammasome was required for this process. These findings have provided a new therapeutic target (NLRP3) for acrolein-induced cardiovascular diseases.
Related Knowledge Centers
- Cell Death
- Enzyme
- Eukaryote
- Inflammasome
- Interleukin 18
- Proteolysis
- Pyroptosis
- Cytokine
- Protein Precursor
- Interleukin 1 Beta