NLRP3 inflammasome activation By 17β-estradiol is a potential therapeutic target in hepatocellular carcinoma treatment

Awwad, Sara F; Assaf, Raymonde; Emam, Ahmed Al; Fouad, Amgad; Arafa, Lamiaa F.; El-Hanafy, Aya A

doi:10.1007/s12032-022-01945-z

Cited by 4 publications

(1 citation statement)

References 56 publications

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“…NLRP3 inflammasome initiation is linked with the onset of liver cancer, particularly HCC (16). New clinical trials should target NLRP3 inflammasome activation and compounds that may be able to act on it (17). The initiation of the NLRP3 inflammasome requires two steps.…”

Section: Nlrp3 Inflammasome and Cancermentioning

confidence: 99%

MASLD and aspartame: are new studies in the horizon?

Sergi

2023

Front. Med.

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Fatty liver disease has been on the rise in the past few decades, and there is no hope that it will stop. The terminology change that has been recently proposed may not be sufficient to advocate for a reduction of steatogenic foods and a change in lifestyle. A course change may be supported by the recent labeling of aspartame sweetener as a possible carcinogenic compound by the International Association for Research on Cancer (IARC), an agency of the World Health Organization (WHO). Aspartame sweeteners and other edulcorating molecular compounds besides colorings may trigger liver cancer other than fatty liver disease, despite limited data supporting it. An essential bias in human cohort studies is indeed the exclusion of all confounding factors, which may be barely impossible for human studies. In this perspective, we suggest that the activation of the NOD-like receptor-enclosing protein 3 (NLRP3) inflammasome and the stimulation of the tumor suppression gene TP53 may be critical in the progression from fatty liver to liver inflammation and liver cancer. Aspartame reduces a transcriptional coactivator, precisely the peroxisomal proliferator-initiated receptor-γ (gamma) coactivator 1-α (alpha) (or PGC1α). This coactivator upregulates mitochondrial bioformation, oxidative phosphorylation, respiratory capacity, and fatty acid β-oxidation. Aspartame acts in this way, probably through the activation of TP53. These events have been accountable for the variations in the lipid outline in serum and total lipid storage as well as for the impairment of gluconeogenesis in the liver, as supported by the downregulation of the gluconeogenic enzymes in experimental animals, and may be relevant in humans as well.

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Section: Nlrp3 Inflammasome and Cancermentioning

confidence: 99%

MASLD and aspartame: are new studies in the horizon?

Sergi

2023

Front. Med.

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Pharmacologically inducing anoikis offers novel therapeutic opportunities in hepatocellular carcinoma

Wang,

Fleishman,

Wang

et al. 2024

Biomedicine & Pharmacotherapy

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Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system

Valiauga,

Talley,

Khemmani

et al. 2024

J Neuroinflammation

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Background Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes. Methods 5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated. Results The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established. Conclusions Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.

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NLRP3 inflammasome activation By 17β-estradiol is a potential therapeutic target in hepatocellular carcinoma treatment

Cited by 4 publications

References 56 publications

MASLD and aspartame: are new studies in the horizon?

MASLD and aspartame: are new studies in the horizon?

Pharmacologically inducing anoikis offers novel therapeutic opportunities in hepatocellular carcinoma

Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system

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