Hormesis: Path and Progression to Significance

Calabrese, Edward J.

doi:10.3390/ijms19102871

Cited by 177 publications

(144 citation statements)

References 70 publications

(104 reference statements)

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“…One possible explanation is that higher concentrations of EtBr may have triggered a defense mechanism, such as efflux of EtBr or upregulated DNA repair pathways, that may explain the lower number of canavanine-resistant colonies. Such an explanation would be consistent with hormesis [36,37]. Nonetheless, the number of canavanine-resistant colonies from yeast grown in EtBr from 0.1 to 10 μg EtBr/L was significantly more than control ( Fig 2B ), demonstrating that we could detect the mutagenic potential of yeast even at concentrations lower than the limit of detection for the Ames test.…”

Section: Discussionsupporting

confidence: 72%

“…Interestingly, we observed that the lower concentrations of EtBr (0.1 and 1.0 μg EtBr/L) produced higher numbers of canavanine-resistant colonies than the highest concentration of EtBr (10 μg EtBr/L), a biphasic response consistent with hormesis. Briefly, hormesis is when a low dose of a toxin produces a higher effect than a lower dose, perhaps because the higher dose induces protective responses not triggered by the lower dose [36,37]. This observation was reproducible in two more independent runs of the parallel chemostats (S1 C and D Figs ).…”

Section: Resultsmentioning

confidence: 75%

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Yeast grown in continuous culture systems can detect mutagens with improved sensitivity relative to the Ames test

Ong

Pence

Molik

et al. 2020

Preprint

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Continuous culture systems allow for the controlled growth of microorganisms over a long period of time. Here, we develop a novel test for mutagenicity that involves growing yeast in continuous culture systems exposed to low levels of mutagen for a period of weeks. In contrast, most microorganism-based tests for mutagenicity expose the potential mutagen to the biological reporter at a high concentration of mutagen for a short period of time. Our test improves upon the sensitivity of the well-established Ames test by at least 20-fold for each of two mutagens that act by different mechanisms (the intercalator ethidium bromide and alkylating agent methylmethane sulfonate). To conduct the tests, cultures were grown in small, inexpensive continuous culture systems in media containing (potential) mutagen, and the resulting mutagenicity of the added compound was assessed via two methods: a canavanine-based plate assay and whole genome sequencing. In the canavanine-based plate assay, we were able to detect a clear relationship between the amount of mutagen and the number of canavanine-resistant mutant colonies over a period of one to three weeks of exposure. Whole genome sequencing of yeast grown in continuous culture systems exposed to MMS demonstrated that quantification of mutations is possible by identifying the number of unique variants across each strain but with lower sensitivity than the plate-based assay. In conclusion, we propose yeast grown in continuous culture systems can provide an improved and more sensitive test for mutagenicity.

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Section: Discussionsupporting

confidence: 72%

Section: Resultsmentioning

confidence: 75%

Yeast grown in continuous culture systems can detect mutagens with improved sensitivity relative to the Ames test

Ong

Pence

Molik

et al. 2020

Preprint

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“…It is possible that CXA‐10, like many signaling agents, exhibits hormesis (inverted U‐shaped dose response curve), which has been observed with CXA‐10 in animal models . Inverted U‐shaped dose response curves are common with drugs that regulate signaling pathways and may protect against overexposure by simply “turning off” functions at high concentrations …”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Effects of OralCXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

Garner¹,

Mould

Chieffo³

et al. 2019

Clinical Translational Sci

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10‐nitro‐9(E)‐octadec‐9‐enoic acid (CXA‐10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA‐10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA‐10. After single and multiple ascending doses, CXA‐10 demonstrated dose‐proportional increases in plasma exposure. CXA‐10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA‐10‐202, a consistent decrease from baseline was observed with CXA‐10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP‐1, and IL‐6. In CXA‐10‐203, after coadministration with CXA‐10, geometric mean peak plasma concentration (Cmax) and area under the plasma concentration‐time curve from time point 0 to the end of the dosing interval (AUC0−t) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA‐10. Adverse events (AEs) were dose‐related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA‐10 was safe and well‐tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA‐10 75–300 mg once daily.

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“…The therapeutic application of ncRNAs cannot be conceived otherwise than by using ultra-low doses in the context of a nanotherapy as currently represented by the BI(G)MED. This is made possible by the principle of Hormesis, borrowed from toxicology, and applied to nanodoses, which explains the rule of reversal of action according to the dose (Figure 12) [28,29].…”

Section: Resultsmentioning

confidence: 99%

Cancer Stem Cells Regulation with a Sublingual Nanotherapy using Ultra Low Doses of Non-Coding RNAs

2019

IJCRT

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Tumors are heterogeneous tissues with abundant phenotypically and functionally distinct cell subpopulations, each having different capacities to grow, differentiate, develop drug resistance and form metastases. Tumors contain a functional subpopulation of cells that exhibit stem cell properties. These cells, named cancer stem cells (CSCs), play significant roles in the initiation and progression of cancer. So far, CSCs have been identified in breast, pancreatic, prostate, colon, head and neck, ovarian and liver cancers, melanoma and brain tumors. CSCs are defined by the following properties: (a) unlimited self-renewal capacities, (b) the ability to differentiate into non-CSC daughter cells, (c) high tumorigenicity upon injection in immunocompromised mice, and (d) have remarkable resistance to conventional therapies. MicroRNAs or miRNAs are short non-coding RNAs that regulate gene expression at the post-transcriptional level by leading to the degradation of target mRNA or repression of mRNA translation. Recent studies have highlighted several miRNAs to be differentially expressed in normal and cancer stem cells and established their role in targeting genes and pathways supporting cancer stemness properties. Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs that have no potential to code proteins and are more than 200 nucleotides in length. LncRNAs can act at the transcriptional, posttranscriptional and translational level. As such, they may be involved in various biological processes such as DNA damage repair, inflammation, metabolism, cell survival, cell signaling, cell growth and differentiation. Accumulating evidence indicates that lncRNAs are key regulators of the CSCs subpopulation, thereby contributing to cancer progression. These non-coding RNA molecules represent, of course, particularly attractive targets for regulating CSCs; for this purpose, we have developed a sublingual nanotherapy delivered without any undesirable side effects thanks to the use of ultra-low doses.

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Hormesis: Path and Progression to Significance

Cited by 177 publications

References 70 publications

Yeast grown in continuous culture systems can detect mutagens with improved sensitivity relative to the Ames test

Yeast grown in continuous culture systems can detect mutagens with improved sensitivity relative to the Ames test

Pharmacokinetic and Pharmacodynamic Effects of OralCXA‐10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects

Cancer Stem Cells Regulation with a Sublingual Nanotherapy using Ultra Low Doses of Non-Coding RNAs

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