Inhibition of TSH/IGF-1 receptor crosstalk by Teprotumumab as a treatment modality of Thyroid Eye Disease

Context We previously presented evidence that TSH receptor (TSHR)-stimulating autoantibodies (TSAbs) bind to and activate TSHRs but do not bind to IGF1 receptors (IGF1Rs). Nevertheless, we showed that IGF1Rs were involved in thyroid eye disease (TED) pathogenesis because TSAbs activated crosstalk between TSHR and IGF1R. Teprotumumab, originally generated to inhibit IGF1 binding to IGF1R, was recently approved for the treatment of TED (Tepezza®). Objective To investigate the role of TSHR/IGF1R crosstalk in teprotumumab treatment of TED. Design We used orbital fibroblasts from patients with TED (TEDOFs) and measured stimulated hyaluronan (HA) secretion as a measure of orbital fibroblast activation by TED immunoglobulins (TED-Igs) and monoclonal TSAb M22. We previously showed that M22, which does not bind to IGF1R, stimulated HA in a biphasic dose-response with the higher-potency phase dependent on TSHR/IGF1R crosstalk and the lower-potency phase independent of IGF1R. Stimulation by TED-Igs and M22 was measured in the absence or presence of Teprotumumab Biosimilar (Tepro) or K1-70, an antibody that inhibits TSHR. Results We show: 1) Tepro dose-dependently inhibits stimulation by TED-Igs; 2) Tepro does not bind to TSHRs; 3) Tepro inhibits IGF1R-dependent M22-induced HA production, which is mediated by TSHR/IGF1R crosstalk, but not IGF1R-independent M22 stimulation; and 4) β-arrestin 1 knockdown, which blocks TSHR/IGF1R crosstalk, prevents Tepro inhibition of HA production by M22 and by a pool of TED-Igs. Conclusion We conclude that Tepro inhibits HA production by TEDOFs by inhibiting TSHR/IGF1R crosstalk and suggest that inhibition of TSHR/IGF1R crosstalk is the mechanism of its action in treating TED.

Contaminants of emerging concern and aquatic organisms: the need to consider hormetic responses in effect evaluations

Contaminants of emerging concern are widespread in the world’s waters, raising concerns regarding their effects on living organisms. To evaluate the effects of and predict risks associated with such chemicals, dose-response studies are needed, while the nature of the dose-response relationship is critical for the outcomes of such evaluations. Here, we summarize the literature reporting hormetic responses of aquatic organisms to contaminants of emerging concern. Hormesis is a biphasic dose response encompassing stimulatory responses to low doses and inhibitory responses to high doses. We demonstrate that it occurs widely in numerous aquatic organisms exposed to a wide array of contaminants, including nano/microplastics, suggesting potential effects at doses/concentrations that are considerably lower than the traditional toxicological threshold, which cannot be identified or predicted unless hormesis is considered in the study design. To tackle the effects and associated risks of nano/microplastics and other contaminants on aquatic organisms, hormesis should therefore be taken into account early in the design of studies as well as in relevant risk assessments.

Biphasic Dose–Response of Components From Coptis chinensis on Feeding and Detoxification Enzymes of Spodoptera litura Larvae

Due to long-term coevolution, secondary metabolites present in plants apparently function as chemical defense against insect feeding, while various detoxification enzymes in insects are adaptively induced as a prosurvival mechanism. Coptis chinensis, a medicinal plant used in traditional Chinese medicine for a thousand years, was found to be less prey to insects in our earlier field observations. Herein, 4 crude extracts obtained from sequential partition of aqueous extract of Rhizoma coptidis with petroleum ether, ethyl acetate, and n-butanol exhibited antifeedant activity against Spodoptera litura (Fabricius) larvae at high doses and inducing activity at low doses. Furthermore, a similar biphasic dose–response of the antifeedant activity against S litura larvae was also observed for jateorhizine, palmatine, and obakunone in Coptis chinensis. Notably, the enzyme activities of glutathione-S-transferase and carboxyl esterase in S litura larvae affected by the different components (jateorhizine, palmatine, obakunone, berberine, and coptisine) of C chinensis also showed a biphasic dose–response with an increasing trend at low doses and a decreasing trend at high doses. Together, our study suggests that the components of C chinensis may play a chemical defensive role against S litura larvae in a hormetic manner.

Biphasic Dose-Response Induced by Phytochemicals: Experimental Evidence

Many phytochemicals demonstrate nonmonotonic dose/concentration-response termed biphasic dose-response and are considered to be hormetic compounds, i.e., they induce biologically opposite effects at different doses. In numerous articles the hormetic nature of phytochemicals is declared, however, no experimental evidence is provided. Our aim was to present the overview of the reports in which phytochemical-induced biphasic dose-response is experimentally proven. Hence, we included in the current review only articles in which the reversal of response between low and high doses/concentrations of phytochemicals for a single endpoint was documented. The majority of data on biphasic dose-response have been found for phytoestrogens; other reports described these types of effects for resveratrol, sulforaphane, and natural compounds from various chemical classes such as isoquinoline alkaloid berberine, polyacetylenes falcarinol and falcarindiol, prenylated pterocarpan glyceollin1, naphthoquinones plumbagin and naphazarin, and panaxatriol saponins. The prevailing part of the studies presented in the current review was performed on cell cultures. The most common endpoint tested was a proliferation of tumor and non-cancerous cells. Very few experiments demonstrating biphasic dose-response induced by phytochemicals were carried out on animal models. Data on the biphasic dose-response of various endpoints to phytochemicals may have a potential therapeutic or preventive implication.

Biphasic effect of abscisic acid on plants: an hormetic viewpoint

Abscisic acid (ABA) is a major phytohormone that regulates development and growth. Increasingly, the literature indicates that ABA enhances and inhibits a spectrum of plant responses within an hormetic-like biphasic dose–response manner. A recent extensive study on the response of a variety of Arabidopsis lines to ABA suggested the widespread occurrence of hormetic dose responses. Our independent reassessment of these data reveals the occurrence of more than 30 hormetic dose–response relationships with quantitative features fully consistent with the substantial and extensively assessed literature on plant hormesis. This analysis significantly extends earlier findings indicating that ABA mediates a broad spectrum of hormetic dose responses in plants. ABA-induced hormesis provides a novel framework for research with the potential to advance the current scientific bases of plant ecology, physiology, and toxicology and to enhance agricultural yields and productivity.

Originator of the hormesis concept: Rudolf Virchow or Hugo Schulz

In 2006, Henschler disputed the claim of Calabrese and Baldwin that Hugo Schulz should be considered the originator of the hormesis concept. Henschler cited an 1854 paper by Rudolf Virchow on the effects of two agents on the beating of cilia, which showed a hormetic–biphasic dose response. The interpretation of Henschler became broadly accepted over the past decade based on citations in the literature. However, a recent translation of the Virchow paper from German into English reveals that the claims of Henschler are not supported by the article.