Cell Growth Dynamics in Bladder Carcinogenesis: Implications for Risk Assessment

1989 ◽  
Vol 8 (6) ◽  
pp. 1103-1114 ◽  
Author(s):  
Samuel M. Cohen ◽  
Leon B. Ellwein
Keyword(s):  
Cell Proliferation ◽  
Dose Response ◽  
Malignant Tumors ◽  
Animal Experiments ◽  
Growth Dynamics ◽  
Threshold Effect ◽  
Male Rats ◽  
Low Doses ◽  
Bladder Tumors ◽  
High Doses

A biological model of carcinogenesis has been developed that can be expressed mathematically, and therefore can be studied using computer-based analyses. It is based on several assumptions: Carcinogenesis occurs in two stages: initiation and transformation (to malignant tumors); the carcinogenic events can occur only in stem cells or their functional equivalents; these events can occur only during the active part of the cell cycle; each of the events occurs in a probabilistic fashion. Cell dynamics are thus an extremely important part of carcinogenesis. Any agent can have an impact on the carcinogenic process by either directly altering the genome (genotoxic) or increasing the proliferative rate of the tissues: increasing the number of cell divisions through which a spontaneous alteration in the genome can occur; or an agent can affect both of these. Effects on the genome and on cell proliferation can have different dose-responses. Extrapolation to low doses requires consideration of the dose-response for each effect. Differences in mechanisms affecting cell proliferation and genetic changes need to be considered in determining thresholds. The model was originally validated utilizing tumor incidence data from multiple experiments with the carcinogen, N-[4-(5-nitro-2-furyl)2-thiazolyl]-formamide (FANFT), in rats. FANFT is a strong mutagen, is metabolically activated to a reactive electrophile, binds to DNA, and also increases cell proliferation. Modeling analyses demonstrate that the tumor dose-response curve for FANFT can be explained based on a combination of the individual dose-response of its genotoxic and cell proliferation effects. Modeling of a nongenotoxic compound, sodium saccharin (Na S), has also been evaluated. It is not metabolized to a reactive electrophile (it is actually nucleophilic), does not bind to DNA, and is not mutagenic. Nevertheless, in two-generation experiments at high doses it induces a significant incidence of bladder tumors in male rats. It is also a strong tumor-promoting substance following chemical initiation or bladder ulceration. These complex protocols can be readily explained by the proliferative response induced in the urothelium following Na S administration. As expected for a nongenotoxic chemical, there is no effect on the probability of initiation or transformation. Unlike the sodium salt, high doses of the calcium and acid forms of saccharin do not increase cell proliferation significantly, and would not be anticipated to induce tumors. Also, there appears to be a threshold effect related to dose of Na S and the induction of urothelial proliferation. Since cell proliferation is the mechanism by which Na S induces bladder tumors in rats, it is expected that there is also a threshold with respect to carcinogenesis. By allowing for agents to be defined in terms of their ability to affect the genome directly or to act as cell proliferators, model-based analyses provide a rational basis for extrapolating from high doses in animal experiments to low doses in assessing risk for humans.

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

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582091634
Author(s):  
Houhui Jiang ◽  
Yin Chen ◽  
Juan Ni ◽  
Jia Song ◽  
Li Li ◽  
...  
Keyword(s):  
Dose Response ◽  
Spodoptera Litura ◽  
Detoxification Enzymes ◽  
Low Doses ◽  
Antifeedant Activity ◽  
Glutathione S Transferase ◽  
Coptis Chinensis ◽  
Defensive Role ◽  
High Doses ◽  
Biphasic Dose Response

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.

scholarly journals Expression of the CLCA4 Gene in Esophageal Carcinoma and Its Impact on the Biologic Function of Esophageal Carcinoma Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Xin Song ◽  
Shuai Zhang ◽  
Shouchuan Li ◽  
Ye Wang ◽  
Xinming Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Esophageal Carcinoma ◽  
Malignant Tumors ◽  
Animal Experiments ◽  
Migration And Invasion ◽  
Western Blot Assay ◽  
Tumor Inhibitor

Background. Esophageal carcinoma (ESCA) is one of the malignant tumors with a high mortality rate worldwide, which seriously affects people’s health. Calcium-activated chloride channel 4 (CLCA4) was reported to be a tumor inhibitor in hepatocellular carcinoma. Nevertheless, the role of CLCA4 in ESCA is still unclear. Methods. RT-qPCR and western blot assay were used to test the expression pattern of CLCA4 in ESCA tissues and cells. CCK-8 assay was performed to detect the effect of CLCA4 overexpression on cell proliferation in ESCA cells. Transwell assay was used to measure the effect of CLCA4 upregulation on migration and invasion abilities of ESCA cells. Animal experiments were conducted to investigate the role of CLCA4 upregulation in tumor growth in vivo. Results. CLCA4 was significantly reduced in ESCA tissues and correlated with T stage, differentiation, and lymph node metastasis. CLCA4 overexpression was found to inhibit cell proliferation, migration, invasion, and EMT progression in ESCA cells. Moreover, CLCA4 overexpression suppressed tumor growth in vivo. Conclusion. CLCA4 was suggested to act as a tumor inhibitor in ESCA and might be a therapeutic target gene for the treatment of patients with ESCA.

scholarly journals Erectile Dysfunction Drugs Changed the Protein Expressions and Activities of Drug-Metabolising Enzymes in the Liver of Male Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Salah A. Sheweita ◽  
Mona Wally ◽  
Mostafa Hassan
Keyword(s):  
Erectile Dysfunction ◽  
Protein Expression ◽  
Phase I ◽  
The Other ◽  
Male Rats ◽  
Low Doses ◽  
Other Hand ◽  
Endogenous Compounds ◽  
High Doses ◽  
Drug Metabolising Enzymes

Erectile dysfunction (ED) is a major health problem and is mainly associated with the persistent inability of men to maintain sufficient erection for satisfactory sexual performance. Millions of men are using sildenafil, vardenafil, and/or tadalafil for ED treatment. Cytochrome P450s (CYPs) play a central role in the metabolism of a wide range of xenobiotics as well as endogenous compounds. Susceptibility of individuals to the adverse effects of different drugs is mainly dependent on the expression of CYPs proteins. Therefore, changes in activities of phase I drug-metabolising enzymes [arylhydrocarbon hydroxylase (AHH), dimethylnitrosamine N-demethylase (DMN-dI), 7-ethoxycoumarin-O-deethylase (ECOD), and ethoxyresorufin-O-deethylase ((EROD)] and the protein expression of different CYPs isozymes (CYP1A2, CYP2E1, CYP2B1/2, CYP3A4, CYP2C23, and CYP2C6) were determined after treatment of male rats with either low or high doses of sildenafil (Viagra), tadalafil (Cialis), and/or vardenafil (Levitra) for 3 weeks. The present study showed that low doses of tadalafil and vardenafil increased DMN-dI activity by 32 and 23%, respectively. On the other hand, high doses of tadalafil, vardenafil, and sildenafil decreased such activity by 50, 56, and 52%, respectively. In addition, low doses of tadalafil and vardenafil induced the protein expression of CYP2E1. On the other hand, high doses of either tadalafil or sildenafil were more potent inhibitors to CYP2E1 expression than vardenafil. Moreover, low doses of both vardenafil and sildenafil markedly increased AHH activity by 162 and 247%, respectively, whereas high doses of tadalafil, vardenafil, and sildenafil inhibited such activity by 36, 49, and 57% and inhibited the EROD activity by 39, 49, and 33%, respectively. Low and high doses of tadalafil, vardenafil, and sildenafil inhibited the activity of NADPH-cytochrome c reductase as well as its protein expression. In addition, such drugs inhibited the expression of CYP B1/2 along with its corresponding enzyme marker ECOD activity. It is concluded that changes in the expression and activity of phase I drug-metabolising enzymes could change the normal metabolic pathways and might enhance the deleterious effects of exogenous as well as endogenous compounds.

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

2021 ◽  
Author(s):  
Evgenios Agathokleous ◽  
Damià Barceló ◽  
Despo Fatta-Kassinos ◽  
Michael N. Moore ◽  
Edward J. Calabrese
Keyword(s):  
Dose Response ◽  
Aquatic Organisms ◽  
Risk Assessments ◽  
Contaminants Of Emerging Concern ◽  
Low Doses ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
High Doses ◽  
Living Organisms ◽  
Biphasic Dose Response

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.

A Network Meta-Analysis of the Efficacy and Safety of Empagliflozin at Different Doses in Patients with Diabetes Mellitus Based on Randomized Controlled Trials

2020 ◽  
Author(s):  
Qian Wu ◽  
Chen Liao ◽  
Mengyu He ◽  
Can Li ◽  
Fang Zou ◽  
...  
Keyword(s):  
Randomized Controlled Trials ◽  
Dose Response ◽  
Meta Analysis ◽  
Cochrane Library ◽  
Pharmacokinetic Parameters ◽  
Controlled Trials ◽  
Low Doses ◽  
Randomized Controlled ◽  
High Doses ◽  
Different Doses

Abstract Background and objective: As an oral hypoglycemic drug that significantly reduces cardiovascular risk, empagliflozin is used in patients with type 2 diabetes. However, the dosage and administration of empagliflozin are still controversial clinically. To determine the appropriate treatment, we performed this network meta-analysis.Methods: We identified randomized controlled trials (RCTs) about empagliflozin from databases including PubMed, Ovid MEDLINE, Embase, ScienceDirect, Web of Science, the Cochrane Library, Scopus and Google Scholar. We analyzed the pharmacodynamics, adverse effects (AEs), and pharmacokinetics of empagliflozin at different doses.Results: We identified 8264 articles, of which 26 RCTs with 11796 patients were included. Regarding hemoglobin A1c (HbA1c ) and fasting plasma glucose (FPG), high doses (10, 25, 50 mg) were significantly better than low doses (1, 2.5, 5 mg). For total AEs, there was a dose-response trend in which safety decreased with increasing doses. According to SUCRA sequencing, the order for lowering HbA1c was 25 > 50 > 10 > 2.5 > 5 > 1 mg, for lowering FPG was 50 > 25 > 10 > 5 > 2.5 > 1 mg and for safety was 1 > 2.5 > 5 > 25 > 10 > 50 mg. When considering HbA1c, FPG and total AEs, we performed a hierarchical cluster analysis and network meta-analysis to find that 25 mg performed best among different doses, which was more significant after long-term use (≥ 12 weeks). Pharmacokinetic parameters exhibited significant dose-response relationships .Conclusions: High doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the different doses. More RCTs exploring unconventional doses are needed to confirm these conclusions.

Commentary on ‘Resveratrol commonly displays hormesis: Occurrence and biomedical significance’

2010 ◽  
Vol 29 (12) ◽  
pp. 1024-1025 ◽  
Author(s):  
David G Lindsay
Keyword(s):  
Dose Response ◽  
Low Doses ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Beneficial Effects ◽  
In Vitro Systems ◽  
High Doses

Many phenolics found naturally in food have the capacity to show beneficial effects at low doses and toxicity at high doses in in vitro systems. Resveratrol is no exception. Nonetheless, in the nutritional context, the evidence that resveratrol shows hormetic effects is very limited and is of questionable relevance given its rapid metabolism in the stomach. Hormesis can only be confirmed if evidence for a J- or U-shaped dose-response relationship is found in in vivo doses that are relevant to human intakes.

High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats

1994 ◽  
Vol 49 (1) ◽  
pp. 101-106 ◽  
Author(s):  
Kerstin Uvnäs-Moberg ◽  
S. Ahlenius ◽  
V. Hillegaart ◽  
P. Alster
Keyword(s):  
Male Rats ◽  
Low Doses ◽  
High Doses

scholarly journals The Effect of Chilli Extract on Gastroprotective Function in Male

2021 ◽  
Vol 8 (1) ◽  
pp. 1
Author(s):  
Tahyatul Bariroh ◽  
Siska Siska
Keyword(s):  
White Male ◽  
Burning Sensation ◽  
Male Rats ◽  
Control Group ◽  
Low Doses ◽  
Mucosal Tissue ◽  
Group A ◽  
High Doses ◽  
Genus Capsicum ◽  
Unique Compound

Chilli is one of plant from genus Capsicum and as vegetable commodities most consumed by the Indonesian people. Chilli contains a unique compound called capsaicin which gives a burning sensation like burning when consumed. This research aims to determine the effect of chilli extract on gastroprotection in the stomach of mice. The study used 35 white male rats were divided into seven groups, one group as the control group, and six groups were given extracts from three varieties of chilli (red chilli, green chilli, and chilli) with high doses (1 g / kg bb) and low doses (0.5 g / kg bb) for 14 days. On the 15th day, gastric decapitation and isolation were carried out to make histological preparations of the rat's stomach. The results showed mucosal tissue in the stomach of rats given a dose of 0.5 g/kg BW remained in normal condition compared to the group of rats given high doses of chilli. In this group, a lot of damage to the gastric mucosal tissue of rats (ulcers). This study concludes that consuming 0.5 g/kg BW chilli does not cause damage to the gastric mucosal tissue of rats.Keywords: Chilli, Gastric mucose, Gastroprotective

Ultrastructural Localization of Acetylcholinesterase in the Arcuate Nucleus and Median Eminence of the Rat

1977 ◽  
Vol 35 ◽  
pp. 440-441
Author(s):  
K.A. Carson ◽  
C.B. Nemeroff ◽  
M.S. Rone ◽  
J.S. Kizer ◽  
J.S. Hanker
Keyword(s):  
Choline Acetyltransferase ◽  
Median Eminence ◽  
Arcuate Nucleus ◽  
Cholinergic Neurons ◽  
Ultrastructural Localization ◽  
Male Rats ◽  
Neonatal Rats ◽  
Good Marker ◽  
Chemical Studies ◽  
High Doses

Biochemical, physiological, pharmacological, and more recently enzyme histo- chemical data have indicated that cholinergic circuits exist in the hypothalamus. Ultrastructural correlates of these pathways such as acetylcholinesterase (AchE) positive neurons in the arcuate nucleus (ARC) and stained terminals in the median eminence (ME) have yet to be described. Initial studies in our laboratories utilizing chemical lesioning and microdissection techniques coupled with microchemical and light microscopic enzyme histo- chemical studies suggested the existence of cholinergic neurons in the ARC which project to the ME (1). Furthermore, in adult male rats with Halasz deafferentations (hypothalamic islands composed primarily of the isolated ARC and the ME) choline acetyltransferase (ChAc) activity, a good marker for cholinergic neurons, was not significantly reduced in the ME and was only somewhat reduced in the ARC (2). Treatment of neonatal rats with high doses of monosodium 1-glutamate (MSG) results in a lesion largely restricted to the neurons of the ARC.

The Effect of Androgen Depletion and Replacement on the Epithelium of the Seminal Vesicle of the Aging Rat

1975 ◽  
Vol 33 ◽  
pp. 590-591
Author(s):  
Venita F. Allison
Keyword(s):  
Cell Proliferation ◽  
Seminal Vesicle ◽  
Male Rats ◽  
Target Cells ◽  
Cell Regeneration ◽  
Secretory Function ◽  
Electron Microscopic ◽  
Aging Rat ◽  
Microscopic Studies ◽  
Androgen Depletion

In 1930, Moore, Hughes and Gallager reported that after castration seminal vesicle epithelial cell atrophy occurred and that cell regeneration could be achieved with daily injections of testis extract. Electron microscopic studies have confirmed those observations and have shown that testosterone injections restore the epithelium of the seminal vesicle in adult castrated male rats. Studies concerned with the metabolism of androgens point out that dihydrotestosterone stimulates cell proliferation and that other metabolites of testosterone probably influence secretory function in certain target cells.Although the influence of androgens on adult seminal vesicle epithelial cytology is well documented, little is known of the effect of androgen depletion and replacement on those cells in aging animals. The present study is concerned with the effect of castration and testosterone injection on the epithelium of the seminal vesicle of aging rats.

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