scholarly journals Biphasic Dose-Response Induced by Phytochemicals: Experimental Evidence

2020 ◽  
Vol 9 (3) ◽  
pp. 718 ◽  
Author(s):  
Jadwiga Jodynis-Liebert ◽  
Małgorzata Kujawska
Keyword(s):  
Experimental Evidence ◽  
Dose Response ◽  
Isoquinoline Alkaloid ◽  
Current Review ◽  
Common Endpoint ◽  
Dose Concentration ◽  
High Doses ◽  
Cancerous Cells ◽  
Different Doses ◽  
Biphasic Dose Response

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.

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 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.

Effects of Two Different Doses of Hirudin on APTT, Determined with Eight Different Reagents

1995 ◽  
Vol 73 (02) ◽  
pp. 219-222 ◽  
Author(s):  
Manuel Monreal ◽  
Luis Monreal ◽  
Rafael Ruiz de Gopegui ◽  
Yvonne Espada ◽  
Ana Maria Angles ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
In Vitro Study ◽  
Ex Vivo Model ◽  
Suitable Candidate ◽  
Significant Prolongation ◽  
High Doses ◽  
Different Doses

SummaryThe APTT has been considered the most suitable candidate to monitor the anticoagulant activity of hirudin. However, its use is hampered by problems of standardization, which make the results heavily dependent on the responsiveness of the reagent used. Our aim was to investigate if this different responsiveness of different reagents when added in vitro is to be confirmed in an ex vivo study.Two different doses of r-hirudin (CGP 39393), 0.3 mg/kg and 1 mg/kg, were administered subcutaneously to 20 New Zealand male rabbits, and the differences in prolongation of APTT 2 and 12 h later were compared, using 8 widely used commercial reagents. All groups exhibited a significant prolongation of APTT 2 h after sc administration of hirudin, both at low and high doses. But this prolongation persisted 12 h later only when the PTTa reagent (Boehringer Mannheim) was used. In general, hirudin prolonged the APTT most with the silica- based reagents.In a further study, we compared the same APTT reagents in an in vitro study in which normal pooled plasma was mixed with increasing amount of hirudin. We failed to confirm a higher sensitivity for silica- containing reagents. Thus, we conclude that subcutaneous administration of hirudin prolongs the APTT most with the silica-based reagents, but this effect is exclusive for the ex vivo model.

Melatonin actions in the heart; more than a hormone

2018 ◽  
Vol 1 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Darío Acuña-Castroviejo ◽  
Maria T Noguiera-Navarro ◽  
Russel J Reiter ◽  
Germaine Escames
Keyword(s):  
Cell Membranes ◽  
Myocardial Cell ◽  
Rat Tissues ◽  
Dependent Manner ◽  
Broad Distribution ◽  
Multiple Organs ◽  
High Doses ◽  
Extrapineal Melatonin ◽  
Dose Dependent ◽  
Different Doses

Due to the broad distribution of extrapineal melatonin in multiple organs and tissues, we analyzed the presence and subcellular distribution of the indoleamine in the heart of rats. Groups of sham-operated and pinealectomized rats were sacrificed at different times along the day, and the melatonin content in myocardial cell membranes, cytosol, nuclei and mitochondria, were measured. Other groups of control animals were treated with different doses of melatonin to monitor its intracellular distribution. The results show that melatonin levels in the cell membrane, cytosol, nucleus, and mitochondria vary along the day, without showing a circadian rhythm. Pinealectomized animals trend to show higher values than sham-operated rats. Exogenous administration of melatonin yields its accumulation in a dose-dependent manner in all subcellular compartments analyzed, with maximal concentrations found in cell membranes at doses of 200 mg/kg bw melatonin. Interestingly, at dose of 40 mg/kg b.w, maximal concentration of melatonin was reached in the nucleus and mitochondrion. The results confirm previous data in other rat tissues including liver and brain, and support that melatonin is not uniformly distributed in the cell, whereas high doses of melatonin may be required for therapeutic purposes.

scholarly journals The Effects of N-Acetylcysteine on the Rat Mesocorticolimbic Pathway: Role of mGluR5 Receptors and Interaction with Ethanol

2021 ◽  
Vol 14 (6) ◽  
pp. 593
Author(s):  
Sandra Fernández-Rodríguez ◽  
Claudia Esposito-Zapero ◽  
Teodoro Zornoza ◽  
Ana Polache ◽  
Luis Granero ◽  
...  
Keyword(s):  
Behavioral Activation ◽  
Ethanol Administration ◽  
Metabotropic Receptors ◽  
Negative Allosteric Modulator ◽  
High Doses ◽  
Cell Expression ◽  
Mucolytic Agent ◽  
Different Doses

N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol use disorder (AUD), although its mechanism of action is already being debated. In this paper, we set out to assess both the potential involvement of the glutamate metabotropic receptors (mGluR) in the possible dual effect of NAC administered at two different doses and NAC’s effect on ethanol-induced activation. To this aim, 30 or 120 mg/kg of NAC was intraperitoneally administered to rats with the presence or absence of the negative allosteric modulator of mGluR5 (MTEP 0.1 mg/kg). Thereafter, the cFOS IR-cell expression was analyzed. Secondly, we explored the effect of 120 mg/kg of NAC on the neurochemical and behavioral activation induced by intra-VTA ethanol administration (150 nmol). Our results showed that the high NAC dose stimulated cFOS expression in the NAcc, and that this effect was suppressed in the presence of MTEP, thus suggesting the implication of mGluR5. Additionally, high doses could attenuate the ethanol-induced increase in cFOS-expression in the NAcc, probably due to a phenomenon based on the long-term depression of the MSNs. Additional experiments are required to corroborate our hypothesis.

Innovatory role of nanomaterials as bio-tools for treatment of cancer

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Khuram Shahzad Ahmad ◽  
Muntaha Talat ◽  
Shaan Bibi Jaffri ◽  
Neelofer Shaheen
Keyword(s):  
Cancer Treatment ◽  
Cancer Therapeutics ◽  
Physicochemical Characteristics ◽  
Global Scale ◽  
Current Review ◽  
Anti Cancer ◽  
Different Types ◽  
Cancerous Cells

AbstractConventional treatment modes like chemotherapy, thermal and radiations aimed at cancerous cells eradication are marked by destruction pointing the employment of nanomaterials as sustainable and auspicious materials for saving human lives. Cancer has been deemed as the second leading cause of death on a global scale. Nanomaterials employment in cancer treatment is based on the utilization of their inherent physicochemical characteristics in addition to their modification for using as nano-carriers and nano-vehicles eluted with anti-cancer drugs. Current work has reviewed the significant role of different types of nanomaterials in cancer therapeutics and diagnostics in a systematic way. Compilation of review has been done by analyzing voluminous investigations employing ERIC, MEDLINE, NHS Evidence and Web of Science databases. Search engines used were Google scholar, Jstore and PubMed. Current review is suggestive of the remarkable performance of nanomaterials making them candidates for cancer treatment for substitution of destructive treatment modes through investigation of their physicochemical characteristics, utilization outputs and long term impacts in patients.

A Random-allocation Graded Dose–Response Study of Norepinephrine and Phenylephrine for Treating Hypotension during Spinal Anesthesia for Cesarean Delivery

2017 ◽  
Vol 127 (6) ◽  
pp. 934-941 ◽  
Author(s):  
Warwick D. Ngan Kee
Keyword(s):  
Blood Pressure ◽  
Spinal Anesthesia ◽  
Cesarean Delivery ◽  
Dose Response ◽  
Relative Potency ◽  
First Episode ◽  
Response Analysis ◽  
Random Allocation ◽  
Dose Response Study ◽  
Different Doses

Abstract Background Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. However, the relative potencies of these two vasopressors have not been fully determined in this context. Methods In a random-allocation, graded dose–response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 µg or phenylephrine in one of six different doses ranging from 60 to 200 µg to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose–response analysis was performed using nonlinear regression to derive four-parameter logistic dose–response curves, which were compared to determine relative potency. Results Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 µg (95% CI, 6 to 17 µg) and phenylephrine 137 µg (95% CI, 79 to 236 µg). The estimated relative potency ratio for the two drugs was 13.1 µg (95% CI, 10.4 to 15.8 µg). Conclusions Comparative dose–response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equivalent to phenylephrine 100 µg was norepinephrine 8 µg (95% CI, 6 to 10 µg). These results may be useful to inform the design of future comparative studies.

scholarly journals HBI-8000, HUYABIO Lead Clinical Program, Is a Selective Histone Deacetylase Inhibitor With Therapeutic Benefits in Leukemia and in Solid Tumors

2022 ◽  
Vol 11 ◽  
Author(s):  
Farbod Shojaei ◽  
Bob Goodenow ◽  
Gloria Lee ◽  
Fairooz Kabbinavar ◽  
Mireille Gillings
Keyword(s):  
Breast Cancer ◽  
Solid Tumors ◽  
Histone Deacetylase Inhibitor ◽  
Therapeutic Benefits ◽  
Current Review ◽  
Molecule Inhibitor ◽  
Deacetylase Inhibitor ◽  
Clinical Program ◽  
Class I Hdacs ◽  
Cancerous Cells

HBI-8000 is a small molecule inhibitor of class I HDACs and has been approved for the treatment of PTCL, ATL and, in combination with exemestane, in a subpopulation of breast cancer. Given the roles of HDACs in normal and cancerous cells, there are currently multiple clinical trials, by HUYABIO International, to test the efficacy of HBI-8000 in monotherapy or in combination settings in leukemias and in solid tumors. The current review is focused on the applications of HDACi HBI-8000 in cancer therapy and its potential in combination with DDR agents.

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