Comparative Toxicity Assessment of Kratom Decoction, Mitragynine and Speciociliatine Versus Morphine on Zebrafish (Danio rerio) Embryos

Background: Kratom (Mitragyna speciosa Korth), a popular opioid-like plant holds its therapeutic potential in pain management and opioid dependence. However, there are growing concerns about the safety or potential toxicity risk of kratom after prolonged use.Aim of the study: The study aimed to assess the possible toxic effects of kratom decoction and its major alkaloids, mitragynine, and speciociliatine in comparison to morphine in an embryonic zebrafish model.Methods: The zebrafish embryos were exposed to kratom decoction (1,000–62.5 μg/ml), mitragynine, speciociliatine, and morphine (100–3.125 μg/ml) for 96 h post-fertilization (hpf). The toxicity parameters, namely mortality, hatching rate, heart rate, and morphological malformations were examined at 24, 48, 72, and 96 hpf, respectively.Results: Kratom decoction at a concentration range of ≥500 μg/ml caused 100% mortality of zebrafish embryos and decreased the hatching rate in a concentration-dependent manner. Meanwhile, mitragynine and speciociliatine exposure resulted in 100% mortality of zebrafish embryos at 100 μg/ml. Both alkaloids caused significant alterations in the morphological development of zebrafish embryos including hatching inhibition and spinal curvature (scoliosis) at the highest concentration. While exposure to morphine induced significant morphological malformations such as pericardial oedema, spinal curvature (lordosis), and yolk edema in zebrafish embryos.Conclusion: Our findings provide evidence for embryonic developmental toxicity of kratom decoction and its alkaloids both mitragynine and speciociliatine at the highest concentration, hence suggesting that kratom consumption may have potential teratogenicity risk during pregnancy and thereby warrants further investigations.

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Exposure to the natural alkaloid Berberine affects cardiovascular system morphogenesis and functionality during zebrafish development

Scientific Reports ◽

10.1038/s41598-020-73661-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Davide Martini ◽

Cecilia Pucci ◽

Chiara Gabellini ◽

Mario Pellegrino ◽

Massimiliano Andreazzoli

Keyword(s):

Cardiovascular System ◽

Therapeutic Potential ◽

System Development ◽

Developmental Toxicity ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Pericardial Edema ◽

Pregnancy And Lactation ◽

Cardiovascular Defects ◽

Natural Alkaloid

Abstract The plant-derived natural alkaloid berberine displays therapeutic potential to treat several pathological conditions, including dyslipidemias, diabetes and cardiovascular disorders. However, data on berberine effects during embryonic development are scarce and in part controversial. In this study, using zebrafish embryos as vertebrate experimental model, we address the effects of berberine treatment on cardiovascular system development and functionality. Starting from the observation that berberine induces developmental toxicity and pericardial edema in a time- and concentration-dependent manner, we found that treated embryos display cardiac looping defects and, at later stages, present an abnormal heart characterized by a stretched morphology and atrial endocardial/myocardial detachment. Furthermore, berberine affected cardiac functionality of the embryos, promoting bradycardia and reducing the cardiac output, the atrial shortening fraction percentage and the atrial stroke volume. We also found that, during development, berberine interferes with the angiogenic process, without altering vascular permeability. These alterations are associated with increased levels of vascular endothelial growth factor aa (vegfaa) mRNA, suggesting an important role for Vegfaa as mediator of berberine-induced cardiovascular defects. Altogether, these data indicate that berberine treatment during vertebrate development leads to an impairment of cardiovascular system morphogenesis and functionality, suggesting a note of caution in its use during pregnancy and lactation.

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Toxicity assessment of precise engineered gold nanoparticles with different shapes in zebrafish embryos

RSC Advances ◽

10.1039/c6ra00632a ◽

2016 ◽

Vol 6 (39) ◽

pp. 33009-33013 ◽

Cited By ~ 11

Author(s):

Zhenjie Wang ◽

Dan Xie ◽

Hongzhuo Liu ◽

Zhihong Bao ◽

Yongjun Wang

Keyword(s):

Gold Nanoparticles ◽

Developmental Toxicity ◽

Toxicity Assessment ◽

Zebrafish Embryos ◽

Zebrafish Model ◽

Different Shapes

The developmental toxicity of gold nanoparticles with different shape in a zebrafish model was investigated and compared.

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Toxicity Assessment of 4 Azo Dyes in Zebrafish Embryos

International Journal of Toxicology ◽

10.1177/1091581819898396 ◽

2020 ◽

Vol 39 (2) ◽

pp. 115-123 ◽

Cited By ~ 3

Author(s):

Ling-Ling Jiang ◽

Kang Li ◽

Dong-Lin Yan ◽

Mi-Fang Yang ◽

Lan Ma ◽

...

Keyword(s):

Azo Dyes ◽

Azo Dye ◽

Developmental Toxicity ◽

Toxicity Assessment ◽

Spinal Curvature ◽

Zebrafish Embryos ◽

Sunset Yellow ◽

Developmental Abnormalities ◽

Allura Red ◽

Median Effective Concentration

Azo dyes are used widely as color additives in food, drugs, and cosmetics; hence, there is an increasing concern about their safety and possible health hazards. In the present study, we chose 4 azo dyes tartrazine, Sunset Yellow, amaranth, and Allura red and evaluated their developmental toxicity on zebrafish embryos. At concentration levels of 5 to 50 mM, we found that azo dyes can induce hatching difficulty and developmental abnormalities such as cardiac edema, decreased heart rate, yolk sac edema, and spinal defects including spinal curvature and tail distortion. Exposure to 100 mM of each azo dye was completely embryolethal. The median lethal concentration (LC50), median effective concentration (EC50), and teratogenic index (TI) were calculated for each azo dye at 72 hours postfertilization. For tartrazine, the LC50 was 47.10 mM and EC50 value was at 42.66 mM with TI ratio of 1.10. For Sunset Yellow, the LC50 was 38.93 mM and EC50 value was at 29.81 mM with TI ratio of 1.31. For amaranth, the LC50 was 39.86 mM and EC50 value was at 31.94 mM with TI ratio of 1.25. For Allura red, the LC50 was 47.42 mM and EC50 value was 40.05 mM with TI ratio of 1.18. This study reports the developmental toxicity of azo dyes in zebrafish embryos at concentrations higher than the expected human exposures from consuming food and drugs containing azo dyes.

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Oxygen modulates the differentiation of human fetal lung in vitro and its responsiveness to cAMP

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1993.264.5.l465 ◽

1993 ◽

Vol 264 (5) ◽

pp. L465-L474 ◽

Cited By ~ 13

Author(s):

M. J. Acarregui ◽

J. M. Snyder ◽

C. R. Mendelson

Keyword(s):

Gene Expression ◽

Atmospheric Oxygen ◽

Protein A ◽

Morphological Differentiation ◽

Fetal Lung ◽

Morphological Development ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Human Fetal Lung

Previously, it was found that lung explants from mid-trimester human abortuses differentiate spontaneously in organ culture in serum-free defined medium in an atmosphere of 95% air-5% CO2. Dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) treatment of human fetal lung in culture increases the rate of morphological differentiation and enhances expression of the surfactant protein A (SP-A) gene. To begin to define the factors responsible for this accelerated in vitro differentiation, we analyzed the effects of atmospheric oxygen on the morphological and biochemical development of human fetal lung in culture and on responsiveness of the cultured tissue to DBcAMP. We found that when lung explants were maintained in an atmosphere containing 1% oxygen they failed to differentiate spontaneously and no induction of SP-A gene expression was apparent. Furthermore, at 1% oxygen, DBcAMP had no effect to stimulate morphological differentiation or SP-A gene expression. When lung tissues that had been maintained for 5 days in 1% oxygen were transferred to an environment containing 20% oxygen, there was rapid morphological development and induction of SP-A gene expression. The effects on morphological development were manifest within 24 h of transfer to the 20% oxygen environment; within 72 h, a marked stimulatory effect of DBcAMP on SP-A gene expression also was observed. Our findings further suggest that the effects of oxygen on the levels of SP-A and SP-A mRNA are concentration dependent. Interestingly, the inductive effects of DBcAMP on SP-A gene expression were apparent only at oxygen concentrations > or = 10%. Morphological differentiation of the cultured human fetal lung tissue also was influenced by oxygen in a concentration-dependent manner. These findings suggest that oxygen plays an important permissive role in the spontaneous differentiation of human fetal lung in vitro.

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Developmental Toxicity of Carbon Quantum Dots to the Embryos/Larvae of Rare Minnow (Gobiocypris rarus)

BioMed Research International ◽

10.1155/2016/4016402 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Yuan-Yuan Xiao ◽

Li Liu ◽

Yao Chen ◽

Yu-Lian Zeng ◽

Ming-Zhi Liu ◽

...

Keyword(s):

Developmental Stages ◽

Developmental Toxicity ◽

Carbon Quantum Dots ◽

Spinal Curvature ◽

Hatching Rate ◽

Gobiocypris Rarus ◽

Spontaneous Movements ◽

Rare Minnow ◽

Pericardial Edema ◽

Cellular Dna

The toxic effects of CDs on rare minnow (Gobiocypris rarus) embryos at different developmental stages were investigated. The results showed that rare minnow embryos had decreased spontaneous movements, body length, increased heart rate, pericardial edema, yolk sac edema, tail/spinal curvature, various morphological malformations, and decreased hatching rate. Biochemical analysis showed the CDs exposure significantly inhibited the activity of Na+/K+-ATPase and Ca2+-ATPase and increased the MDA contents and the activity of SOD, CAT, and GPX. Further examination suggested that the CDs exposure induced serious embryonic cellular DNA damage. Moreover, the CDs exposure induced upregulation of development related genes (Wnt8aandMstn) along with the downregulation ofVezf1. Overall, the present study revealed that the CDs exposure has significant development toxicity on rare minnow embryos/larvae. Mechanistically, this toxicity might result from the pressure of induced oxidative stress coordinate with the dysregulated development related gene expression mediated by the CDs exposure.

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Methanol Extract ofArtemisia apiaceaHance Attenuates the Expression of Inflammatory Mediators via NF-κB Inactivation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/494681 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 9

Author(s):

Ji Choul Ryu ◽

Sang Mi Park ◽

Min Hwangbo ◽

Sung Hui Byun ◽

Sae Kwang Ku ◽

...

Keyword(s):

Nitric Oxide ◽

Therapeutic Potential ◽

Interleukin 1 ◽

Dependent Manner ◽

Nuclear Factor ◽

Paw Edema ◽

Concentration Dependent Manner ◽

Proinflammatory Mediators ◽

Inducible Nitric Oxide

Artemisia apiaceaHance is one of the most widely used herbs for the treatment of malaria, jaundice, and dyspeptic complaint in oriental medicine. This study investigated the effects of methanol extracts ofA. apiaceaHance (MEAH) on the induction of inducible nitric oxide synthase (iNOS) and proinflammatory mediators by lipopolysaccharide (LPS) in Raw264.7 macrophage cells and also evaluated thein vivoeffect of MEAH on carrageenan-induced paw edema in rats. MEAH treatment in Raw264.7 cells significantly decreased LPS-inducible nitric oxide production and the expression of iNOS in a concentration-dependent manner, while MEAH (up to 100 μg/mL) had no cytotoxic activity. Results from immunoblot analyses and ELISA revealed that MEAH significantly inhibited the expression of cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in LPS-activated cells. As a plausible molecular mechanism, increased degradation and phosphorylation of inhibitory-κBαand nuclear factor-κB accumulation in the nucleus by LPS were partly blocked by MEAH treatment. Finally, MEAH treatment decreased the carrageenan-induced formation of paw edema and infiltration of inflammatory cells in rats. These results demonstrate that MEAH has an anti-inflammatory therapeutic potential that may result from the inhibition of nuclear factor-κB activation, subsequently decreasing the expression of proinflammatory mediators.

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Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exhibit single agent therapeutic activity and sensitize glioblastoma cells to ionizing radiation

Neuro-Oncology ◽

10.1093/neuonc/noz167.049 ◽

2019 ◽

Vol 21 (Supplement_4) ◽

pp. iv12-iv12

Author(s):

Mark Jackson ◽

Natividad Gomez-Roman ◽

Anthony Chalmers

Keyword(s):

Ionizing Radiation ◽

Therapeutic Potential ◽

Parp Inhibitor ◽

Single Agent ◽

Unmet Need ◽

Clonogenic Survival ◽

Dependent Manner ◽

Therapeutic Activity ◽

Intrinsic Resistance ◽

Concentration Dependent Manner

Abstract Objective The lack of an effective therapy for glioblastoma (GBM) largely results from the intrinsic resistance of GBM cells. The radiosensitizing activity of inhibitors of poly(ADP-ribose) polymerases (PARPs) highlights the important role of poly(ADP-ribose) (PAR) in the DNA damage response. In contrast to PARPs, inhibition of poly(ADP-ribose) glycohydrolase (PARG), the enzyme responsible for degrading PAR chains, has shown single agent therapeutic activity in non-glioma cancer cells. This work aims to validate the therapeutic potential of PARG inhibitors (PARGi) in GBM. Results Baseline PAR levels were found to vary between different primary and commercial GBM cells, with PARylation increasing upon exposure of cells to ionizing radiation (IR), as expected. Target engagement of a novel PARGi, PDD00017273, was confirmed by the accumulation of nuclear PAR in treated cells. Inhibitor specificity was demonstrated using an inactive control compound and by combining PARGi with the PARP inhibitor olaparib, which blocked the effect. Single agent treatment with PARGi reduced the clonogenic survival of GBM cells in a concentration-dependent manner. Importantly, PARGi also sensitized GBM cells to IR (sensitizer enhancement ratios, SER, ≥ 1.40) Conclusion In contrast to PARP inhibitors, novel PARGi exhibit single agent activity against a panel of GBM cell lines, and also show robust radiosensitizing activity. PARGi therefore have therapeutic potential in this cancer of unmet need.

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An approach to evaluating the potential teratogenic and neurotoxic mechanism of BHA based on apoptosis induced by oxidative stress in zebrafish embryo (Danio rerio)

Human & Experimental Toxicology ◽

10.1177/0960327120952140 ◽

2020 ◽

pp. 096032712095214

Author(s):

A Baran ◽

S Yildirim ◽

A Ghosigharehaghaji ◽

İ Bolat ◽

E Sulukan ◽

...

Keyword(s):

Oxidative Dna Damage ◽

Cellular Level ◽

Whole Body ◽

Hatching Rate ◽

Hydroxyl Groups ◽

Zebrafish Embryos ◽

Dependent Manner ◽

Zebrafish Larvae ◽

Induced Apoptosis ◽

The Brain

Butylated hydroxyanisole (BHA) has been widely used in the cosmetics, pharmaceutical, and food industries due to its antioxidant activity. Despite the antioxidant effects, reported adverse effects of BHA at the cellular level have made its use controversial. In this regard, this study was performed to elucidate the potential toxicity mechanism caused by BHA at the molecular level in zebrafish embryos. For this purpose, zebrafish embryos were exposed to BHA at levels of 0.5, 1, 5, 7.5 and 10 ppm and monitored at 24, 48, 72 and 96 hours. Survival rate, hatching rate and malformations were evaluated. We examined the potential for reactive oxygen species (ROS) production and apoptosis signalling accumulation in the whole body. Moreover, we evaluated histopathological and immunohistochemical (8-OHDG) characterization of the brain in zebrafish embryos at the 96th hour. We also examined apoptosis, histopathological and immunohistochemical (8-OHDG) characteristics in 96 hpf zebrafish larvae exposed to tertiary butylhydroquinone (TBHQ), one of the major metabolites of BHA, at doses of 0.5, 2.5, 3.75 and 5 ppm. Consequently, it has been considered that increased embryonic and larval malformations in this study may have been caused by ROS-induced apoptosis. After 96 h of exposure, positive 8-OHdG immunofluorescence, degenerative changes, and necrosis were observed in the brain of BHA and TBHQ-treated zebrafish larvae in a dose-dependent manner. BHA and TBHQ exposure could lead to an increase in 8-OHdG activities by resulting oxidative DNA damage. In particular, the obtained data indicate that the induction of ROS formation, occurring during exposure to BHA and/or multiple hydroxyl groups, could be responsible for apoptosis.

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Anti-Inflammatory and Neuroprotective Effects of Constituents Isolated fromRhodiola rosea

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/514049 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Yeonju Lee ◽

Jae-Chul Jung ◽

Soyong Jang ◽

Jieun Kim ◽

Zulfiqar Ali ◽

...

Keyword(s):

Biological Activity ◽

Crude Extract ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Rhodiola Rosea ◽

Dependent Manner ◽

Neuroprotective Effects ◽

Concentration Dependent Manner ◽

Bv2 Cells ◽

Proinflammatory Factors

To determine the biological activity ofRhodiola rosea, the protein expression of iNOS and proinflammatory cytokines was measured after the activation of murine microglial BV2 cells by LPS under the exposure of constituents ofRhodiola rosea: crude extract, rosin, rosarin, and salidroside (each 1–50 μg/mL). The LPS-induced expression of iNOS and cytokines in BV2 cells was suppressed by the constituents ofRhodiola roseain a concentration-dependent manner. Also the expression of the proinflammatory factors iNOS, IL-1β, and TNF-αin the kidney and prefrontal cortex of brain in mice was suppressed by the oral administration ofRhodiola roseacrude extract (500 mg/kg). To determine the neuroprotective effect of constituents ofRhodiola rosea, neuronal cells were activated by L-glutamate, and neurotoxicity was analyzed. The L-glutamate-induced neurotoxicity was suppressed by the treatment with rosin but not by rosarin. The level of phosphorylated MAPK, pJNK, and pp38 was increased by L-glutamate treatment but decreased by the treatment with rosin and salidroside. These results indicate thatRhodiola roseamay have therapeutic potential for the treatment of inflammation and neurodegenerative disease.

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Antiadipogenic Effects ofAster glehniExtract: In Vivo and In Vitro Effects

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/859624 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Heon-Myung Lee ◽

Gabsik Yang ◽

Tae-Gue Ahn ◽

Myung-Dong Kim ◽

Agung Nugroho ◽

...

Keyword(s):

Therapeutic Potential ◽

Control Diet ◽

Epididymal Adipose Tissue ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Master Regulators ◽

In Vitro Effects

Aster glehni(AG) is a Korean traditional herb that grows in Ulleungdo Island, Republic of Korea. None of the several reports on AG include a determination of the effect of AG on adipogenesis. The primary aim of this study was to determine whether AG attenuates adipogenesis in mouse 3T3-L1 cells and epididymal fat tissue. AG blocked the differentiation of 3T3-L1 preadipocytes in a concentration-dependent manner and suppressed the expression of adipogenesis-related genes such asPPARγ,C/EBPα, andSREBP1c, the master regulators of adipogenesis. Male C57BL/6J mice were divided randomly and equally into 4 diet groups: control diet (CON), high-fat diet (HFD), HFD with 1% AG extract added (AG1), and HFD with 5% AG extract added (AG5). The experimental animals were fed HFD and the 2 combinations for 10 weeks. Mice fed HFD with AG gained less body weight and visceral fat-pad weight than did the mice fed HFD alone. Moreover, AG inhibited the expression of important adipogenic genes such asPPARγ,C/EBPα,SREBP1c,LXR, and leptin in the epididymal adipose tissue of the mice treated with AG1 and AG5. These findings indicate antiadipogenic and antiobesity effects of AG and suggest its therapeutic potential in obesity and obesity-related diseases.

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