Effects associated with exposure to the emerging contaminant octyl-methoxycinnamate (a UV-B filter) in the aquatic environment: a review.

Given the increasing concern surrounding ultraviolet (UV) radiation-induced skin damage, there has been a rise in demand for UV filters. Currently, UV-filters are considered emerging contaminants. The extensive production and use of UV filters have led to their widespread release into the aquatic environment. Thus, there is growing concern that UV filters may bioaccumulate and exhibit persistent properties within the environment, raising several safety health concerns. Octyl-methoxycinnamate (OMC) is extensively employed as a UV-B filter in the cosmetic industry. While initially designed to mitigate the adverse photobiological effects attributed to UV radiation, the safety of OMC has been questioned with some studies reporting toxic effects on environment. The aim of this review to provide an overview of the scientific information regarding the most widely used organic UV-filter (OMC), and its effects on biodiversity and aquatic environment.

Post-fertilization 2-ethylhexyl-4-methoxycinnamate (EHMC) exposure affects axonal growth, muscle fiber length, and motor behavior in zebrafish embryos.

Organic UV filters, which are often found in the environment, have been the focus of much public health concern. 2-ethylhexyl-4-methoxycinnamate (EHMC) is one of the most common organic UV filters present in the environment. However, few studies have investigated its developmental neurotoxic (DNT) effects and the underlying molecular mechanisms. In the present study, zebrafish embryos were exposed to low concentration of EHMC (0, 0.01, 0.1, 1 mg/L) in static water starting from 6 h post-fertilization (hpf). Results showed that EHMC exposure caused a reduction in somite count at 13 hpf, a diminishment in head-trunk angle at 30 hpf, a delay in hatching at 48 hpf, and a decrease in head depth and head length at both 30 and 48 hpf. Additionally, EHMC led to abnormal motor behaviors at various developmental stages including altered spontaneous movement at both 23 and 24 hpf, and decreased touch response at 30 hpf. Consistent with these morphological changes and motor behavior deficits, EHMC inhibited axonal growth of primary motor neurons at 30 and 48 hpf, and yielded subtle changes in muscle fiber length at 48 hpf, suggesting the functional relevance of structural changes. Moreover, EHMC exposure induced excessive cell apoptosis in the head and spinal cord regions, increased the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and reduced the level of glutathione (GSH). Defects of lateral line system neuromasts were also observed, but no structural deformity of blood vessels was seen in developing zebrafish. Abnormal expression of axonal growth-related genes (gap43, mbp, shha, and α1-tubulin) and apoptosis-related genes (bax/bcl-2 and caspase-3) revealed potential molecular mechanisms regarding the defective motor behaviors and aberrant phenotype. In summary, our findings indicate that EHMC induced developmental neurotoxicity in zebrafish, making it essential to assess its risks and provide warnings regarding EHMC exposure.

Ethylhexyl methoxycinnamate and butyl methoxydibenzoylmethane: Toxicological effects on marine biota and human concerns.

Ethylhexyl methoxycinnamate (EHMC) (CAS number: 5466-77-3) and butyl methoxydibenzoylmethane (BMDM) (CAS number: 70356-09-1) are important sunscreens. However, frequent application of large amounts of these compounds may reflect serious environmental impact, once it enters the environment through indirect release via wastewater treatment or immediate release during water activities. In this article, we reviewed the toxicological effects of EHMC and BMDM on aquatic ecosystems and the human consequences. According to the literature, EHMC and BMDM have been detected in water samples and sediments worldwide. Consequently, these compounds are also present in several marine organisms like fish, invertebrates, coral reefs, marine mammals, and other species, due to its bioaccumulation potential. Studies show that these chemicals are capable of damaging the aquatic beings in different ways. Further, bioaccumulation studies have shown that EHMC biomagnifies through trophic levels, which makes human seafood consumption a concern because the higher position in the trophic chain, the more elevate levels of ultraviolet (UV) filters are detected, and it is established that EHMC present adverse effects on the human organism. In contrast, there are no studies on the BMDM bioaccumulation and biomagnification potential. Different strategies can be adopted to avoid the damage caused by sunscreens in the environment and human organism. Two of them include the use of natural photoprotectors, such as polyphenols, in association with UV filters in sunscreens and the development of new and safer UV filters. Overall, this review shows the importance of studying the impacts of sunscreens in nature and developing safer sunscreens and formulations to safeguard marine fauna, ecosystems, and humans.

Suppression of inflammatory cascades via novel cinnamic acid nanoparticles in acute hepatitis rat model.

Hepatitis was characterized by extreme inflammation and hepatocellular damage. Therefore, the current study aimed to gain insights into the modulation role of Cinnamic acid nanoparticles (CANPs) against acute hepatitis induced by d-Galactosamine and gamma radiation exposure (D-Gal/radiation) in the rat model and to suggest the implied molecular mechanism of CANPs. Acute hepatitis seriousness and the serum enzyme activities of ALT, AST, and ALP have been diminished upon oral administration of CANPs. Besides, the hepatic tissue levels of malondialdehyde (MDA) and nitric oxide (NO) have been significantly decreased, and the total antioxidant activity (TAO) depletion was extremely restored. Furthermore, the reduction of hepatic damage caused by pretreatment with CANPs was accompanied by significant suppression in the levels of hepatic proinflammatory cytokines (TNF-α, IL-1ß, and IL-18), NF-κB, NLRP3, caspase-1 and proapoptotic protein BAX whereas anti-apoptotic protein Bcl-2 level significantly elevated as compared with D-Gal/radiation-induced acute hepatitis (AH) group. Also, CANPs suppress the D-Gal/radiation-induced IL-1ß, IL-18, and ASK1 mRNA gene expression and the protein expression of TLR4 and MyD88 in the hepatic tissue. These biochemical parameters are confirmed by histological examination of the liver tissues. The present results indicated that CANPs can protect the hepatic cells from damage by both its anti-inflammatory and antioxidant influence as well as by modulating oxidation cellular pathways that have contributed to the acute severity of hepatitis. Also, CANPs is capable of suppressing apoptosis. Consequently, Nanoparticles of Cinnamic acid have the medicinal ability to protect the liver from acute hepatitis.

Antioxidant, anti-tyrosinase and anti-melanogenic effects of (E)-2,3-diphenylacrylic acid derivatives.

During our continued search for strong skin whitening agents over the past ten years, we have investigated the efficacies of many tyrosinase inhibitors containing a common (E)-ß-phenyl-α,ß-unsaturated carbonyl scaffold, which we found to be essential for the effective inhibition of mushroom and mammalian tyrosinases. In this study, we explored the tyrosinase inhibitory effects of 2,3-diphenylacrylic acid (2,3-DPA) derivatives, which also possess the (E)-ß-phenyl-α,ß-unsaturated carbonyl motif. We synthesized fourteen (E)-2,3-DPA derivatives 1a-1n and one (Z)-2,3-DPA-derivative 1l' using a Perkin reaction with phenylacetic acid and appropriate substituted benzaldehydes. In our mushroom tyrosinase assay, 1c showed higher tyrosinase inhibitory activity (76.43 ±â€¯3.53%, IC50 = 20.04 ±â€¯1.91 µM) with than the other 2,3-DPA derivatives or kojic acid (21.56 ±â€¯2.93%, IC50 = 30.64 ±â€¯1.27 µM). Our mushroom tyrosinase inhibitory results were supported by our docking study, which showed compound 1c (-7.2 kcal/mole) exhibited stronger binding affinity for mushroom tyrosinase than kojic acid (-5.7 kcal/mole). In B16F10 melanoma cells (a murine cell-line), 1c showed no cytotoxic effect up to a concentration of 25 µM and exhibited greater tyrosinase inhibitory activity (68.83%) than kojic acid (49.39%). In these cells, arbutin (a well-known tyrosinase inhibitor used as the positive control) only inhibited tyrosinase by 42.67% even at a concentration of 400 µM. Furthermore, at 25 µM, 1c reduced melanin contents in B16F10 melanoma cells by 24.3% more than kojic acid (62.77% vs. 38.52%). These results indicate 1c is a promising candidate treatment for pigmentation-related diseases and potential skin whitening agents.

Sunscreen bans: Coral reefs and skin cancer.

WHAT IS KNOWN AND OBJECTIVE: Hawaii will ban two major ingredients of sunscreens. This article reviews the reasons and future directions. Hawaii recently enacted legislation that will ban the use of two major ingredients of the majority of commonly used sunscreens. The reason for the ban is the ingredients' putative deleterious impact on marine ecosystems, particularly coral reefs. But sunscreens also save lives by decreasing the risk of UV-induced skin cancers. We review both sides of the issue and potential implications for the healthcare system. COMMENT: Coral reefs consist of organisms in delicate equilibria that are susceptible to small changes in their surroundings. Recent natural and man-made disruptions, direct or indirect, such as changes in ocean temperature and chemistry, ingress of invasive species, pathogens, pollution and deleterious fishing practices, have been blamed for the poor health, or even the outright destruction, of some coral reefs. The most popular sunscreen products contain two ingredients-oxybenzone and octinoxate-that have also been implicated in coral toxicity and will be banned. This creates a healthcare dilemma: Will the protection of coral reefs result in an increase in human skin cancers? WHAT IS NEW AND CONCLUSION: Concentration estimates and mechanism studies support an association-direct or indirect (via promotion of viral infection)-of sunscreens with bleaching of coral reefs. A ban on the two most common sunscreen ingredients goes into effect in Hawaii on January 1, 2021. Proponents suggest that this is a trend, just the first of many such bans worldwide; opponents warn of a dire increase in human skin cancers. As a result, alternative sunscreen compounds are being sought.

The application of the improved 3D rat testicular cells co-culture model on the in vitro toxicity research of HZ1006.

The aims of the present research are to further validate the application of the improved three-dimensional (3 D) rat testicular cell co-culture model to evaluate the effects of various reprotoxic chemicals on the function of the main somatic cells, as well as on spermatogonial cell differentiation and even spermatogenesis, and to investigate the specific toxicant mechanisms in testes treated with HZ1006, a hydroxamate-based a hydroxamate-based histone deacetylase inhibitor (HDACI). Based on the characteristics of HZ1006, the appropriate exposure duration (8, 16, or 24 days), dosage (0, 3.125, 6.25, 12.5, or 25 µM) and toxic endpoints suitable for detection were selected in the experiments. The results showed inhibition of cell proliferation, reduced testosterone levels, and decreased spermatogonial cell meiosis-specific gene expression, as well as decreased protein levels of androgen receptor (AR) and decreased expression of the AR target gene PSA, accompanied by inhibition of Hdac6 expression after HZ1006 exposure in the 3 D rat testicular cell co-culture model. These findings indicate that the improved 3 D rat testicular cell co-culture model we have established has the potential to become a new testicular toxicity test system that can be used to test toxic characteristics and mechanisms of new compounds and has good application prospects, although more research on the model is required.

Design, synthesis and anti-melanogenic effect of cinnamamide derivatives.

Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-ß-phenyl-α,ß-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 µM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4, 9, and 10, bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-ß-phenyl-α,ß-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents.

Quinazolinone derivatives as inhibitors of homologous recombinase RAD51.

RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation. Additionally, compound 17 significantly inhibits TNBC cell sensitivity to DNA damage, implying a potentially targeted therapy for cancer treatment.

Safety assessment and toxicological profiling of a novel combinational sunprotective dermal formulation containing melatonin and pumpkin seed oil.

Ultraviolet (UV) radiation exposure has been known to cause irreparable damages to human skin. The daunting risk of UV radiation exposure faced by military personnel led to the development of a sunscreen formulation which has superior sun protection factor combined with the ability to counteract reactive oxygen species. The present work deals with the preclinical safety evaluation of the sunscreen formulation comprising of four US FDA approved UV filters; namely avobenzone, octinoxate, oxybenzone, titanium dioxide along with melatonin and pumpkin seed oil, via OECD protocols of assessing acute oral and dermal toxicity; skin sensitizing; skin irritating; ocular irritating and genotoxic potential. Both oral and dermal LD50 values were found to be ˃2000 mg/kg body weight in adult Wistar albino rats using acute dermal and oral toxicity tests. The sunscreen formulation was found to be non-sensitizing to the skin of guinea pigs and non-irritating to both skin and eyes of rabbits. The sunscreen formulation was also found to be non-mutagenic which was affirmed by a battery of genotoxicity and muagenicity assays. The results obtained from this preclinical study indicated that the sunscreen formulation is non toxic and safe in animal models. This study along with additional preclinical evaluations may serve as a basis for considering the formulation as a potential candidate for further trials to establish its efficacy, tolerability and applicability.

Single- and mixture toxicity of three organic UV-filters, ethylhexyl methoxycinnamate, octocrylene, and avobenzone on Daphnia magna.

In freshwater environments, aquatic organisms are generally exposed to mixtures of various chemical substances. In this study, we tested the toxicity of three organic UV-filters (ethylhexyl methoxycinnamate, octocrylene, and avobenzone) to Daphnia magna in order to evaluate the combined toxicity of these substances when in they occur in a mixture. The values of effective concentrations (ECx) for each UV-filter were calculated by concentration-response curves; concentration-combinations of three different UV-filters in a mixture were determined by the fraction of components based on EC25 values predicted by concentration addition (CA) model. The interaction between the UV-filters were also assessed by model deviation ratio (MDR) using observed and predicted toxicity values obtained from mixture-exposure tests and CA model. The results from this study indicated that observed ECxmix (e.g., EC10mix, EC25mix, or EC50mix) values obtained from mixture-exposure tests were higher than predicted ECxmix (e.g., EC10mix, EC25mix, or EC50mix) values calculated by CA model. MDR values were also less than a factor of 1.0 in a mixtures of three different UV-filters. Based on these results, we suggest for the first time a reduction of toxic effects in the mixtures of three UV-filters, caused by antagonistic action of the components. Our findings from this study will provide important information for hazard or risk assessment of organic UV-filters, when they existed together in the aquatic environment. To better understand the mixture toxicity and the interaction of components in a mixture, further studies for various combinations of mixture components are also required.

Evaluation of larvicidal activity and ecotoxicity of linalool, methyl cinnamate and methyl cinnamate/linalool in combination against Aedes aegypti.

The frequent use of synthetic pesticides to control Aedes aegypti population can lead to environmental and/or human contamination and the emergence of resistant insects. Linalool and methyl cinnamate are presented as an alternative to the synthetic pesticides, since they can exhibit larvicidal, repellent and/or insecticidal activity and are considered safe for use. The aim of this study was to evaluate the larvicidal activity of methyl cinnamate, linalool and methyl cinnamate/linalool in combination (MC-L) (1:4 ratio, respectively) against Aedes aegypti. The in vitro preliminary toxicity through brine shrimp lethality assay and hemolytic activity, and the phytotoxic potential were also investigated to assess the safety of their use as larvicide. Methyl cinnamate showed significant larvicidal activity when compared to linalool (LC50 values of 35.4µg/mL and 275.2µg/mL, respectively) and to MC-L (LC50 138.0µg/mL). Larvae morphological changes subjected to the specified treatments were observed, as the flooding of tracheal system and midgut damage, hindering the larval development and survival. Preliminary in vitro toxicity through brine shrimp showed the high bioactivity of the substances (methyl cinnamate LC50 35.5µg/mL; linalool LC50 96.1µg/mL) and the mixture (MC-L LC50 57.7µg/mL). The results showed that, despite the higher larvicidal activity of methyl cinnamate, the use of MC-L as a larvicide seems to be more appropriate due to its significant larvicidal activity and low toxicity.

Use of in vitro assays to assess the potential cytotoxic, genotoxic and antigenotoxic effects of vanillic and cinnamic acid.

Vanillic acid (VA) found in vanilla and cinnamic acid (CA) the precursor of flavonoids and found in cinnamon oil, are natural plant phenolic acids which are secondary aromatic plant products suggested to possess many physiological and pharmacological functions. In vitro and in vivo experiments have shown that phenolic acids exhibit powerful effects on biological responses by scavenging free radicals and eliciting antioxidant capacity. In the present study, we investigated the antioxidant capacity of VA and CA by the trolox equivalent antioxidant capacity (TEAC) assay, cytotoxicity by neutral red uptake (NRU) assay in Chinese Hamster Ovary (CHO) cells and also the genotoxic and antigenotoxic effects of these phenolic acids using the cytokinesis-blocked micronucleus (CBMN) and the alkaline comet assays in human peripheral blood lymphocytes. At all tested concentrations, VA (0.17-67.2 µg/ml) showed antioxidant activity but CA (0.15-59.2 µg/ml) did not show antioxidant activity against 2,2-azino-bis (3-ethylbenz-thiazoline-6-sulphonic acid) (ABTS). VA (0.84, 4.2, 8.4, 16.8, 84 and 168 µg/ml) and CA (0.74, 3.7, 7.4, 14.8, 74, 148 µg/ml) did not have cytotoxic and genotoxic effects alone at the studied concentrations as compared with the controls. Both VA and CA seem to decrease DNA damage induced by H2O2 in human lymphocytes.

New probabilistic risk assessment of ethylhexyl methoxycinnamate: Comparing the genotoxic effects of trans- and cis-EHMC.

Ethylhexyl methoxycinnamate (EHMC) is a widely used UV filter present in a large number of personal care products (PCPs). Under normal conditions, EHMC occurs in a mixture of two isomers: trans-EHMC and cis-EHMC in a ratio of 99:1. When exposed to sunlight, the trans isomer is transformed to the less stable cis isomer and the efficiency of the UV filter is reduced. To date, the toxicological effects of the cis-EHMC isomer remain largely unknown. We developed a completely new method for preparing cis-EHMC. An EHMC technical mixture was irradiated using a UV lamp and 98% pure cis-EHMC was isolated from the irradiated solution using column chromatography. The genotoxic effects of the isolated cis-EHMC isomer and the nonirradiated trans-EHMC were subsequently measured using two bioassays (SOS chromotest and UmuC test). In the case of trans-EHMC, significant genotoxicity was observed using both bioassays at the highest concentrations (0.5 - 4 mg mL-1 ). In the case of cis-EHMC, significant genotoxicity was only detected using the UmuC test at concentrations of 0.25 - 1 mg mL-1 . Based on these results, the NOEC was calculated for both cis- and trans-EHMC, 0.038 and 0.064 mg mL-1 , respectively. Risk assessment of dermal, oral and inhalation exposure to PCPs containing EHMC was carried out for a female population using probabilistic simulation and by using Quantitative in vitro to in vivo extrapolation (QIVIVE). The risk of cis-EHMC was found to be ∼1.7 times greater than trans-EHMC. In the case of cis-EHMC, a hazard index of 1 was exceeded in the 92nd percentile. Based on the observed differences between the isomers, EHMC application in PCPs requires detailed reassessment. Further exploration of the toxicological effects and properties of cis-EHMC is needed in order to correctly predict risks posed to humans and the environment. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 569-580, 2017.

Toxicity of Plant Secondary Metabolites Modulating Detoxification Genes Expression for Natural Red Palm Weevil Pesticide Development.

This study aimed to explore the larvicidal and growth-inhibiting activities, and underlying detoxification mechanism of red palm weevil against phenylpropanoids, an important class of plant secondary metabolites. Toxicity of α-asarone, eugenol, isoeugenol, methyl eugenol, methyl isoeugenol, coumarin, coumarin 6, coniferyl aldehyde, diniconazole, ethyl cinnamate, and rosmarinic acid was evaluated by incorporation into the artificial diet. All of the phenylpropanoids exhibited dose- and time-dependent insecticidal activity. Among all the tested phenylpropanoids, coumarin exhibited the highest toxicity by revealing the least LD50 value (0.672 g/L). In addition, the most toxic compound (coumarin) observed in the current study, deteriorated the growth resulting tremendous reduction (78.39%) in efficacy of conversion of digested food (ECD), and (ECI) efficacy of conversion of ingested food (70.04%) of tenth-instar red palm weevil larvae. The energy-deficient red palm weevil larvae through their intrinsic abilities showed enhanced response to their digestibility resulting 27.78% increase in approximate digestibility (AD) compared to control larvae. The detoxification response of Rhynchophorus ferrugineus larvae determined by the quantitative expression of cytochrome P450, esterases, and glutathione S-transferase revealed enhanced expression among moderately toxic and ineffective compounds. These genes especially cytochrome P450 and GST detoxify the target compounds by enhancing their solubility that leads rapid excretion and degradation resulting low toxicity towards red palm weevil larvae. On the other hand, the most toxic (coumarin) silenced the genes involved in the red palm weevil detoxification mechanism. Based on the toxicity, growth retarding, and masking detoxification activities, coumarin could be a useful future natural red palm weevil-controlling agent.

Synthesis of new dicinnamoyl 4-deoxy quinic acid and methyl ester derivatives and evaluation of the toxicity against the pea aphid Acyrthosiphon pisum.

New dicinnamoyl (caffeoyl, feruloyl, ortho and para-coumaroyl) 4-deoxyquinic acid and esters were synthesized by using a new 4-deoxy quinic acid triol intermediate. The optimisation of both coupling and deprotection steps allowed the preparation in good yields of the target products either as the carboxylic acid or the methyl ester form. Eight new compounds were evaluated for their ability to influence the feeding behaviour of the pea aphid Acyrthosiphon pisum. Artificial diet bioassays showed that two compounds are toxic (mortality and growth inhibition) at lower concentrations than the reference 3,5-dicaffeoyl quinic acid.

In vitro and in vivo toxicological evaluations of methyl ferulate, methyl p-coumarate, and pulegone 1,2-epoxide.

CONTEXT: Toxicological screening of natural compounds for medicinal purposes. OBJECTIVES: The objective of this study is to evaluate the toxicity of methyl ferulate (MF), methyl p-coumarate (MpC), and pulegone 1,2-epoxide (PE) with in vitro and in vivo assays. MATERIALS AND METHODS: The in vitro toxicity of MF, MpC, and PE was assessed at a concentration of 10 mg/ml with the Ames assay using two strains of Salmonella typhimurium TA98 and TA100. Human red blood cells (RBC) were used to determine the hemolytic activity of these compounds. The cytotoxicity of above compounds was determined with brine shrimp lethality bioassay (BSLB) at the concentrations of 0.1-20 mg/ml. While dermal and ocular irritation studies were conducted on healthy rabbits (n = 8) for 96 and 12 h post-topical application of test compounds, respectively. RESULTS: PE produced 6-8% hemolysis of RBCs at all the tested concentrations while MF and MpC produced 10-5% hemolysis up to 20 mg/ml, and 50-85% hemolysis at concentrations of 40 and 80 mg/ml, respectively. The Ames assay indicated that MF, MpC, and PE were non-mutagenic as the test values were not significantly higher as compared with background values of the assay. BSLB suggested the lethal concentration (LC50) values of MF, MpC, and PE as 4.38, 6.74, and 25.91 mg/ml, respectively. In vivo ocular and dermal irritation scores of MF, MpC, and PE were comparable with ethanol (control) in rabbits indicating the non-irritant nature of these natural compounds. CONCLUSION: The present studies suggest that these compounds are non-toxic/non-irritant and might be used for medicinal purposes.

PRELIMINARY EVALUATION OF CENTRAL NERVOUS SYSTEM ACTIVITY OF (E)-N-2-METHYL-3-PHENYLPROP-2-ENYL ((E)-N- α-METHYLCINNAMYL) DERIVATIVES OF SELECTED AMINOALKANOLS.

A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2-aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors.

Anthelmintic efficacy of cinnamaldehyde and cinnamic acid from cortex cinnamon essential oil against Dactylogyrus intermedius.

Utilization of chemical pesticide to control monogenean diseases is often restricted in many countries due to the development of pesticide resistance and concerns of chemical residues and environmental contamination. Thus, the use of antiparasitic agents from plants has been explored as a possible way for controlling monogenean infections. Extracts from Cinnamomum cassia were investigated under in vivo conditions against Dactylogyrus intermedius in goldfish. The two bioactive compounds, cinnamaldehyde and cinnamic acid, were identified using nuclear magnetic resonance and electrospray ionization mass spectrometry. The 48 h median effective concentrations (EC(50)) for these compounds against D. intermedius were 0·57 and 6·32 mg L(-1), respectively. The LD(50) of cinnamaldehyde and cinnamic acid were 13·34 and 59·66 mg L(-1) to goldfish in 48 h acute toxicity tests, respectively. These data confirm that cinnamaldehyde is effective against D. intermedius, and the cinnamaldehyde exhibits potential for the development of a candidate antiparasitic agent.

Late-life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters.

This study examined late-life effects of perinatal exposure of rats to a mixture of endocrine-disrupting contaminants. Four groups of 14 time-mated Wistar rats were exposed by gavage from gestation day 7 to pup day 22 to a mixture of 13 anti-androgenic and estrogenic chemicals including phthalates, pesticides, u.v.-filters, bisphenol A, parabens, and the drug paracetamol. The groups received vehicle (control), a mixture of all 13 chemicals at 150-times (TotalMix150) or 450-times (TotalMix450) high-end human exposure, or 450-times a mixture of nine predominantly anti-androgenic chemicals (AAMix450). Onset of puberty and estrous cyclicity at 9 and 12 months of age were assessed. Few female offspring showed significantly regular estrus cyclicity at 12 months of age in the TotalMix450 and AAMix450 groups compared with controls. In 19-month-old male offspring, epididymal sperm counts were lower than controls, and in ventral prostate an overrepresentation of findings related to hyperplasia was observed in exposed groups compared with controls, particularly in the group dosed with anti-androgens. A higher incidence of pituitary adenoma at 19 months of age was found in males and females in the AAMix450 group. Developmental exposure of rats to the highest dose of a human-relevant mixture of endocrine disrupters induced adverse effects late in life, manifested as earlier female reproductive senescence, reduced sperm counts, higher score for prostate atypical hyperplasia, and higher incidence of pituitary tumors. These delayed effects highlight the need for further studies on the role of endocrine disrupters in hormone-related disorders in aging humans.