Phytochemicals: Potential Lead Molecules for MDR Reversal.

Multidrug resistance (MDR) is one of the main impediments in the treatment of cancers. MDR cancer cells are resistant to multiple anticancer drugs. One of the major mechanisms of MDR is the efflux of anticancer drugs by ABC transporters. Increased activity and overexpression of these transporters are important causes of drug efflux and, therefore, resistance to cancer chemotherapy. Overcoming MDR is a fundamental prerequisite for developing an efficient treatment of cancer. To date, various types of ABC transporter inhibitors have been employed but no effective anticancer drug is available at present, which can completely overcome MDR. Phytochemicals can reverse MDR in cancer cells via affecting the expression or activity of ABC transporters, and also through exerting synergistic interactions with anticancer drugs by addressing additional molecular targets. We have listed numerous phytochemicals which can affect the expression and activity of ABC transporters in MDR cancer cell lines. Phytochemicals in the groups of flavonoids, alkaloids, terpenes, carotenoids, stilbenoids, lignans, polyketides, and curcuminoids have been examined for MDR-reversing activity. The use of MDR-reversing phytochemicals with low toxicity to human in combination with effective anticancer agents may result in successful treatment of chemotherapy-resistant cancer. In this review, we summarize and discuss published evidence for natural products with MDR modulation abilities.

Disruptive effects of nonylphenol on reproductive hormones, antioxidant enzymes, and histology of liver, kidney and gonads in Caspian trout smolts.

The endocrine-disrupting effect of pollutants such as alkylphenols has been considered a major concern during recent years. Although the effects of nonylphenol on the reproductive hormones of fish have been investigated in several studies, the effect of this endocrine disruptor on reproductive hormones of immature fish and salmonid smolts has been less addressed. The present work studied the effects of 1, 10 and 100 µg/l concentrations of nonylphenol on the levels of plasma reproductive hormones and liver antioxidant enzymes as well as on histopathology of reproductive and non-reproductive organs of male and female Caspian brown trout (Salmo trutta caspius) smolts after 21 days of exposure. The results of the present study showed that environmentally relevant concentrations of nonylphenol affected plasma levels of sex steroids; gonadotropins, phosphorus, estradiol to testosterone ratio, and also caused histopathological lesions in liver, kidney and testis tissues of immature Caspian brown trout during smolting. Nonylphenol significantly increased the levels of estradiol in plasma of both male and female smolts exposed to nonylphenol compared with the control groups. Exposure to nonylphenol decreased testosterone and FSH levels in both genders. It has also increased plasma levels of LH in females but did not affect LH levels in male fish. Liver SOD and CAT content was decreased in nonylphenol-exposed smolts. Therefore, the release of this economically valuable and endangered species into the rivers contaminated with nonylphenol should be avoided as it can have significant effects on the development and reproductive function of smolts.

Perturbation of fatty acid composition, pigments, and growth indices of Chlorella vulgaris in response to silver ions and nanoparticles: A new holistic understanding of hidden ecotoxicological aspect of pollutants.

This study assesses and compares the influence of silver nanoparticles (AgNPs) and silver nitrate (AgNO3) on the fatty acid composition, pigments, and growth indices of Chlorella vulgaris. Toxicity testing was carried at the estimated and/or above predicted environmental concentrations of AgNPs and AgNO3. AgNO3 treatments impaired the population growth of C. vulgaris about 2-183 times more than the respective AgNPs ones. The pigments displayed a concentration-dependent decrease in response to both forms of silver; however, AgNO3 displayed higher severity to the pigments than AgNPs. In exposure to 10 µg L-1 AgNO3, the contents of chlorophyll a, chlorophyll b, total chlorophyll, and carotenoid, respectively, demonstrated a reduction of about 5, 3, 4, and 4 times when compared with the same respective concentration of AgNPs. Total amounts of saturated (∑SFA), monounsaturated (∑MUFA), and polyunsaturated (∑PUFA) fatty acids as well as the ratio of unsaturated to saturated ones (Unsat./Sat.) displayed somewhat similar-concentration responses. ∑SFA exhibited a hormesis response, and ∑MUFA, ∑PUFA, and Unsat./Sat. did a decreasing trend with increasing concentration of AgNPs and AgNO3. Myristoleic acid, nervonic acid, and eicosadienoic acid revealed the highest sensitivity. Pearson analysis illustrated the highest correlation among myristoleic acid, eicosenoic acid, and nervonic acid as well as among palmitic acid, stearic acid, palmitoleic acid, and oleic acid. Taken together, AgNPs and the released ions could disrupt physiological health state of microalgae through perturbation in the fatty acid composition (especially MUFAs and PUFAs) and other macromolecules. These types of bioperturbations could change the good health state of aquatic ecosystems.

Defensins: Transcriptional regulation and function beyond antimicrobial activity.

Defensins are one the largest group of antimicrobial peptides and are part of the innate defence. Defensins are produced by animals, plants and fungi. In animals and plants, defensins can be constitutively or differentially expressed both locally or systemically which confer defence before and a stronger response after infection. Immune signalling pathways regulate the gene expression of defensins. These pathways include cellular receptors, which recognise pathogen-associated molecular patterns and are found both in plants and animals. After recognition, signalling pathways and, subsequently, transcriptional factors are activated. There is an increasing number of novel functions in defensins, such as immunomodulators and immune cell attractors. Identification of defensin triggers could help us to elucidate other new functions. The present article reviews the different elicitors of defensins with a main focus on human, fish and marine invertebrate defensins.

Cloning, characterization and tissue-specific expression of the antimicrobial peptide hepcidin from caspian trout (Salmo caspius) and the antibacterial activity of the synthetic peptide.

Antimicrobial peptides have a wide range of antimicrobial activity and widely occur in different organisms including mollusks, crustaceans and vertebrates. Hepcidins are a group of cysteine-rich antimicrobial peptides that are active against a variety of pathogens including gram-positive and gram-negative bacteria, as well as viruses. In this study, the hepcidin gene of Caspian trout (CtHep) was identified and characterized. Our results showed that CtHep cDNA has a 267-bp Open Reading Frame (ORF), which is translated to 88 amino acids. The CtHep was classified in the HAMP1 class of hepcidins. Comparison of DNA and cDNA sequences showed that CtHep has 3 exons and 2 introns. The signal, prodomain and mature part of CtHep have 24, 39 and 25 amino acids, respectively. The mature peptide has a molecular weight of 2881.43 Da and a theoretical isoelectric point of 8.53. The expression of CtHep mRNA was detected in different tissues of healthy and infected fish. CtHep expression in the liver, head kidney, spleen and skin was significantly enhanced after bacterial challenge. Expression of CtHep in different embryonic development stages was also substantial. Antibacterial activity of synthetic CtHep peptides was investigated against a number of Gram-positive and Gram-negative bacteria. CtHep inhibited some pathogenic bacteria such as Streptococcus iniae and Aeromonas hydrophila. In the in vivo experiment, CtHep upregulated the cytokines IL-6 and TNF-α in both kidney and spleen tissues after 24 h of the peptide injection. In conclusion, our study showed that CtHep plays an important role in the immune system of Caspian trout and also in the embryonic stages. Moreover, CtHep peptide has a potential to be used as an antimicrobial therapeutic agent as well as an immunostimulant in aquaculture.

The response of thyroid hormones, biochemical and enzymological biomarkers to pyrene exposure in common carp (Cyprinus carpio).

Polycyclic Aromatic Hydrocarbons (PAHs) are discharged into aquatic environments through anthropogenic activities mainly industrial and municipal effluents. There is little information on the adverse effects of pyrene, a member of the PAH family which is classified as a priority pollutant by the USEPA, on fish biochemical and physiological endpoints, particularly thyroid hormones. The present study investigated the effects of subacute semi-static pyrene exposure on biochemical, enzymological and ionoregulatory responses as well as thyroid hormones in common carp (Cyprinus carpio). The fish (140±10g, 1(+) year) were exposed to 10, 50 and 100µg/l nominal concentrations of pyrene for 35 days. The results revealed that pyrene at these concentrations significantly altered plasma levels of glucose, cholesterol, triglyceride, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Moreover, plasma thyroid hormones (T3 and T4) were significantly decreased in fish exposed to pyrene. In contrast, plasma electrolytes (sodium, potassium and calcium) levels remained statistically unchanged after exposure to the various pyrene concentrations. In conclusion, the studied biomarkers may be used as monitoring tools to evaluate pyrene toxicity. Pyrene induced diverse effects on the physiological endpoints of common carp, thus this chemical should be considered in toxicity studies concerning PAHs. Furthermore, this study confirmed that there was an interaction between pyrene and the thyroid system in fish. Therefore, the thyroid system may be used to assess the impact of pyrene on fish.

Effects of nonylphenol on key hormonal balances and histopathology of the endangered Caspian brown trout (Salmo trutta caspius).

Endocrine disruptor chemicals (EDCs) potentially pose a hazard to endangered species. Evaluation of the sensitivity of these species to EDCs could be helpful for protecting their populations. So, the present study investigated the adverse effects of nonylphenol, an EDC, on the endocrine hormones and histopathology of male and female juvenile Caspian brown trout (Salmo trutta caspius) following 21 days of exposure to nominal concentrations of 1, 10 and 100 µg/l. The results showed that the HSI and plasma total calcium of male and female fishes exposed to 100 µg/l nonylphenol were significantly increased compared with the control groups (P<0.001). The male plasma T3 level was significantly decreased in 10 (P<0.01) and 100 (P<0.001) µg/l nonylphenol. The female T3 level increased in 1 µg/l nonylphenol concentration (P<0.05). The plasma T4 of males showed significant elevation in fishes exposed to 100 µg/l nonylphenol (P<0.05), but no change for females in any of treatment groups relative to controls (P>0.05). No significant effect of nonylphenol exposure was observed on male plasma TSH levels (P>0.05), whereas, in females, nonylphenol at all concentrations significantly reduced TSH levels. A bell-shaped response was observed in male and female plasma GH levels. Moreover, various histopathological lesions were observed in gill and intestine tissues of fishes exposed to different nonylphenol concentrations. These results demonstrate the high sensitivity of this endangered species to even environmentally relevant concentrations of nonylphenol. Furthermore, Caspian brown trout could be used as bioindicators reflecting the toxicity of nonylphenol.