Ana Amélia de Carvalho Melo-Cavalcante

Therapeutic Potential of Essential Oils Focusing on Diterpenes.

Among all plant derivates, essential oils (EOs) have gained the attention of many scientists. Diterpenes, a family of components present in some EO, are becoming a milestone in the EOs world. The goal of this review is to describe a scenario of diterpenes taking into health‐consumption deportment. Previous studies revealed that diterpenes have antioxidant, antimicrobial, antiviral, antiprotozoal, cytotoxic, anticancer, antigenotoxic, antimutagenic, chemopreventive, antiinflammatory, antinociceptive, immunostimulatory, organoprotective, antidiabetic, lipid‐lowering, antiallergic, antiplatelet, antithrombotic, and antitoxin activities. In conclusion, diterpenes may be an immense featuring concern in pharmaceutical consumption from a drug discovery point of view. Copyright

Bufadienolides from amphibians: A promising source of anticancer prototypes for radical innovation, apoptosis triggering and Na+/K+-ATPase inhibition

ABSTRACT Amphibians present pharmacologically active aliphatic, aromatic and heterocyclic molecules in their skin as defense against microorganisms, predators and infections, such as steroids, alkaloids, biogenic amines, guanidine derivatives, proteins and peptides. Based on the discovered bioactive potential of bufadienolides, this work reviewed the contribution of amphibians, especially from members of Bufonidae family, as source of new cytotoxic and antitumor molecules, highlighting the mechanisms responsible for such amazing biological potentialities. Bufonidae species produce bufadienolides related to cholesterol through the mevalonate‐independent and acidic bile acid pathways as polyhydroxy steroids with 24 carbons. In vitro antitumor studies performed with skin secretions and its isolated components (specially marinobufagin, telocinobufagin, bufalin and cinobufagin) from Rhinella, Bufo and Rhaebo species have shown remarkable biological action on hematological, solid, sensitive and/or resistant human tumor cell lines. Some compounds revealed higher selectivity against neoplastic lines when compared to dividing normal cells and some molecules may biochemically associate with Na+/K+‐ATPase and there is structural similarity to the digoxin‐ and ouabain‐Na+/K+‐ATPase complexs, implying a similar mechanism of the Na+/K+‐ATPase inhibition by cardenolides and bufadienolides. Some bufadienolides also reduce levels of antiapoptotic proteins and DNA synthesis, cause morphological changes (chromatin condensation, nuclear fragmentation, cytoplasm shrinkage, cytoplasmic vacuoles, stickiness reduction and apoptotic bodies), cell cycle arrest in G2/M or S phases, mitochondrial depolarization, PARP [poly (ADPribose) polymerase] and Bid cleavages, cytochrome c release, activation of Bax and caspases (−3, −9, −8 and −10), increased expression of the Fas‐Associated protein with Death Domain (FADD), induce topoisomerase II inhibition, DNA fragmentation, cell differentiation, angiogenesis inhibition, multidrug resistance reversion, and also regulate immune responses. Then, bufadienolides isolated from amphibians, some of them at risk of extinction, emerge as a natural class of incredible chemical biodiversity, has moderate selectivity against human tumor cells and weak activity on murine cells, probably due to structural differences between subunits of human and mice Na+/K+‐ATPases. HIGHLIGHTSCardenolides and bufadienolides present similar mechanism of Na+/K+‐ATPase inhibition.Bufadienolides show moderate selectivity against human tumor cells and weak activity on murine cells.Bufalin, cinobufagin, telocinobufagin and marinobufagin exhibited remarkable antitumor potential triggered by caspase‐dependent apoptosis.Bufalin or Cinobufagin have been used in clinical therapy against advanced carcinomas of liver, lung, pancreas and bladder.

Diterpenes: Advances in Neurobiological Drug Research

A significant number of studies have been performed with diterpene effect on the brain. Our study aims to make a systematic revision on them. The initial purpose of this review was to screen diterpenes with neurological activity, in particular those that have already been studied and published in different journals (databases until August 2015). The second purpose was to make an action‐wise discussion as results viewed on them by taking into drug discovery and development account. Diterpenes considered in this review were selected on the basis of updated information on them and having sufficient information on their screenings. We identified several examples of diterpenes having an interest in further study. We have included the possible sources of them as observed in evidence, their known molecular neurobiological mechanisms, and the active constituents responsible for such activities with the doses and test systems. Results suggest diterpenes to have neurobiological activities like neuro‐protection, anti‐epileptic, anxiolytic, anti‐Alzheimers disease, anti‐Parkinsons disease, anti‐cerebral ischemia, anti‐neuropathic pain, anti‐neuro‐inflammatory, and many more. In conclusion, diterpenes may be the prominent candidates in neurobiological drug research. Copyright

Antimutagenic activity of cashew apple (Anacardium occidentale Sapindales, Anacardiaceae) fresh juice and processed juice (cajuína) against methyl methanesulfonate, 4-nitroquinoline N-oxide and benzo[a]pyrene

Cashew apple juice (CAJ), produced from the native Brazilian cashew tree (Anacardium occidentale), and has been reported to have antibacterial, antifungal, antitumor, antioxidant and antimutagenic properties. Both the fresh unprocessed juice and the processed juice (cajuina in Portuguese) has been shown to consist of a complex mixture containing high concentrations of anacardic and ascorbic acids plus several carotenoids, phenolic compounds and metals. We assessed both types of juice for their antimutagenic properties against the direct mutagens methyl methanesulfonate (MMS) and 4-nitroquinoline-N-oxide (4-NQO) and the indirect mutagen benzo[a]pyrene (BaP) using pre-treatment, co-treatment and post-treatment assays with Salmonella typhimurium strains TA100, TA102, and TA97a. In pre-treatment experiments with strains TA100 and TA102 the fresh juice showed high antimutagenic activity against MMS but, conversely, co-treatment with both juices enhanced MMS mutagenicity and there was an indication of toxicity in the post-treatment regime. In pre-, co-, and post-treatments with TA97a as test strain, antimutagenic effects were also observed against 4-NQO and BaP. These results suggest that both fresh and processed CAJ can protect the cells against mutagenesis induced by direct and indirect mutagens.

In vivo Antigenotoxic and Anticlastogenic Effects of Fresh and Processed Cashew (Anacardium occidentale) Apple Juices

Cashew apple juice and cajuina (processed juice) are drinks widely consumed in northeast Brazil. In vitro studies have shown that both juices have antimutagenic activity as well as antioxidant effects. These juices contain vitamins, carotenoids, and phenolic compounds. This in vivo study assessed the antigenotoxic and anticlastogenic effects of both drinks against genotoxicity and mutagenicity induced by cyclophosphamide. The comet, micronucleus, and chromosome aberrations tests were used. Male Swiss mice were divided into 6 groups (5 animals per group) and received the following by gavage, 0.15 mL/10 g body weight: group 1, water; group 2, cashew apple juice; group 3, cajuina juice; group 4, cashew apple juice and cyclophosphamide (50 mg/kg); group 5, cajuina juice and cyclophosphamide; group 6: cyclophosphamide. Both drinks significantly reduced DNA damage of peripheral blood cells (P<.001), with modulation percentages of 60.82% (cashew apple juice) and 82.19% (cajuina) when compared with the cyclophosphamide group. Cashew apple juice and cajuina modulated cyclophosphamide-induced micronucleus frequency, with up to 80.0% inhibition. Cashew apple juice and cajuina decreased the average number of cells with chromosome aberrations in bone marrow of mice by 53% and 65%, respectively. These findings demonstrate the high antigenotoxic and anticlastogenic potential of cashew apple juice and cajuina in vivo, which can be related to the antioxidant compounds found in both drinks.

Assessment of chemotherapy on various biochemical markers in breast cancer patients

Chemotherapy is a standard treatment method for the patients with locally advanced breast cancer. Lately, cyclophosphamide (CYP) and doxorubicin (DOX) are used as the major chemotherapeutic agents especially for the treatment of breast cancer. Till date, no serum biomarker has been able to provide an early diagnosis of breast cancer. This study aimed to assess inflammatory, cardiac, renal and hematological markers in 56 breast cancer patients (BCP) before, during and after termination of chemotherapy with CYP and DOX. Blood samples were collected from the patients at the each treatment stages mentioned above. These samples were assessed for interleukin 6 (IL‐6), interleukin 10 (IL‐10), lactate dehydrogenase (LDH), creatine kinase (CK), creatinine, hemoglobin (Hb), leukocyte, platelet and Na+/K+‐ATPase levels either by ELISA or colorimetric methods. The results suggest a significant increase in IL‐6 level at all the stages in BCP as compared to control group. On the other hand, IL‐10, CK and Na+/K+‐ATPase levels were found to be significantly declined during all the stages. Moreover, the majority of hematological parameters remained unchanged throughout the treatment period with the exception of creatinine and Hb which showed slight modulation in their level at different stages. Based on the results, we conclude that breast cancer and co‐treatment with CYP and DOX, interfere arious biological markers, thereby, showing the physiological imbalance.

Cytotoxicity and genotoxicity of Guaribas river water (Piauí, Brazil), influenced by anthropogenic action

In general, tropical rivers have a great impact on human activities. Bioaccumulation of toxins is a worldwide problem nowadays and has been, historically, overlooked by the supervisory authorities. This study evaluated cytogenotoxic effects of Guaribas river (a Brazilian river) water during dry and rainy seasons of 2014 by using the Allium cepa test system. The toxicogenetic variables, including root growth, mitotic index, and chromosomal aberrations, were analyzed in meristematic cells of A. cepa exposed to water samples taken from the up-, within, and downstream of the city Picos (state: Piauí). The physical-chemical parameters were also analyzed to explain water quality and possible anthropogenic action. Additionally, the presence of heavy metals was also analyzed to explain water quality and possible damaging effects on eukaryotic cells. The results suggest that the river water exerted cytotoxic, mutagenic, and genotoxic effects, regardless of the seasons. In addition, Guaribas river presented physico-chemical values outside the Brazilian laws, which can be a characteristic of human pollution (domestic sewage, industrial, and local agriculture). The genetic damage was positively correlated with higher levels of heavy metals. The pollution of the Guaribas river water may link to the chemical contamination, including the action of heavy metals and their impacts on genetic instability in the aquatic ecosystem. In conclusion, necessary steps should be taken into account for further toxicogenetic studies of the Guaribas river water, as it has an influence in human health of the same region of Brazil.

A Possible Phytol-cytoprotective Trait through Reactive Species-Induced Oxidative Stress Ebbing Pathway

This study aims at investigating a possible pathway of cytotoxicological status of the diterpenoid essential oil, phytol (PYL). For this brine shrimp lethality bioassay (BSLB) and hemolysis (HL) test systems were selected. In the BSLB, PYL either alone or co-treated with ethylenediaminetetraacetic acid (EDTA), potassium di-chromate (K2Cr2O7; KD), copper sulphate (CuSO4.5H2O; CS) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox, TRO) as membrane lyser, strong oxidizer, oxidizer-cytogenotoxicant and antioxidative-cell-protestant, respectively. The HL was carried out in rat erythrocytes (RBCs) taking TRO as a standard. In addition, to view a time-dependent cytotoxic activity of PYL, the mortality of the shrimps was counted at 24 and 48 h. Results suggest PYL is non-cytotoxic at low (40-160 µM) but toxic at high concentration (2-8 mM) to the shrimps and RBCs. An increased cytotoxicity was observed for 24 h to 48 h in brine shrimps. In both cases groups co-treated with cytotoxicants/protestant suggest that PYL is cytoprotective in the presence of oxidizer. The cytoprotectivityof PYL may be connected to its antioxidant potential and cytotoxicity for antioxidant-mediated pro-oxidative effects. In conclusion, PYL is cytoprotective at low concentration but toxic at high, activities found, however, may be linked to the radical scavenging pathway

Diterpenes as lead molecules against neglected tropical diseases.

Nowadays, neglected tropical diseases (NTDs) are reported to be present everywhere. Poor and developing areas in the world have received great attention to NTDs. Drug resistance, safety profile, and various challenges stimulate the search for alternative medications. Plant‐based drugs are viewed with great interest, as they are believed to be devoid of side effects. Diterpenes, a family of essential oils, have showed attractive biological effects. A systematic review of the literature was carried out to summarize available evidences of diterpenes against NTDs. For this, databases were searched using specific search terms. Among the 2338 collected reports, a total of 181 articles were included in this review. Of them, 148 dealt with investigations using single organisms, and 33 used multiple organisms. No mechanisms of action were reported in the case of 164 reports. A total of 93.92% were related to nonclinical studies, and 4.42% and 1.66% dealt with preclinical and clinical studies, respectively. The review displays that many diterpenes are effective upon Chagas disease, chikungunya, echinococcosis, dengue, leishmaniasis, leprosy, lymphatic filariasis, malaria, schistosomiasis, and tuberculosis. Indeed, diterpenes are amazing drug candidates against NTDs. Copyright

Thymoquinone is Knocking at the Door of Clinical Trial

This review aimed at summarizing the therapeutic potentials in a mechanistic context of a vastly studied quinone, naturally derived product from the seed oil of Nigella sativa called thymoquinone (TQ). The proposed underlyng mechanism may be attributed to its lowdose-mediated antioxidative effect while pro-oxidative at high doses. The TQ is able to form unstable and stable redox compounds in the presence of a variety of internal or external factors such as light, pH, catalyst. Antioxidant-mediated cytoprotectivity while pro-oxidative effect mediated cytotoxicity are the features of TQ with the possibility of redox balancing capacity. In addition, induced autophagy with the redox balancing potential may be a novel consideration in the cancer chemotherapy. Up to date investigated therapeutic potentials of TQ are- antioxidant, anti-inflammatory, antimicrobial, anticancer, immunomodulatory, neuro-, gastro-, cardio-, hepato- and nephroprotective. It also imparts beneficial effects in oral hygene, metabolic disorders, diabetes (especially type 2), reproductive and respiratory tract disorders, fibrosis, bone formation and decay. TQ needs clinical trial reports, despite of having a massive animal model data, combinatorial effects with some currently used chemotherapeutic agents as well as action against resistant antibiotics making TQ interesting. TQ should be taken into pharmaceutical account as a novel drug to be developed for clinical trials.