Approaches of marine compounds and relevant immune mediators in Autism Spectrum Disorder: Opportunities and challenges.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that affects social skills, language, communication, and behavioral skills, significantly impacting the individual's quality of life. Recently, numerous works have centered on the connections between the immune and central nervous systems and the influence of neuroinflammation on autism symptomatology. Marine natural products are considered as important alternative sources of different types of compounds, including polysaccharides, polyphenols, sterols, carotenoids, terpenoids and, alkaloids. These compounds present anti-inflammatory, neuroprotective and immunomodulatory activities, exhibiting a potential for the treatment of many diseases. Although many studies address the marine compounds in the modulation of inflammatory mediators, there is a gap regarding their use in the regulation of the immune system in ASD. Thus, this review aims to provide a better understanding regarding cytokines, chemokines, growth factors and immune responses in ASD, as well as the potential of bioactive marine compounds in the immune regulation in ASD. We expect that this review would contribute to the development of therapeutic alternatives for controlling immune mediators and inflammation in ASD.

Effect of diterpenes isolated of the marine alga Canistrocarpus cervicornis against some toxic effects of the venom of the bothrops jararaca snake.

Snake venoms are composed of a complex mixture of active proteins and peptides which induce a wide range of toxic effects. Envenomation by Bothrops jararaca venom results in hemorrhage, edema, pain, tissue necrosis and hemolysis. In this work, the effect of a mixture of two secodolastane diterpenes (linearol/isolinearol), previously isolated from the Brazilian marine brown alga, Canistrocarpus cervicornis, was evaluated against some of the toxic effects induced by B. jararaca venom. The mixture of diterpenes was dissolved in dimethylsulfoxide and incubated with venom for 30 min at room temperature, and then several in vivo (hemorrhage, edema and lethality) and in vitro (hemolysis, plasma clotting and proteolysis) assays were performed. The diterpenes inhibited hemolysis, proteolysis and hemorrhage, but failed to inhibit clotting and edema induced by B. jararaca venom. Moreover, diterpenes partially protected mice from lethality caused by B. jararaca venom. The search for natural inhibitors of B. jararaca venom in C. cervicornis algae is a relevant subject, since seaweeds are a rich and powerful source of active molecules which are as yet but poorly explored. Our results suggest that these diterpenes have the potential to be used against Bothropic envenomation accidents or to improve traditional treatments for snake bites.

Antiplatelet and anticoagulant effects of diterpenes isolated from the marine alga, Dictyota menstrualis.

Cardiovascular diseases represent a major cause of disability and death worldwide. Therapeutics are available, but they often have unsatisfactory results and may produce side effects. Alternative treatments based on the use of natural products have been extensively investigated, because of their low toxicity and side effects. Marine organisms are prime candidates for such products, as they are sources of numerous and complex substances with ecological and pharmacological effects. In this work, we investigated, through in vitro experiments, the effects of three diterpenes (pachydictyol A, isopachydictyol A and dichotomanol) from the Brazilian marine alga, Dictyota menstrualis, on platelet aggregation and plasma coagulation. Results showed that dichotomanol inhibited ADP- or collagen-induced aggregation of platelet-rich plasma (PRP), but failed to inhibit washed platelets (WP). In contrast, pachydictyol A and isopachydictyol A failed to inhibit the aggregation of PRP, but inhibited WP aggregation induced by collagen or thrombin. These diterpenes also inhibited coagulation analyzed by the prothrombin time and activated partial thromboplastin time and on commercial fibrinogen. Moreover, diterpenes inhibited the catalytic activity of thrombin. Theoretical studies using the Osiris Property Explorer software showed that diterpenes have low theoretical toxicity profiles and a drug-score similar to commercial anticoagulant drugs. In conclusion, these diterpenes are promising candidates for use in anticoagulant therapy, and this study also highlights the biotechnological potential of oceans and the importance of bioprospecting to develop medicines.

Diterpenes from marine brown alga Dictyota guineensis (Dictyotaceae, Phaeophyceae)

The crude extract of the marine brown alga Dictyota guineensis was analyzed by high-resolution gas chromatography-mass spectrometry (HRGC-MS). Five diterpenes were identified: dictyol E (the most abundant diterpene), dictyotadiol, dictyoxide, isopachydictyol A and pachydictyol A, all diterpenes from the chemical group I, i.e., mainly prenylated derivatives of known sesquiterpene skeletons that result from a first cyclization of geranyl-geraniol between positions 1 and 10. These diterpenes are known for their activity against bacteria, fungi and other activities. The results characterize D. guineensis as a species that yields exclusively diterpenes from group I, with low oxidation and low structural complexity. On Brazilian coasts, only D. mertensii provides exclusively prenylated guaiane diterpenes. Although D. guineensis presents alternate branches and fixing by rhizoidal branches, it is easily distinguishable from D. mertensii by the much narrower stem, short stature and flabelliform habit of the former species. On the other hand, both species have been characterized as producers of diterpenes of group I, in particular, prenylated guaiane. However, D. guineensis has a majority dictyol E in the lipophilic extract, while D. mertensii produces more complex prenylated guaianes, like dictyol H.

Evaluation of Marine Brown Algae and Sponges from Brazil as Anticoagulant and Antiplatelet Products.

The ischemic disorders, in which platelet aggregation and blood coagulation are involved, represent a major cause of disability and death worldwide. The antithrombotic therapy has unsatisfactory performance and may produce side effects. So, there is a need to seek molecules with antithrombotic properties. Marine organisms produce substances with different well defined ecological functions. Moreover, some of these molecules also exhibit pharmacological properties such as antiviral, anticancer, antiophidic and anticoagulant properties. The aim of this study was to evaluate, through in vitro tests, the effect of two extracts of brown algae and ten marine sponges from Brazil on platelet aggregation and blood coagulation. Our results revealed that most of the extracts were capable of inhibiting platelet aggregation and clotting measured by plasma recalcification tests, prothrombin time, activated partial thromboplastin time, and fibrinogenolytic activity. On the other hand, five of ten species of sponges induced platelet aggregation. Thus, the marine organisms studied here may have molecules with antithrombotic properties, presenting biotechnological potential to antithrombotic therapy. Further chemical investigation should be conducted on the active species to discover useful molecules for the development of new drugs to treat clotting disorders.

Anti-herpetic activities of chemical components from the Brazilian red alga Plocamium brasiliense.

The CH2Cl2 crude extract and a fraction enriched with halogenated monoterpenes of the Brazilian red alga Plocamium brasiliense were evaluated for cytotoxicity and against the virus HSV-1. The extract showed low cytotoxicity compared with the fraction containing monoterpenes. The crude extract showed, in vitro, a high reduction of infectivity of the virus HSV-1.

Diterpenes from the Brown Alga Dictyota crenulata.

The crude extract of the Brazilian brown alga Dictyota crenulata was analyzed by NMR spectroscopy and HRGC-MS techniques. Seven diterpenes were identified: pachydictyol A, dictyodial, 4beta-hydroxydictyodial A, 4beta-acetoxydictyodial A, isopachydictyol A, dictyol C and dictyotadiol. Xeniane diterpenes have previously been found in D. crenulata from the Pacific Ocean. The results characterize D. crenulata as a species that provides prenylated guaiane (group I) and xeniane diterpenes (group III), thus making it a new source of potential antiviral products.

Effects of diterpenes isolated from the Brazilian marine alga Dictyota menstrualis on HIV-1 reverse transcriptase.

It has been recently demonstrated that HIV-1 reverse transcriptase is the target of two diterpenes, (6 R)-6-hydroxydichotoma-3,14-diene-1,17-dial (compound 1) and (6 R)-6-acetoxydichotoma-3,14-diene-1,17-dial (compound 2), that inhibit HIV-1 replication in vitro. In this work, the effects of both diterpenes on the kinetic properties of the recombinant HIV-1 reverse transcriptase (RT) enzyme were evaluated. RNA-dependent DNA-polymerase (RDDP) activity assays demonstrated that both diterpenes behave as non-competitive inhibitors with respect to dTTP and uncompetitive inhibitors with respect to poly(rA).oligo(dT) template primers. The K(i) values obtained for compounds 1 and 2 were 10 and 35 microM, respectively. Neither of these diterpenes affected the DNA-dependent DNA-polymerase (DDDP) activity of the HIV-1 RT. The RDDP activities of AMV-RT and MMLV-RT enzymes were also inhibited by compounds 1 and 2. In contrast to the HIV-1 enzyme, the DDDP activities of AMV-RT and MMLV-RT enzymes were significantly reduced by compound 1. Taken together, our results demonstrate that compound 1 is a more effective inhibitor of the viral reverse transcriptases from HIV-1, AMV and MMLV than compound 2. The kinetic behavior analyses of the HIV-1 RT demonstrate that both diterpenes have similar mechanisms of inhibition of RDDP activity.