A number of natural products from marine sponges, such as cyclodepsipeptides, have been identified. The structural characteristics of this family of cyclic peptides include various unusual amino acid residues and unique N-terminal polyketide-derived moieties. Papuamides are representatives of a class of marine sponge derived cyclic depsipeptides, including callipeltin A, celebesides A and B, homophymine A, mirabamides, microspinosamide, neamphamide A and theopapuamides. They are thought to have cytoprotective activity against HIV-1 in vitro by inhibiting viral entry. Jasplakinolide, a representative member of marine sponge-derived cyclodepsipeptides that include arenastatin A, geodiamolides, homophymines, spongidepsin and theopapuamides, is a potent inducer of actin polymerization in vitro. Although actin dynamics is essential for tumor metasasis, no actin targeting drugs have been used in clinical trials due to their severe cytotoxicity. Nonetheless, the actin cytoskeleton remains a potential target for anti-cancer drug development. These features imply the use of cyclodepsipeptides as molecular models in drug research.

The amiloride-sensitive epithelial sodium channel (ENaC) plays a prominent role in sodium uptake from alveolar fluid, and is the major component in alveolar fluid clearance in normal and diseased lungs. The lectin-like domain of TNF-α has been shown to activate amiloride-sensitive sodium uptake in type II alveolar epithelial cells. Therefore, several synthetic peptides that mimic the lectin-like domain of TNF-α (TIP) were synthesised and their ability to enhance sodium current through ENaC was studied in A549 cells with the patch clamp technique. Our data suggest that a free positively-charged N-terminal amino group on residue 1 and/or a free negatively-charged carboxyl group on residue 17 of the TIP peptide is essential for the ENaC-activating effect. Ventilation strategies apart, no standard treatment exists for pulmonary permeability oedema. Therefore, novel therapies activating sodium uptake from the alveolar fluid via ENaC could improve clinical outcome.

Voltage-gated sodium channels produce fast depolarization, which is responsible for the rising phase of the action potential in neurons, muscles and heart. These channels are very large membrane proteins and are encoded by ten genes in mammals. Sodium channels are a crucial component of excitable tissues; hence, they are a target for various neurotoxins that are produced by plants and animals for defence and protection, such as tetrodotoxin, scorpion toxins and batrachotoxin. Several mutations in various sodium channel subtypes cause multiple inherited diseases known as channelopathies. When these mutated sodium channel subtypes are expressed in various tissues, channelopathies in brain, skeletal muscle and cardiac muscle develop as well as neuropathic pain. In this review, we discuss aspects of voltage-gated sodium channel genes with an emphasis on cardiac muscle sodium channels. In addition, we report novel mutations that underlie a spectrum of diseases, such as Brugada, long QT syndrome and inherited conduction disorders. Furthermore, this review explains commonalities and differences among the channel subtypes, the channelopathies caused by the sodium channel gene mutation and the specificity of toxins and blockers of the channel subtypes.

Background/Aims: Post-translational modifications such as phosphorylation and dephosphorylation can finely tune the function of ion channels. Na_v1.5 is the main sodium channel in human hearts and alternative splicing of the transcript generates two major splice variants, characterized by the presence (Q-pre) or absence (Q-del) of glutamine at position 1077. In the heart, both the Na_v1.5 channel and Fyn tyrosine kinase are colocalized at adherens junctions. This study aimed to investigate the modulation of the aforementioned splice variants by Fyn tyrosine kinase. Methods and Results: Q-del and Q-pre were transiently expressed alone, with catalytically active Fyn kinase (FynKa) or with a catalytically dead Fyn kinase (FynKd). Co-expression of Na_v1.5 channel splice variants and Fyn kinase was confirmed by Western blotting and their Interaction was established by co-immunoprecipitation experiments. The enzymatic activity of Fyn kinase and phosphorylation of Na_v1.5 channel were ascertained by immunoprecipitation and anti-phosphotyrosine immunoblotting. Whole-cell ionic currents were recorded in patch clamp experiments to examine the modulation of Na_v1.5 channel variants by Fyn kinase, which indicated a hyperpolarizing shift of 9.68 mV in fast inactivation of Q-del. In contrast, a depolarizing shift of 8.77 mV in fast inactivation was observed in the case of Q-pre, while activation curves remained unaltered for both splice variants. This differential modulation in fast inactivation was further assessed by mutating tyrosine 1495 to phenylalanine in the inactivation loop, which completely removed the modulatory effect of Fyn kinase in Q-pre splice variant, while in Q-del variant hyperpolarizing shift in fast inactivation was reduced to 4.74 mV. Finally, the modulatory effect of Fyn kinase was compensated at a mid-value of 94.63 ± 0.34, when both splice variants were co-expressed at a normal physiological ratio. Conclusion: Q-del and Q-pre were differentially modulated by Fyn kinase, and this fine modification resulted in smooth electrical activity in the heart.

Background: Psoralea corylifolia and Mimusops elengi could be a source for new bioactive compounds for treating filariasis Psoralea corylifolia and Mimusops elengi. These plants are rich in medicinally and phytochemically has been proved. These plants played an important role in ancient medicine for the treatments of various ailments and especially against many helminths. Methods: Psoralea corylifolia and Mimusops elengi could be a source for new bioactive compounds for treating filariasis. 20g of dried powder of Psoralea corylifolia and Mimusops elengi were extracted using a Soxhlet apparatus using various solvents like methanol, chloroform, acetone and water for about 30 cycles and then concentrated using a rotary evaporator and stored at 4 °C in air tight containers. It is effective against Setaria cervi at 100 and 200 µg respectively. In-vitro studies have been done for the respective compounds. Homology models of Glutathione S transferase, Chitinase and Transglutaminase were constructed using MODELLER v9.20 (Accelrys). Results: The results from the in vitro studies were confirmed by TLC and GC MS analysis of the extracts which showed the presence of different phytochemical compounds in the extracts. Among the compounds identified in GC MS 7,10-Octadecadienoic acid, methyl ester, Pentadecanoic acid, 14-methyl-, methyl ester, 2-Nonadecanone2,4-dinitrophenylhydrazine, Aspidospermidin-17-ol, 1-acetyl-19,21-epoxy-15,16-dimethoxy-, 9- (2’,2’-Dimethylpropanihydrozano)-3,6 dichloro-2,7-bis-[2-(diethylamino)-ethoxy] fluorine, 2,2,4-Trimethyl-3-(3,8,12,16-tetramethyl-heptadeca-3,7,11,15-tetraenyl)-cyclohexanol were docked against crystallised bioactive compounds. Conclusion: As a result of this study, it was concluded that arresting these proteins will help in arresting the growth and multiplication of parasites, thus leading to the development of a new anti-filarial drug.