Stingray Venom Proteins: Mechanisms of Action Revealed Using a Novel Network Pharmacology Approach

Animal venoms offer a valuable source of potent new drug leads, but their mechanisms of action are largely unknown. We therefore developed a novel network pharmacology approach based on multi-omics functional data integration to predict how stingray venom disrupts the physiological systems of target animals. We integrated 10 million transcripts from five stingray venom transcriptomes and 848,640 records from three high-content venom bioactivity datasets into a large functional data network. The network featured 216 signaling pathways, 29 of which were shared and targeted by 70 transcripts and 70 bioactivity hits. The network revealed clusters for single envenomation outcomes, such as pain, cardiotoxicity and hemorrhage. We carried out a detailed analysis of the pain cluster representing a primary envenomation symptom, revealing bibrotoxin and cholecystotoxin-like transcripts encoding pain-inducing candidate proteins in stingray venom. The cluster also suggested that such pain-inducing toxins primarily activate the inositol-3-phosphate receptor cascade, inducing intracellular calcium release. We also found strong evidence for synergistic activity among these candidates, with nerve growth factors cooperating with the most abundant translationally-controlled tumor proteins to activate pain signaling pathways. Our network pharmacology approach, here applied to stingray venom, can be used as a template for drug discovery in neglected venomous species.

Contemporary nano-architectured drugs and leads for ανβ3 integrin-based chemotherapy: Rationale and retrospect

The integrins belong to the cell-surface polypeptide family and are the mediating partners among the cells, and extracellular matrix (ECM). They are also involved in the biological processes of cell migration, wound healing, blood clotting, immunological response generation, tissue morphogenesis, leucocyte reticulations, and angiogenesis and are therefore very relevant in stem cell technology and are useful as biomarkers, diagnostic probes, and drug-target ligands. The ανβ3 (alpha-nu-beta3) integrin antagonists are an excellent target example for designing and developing newer drug candidates, drug leads and templates for various diseases, and physiological malfunctioning, including cancers. The current review examines the ανβ3 integrin structural features involved in the drug design and its antagonistic ligands and highlights the development of anti-ανβ3 integrin-antagonists as nano-architectural design-based nanomedicine, especially for cancer chemotherapy. The perspectival review discusses the ανβ3 integrin structure, mode of action, involved pathways, and the concepts utilized in nanomedicine design, and ligands related to integrins. It also covers the latest thyrointegrin approaches toward the development of anti-angiogenesis agents and entails the anti-angiogenesis approach to cancer growth inhibition through targeting by the anti-integrin ligands and related chemical entities. The current perspective on the nano-architectural design approach for the known anti-integrin compounds is also outlined.

Naturally Occurring Chromone Glycosides: Sources, Bioactivities, and Spectroscopic Features

Chromone glycosides comprise an important group of secondary metabolites. They are widely distributed in plants and, to a lesser extent, in fungi and bacteria. Significant biological activities, including antiviral, anti-inflammatory, antitumor, antimicrobial, etc., have been discovered for chromone glycosides, suggesting their potential as drug leads. This review compiles 192 naturally occurring chromone glycosides along with their sources, classification, biological activities, and spectroscopic features. Detailed biosynthetic pathways and chemotaxonomic studies are also described. Extensive spectroscopic features for this class of compounds have been thoroughly discussed, and detailed 13C-NMR data of compounds 1–192, have been added, except for those that have no reported 13C-NMR data.

Exploring the Molecular Mechanisms of Action of Samoan Medicinal Plants via Chemical Genetic Analyses

<p>Natural products are a robust source of drug leads, and medicinal plants have been the source of natural products that are important pharmaceuticals in modern medicine. Samoan medicinal plants have been investigated in the past, but their potential as a source of new drug leads has not been realized. I hypothesized that determining the mechanism of action of Samoan medicinal plant extracts would provide insight into their pharmaceutical potential. The work described herein was carried out on 11 Samoan medicinal plants, from which 22 extracts were prepared. A bioactivity rate of 68% was determined when 15 of the 22 extracts inhibited the growth of yeast (Saccharomyces cerevisiae). The medicinal plant Psychotria insularum was the most potent, thus genome-wide analyses were completed using the haploid deletion mutant library of S. cerevisiae. Yeast strains deficient in iron transport were hypersensitive to the P. insularum aqueous extract. Further investigations showed that exogenous iron supplementation rescued the growth defect induced by P. insularum extracts, suggesting that P. insularum reduced intracellular iron. Fittingly, yeast cells treated with P. insularum extracts contained less intracellular iron than control cells. Paraxodically, the expression levels of iron transporter proteins were upregulated upon extract treatment. When we investigated iron-requiring cellular processes, we found that yeast cells treated with P. insularum extracts exhibited a respiratory deficient phenotype and reduced heme synthesis, indicative of an impaired cellular iron status. These findings suggested that P. insularum reduced bioavailable iron leading to the induction of the low iron response, and indeed the extracts of P. insularum were shown to chelate iron via the iron-chelating CAS assay. To translate results from yeast to mammalian cells, we treated primary murine macrophages with P. insularum extracts and detected an anti-inflammatory response, which we found to correlate with reduced activity of the iron-requiring aconitase enzyme. We further determined using pooled diploid mutant genetic analyses that the extracts of P. insularum did not have a genetic target. To identify the compound mediating the iron chelation mechanism, bioassay-guided isolation was conducted. Fractionation of the crude aqueous extract of P. insularum produced a relatively pure fraction that NMR and the acid-butanol assay identified as a condensed tannin. Together, these results indicate a relationship between iron chelation, a condensed tannin and inflammation. Further, we established an iron chelation mechanism of action by which P. insularum extracts are used to treat inflammation-associated symptoms in traditional Samoan medicine. Lastly, the findings presented here substantiate the reliability of plants with ethnobotanical background as sources for bioactive natural products.</p>

Analysis of Plant Origin Antibiotics against Oral Bacterial Infections Using In Vitro and In Silico Techniques and Characterization of Active Constituents

The pervasiveness of oral bacterial infections in diabetic patients is a serious health concern that may produce severe complications. We investigated 26 Ayurvedic medicinal plants traditionally used for treatment of the oral bacterial infections with the aim to look for new promising drug leads that can be further employed for herbal formulation design. The plants were grouped into three categories based on traditional usage. All plant extracts were examined for antibacterial, antibiofilm and antiquorum-sensing properties. The plants with significant activities including Juglans regia, Syzygium aromaticum, Eruca sativa, Myristica fragrans, Punica granatum and Azadirachta indica were further analyzed using HPLC-DAD-QToF and GC-MS. In silico and in vitro activity was evaluated for selected constituents. Finally, it could be concluded that eugenol and 2-phenylethylisothiocyanate are major contributors towards inhibition of bacterial biofilms and quorum sensing.