For this special issue, we, the Editors of Drug Discoveries & Therapeutics, have asked researchers who are using silkworms to actively develop drugs and study foods to summarize their recent work. Our profound hope is that this special issue encourages researchers who are helping to develop the new field of "using silkworms as a laboratory animal to evaluate medicines and foods".
Bombyx mori (silkworm) is the most famous lepidopteran in Japan. B. mori has long been used in the silk industry and also as a model insect for agricultural research. In recent years, B. mori has attracted interest in its potential for use in pathological analysis of model animals. For example, the human macular carotenoid transporter was discovered using information of B. mori carotenoid transporter derived from yellow-cocoon strain. The B. mori carotenoid transport system is useful in human studies. To develop a human disease model, we characterized the human homologs of B. mori, and by constructing KAIKO functional annotation pipeline, and to analyze gene expression profile of a unique B. mori mutant strain using microarray analysis. As a result, we identified a novel molecular network involved in Parkinson's disease. Here we describe the potential use of a spontaneous mutant silkworm strain as a human disease model. We also summarize recent progress in the application of genomic information for annotation of human homologs in B. mori. The B. mori mutant will provide a clue to pathological mechanisms, and the findings will be helpful for the development of therapies and for medical drug discovery.
We propose Cryptococcus neoformans infection model using silkworm for understanding cryptococcosis and screening of therapeutically effective antibiotics. Silkworm is an insect whose rearing methods were established through a long history of the sericulture industry. Silkworm facilitates experiments using a large number of individuals because of low cost for rearing and few ethical problems caused by killing animals. Silkworm can be reared at 37˚C to perform infection experiments at same temperature to human body. Injection of accurate amounts of samples into hemolymph of silkworm by usual syringes is easy to be done since silkworm has an appropriate size to handle. Moreover two injection methods, injection into hemolymph and intestine, are distinguishable for silkworms. The former is correspondent to intravenous injection, and the latter is to oral administration in humans. Taking these advantages of silkworms as host animals, it is possible to evaluate the virulence factors in C. neoformans and the therapeutic efficacy of antifungal agents.
Silkworm shows hyperglycemia after intake of diet containing large amount of glucose. The hyperglycemic silkworm model is useful for evaluation of anti-diabetic drugs. A hot water extract of Rehmanniae Radix, an herbal medicine, showed hypoglycemic effect against the hyperglycemic silkworms. This method is applicable for quick and simple evaluation of the hypoglycemic activities of different batches of Rehmanniae Radix. Our findings suggest that silkworms have a lot of merit as experimental animals for evaluation of various herbal medicines.
Since diabetes patients are increasing in the world, establishment of a novel method for development of anti-diabetic drugs is desired. In this review, we describe recent results of our studies regarding diabetic model using silkworms for evaluation of anti-diabetic drugs for patients of both type I and type II diabetes. The use of the evaluation systems using silkworms is expected to contribute to reduction in cost and in the number of mammals sacrificed for screening of anti-diabetic drugs.
New antimicrobials with novel mechanisms need to be developed to combat antimicrobial-resistant pathogenic bacteria. The current authors recently reported discovery of a new antibiotic named "Lysocin E". Lysocin E was identified using a silkworm model of bacterial infection. The current review discusses the advantages of using a silkworm model of bacterial infection to identify and develop therapeutically efficacious antimicrobials. This review also discusses the discovery of lysocin E and its novel mechanism of action.
We have used silkworms, larva of Bombyx mori, to investigate host-pathogen interactions. Silkworms have several advantages, such as high availability of a large number of animals and ease of injection of quantitative amounts of samples. Human pathogenic bacteria such as Staphylococcus aureus, Streptococcus pyogenes, or Pseudomonas aeruginosa kill silkworms. In this review, I would like to summarize our approach identifying S. aureus virulence factors by using the silkworm infection model.
Since 2000, transgenic silkworms have been developed to produce recombinant proteins with therapeutic potential for future clinical use, including antibody preparations. Lysosomal storage diseases (LSDs) are inherited metabolic disorders caused by mutations of lysosomal enzymes associated with excessive accumulation of natural substrates and neurovisceral symptoms. Over the past few years, enzyme replacement therapy (ERT) with human lysosomal enzymes produced by genetically engineered mammalian cell lines has been used clinically to treat several patients with an LSD involving multi-organ symptoms. ERT is based on the incorporation of recombinant glycoenzymes by their binding to glycan receptors on the surface of target cells and their subsequent delivery to lysosomes. However, ERT has several disadvantages, including difficulty mass producing human enzymes, dangers of pathogen contamination, and high costs. Recently, the current authors have succeeded in producing transgenic silkworms overexpressing human lysosomal enzymes in the silk glands and the authors have purified catalytically active enzymes from the middle silk glands. Silk gland-derived human enzymes carrying high-mannose and pauci-mannose N-glycans were endocytosed by monocytes via the mannose receptor pathway and were then delivered to lysosomes. Conjugates with cell-penetrating peptides were also taken up by cultured fibroblasts derived from patients with enzyme deficiencies to restore intracellular catalytic activity and reduce the excessive accumulation of substrates in patient fibroblasts. Transgenic silkworms overexpressing human lysosomal enzymes in the silk glands could serve as future bioresources that provide safe therapeutic enzymes for the treatment of LSDs. Combining recent developments in transglycosylation technology with microbial endoglycosidases will promote the development of therapeutic glycoproteins as bio-medicines.
Evaluation of tissue injury induced by chemicals is crucial to drug development. Mice and rats, which are effectively used to analyze drug-induced tissue injury, present problems in terms of cost and ethical issues. Although alternative methods have been developed using in vitro techniques or invertebrates, evaluation of ADME and the size of animals are still issues that need to be addressed. Use of silkworms can resolve these problems. Silkworms have pharmacokinetic characteristics similar to those of mammals. Injection of various hepatotoxic chemicals also leads to elevated alanine aminotransferase (ALT) activity in the hemolymph of silkworms. Furthermore, transparent transgenic silkworms expressing GFP have been produced to facilitate continuous analysis without the need to collect hemolymph. Analyses using this silkworm have indicated that the intensity of GFP fluorescence observed on the body surface of the silkworm decreases in a time- and dose-dependent manner when hepatotoxic chemicals are injected. These results suggest that the silkworms can serve as alternative animal model for evaluation of drug-induced tissue injury.
The silkworm infection assay is a useful method for directly evaluating the in vivo therapeutic effects of drug candidates. In the present study, 3 known trichothecenes, trichodermin, epiisororidin E, and verrucarin A, were evaluated as antifungal agents in the silkworm-Candida albicans assay. Trichodermin and epiisororidin E yielded effective therapeutic effects, while verrucarin A exhibited no efficacy in this assay system. These results strongly suggest that trichodermin and epiisororidin E are the lead compounds for developing a new antifungal agent.
Lactic acid bacteria (LAB) have been thought to be helpful for human heath in the gut as probiotics. It recently was noted that activity of LAB stimulating immune systems is important. Innate immune systems are conserved in mammals and insects. Silkworm has innate immunity in response to microbes. Microbe-associated molecular pattern (ex. peptidoglycan and β-glucan) induces a muscle contraction of silkworm larva. In this study, we established an efficient method to isolate lactic acid bacteria derived from natural products. We selected a highly active LAB to activate the innate immunity in silkworm by using the silkworm muscle contraction assay, as well. The assay revealed that Lactococcus lactis 11/19-B1 was highly active on the stimulation of the innate immunity in silkworm. L. lactis 11/19-B1 solely fermented milk with casamino acid and glucose. This strain would be a starter strain to make yogurt. Compared to commercially available yogurt LAB, L. lactis 11/19-B1 has higher activity on silkworm contraction. Silkworm normally ingested an artificial diet mixed with L. lactis 11/19-B1 or a yogurt fermented with L. lactis 11/19-B1. Interestingly, silkworms that ingested the LAB showed tolerance against the pathogenicity of Pseudomonas aeruginosa. These data suggest that Lactococcus lactis 11/19-B1 would be expected to be useful for making yogurt and probiotics to activate innate immunity.
This study performed an acute oral toxicity test of 59 compounds in silkworms. These compounds are listed in OECD guidelines as standard substances for a cytotoxicity test, and median lethal dose (LD50) werecalculated for each compound. Acute oral LD50 values in mammals are listed in OECD guidelines and acute oral LD50 values in silkworms were determined in this study. R2 for the correlation between LD50 values in mammals and LD50 values in silkworms was 0.66. In addition, the acute oral toxicity test in silkworms was performed by two different facilities, and test results from the facilities were highly reproducible. These findings suggest that an acute oral toxicity test in silkworms is a useful way to evaluate the toxicity of compounds in mammals.
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