Dataset Information

Toddaculin, Isolated from of Toddalia asiatica (L.) Lam., Inhibited Osteoclastogenesis in RAW 264 Cells and Enhanced Osteoblastogenesis in MC3T3-E1 Cells.

ABSTRACT: Osteoporosis with bone loss is widely recognized as a major health problem. Bone homeostasis is maintained by balancing bone formation and bone resorption. The imbalance caused by increased bone resorption over bone formation can lead to various bone-related diseases such as osteoporosis and rheumatoid arthritis. Osteoclasts are the principal cells responsible for bone resorption and the main targets of anti-resorptive therapies. However, excessive inhibition of osteoclast differentiation may lead to inhibition of osteoblast differentiation. Therefore, it is important to screen for new compounds capable of inhibiting bone resorption and enhancing bone formation. Toddalia asiatica (L.) Lam. has been utilized traditionally for medicinal purposes such as the treatment of rheumatism. Currently, the extract is considered to be a good source of pharmacological agents for the treatment of bone-related diseases, but the active compounds have yet to be identified. We investigated whether toddaculin, derived from Toddalia asiatica (L.) Lam., affects both processes by inhibiting bone resorption and enhancing bone formation. Towards this end, we used pre-osteoclastic RAW 264 cells and pre-osteoblastic MC3T3-E1 cells. We found that toddaculin not only inhibited the differentiation of osteoclasts via activation of the NF-?B, ERK 1/2, and p38 MAPK signaling pathways, but it also induced differentiation and mineralization of osteoblasts by regulating differentiation factors. Thus, toddaculin might be beneficial for the prevention and treatment of osteoporosis.

SUBMITTER: Watanabe A

PROVIDER: S-EPMC4436367 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Toddaculin, Isolated from of Toddalia asiatica (L.) Lam., Inhibited Osteoclastogenesis in RAW 264 Cells and Enhanced Osteoblastogenesis in MC3T3-E1 Cells.

Watanabe Akio A Kumagai Momochika M Mishima Takashi T Ito Junya J Otoki Yurika Y Harada Teppei T Kato Tsuyoshi T Yoshida Mikihiko M Suzuki Misora M Yoshida Izumi I Fujita Kazuhiro K Watai Masatoshi M Nakagawa Kiyotaka K Miyazawa Teruo T

PloS one 20150518 5

Osteoporosis with bone loss is widely recognized as a major health problem. Bone homeostasis is maintained by balancing bone formation and bone resorption. The imbalance caused by increased bone resorption over bone formation can lead to various bone-related diseases such as osteoporosis and rheumatoid arthritis. Osteoclasts are the principal cells responsible for bone resorption and the main targets of anti-resorptive therapies. However, excessive inhibition of osteoclast differentiation may le ...[more]

PMID: 25993011

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Project description:In the present study, two samples of Toddalia asiatica species, both collected from Kenya, were sequenced and comparison of their genome structures carried out with T. asiatica species from China, available in the NCBI database. The genome size of both species from Africa was 158, 508 base pairs, which was slightly larger, compared to the reference genome of T. asiatica from Asia (158, 434 bp). The number of genes was 113 for both species from Africa, consisting of 79 protein-coding genes, 30 transfer RNA (tRNA) genes, and 4 ribosomal RNA (rRNA) genes. Toddalia asiatica from Asia had 115 genes with 81 protein-coding genes, 30 transfer RNA (tRNA) genes, and 4 ribosomal RNA (rRNA) genes. Both species compared displayed high similarity in gene arrangement. The gene number, orientation, and order were highly conserved. The IR/SC boundary structures were the same in all chloroplast genomes. A comparison of pairwise sequences indicated that the three regions (trnH-psbA, rpoB, and ycf1) were more divergent and can be useful in developing effective genetic markers. Phylogenetic analyses of the complete cp genomes and 79 protein-coding genes indicated that the Toddalia species collected from Africa were sister to T. asiatica collected from Asia. Both species formed a sister clade to the Southwest Pacific and East Asian species of Zanthoxylum. These results supported the previous studies of merging the genus Toddalia with Zanthoxylum and taxonomic change of Toddalia asiatica to Zanthoxylum asiaticum, which should also apply for the African species of Toddalia. Biogeographic results demonstrated that the two samples of Toddalia species from Africa diverged from T. asiatica from Asia (3.422 Mya, 95% HPD). These results supported an Asian origin of Toddalia species and later dispersal to Africa and Madagascar. The maxent model analysis showed that Asia would have an expansion of favorable areas for Toddalia species in the future. In Africa, there will be contraction and expansion of the favorable areas for the species. The availability of these cp genomes will provide valuable genetic resources for further population genetics and biogeographic studies of these species. However, more T. asiatica species collected from a wide geographical range are required.

Project description:BACKGROUND:Acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) is an immunosuppressive disease. Over the past decades, it has plagued human health due to the grave consequences in its harness. OBJECTIVE:For this reason, anti-HIV agents are imperative, and the search for the same from natural resources would assure the safety. MATERIALS AND METHODS:In this investigation we have performed molecular docking, molecular property prediction, drug-likeness score, and molecular dynamics (MD) simulation to develop a novel anti-HIV drug. We have screened 12 alkaloids from a medicinal plant Toddalia asiatica for its probabilistic binding with the active site of the HIV-1-reverse transcriptase (HIV-1-RT) domain (the major contributor to the onset of the disease). RESULTS:The docking results were evaluated based on free energies of binding (?G), and the results suggested toddanol, toddanone, and toddalenone to be potent inhibitors of HIV-1-RT. In addition, the alkaloids were subjected to molecular property prediction analysis. Toddanol and toddanone with more rotatable bonds were found to have a drug-likeness score of 0.23 and 0.11, respectively. These scores were comparable with the standard anti-HIV drug zidovudine with a model score 0.28. Finally, two characteristic protein-ligand complexes were exposed to MD simulation to determine the stability of the predicted conformations. CONCLUSION:The toddanol-RT complex showed higher stability and stronger H-bonds than toddanone-RT complex. Based on these observations, we firmly believe that the alkaloid toddanol could aid in efficient HIV-1 drug discovery. SUMMARY:In the present study, the molecular docking and MD simulations are performed to explore the possible binding mode of HIV 1 RT with 12 alkaloids of T. asiatica. Molecular docking by AutoDock4 revealed three alkaloids toddanol, toddanone, and toddalenone with highest binding affinity towards HIV 1 RT. The drug likeness model score revealed a positive score for toddanol and toddanone which is comparable to the drug likeness score of the standard anti HIV drug zidovudine. Results from simulation analysis revealed that toddanol RT complex is more stable than toddanone RT complex inferring toddanol as a potential anti HIV drug molecule. Abbreviations used: HIV: Human immunodeficiency virus, HIV 1 RT: HIV 1 reverse transcriptase, RNase H: Ribonuclease H, MD: Molecular dynamics, PDB: Protein databank, RMSD: Root mean square deviation, RMSF: Root mean square fluctuation.

Dataset Information

Toddaculin, Isolated from of Toddalia asiatica (L.) Lam., Inhibited Osteoclastogenesis in RAW 264 Cells and Enhanced Osteoblastogenesis in MC3T3-E1 Cells.

Publications

Toddaculin, Isolated from of Toddalia asiatica (L.) Lam., Inhibited Osteoclastogenesis in RAW 264 Cells and Enhanced Osteoblastogenesis in MC3T3-E1 Cells.

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