Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells

Mazzio, Elizabeth; Georges, Beatrice; McTier, O.; Soliman, Karam F.A.

doi:10.1007/s11064-015-1560-y

Cited by 9 publications

(9 citation statements)

References 74 publications

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“…The findings in this study corroborate our previous finding in that the seed also contains a neuritogenic factor [ 19 ], further classified as a protein or peptide having a mass of 17 kDa. Given the lack of annotation for the Momordica cochinchinensis proteome, identification of proteins was limited to that previously sequenced confirming some sequences similar to the highly ubiquitous 11S globulin and napin seed storage proteins, oleosin, and specific Momordica genus cyclotides: trypsin inhibitors I (MCoTI-I), 2 (MCoTI-II), and TIPTOP proteins.…”

Section: Discussionsupporting

confidence: 91%

“…Recently, in a discovery-based approach, we screened over an 1100 food/plant-based product to determine if any of these could elicit basic neurite outgrowth in PC-12 cells to an extent similar to NGF. We elucidated the seed of Mu Bie Zi , Momordica cochinchinensis, while finding no mimetic effects in the fruit [ 19 ]. In the current study we explore the biological nature of constituents responsible for neuritogenic effects.…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, we recently completed a high throughput screening of over 1100 nutraceuticals (polyphenolics, crude herbs, vitamins, seeds, nuts, fruits, vegetables, etc.) to determine if there any plant or traditionally used natural medicines that contain a neuritogenic factor [ 19 ]. The results were remarkable in that we only found a single hit, which was the crude extract of Gac fruit seed (aril removed), with a botanical name of Momordica cochinchinensis (MCS) .…”

Section: Introductionmentioning

confidence: 99%

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Bioactivity-Guided Isolation of Neuritogenic Factor from the Seeds of the Gac Plant (Momordica cochinchinensis)

Mazzio

Badisa

Eyunni

et al. 2018

Evidence-Based Complementary and Alternative Medicine

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Nerve growth factor (NGF) is an endogenously produced protein with the capacity to induce central nervous system (CNS) neuronal differentiation and repair. NGF signaling involves its binding to tropomyosin-related kinase (Trk) receptors, internalization, and initiation of phosphorylation cascades which cause microtubule reorganization and neuronal outgrowth. Because NGF cannot cross the blood-brain barrier, its therapeutic use is limited. Synthetic peptides that can act as NGF receptor agonists (NGF mimetics) are known to attenuate neurodegenerative pathologies in experimental models of Alzheimer's disease and Parkinson's disease; however, the existence of plant-based NGF mimetics is uncertain. For this reason, we recently completed a high throughput screening of over 1100 nutraceuticals (vitamins, herbal plant parts, polyphenolics, teas, fruits, and vegetables) to identify neuritogenic factor using a PC-12 cell model. Remarkably we found only one, commonly known as the seed of Gac plant (Momordica cochinchinensis) (MCS). In the current study, we further investigated this seed for its neuritogenic effect using bioactivity-guided chemical separations. The data show no biological neuritogenic activity in any chemical solvent fraction, where activity was exclusive to the crude protein. MSC crude proteins were then separated by 1D electrophoresis, where the active neuritogenic activity was confirmed to have a molecular mass of approximately 17 kDa. Subsequently, the 17kDa band was excised, digested, and run on a UPLC-MS/MS with a Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer with data evaluated diverse tools such as X! Tandem, OMS, and K-score algorithms. Proteomic evaluation of the 17kDa band confirmed evidence for 11S globulin subunit beta, napin, oleosin, Momordica trypsin inhibitors (TI) MCoTI-I /II, and many isoforms of Two Inhibitor Peptide Topologies (TIPTOPs). While all peptides identified correspond to the genus/species, Momordica cochinchinensis and Cucumis Sativus, a significant limitation of the analysis is the nonexistence of full annotation for the Momordica cochinchinensis proteome. In conclusion, these findings demonstrate that there is a stable protein within MCS having a mass of 17kDa with the capacity to induce neurite outgrowth. Future work will be required to establish the therapeutic value of the MCS for the treatment of neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bioactivity-Guided Isolation of Neuritogenic Factor from the Seeds of the Gac Plant (Momordica cochinchinensis)

Mazzio

Badisa

Eyunni

et al. 2018

Evidence-Based Complementary and Alternative Medicine

Self Cite

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“…For example, Seow et al (13) suggested that 6-shogaol, a compound derived from ginger (Zingiber officinale var officinale), induced neurite outgrowth. In another study, Momordica cochinchinensis seed displayed NGF-mimetic activity and induced neurite outgrowth in PC-12 cells (14). Moreover, the neuronal differentiation effect of growth factors has been extensively studied.…”

Section: Introductionmentioning

confidence: 98%

Recombinant stromal cell‑derived factor‑1 protein promotes neurite outgrowth in PC‑12 cells

Yun¹,

Jang

2020

Mol Med Rep

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Stromal cell-derived factor-1 (SDF-1) is a chemokine involved in neuronal differentiation, as well as proliferation and migration. In the present study, the effects of recombinant SDF-1 on neurite outgrowth for nerve regeneration and engineering were evaluated in PC-12 cells. The effects of purified SDF-1 protein on cell toxicity, proliferation and migration were also assessed. SDF-1 significantly augmented cell proliferation in a dose-dependent manner, with low cytotoxicity in PC-12 cells. Cell migration also increased in the presence of SDF-1. SDF-1 significantly increased neurite number and length, compared with the control (untreated cells). Neurofilament mRNA levels, which are involved in neuronal differentiation, were also significantly upregulated in the presence of SDF-1. These results suggested that SDF-1 might prove useful for tissue engineering through induction of neuronal differentiation.

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“…Previously, we discovered that an extract of the seed of the Momordica cochinchinensis exerted neurotrophic, NGF mimetic effects in PC-12 cells . While the molecular basis of this effect remains to be determined, the cystine-knot motif of NGF put us in mind of the MCoTI plant defense proteins, which similarly contain a cystine knot and also could bind with high affinity to Family S1 serine endopeptidases. − MCoTI-I and -II are found in the M.…”

Section: Introductionmentioning

confidence: 99%

In Silico Investigation of the Binding of MCoTI-II Plant Defense Knottin to the γ-NGF Serine Protease of the 7S Nerve Growth Factor Complex and Biological Activity of Its NGF Mimetic Properties

et al. 2019

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Nerve growth factor (NGF) is an endogenously produced polypeptide that promotes the differentiation, survival, and repair of neurons in the central and peripheral nervous systems. While trophic proteins hold promise for the treatment of neuronal injury and disease, use of NGF is limited by its large molecular weight, lack of permeability through the blood–brain barrier, and peripheral side effects. Previously, we found that an extract of the Momordica cochinchinensis seed stimulated PC-12 neurite outgrowth. Bioactivity-guided fractioning of the seed extract suggested that the NGF mimetic agent was one of few defined proteins from this plant: one group being the defense Knottins and the other group of the lowest mass is the potent trypsin inhibitor MCoTI-II. Here, the NGF mimetic potential of this latter protein was investigated using two concurrent but different approaches. A biological study used recombinant purified MCoTI-II, which when tested in rat PC-12 cells grown on collagen, failed to initiate outgrowth relative to the positive control 7S NGF. In a separate computational study, the possibility was investigated such that MCoTI-II could exert an effect through binding to the serine protease γ-NGF subunit of the 7S NGF complex, analogous to its binding to its native receptor trypsin. Molecular dynamics simulations showed that MCoTI-II can bind stably to γ-NGF for >350 ns. Modeling indicated that this interaction could sterically inhibit 7S NGF complex formation, potentially altering the equilibrium between inactive complexed and free active NFG protein. In conclusion, the biological study now excludes the MCoTI-II protein as the NGF mimetic factor in the Momordica extract, an important and required step to identify the active component in this seed. On the other hand, the theoretical study has revealed a novel observation that may be of use in the development of strategies to affect NGF activity.

show abstract

Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells

Cited by 9 publications

References 74 publications

Bioactivity-Guided Isolation of Neuritogenic Factor from the Seeds of the Gac Plant (Momordica cochinchinensis)

Bioactivity-Guided Isolation of Neuritogenic Factor from the Seeds of the Gac Plant (Momordica cochinchinensis)

Recombinant stromal cell‑derived factor‑1 protein promotes neurite outgrowth in PC‑12 cells

In Silico Investigation of the Binding of MCoTI-II Plant Defense Knottin to the γ-NGF Serine Protease of the 7S Nerve Growth Factor Complex and Biological Activity of Its NGF Mimetic Properties

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