Nov 2016, Volume 11 Issue 5
    

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  • REVIEW
    Modeling axonal defects in hereditary spastic paraplegia with human pluripotent stem cells
    Kyle R. Denton,Chongchong Xu,Harsh Shah,Xue-Jun Li
    2016, 11(5): 339-354. https://doi.org/10.1007/s11515-016-1416-0
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    BACKGROUND: Cortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders including hereditary spastic paraplegia (HSP). Since the discovery of the first HSP gene, SPAST that encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remain largely unknown. The development of induced pluripotent stem cell (iPSC) technology has provided researchers an excellent resource to generate patient-specific human neurons to model human neuropathological processes including axonal defects.

    METHODS: In this article, we will first review the pathology and pathways affected in the common forms of HSP subtypes by searching the PubMed database. We will then summarize the findings and insights gained from studies using iPSC-based models, and discuss challenges and future directions.

    RESULTS: HSPs, a heterogeneous group of genetic neurodegenerative disorders, exhibit similar pathological changes that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport, recapitulating disease-specific axonal defects.

    CONCLUSIONS: These patient-derived neurons offer a unique tool to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy.

  • REVIEW
    Metabolism of pluripotent stem cells
    Liang Hu,Edward Trope,Qi-Long Ying
    2016, 11(5): 355-365. https://doi.org/10.1007/s11515-016-1417-z
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    BACKGROUND: Recently, growing attention has been directed toward stem cell metabolism, with the key observation that metabolism not only fuels the proper functioning of stem cells but also regulates the fate of these cells. There seems to be a clear link between the self-renewal of pluripotent stem cells (PSCs), in which cells proliferate indefinitely without differentiation, and the activity of specific metabolic pathways. The unique metabolism in PSCs plays an important role in maintaining pluripotency by regulating signaling pathways and resetting the epigenome.

    OBJECTIVE: To review the most recent publications concerning the metabolism of pluripotent stem cells and the role of metabolism in PSC self-renewal and differentiation.

    METHODS: A systematic literature search related to the metabolism of PSCs was conducted in databases including Medline, Embase, and Web of Science. The search was performed without language restrictions on all papers published before May 2016. The following keywords were used: “metabolism” combined with either “embryonic stem cell” or “epiblast stem cell.”

    RESULTS: Hundreds of papers focusing specifically on the metabolism of pluripotent stem cells were uncovered and summarized.

    CONCLUSION: Identifying the specific metabolic pathways involved in pluripotency maintenance is crucial for progress in the field of developmental biology and regenerative medicine. Additionally, better understanding of the metabolism in PSCs will facilitate the derivation and maintenance of authentic PSCs from species other than mouse, rat, and human.

  • REVIEW
    Finding neoepitopes in mouse models of personalized cancer immunotherapy
    Sahar Al Seesi,Alok Das Mohapatra,Arpita Pawashe,Ion I. Mandoiu,Fei Duan
    2016, 11(5): 366-375. https://doi.org/10.1007/s11515-016-1422-2
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    BACKGROUND: Cancer immunotherapy uses one’s own immune system to fight cancerous cells. As immune system is hard-wired to distinguish self and non-self, cancer immunotherapy is predicted to target cancerous cells specifically, therefore is less toxic than chemotherapy and radiation therapy, two major treatments for cancer. Cancer immunologists have spent decades to search for the specific targets in cancerous cells.

    METHODS: Due to the recent advances in high throughput sequencing and bioinformatics, evidence has merged that the neoantigens in cancerous cells are probably the cancer-specific targets that lead to the destruction of cancer. We will review the transplantable murine tumor models for cancer immunotherapy and the bioinformatics tools used to navigate mouse genome to identify tumor-rejecting neoantigens.

    RESULTS: Several groups have independently identified point mutations that can be recognized by T cells of host immune system. It is consistent with the note that the formation of peptide-MHC I-TCR complex is critical to activate T cells. Both anchor residue and TCR-facing residue mutations have been reported. While TCR-facing residue mutations may directly activate specific T cells, anchor residue mutations improve the binding of peptides to MHC I molecules, which increases the presentation of peptides and the T cell activation indirectly.

    CONCLUSIONS: Our work indicates that the affinity of neoepitopes for MHC I is not a predictor for anti-tumor immune responses in mice. Instead differential agretopic index (DAI), the numerical difference of epitope-MHC I affinities between the mutated and un-mutated sequences is a significant predictor. A similar bioinformatics pipeline has been developed to generate personalized vaccines to treat human ovarian cancer in a Phase I clinical trial.

  • REVIEW
    Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities
    Christopher M. Olsen,Qing-Song Liu
    2016, 11(5): 376-386. https://doi.org/10.1007/s11515-016-1424-0
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    BACKGROUND: Long-term exposure to drugs of abuse causes an upregulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects of drug tolerance and dependence. Phosphodiesterase 4 (PDE4) is an enzyme that the selective hydrolyzes intracellular cAMP. It is expressed in several brain regions that regulate the reinforcing effects of drugs of abuse.

    OBJECTIVE: Here, we review the current knowledge about central nervous system (CNS) distribution of PDE4 isoforms and the effects of systemic and brain-region specific inhibition of PDE4 on behavioral models of drug addiction.

    METHODS: A systematic literature search was performed using the Pubmed.

    RESULTS: Using behavioral sensitization, conditioned place preference and drug self-administration as behavioral models, a large number of studies have shown that local or systemic administration of PDE4 inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids in rats or mice.

    CONCLUSIONS: Preclinical studies suggest that PDE4 could be a therapeutic target for several classes of substance use disorder. We conclude by identifying opportunities for the development of subtype-selective PDE4 inhibitors that may reduce addiction liability and minimize the side effects that limit the clinical potential of non-selective PDE4 inhibitors. Several PDE4 inhibitors have been clinically approved for other diseases. There is a promising possibility to repurpose these PDE4 inhibitors for the treatment of drug addiction as they are safe and well-tolerated in patients.

  • REVIEW
    Antibacterial effect of bestatin during periodontitis
    Hansa Jain
    2016, 11(5): 387-390. https://doi.org/10.1007/s11515-016-1418-y
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    Periodontitis is a polymicrobial disease inciting inflammatory destruction of the tooth-supporting tissues, i.e., periodontium. The initiation of this infectious disease is ascribed to the formation of subgingival biofilms. These biofilms cause stimulation of myriad of chronic inflammatory reactions by the affected tissue. The Gram-negative anaerobe Porphyromonas gingivalis is commonly found as part of the microbiota of subgingival biofilms, and is involved in the occurrence of the disease. P. gingivalis possesses numerous virulence factors supporting its survival, regulating its communication with other species in the biofilm, degrading host tissues. Fusobacterium nucleatum is pivotal for formation of biofilm and promotes growth and invasion properties of P. gingivalis. Bestatin is an aminopeptide inhibitor, produced by actinomycetes. It possesses antibacterial properties against P. gingivalis and F. nucleatum. The following review focuses on action of bestatin on the mentioned bacteria.

  • SHORT COMMUNICATION
    Nucleotide binding domain 1 pharmacophore modeling for visualization and analysis of P-glycoprotein–flavonoid molecular interactions
    Pathomwat Wongrattanakamon,Vannajan Sanghiran Lee,Piyarat Nimmanpipug,Supat Jiranusornkul
    2016, 11(5): 391-395. https://doi.org/10.1007/s11515-016-1421-3
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    BACKGROUND: P-glycoprotein (P-gp) is a 170-kDa membrane protein. It provides a barrier function and help to excrete toxins from the body as a transporter. Some bioflavonoids have been shown to block P-gp activity.

    OBJECTIVE: To evaluate the important amino acid residues within nucleotide binding domain 1 (NBD1) of P-gp that play a key role in molecular interactions with flavonoids using structure-based pharmacophore model.

    METHODS: In the molecular docking with NBD1 models, a putative binding site of flavonoids was proposed and compared with the site for ATP. The binding modes for ligands were achieved using LigandScout to generate the P-gp–flavonoid pharmacophore models.

    RESULTS: The binding pocket for flavonoids was investigated and found these inhibitors compete with the ATP for binding site in NBD1 including the NBD1 amino acid residues identified by the in silico techniques to be involved in the hydrogen bonding and van der Waals (hydrophobic) interactions with flavonoids.

    CONCLUSION: These flavonoids occupy with the same binding site of ATP in NBD1 proffering that they may act as an ATP competitive inhibitor.

  • RESEARCH ARTICLE
    Liver regeneration is associated with lipid reorganization in membranes of the endoplasmic reticulum
    Anatoly I. Bozhkov,Natalia G. Menzyanova,Vadim V. Davydov,Natalia I. Kurguzova,Vadim I. Sidorov,Anastasia S. Vasilieva
    2016, 11(5): 396-403. https://doi.org/10.1007/s11515-016-1420-4
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    BACKGROUND: In recent years, an adaptive endoplasmic reticulum (ER) stress response has been actively investigated. The ER membrane, isolated from the intact and regenerating liver, may be an appropriate model for investigating the association between structural and functional characteristics of ER in vivo and their corresponding behavioral characteristics in vitro. The rate of lipid synthesis and that of intracellular lipid exchange between the ER and cytosol were investigated in the intact and regenerating liver (13 h after partial hepatectomy). Particularly, membrane characteristics, surface potential, and glucose 6-phosphatase (G6Pase) activity were investigated, along with the degradation rate of G6Pase in vitro, which was estimated by the loss of G6Pase activity, formation of lipid peroxides, and size of excreted membrane vesicles.

    METHODS: The rate of lipid synthesis was determined by measuring the intensity of radioactive precursor (C14-sodium acetate) in different fractions of lipids (phospholipids, non-esterified fatty acids, and triacylglycerides) after 30 min exposure. The rate of lipid metabolism was assessed by measuring the quantity of lipids with radioactive labels emerging in the cytosol of hepatocytes (CPM). Viscosity and surface potential were determined by fluorescent probes.

    RESULTS: It was observed that after 13 h of partial hepatectomy, the rate of lipid synthesis in the ER of hepatocytes in the regenerating liver was 3 times lower than that in ER of hepatocytes in the intact liver, wherein the rate of incorporation of newly synthesized lipids in cytosol was several times higher in the regenerating liver. Increase in the rate of exchange of neutral lipids in cells of the regenerating liver was accompanied by lipid reconstruction in the ER, changing the structural and functional characteristics of the membrane. Such membrane rebuilding also contributed to the rate of degradation of the ER in vitro, which that must be taken into account during development of systems for in vitro assessment of xenobiotic metabolism.

    CONCLUSIONS: An increase in the rate of direct (microsomes→cytosol) and reverse transport of lipids (cytosol→microsomes) was observed in the regenerating liver. Microsomes, isolated from the regenerating liver, were degraded in the in vitro system at a higher rate.

  • RESEARCH ARTICLE
    Incidence of T315I mutation in BCR/ABL-positive CML and ALL patients
    Fatemeh Norozi,Javad Mohammadi-asl,Tina Vosoughi,Mohammad Ali Jalali Far,Amal Saki Malehi,Najmaldin Saki
    2016, 11(5): 404-411. https://doi.org/10.1007/s11515-016-1423-1
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    OBJECTIVES: Targeted therapy of Philadelphia-positive ALL and CML patients using imatinib (IM) has caused significant changes in treatment course and has increased the survival of patients. A small group of patients show resistance to IM. Acquired mutations in tyrosine kinase domain of BCR-ABL protein are a mechanism for development of resistance. T315I is one of the most common acquired mutations in this domain, which occurs in ATP binding site and inhibits the formation of hydrogen bond with IM. The aim of this study was to evaluate the prevalence of this mutation in BCR/ABL-positive CML and ALL patients.

    METHODS: To conduct this study, 60 BCR-ABL-positive patients (including 50 CML and 10 ALL patients) who were subject to treatment with IM were selected. After taking the samples, presence of T315I mutation was assessed using ARMS-PCR on cDNA and its polymorphism was evaluated by sequencing.

    RESULTS: The results showed that among 60 patients, only three patients had T315I mutation, which was detected using ARMS technique. The three patients bearing mutation were afflicted with CML and no significant association was found between blood parameters with duration of treatment in presence of mutation.

    CONCLUSIONS: The mutation was found in three CML patients, which indicated lower likelihood and diagnostic value of this mutation in ALL patients. Given the negative direct sequencing results in T315I patients, it can be concluded that ARMS-PCR is a more sensitive technique when the number of cancer cells is low in patients during treatment.