scholarly journals Therapeutic suppression of proteolipid protein rescues Pelizaeus-Merzbacher Disease in mice

2018 ◽  
Author(s):  
Matthew S. Elitt ◽  
Lilianne Barbar ◽  
H. Elizabeth Shick ◽  
Berit E. Powers ◽  
Yuka Maeno-Hikichi ◽  
...  
Keyword(s):  
Motor Behavior ◽  
Therapeutic Potential ◽  
Point Mutations ◽  
Proteolipid Protein ◽  
Neurological Dysfunction ◽  
Extended Lifespan ◽  
Myelin Disorders ◽  
New Treatment ◽  
Pelizaeus Merzbacher Disease

Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and severe neurological dysfunction in the X-linked pediatric leukodystrophy Pelizaeus-Merzbacher disease (PMD). The majority of PLP1 variants, including supernumerary copies and various point mutations, lead to early mortality. However, PLP1-null patients and mice display comparatively mild phenotypes, suggesting that reduction of aberrant PLP1 expression might provide a therapeutic strategy across PMD genotypes. Here we show, CRISPR-Cas9 mediated germline knockdown of Plp1 in the severe jimpy (Plp1jp) point mutation mouse model of PMD rescued myelinating oligodendrocytes, nerve conduction velocity, motor function, and lifespan to wild-type levels, thereby validating PLP1 suppression as a therapeutic approach. To evaluate the therapeutic potential of Plp1 suppression in postnatal PMD mice, we tested antisense oligonucleotides (ASOs) that stably decrease mouse Plp1 mRNA and protein in vivo. Administration of a single intraventricular dose of Plp1-targeted ASOs to postnatal jimpy mice increased myelination, improved motor behavior, and extended lifespan through an 8-month endpoint. Collectively, these results support the development of PLP1 suppression as a disease-modifying therapy for most PMD patients. More broadly, we demonstrate that RNA therapeutics can be delivered to oligodendrocytes in vivo to modulate neurological function and lifespan, opening a new treatment modality for myelin disorders.

scholarly journals Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia

Blood ◽  
2012 ◽  
Vol 120 (17) ◽  
pp. 3510-3518 ◽  
Author(s):  
Shannon L. Maude ◽  
Sarah K. Tasian ◽  
Tiffaney Vincent ◽  
Junior W. Hall ◽  
Cecilia Sheen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Therapeutic Potential ◽  
Lymphoblastic Leukemia ◽  
Mammalian Target Of Rapamycin ◽  
Philadelphia Chromosome ◽  
Point Mutations ◽  
Human Leukemia ◽  
Xenograft Models

Abstract CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)–like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK-activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared with vehicle (P < .01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and highlight the therapeutic potential of targeted kinase inhibition in Ph-like ALL.

The myelin proteolipid DMalpha in fishes

2009 ◽  
Vol 6 (2) ◽  
pp. 109-112 ◽  
Author(s):  
Christian Brösamle
Keyword(s):  
Fish Species ◽  
Sequence Data ◽  
Point Mutations ◽  
Proteolipid Protein ◽  
Scaffolding Protein ◽  
Extant Species ◽  
Actinopterygian Fishes ◽  
The Central Nervous System ◽  
Pelizaeus Merzbacher Disease ◽  
Myelin Proteolipid

Vertebrate myelin membranes are compacted and held in close apposition by three structural proteins of myelin, myelin basic protein, myelin protein zero (MPZ) and myelin proteolipid protein (PLP1/DMalpha). PLP1/DMalpha is considered to function as a scaffolding protein and play a role in intracellular trafficking in oligodendrocytes. In humans, point mutations, duplications or deletions of PLP1 are associated with Pelizaeus–Merzbacher disease and spastic paraplegia Type 2. PLP1 is highly conserved between mammals, but less so in lower vertebrates. This has led some researchers to question whether certain fish species express PLP1 orthologues at all, and to suggest that the function of PLP1/DMalpha in the central nervous system (CNS) may have been taken over by MPZ. Here, we review the evidence for the conservation of orthologues of PLP1/DMalpha in actinopterygian fishes and provide a comparison of currently available sequence data across 17 fish species. Our analysis demonstrates that orthologues of PLP1/DMalpha have been retained and are functionally expressed in many, if not all, extant species of bony fish. Many of the amino acids that, when mutated, are associated with severe CNS pathology are conserved in teleosts, demonstrating conservation of essential functions and justifying the development of novel disease models in species such as the zebrafish.

Bispecific antibodies targeting cancer cells

2002 ◽  
Vol 30 (4) ◽  
pp. 507-511 ◽  
Author(s):  
M. Peipp ◽  
T. Valerius
Keyword(s):  
Animal Studies ◽  
Therapeutic Potential ◽  
Antibody Therapy ◽  
Fc Receptor ◽  
Bispecific Antibodies ◽  
Immune Effector ◽  
Effector Cells ◽  
New Treatment

In recent years, antibody therapy has become a new treatment modality for tumour patients, although the majority of responses are only partial and not long lasting. Based on evidence that effector-cell-mediated mechanisms significantly contribute to antibody efficacy in vivo, several approaches are currently persued to improve the interaction between Fc receptor-expressing effector cells and tumour target antigens. These approaches include application of Fc receptor-directed bispecific antibodies, which contain one specificity for a tumour-related antigen and another for a cytotoxic Fc receptor on immune effector cells. Thereby, bispecific antibodies selectively engage cytotoxic trigger molecules on killer cells, avoiding, for example, interaction with inhibitory Fc receptors. In vitro, chemically linked bispecific antibodies directed against the Fcγ receptors FcγRIII (CD16) and FcγRI (CD64), and the Fc α receptor FcαRI (CD89), were significantly more effective than conventional IgG antibodies. Recent animal studies confirmed the therapeutic potential of these constructs. However, results from clinical trials have been less promising so far and have revealed clear limitations of these molecules, such as short plasma half-lives compared with conventional antibodies. In this review, we briefly summarize the scientific background for bispecific antibodies, and describe the rationale for the generation of novel recombinant molecules. These constructs may allow us to more specifically tailor pharmacokinetic properties to the demands of clinical applications.

The molecular and cellular defects underlying Pelizaeus–Merzbacher disease

2008 ◽  
Vol 10 ◽  
Author(s):  
Karen J. Woodward
Keyword(s):  
Current Knowledge ◽  
Point Mutations ◽  
Proteolipid Protein ◽  
Major Protein ◽  
Cellular Mechanisms ◽  
Underlying Causes ◽  
The Central Nervous System ◽  
Genomic Disorders ◽  
Pelizaeus Merzbacher Disease

Pelizaeus–Merzbacher disease (PMD) is a recessive X-linked dysmyelinating disorder of the central nervous system (CNS). The most frequent cause of PMD is a genomic duplication of chromosome Xq22 including the region encoding the dosage-sensitive proteolipid protein 1 (PLP1) gene. The PLP1 duplications are heterogeneous in size, unlike duplications causing many other genomic disorders, and arise by a distinct molecular mechanism. Other causes of PMD include PLP1 deletions, triplications and point mutations. Mutations in the PLP1 gene can also give rise to spastic paraplegia type 2 (SPG2), an allelic form of the disease. Thus, there is a spectrum of CNS disorder from mild SPG2 to severe connatal PMD. PLP1 encodes a major protein in CNS myelin and is abundantly expressed in oligodendrocytes, the myelinating cells of the CNS. Significant advances in our understanding of PMD have been achieved by investigating mutant PLP1 in PMD patients, animal models and in vitro studies. How the different PLP1 mutations and dosage effects give rise to PMD is being revealed. Interestingly, the underlying causes of pathogenesis are distinct for each of the different genetic abnormalities. This article reviews the genetics of PMD and summarises the current knowledge of causative molecular and cellular mechanisms.

scholarly journals Non-coding nucleotides and amino acids near the active site regulate peptide deformylase expression and inhibitor susceptibility in Chlamydia trachomatis

Microbiology ◽  
2011 ◽  
Vol 157 (9) ◽  
pp. 2569-2581 ◽  
Author(s):  
Xiaofeng Bao ◽  
Niseema D. Pachikara ◽  
Christopher B. Oey ◽  
Amit Balakrishnan ◽  
Lars F. Westblade ◽  
...  
Keyword(s):  
Amino Acids ◽  
Chlamydia Trachomatis ◽  
Active Site ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Point Mutations ◽  
Peptide Deformylase ◽  
Sequencing Data

Chlamydia trachomatis, an obligate intracellular bacterium, is a highly prevalent human pathogen. Hydroxamic-acid-based matrix metalloprotease inhibitors can effectively inhibit the pathogen both in vitro and in vivo, and have exhibited therapeutic potential. Here, we provide genome sequencing data indicating that peptide deformylase (PDF) is the sole target of the inhibitors in this organism. We further report molecular mechanisms that control chlamydial PDF (cPDF) expression and inhibition efficiency. In particular, we identify the σ66-dependent promoter that controls cPDF gene expression and demonstrate that point mutations in this promoter lead to resistance by increasing cPDF transcription. Furthermore, we show that substitution of two amino acids near the active site of the enzyme alters enzyme kinetics and protein stability.

Gene Silencing using siRNA for Preventing Liver Ischaemia-Reperfusion Injury

2018 ◽  
Vol 24 (23) ◽  
pp. 2692-2700 ◽  
Author(s):  
H. Susana Marinho ◽  
Paulo Marcelino ◽  
Helena Soares ◽  
Maria Luísa Corvo
Keyword(s):  
Gene Silencing ◽  
Reperfusion Injury ◽  
Therapeutic Potential ◽  
Major Complication ◽  
Ischaemia Reperfusion Injury ◽  
Small Interference Rna ◽  
Ischaemia Reperfusion ◽  
Promising Therapeutic Approach ◽  
Sirna Therapy

Background: Ischaemia-reperfusion injury (IRI), a major complication occurring during organ transplantation, involves an initial ischemia insult, due to loss of blood supply, followed by an inflammation-mediated reperfusion injury. A variety of molecular targets and pathways involved in liver IRI have been identified. Gene silencing through RNA interference (RNAi) by means of small interference RNA (siRNA) targeting mediators of IRI is a promising therapeutic approach. Objective: This study aims at reviewing the use of siRNAs as therapeutic agents to prevent IRI during liver transplantation. Method: We review the crucial choice of siRNA targets and the advantages and problems of the use of siRNAs. Results: We propose possible targets for siRNA therapy during liver IRI. Moreover, we discuss how drug delivery systems, namely liposomes, may improve siRNA therapy by increasing siRNA stability in vivo and avoiding siRNA off-target effects. Conclusion: siRNA therapeutic potential to preclude liver IRI can be improved by a better knowledge of what molecules to target and by using more efficient delivery strategies.

Phytosomal Curcumin Elicits Anti-tumor Properties Through Suppression of Angiogenesis, Cell Proliferation and Induction of Oxidative Stress in Colorectal Cancer

2019 ◽  
Vol 24 (39) ◽  
pp. 4626-4638 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Seyed M. Hassanian ◽  
Farzad Rahmani ◽  
Seyed H. Aghaee-Bakhtiari ◽  
Amir Avan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Vegf Signaling ◽  
Anticancer Effects ◽  
Inhibition Of Angiogenesis ◽  
Underlying Mechanisms ◽  
Apoptotic Activity

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-associated mortality in the world. Anti-tumor effect of curcumin has been shown in different cancers; however, the therapeutic potential of novel phytosomal curcumin, as well as the underlying molecular mechanism in CRC, has not yet been explored. Methods: The anti-proliferative, anti-migratory and apoptotic activity of phytosomal curcumin in CT26 cells was assessed by MTT assay, wound healing assay and Flow cytometry, respectively. Phytosomal curcumin was also tested for its in-vivo activity in a xenograft mouse model of CRC. In addition, oxidant/antioxidant activity was examined by DCFH-DA assay in vitro, measurement of malondialdehyde (MDA), Thiol and superoxidedismutase (SOD) and catalase (CAT) activity and also evaluation of expression levels of Nrf2 and GCLM by qRT-PCR in tumor tissues. In addition, the effect of phytosomal curcumin on angiogenesis was assessed by the measurement of VEGF-A and VEGFR-1 and VEGF signaling regulatory microRNAs (miRNAs) in tumor tissue. Results: Phytosomal curcumin exerts anti-proliferative, anti-migratory and apoptotic activity in-vitro. It also decreases tumor growth and augmented 5-fluorouracil (5-FU) anti-tumor effect in-vivo. In addition, our data showed that induction of oxidative stress and inhibition of angiogenesis through modulation of VEGF signaling regulatory miRNAs might be underlying mechanisms by which phytosomal curcumin exerted its antitumor effect. Conclusion: Our data confirmed this notion that phytosomal curcumin administrates anticancer effects and can be used as a complementary treatment in clinical settings.

Medicinal Plants and Bioactive Compounds for Diabetes Management: Important Advances for Drug Discovery

2020 ◽  
Vol 26 ◽  
Author(s):  
Kondeti Ramudu Shanmugam ◽  
Bhasha Shanmugam ◽  
Gangigunta Venkatasubbaiah ◽  
Sahukari Ravi ◽  
Kesireddy Sathyavelu Reddy
Keyword(s):  
Herbal Medicine ◽  
Medicinal Plants ◽  
Bioactive Compounds ◽  
Diabetes Management ◽  
Therapeutic Potential ◽  
Public Health Problem ◽  
In Vivo Studies ◽  
Major Public Health Problem

Background : Diabetes is a major public health problem in the world. It affects each and every part of the human body and also leads to organ failure. Hence, great progress made in the field of herbal medicine and diabetic research. Objectives: Our review will focus on the effect of bioactive compounds of medicinal plants which are used to treat diabetes in India and other countries. Methods: Information regarding diabetes, oxidative stress, medicinal plants and bioactive compounds were collected from different search engines like Science direct, Springer, Wiley online library, Taylor and francis, Bentham Science, Pubmed and Google scholar. Data was analyzed and summarized in the review. Results and Conclusion: Anti-diabetic drugs that are in use have many side effects on vital organs like heart, liver, kidney and brain. There is an urgent need for alternative medicine to treat diabetes and their disorders. In India and other countries herbal medicine was used to treat diabetes. Many herbal plants have antidiabetic effects. The plants like ginger, phyllanthus, curcumin, aswagandha, aloe, hibiscus and curcuma showed significant anti-hyperglycemic activities in experimental models and humans. The bioactive compounds like Allicin, azadirachtin, cajanin, curcumin, querceitin, gingerol possesses anti-diabetic, antioxidant and other pharmacological properties. This review focuses on the role of bioactive compounds of medicinal plants in prevention and management of diabetes. Conclusion: Moreover, our review suggests that bioactive compounds have the potential therapeutic potential against diabetes. However, further in vitro and in vivo studies are needed to validate these findings.

Induction of Apoptosis by Nano‐Synthesized Complexes of H2L and its Cu(II) Complex in Human Hepatocellular Carcinoma Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Thoria Diab ◽  
Tarek M. Mohamed ◽  
Alaa Hamed ◽  
Mohamed Gaber
Keyword(s):  
Cell Cycle ◽  
Metal Complexes ◽  
Hepg2 Cells ◽  
Therapeutic Potential ◽  
Free Ligand ◽  
Organometallic Complexes ◽  
Phase Cell ◽  
Sod Activity ◽  
Induced Apoptosis

Background: Chemotherapy is currently the most utilized treatment for cancer. Therapeutic potential of metal complexes in cancer therapy has attracted a lot of interest. The mechanisms of action of most organometallic complexes are poorly understood. Objective: This study was designed to explore the mechanisms governing the anti-proliferative effect of the free ligand N1,N6‐bis((2‐hydroxynaphthalin‐1‐yl)methinyl)) adipohydrazone (H2L) and its complexes of Mn(II), Co(II), Ni(II) and Cu(II). Methods: Cells were exposed to H2L or its metal complexes where cell viability determined by MTT assay. Cell cycle was analysed by flow cytometry. In addition, qRT-PCR was used to monitor the expression of Bax and Bcl-2. Moreover, molecular docking was carried out to find the potentiality of Cu(II) complex as an inhibitor of Adenosine Deaminase (ADA). ADA, Superoxide Dismutase (SOD) and reduced Glutathione (GSH) levels were measured in the most affected cancer cell line. Results: The obtained results demonstrated that H2L and its Cu(II) complex exhibited a strong cytotoxic activity compared to other complexes against HepG2 cells (IC50 = 4.14±0.036μM/ml and 3.2±0.02μM/ml), respectively. Both H2L and its Cu(II) complex induced G2/M phase cell cycle arrest in HepG2 cells. Additionally, they induced apoptosis in HepG2 cells via upregulation of Bax and downregulation of Bcl-2. Interestingly, the activity of ADA was decreased by 2.8 fold in HepG2 cells treated with Cu(II) complex compared to untreated cells. An increase of SOD activity and GSH level in HepG2 cells compared to control was observed. Conclusion: The results concluded that Cu(II) complex of H2L induced apoptosis in HepG2 cells. Further studies are needed to confirm its anti-cancer effect in vivo.

scholarly journals mRNA-Driven Generation of Transgene-Free Neural Stem Cells from Human Urine-Derived Cells

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1043 ◽  
Author(s):  
Phil Jun Kang ◽  
Daryeon Son ◽  
Tae Hee Ko ◽  
Wonjun Hong ◽  
Wonjin Yun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Urine ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Global Gene Expression ◽  
Patient Specific ◽  
Human Neural Stem Cells

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

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