ABSTRACT
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by resting tremor, bradykinesia, muscle rigidity, and abnormal gait. The low-density lipoprotein receptor-related protein 10 (LRP10) was recently shown to be a causal gene for PD, and different ethnic cohorts have distinct frequencies and spectrum of LRP10 variants. METHODS: We sequenced the full coding regions and exon-intron boundaries of LRP10 in 129 patients with sporadic Chinese PD to further investigate the connection of LRP10 with PD in a sample of Chinese patients. RESULTS: In this study, we identified four potentially pathogenic mutations, including one novel mutation of p.Gly328Asp and three known mutations of p.Cys165Tyr, p.Arg230Trp, and p.Arg661His in four of the 129 Chinese patients with PD. CONCLUSION: According to our study, the LRP10 gene may attribute to PD pathogenesis.
Subject(s)
LDL-Receptor Related Proteins , Parkinson Disease , Humans , East Asian People , Exons , Introns , LDL-Receptor Related Proteins/genetics , Mutation , Parkinson Disease/geneticsABSTRACT
Neurodegenerative diseases (NDs) are a group of neurological diseases caused by the progressive degeneration of neurons and glial cells in the brain and spinal cords. Usually there is a selective loss of specific neuronal cells in a restricted brain area from any neurodegenerative diseases, such as dopamine (DA) neuron death in Parkinson disease (PD) and motor neuron loss in amyotrophic lateral sclerosis (ALS), or a widespread degeneration affecting many types of neurons in Alzheimer's disease (AD). As there is no effective treatment to stop the progression of these neurodegenerative diseases, stem cell-based therapies have provided great potentials for these disorders. Currently transplantation of different stem cells or their derivatives has improved neural function in animal models of neurodegenerative diseases by replacing the lost neural cells, releasing cytokines, modulation of inflammation, and mediating remyelination. With the advance in somatic cell reprogramming to generate induced pluripotent stem cells (iPS cells) and directly induced neural stem cells or neurons, pluripotent stem cell can be induced to differentiate to any kind of neural cells and overcome the immune rejection of the allogeneic transplantation. Recent studies have proved the effectiveness of transplanted stem cells in animal studies and some clinical trials on patients with NDs. However, some significant hurdles need to be resolved before these preclinical results can be translated to clinic. In particular, we need to better understand the molecular mechanisms of stem cell transplantation and develop new approaches to increase the directed neural differentiation, migration, survival, and functional connections of transplanted stem cells in the pathological environment of the patient's central nerve system.
Subject(s)
Induced Pluripotent Stem Cells , Neurodegenerative Diseases , Pluripotent Stem Cells , Stem Cell Transplantation , Amyotrophic Lateral Sclerosis/therapy , Animals , Humans , Neural Stem Cells , Neurodegenerative Diseases/therapy , Parkinson Disease/therapyABSTRACT
Parkinson's disease (PD) is one of the most common neurodegenerative diseases caused by specific degeneration and loss of dopamine neurons in substantia nigra of the midbrain. PD is clinically characterized by motor dysfunctions and non-motor symptoms. Even though the dopamine replacement can improve the motor symptoms of PD, it cannot stop the neural degeneration and disease progression. Electrical deep brain stimulation (DBS) to the specific brain areas can improve the symptoms, but it eventually loses the effectiveness. Stem cell transplantation provides an exciting potential for the treatment of PD. Current available cell sources include neural stem cells (NSCs) from fetal brain tissues, human embryonic stem cells (hESCs) isolated from blastocyst, and induced pluripotent stem cells (iPSCs) reprogrammed from the somatic cells such as the fibroblasts and blood cells. Here, we summarize the research advance in experimental and clinical studies to transplant these cells into animal models and clinical patients, and specifically highlight the studies to use hESCs /iPSCs-derived dopaminergic precursor cells and dopamine neurons for the treatment of PD, at last propose future challenges for developing clinical-grade dopaminergic cells for treating the PD.
Subject(s)
Embryonic Stem Cells , Induced Pluripotent Stem Cells , Parkinson Disease , Stem Cell Transplantation , Animals , Dopaminergic Neurons/pathology , Humans , Parkinson Disease/therapyABSTRACT
In the past decade, progress in the research on human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) has provided the solid basis to derive retinal pigment epithelium, photoreceptors, and ganglion cells from hESCs/iPSCs for transplantation therapy of retinal degenerative diseases (RDD). Recently, the iPSC-derived retinal pigment epithelium cells have achieved efficacy in treating patients with age-related macular degeneration (AMD). However, there is still much work to be done about the differentiation of hESCs/iPSCs into clinically required retinal cells and improvement in the methods to deliver the cells into the retina of patients. Here we will review the research advances in stem cell transplantation in animal studies and clinical trials as well as propose the challenges for improving the clinical efficacy and safety of hESCs/iPSCs-derived retinal neural cells in treating retinal degenerative diseases.
Subject(s)
Retinal Degeneration , Stem Cell Transplantation , Animals , Cell Differentiation , Embryonic Stem Cells , Humans , Induced Pluripotent Stem Cells , Retinal Degeneration/therapy , Retinal Pigment EpitheliumABSTRACT
Stem cell-based therapy has shown exciting efficacy in pre-clinical studies on different neurodegenerative diseases (NDs). However, no clinically applicable stem-cell-derived neurons are available to the patients with NDs. There exist some obstacles associated with stem cell therapy, which need to be overcome in future clinical studies. In this chapter, more challenges and new strategies will be explored to accelerate the clinical translation of a human embryonic stem cell (hESC)/induced pluripotent stem cell (iPSC)-derived neural cell product to patients with NDs.
Subject(s)
Neurodegenerative Diseases , Stem Cell Transplantation , Cell Differentiation , Embryonic Stem Cells , Humans , Induced Pluripotent Stem Cells , Neurodegenerative Diseases/therapy , NeuronsABSTRACT
A large number of experimental and clinical studies have shown that cell transplantation has therapeutic effects for PD, AD and other neurodegenerative diseases or damages. Good Manufacturing Practice (GMP) guidance must be defined to produce clinical-grade cells for transplantation to the patients. Standardized quality and clinical preparation procedures of the transplanted cells will ensure the therapeutic efficacy and reduce the side-effect risk of cell therapy. Here we review the cell quality standards governing the clinical transplantation of stem cells for neurodegenerative diseases to clinical practitioners. These quality standards include cell quality control, minimal suggested cell doses for undergoing cell transplantation, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, not charging the patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.
Subject(s)
Cell- and Tissue-Based Therapy/standards , Neurodegenerative Diseases , Stem Cells/cytology , Humans , Neurodegenerative Diseases/therapy , Quality ControlABSTRACT
Alzheimer's disease (AD) is the most common neurodegenerative disease caused by eventually aggregated amyloid ß (Aß) plaques in degenerating neurons of the aging brain. These aggregated protein plaques mainly consist of Aß fibrils and neurofibrillary tangles (NFTs) of phosphorylated tau protein. Even though some cholinesterase inhibitors, NMDA receptor antagonist, and monoclonal antibodies were developed to inhibit neurodegeneration or activate neural regeneration or clear off the Aß deposits, none of the treatment is effective in improving the cognitive and memory dysfunctions of the AD patients. Thus, stem cell therapy represents a powerful tool for the treatment of AD. In addition to discussing the advents in molecular pathogenesis and animal models of this disease and the treatment approaches using small molecules and immunoglobulins against AD, we will focus on the stem cell sources for AD using neural stem cells (NSCs); embryonic stem cells (ESCs); and mesenchymal stem cells (MSCs) from bone marrow, umbilical cord, and umbilical cord blood. In particular, patient-specific-induced pluripotent stem cells (iPS cells) are proposed as a future prospective and the challenges for the treatment of AD.
Subject(s)
Alzheimer Disease , Stem Cell Transplantation , Alzheimer Disease/therapy , Amyloid beta-Peptides , Amyloid beta-Protein Precursor , Animals , Disease Models, Animal , Embryonic Stem Cells , Humans , Induced Pluripotent Stem Cells , Mesenchymal Stem Cells , Mice , Mice, Transgenic , Neural Stem Cells , Plaque, AmyloidABSTRACT
Spinal muscular atrophy (SMA) is a devastating neurodegenerative disease characterized by the degeneration of lower motor neurons in the spinal cord, leading to progressive paralysis and early death in the severe cases. SMA is primarily caused by the mutations in the gene of SMN (survival motor neuron). More research has focused on the development of SMN-targeted replacement therapy for SMA. The first US Food and Drug Administration (FDA)-approved modified antisense oligonucleotide (nusinersen) to treat SMA is to reverse intronic splicing silencer of SMN to produce fully functional SMN2. Recently, stem cell transplantation has shown the potential to repair the injured tissue and differentiate into neurons to rescue the phenotypes of SMA in animal models. In this chapter, we first review the clinical, genetic, and pathogenic mechanisms of SMA. Then, we discuss current pharmacological treatments and point out the therapeutic efficacy of stem cell transplantation and future directions and priorities for SMA.
Subject(s)
Muscular Atrophy, Spinal , Stem Cell Transplantation , Animals , Disease Models, Animal , Humans , Motor Neurons , Muscular Atrophy, Spinal/drug therapy , Muscular Atrophy, Spinal/genetics , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/therapeutic use , RNA Splicing , SMN Complex Proteins/geneticsABSTRACT
The tissue factor pathway inhibitor (TFPI) gene encodes a protease inhibitor with a critical role in regulation of blood coagulation. Some genomic variants in TFPI were previously associated with plasma TFPI levels, however, it remains to be further determined whether TFPI variants are associated with other coagulation factors. In this study, we carried out a large population-based study with 2313 study subjects for blood coagulation data, including fibrinogen levels, prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). We identified significant association of TFPI variant rs10931292 (a functional promoter variant with reduced transactivation) with increased plasma fibrinogen levels (P = 0.017 under a recessive model), but not with PT, APTT or TT (P > 0.05). Using a large case-control association study population with 4479 CAD patients and 3628 controls, we identified significant association between rs10931292 and CAD under a recessive model (OR 1.23, P = 0.005). For the first time, we show that a TFPI variant is significantly associated with fibrinogen levels and risk of CAD. Our finding contributes significantly to the elucidation of the genetic basis and biological pathways responsible for fibrinogen levels and development of CAD.
Subject(s)
Blood Coagulation/genetics , Coronary Artery Disease/genetics , Fibrinogen/genetics , Genetic Association Studies , Lipoproteins/genetics , Coronary Artery Disease/blood , Coronary Artery Disease/pathology , Female , Humans , Male , Partial Thromboplastin Time , Polymorphism, Single Nucleotide/genetics , Prothrombin Time , Risk Factors , Thrombin TimeABSTRACT
BACKGROUND: This study explored the neural differentiation and therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) in a rat model of Parkinson's disease (PD). METHODS: The SHED were isolated from fresh dental pulp and were induced to differentiate to neurons and dopamine neurons by inhibiting similar mothers against dpp (SMAD) signaling with Noggin and increase conversion of dopamine neurons from SHED with CHIR99021, Sonic Hedgehog (SHH) and FGF8 in vitro. The neural-primed SHED were transplanted to the striatum of 6-hydroxydopamine (6-OHDA)-induced PD rats to evaluate their neural differentiation and functions in vivo. RESULTS: These SHED were efficiently differentiated to neurons (62.7%) and dopamine neurons (42.3%) through a newly developed method. After transplantation, the neural-induced SHED significantly improved recovery of the motor deficits of the PD rats. The grafted SHED were differentiated into neurons (61%), including dopamine neurons (22.3%), and integrated into the host rat brain by forming synaptic connections. Patch clamp analysis showed that neurons derived from grafted SHED have the same membrane potential profile as dopamine neurons, indicating these cells are dopamine neuron-like cells. The potential molecular mechanism of SHED transplantation in alleviating motor deficits of the rats is likely to be mediated by neuronal replacement and immune-modulation as we detected the transplanted dopamine neurons and released immune cytokines from SHED. CONCLUSION: Using neural-primed SHED to treat PD showed significant restorations of motor deficits in 6-OHDA-induced rats. These observations provide further evidence that SHED can be used for cell-based therapy of PD.
Subject(s)
Corpus Striatum/transplantation , Motor Activity , Parkinson Disease/physiopathology , Parkinson Disease/therapy , Stem Cell Transplantation , Stem Cells/cytology , Tooth Exfoliation/pathology , Tooth, Deciduous/cytology , Animals , Behavior, Animal , Cell Differentiation , Cell Survival , Child , Child, Preschool , Cytokines/metabolism , Dopaminergic Neurons/cytology , Humans , Male , Oxidopamine , Rats, WistarABSTRACT
OBJECTIVE: To explore the role of sphingomyedlin phosphodiesterase 1 (SMPD1) gene mutations in the pathogenesis of Parkinson's disease (PD). METHODS: For 110 Chinese patients with PD, all exons of the SMPD1 gene were sequenced, and the results were compared with reference sequence from GenBank to identify possible mutations. RESULTS: A novel heterozygous mutation Ex2:c.677C>A/p.P226Q (likely pathogenic) was identified in a patient, which resulted in substitution of Glutamic acid by Proline at position 226. In addition, two known single nucleotide polymorphisms (SNPs) Ex1:c.107T>C/p.V36A (benign) and Ex6:c.1522G>A/p.G508R (benign), and three previously reported SMPD1 mutations Ex2:c.T371T>G/p.L124R (uncertain significance), Ex2:c.636T>C/P.(=)(benign) and Ex6:c.1598C>T/p.P533L (uncertain significance) were identified. The novel p.P226Q mutation and p.P533L mutation were predicted to have a possibly damaging effect on the structure and function of SMPD1 protein, which in turn may lead to PD. CONCLUSION: The mutation rate of the SMPD1 gene was 3.64% among Chinese PD patients. Genetic variants of SMPD1 may increase the risk of PD.
Subject(s)
Asian People/genetics , Mutation , Parkinson Disease/genetics , Sphingomyelin Phosphodiesterase/genetics , Aged , China , Exons , Female , Genetic Association Studies , Genetic Variation , Humans , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Mutations in the ß-glucocerebrosidase gene (GBA) have been implicated as a risk factor for Parkinson's disease (PD). However, GBA mutations in PD patients of different ethnic origins were reported to be inconsistent. METHODS: We sequenced all exons of the GBA gene in 225 PD patients and 110 control individuals from Eastern Canada. RESULT: Two novel GBA variants of c.-119 A/G and S(-35)N, five known GBA mutations of R120W, N370S, L444P, RecNciI and RecTL mutation (del55/D409H/RecNciI) as well as two non-pathological variants of E326K and T369M were identified from PD patients while only one mutation of S13L and two non-pathological variants of E326K and T369M were found in the control individuals. The frequency of GBA mutations within PD patients (4.4%) is 4.8 times higher than the 0.91% observed in control individuals (X(2) = 2.91, p = 0.088; odds ratio = 4.835; 95% confidence interval = 2.524-9.123). The most common mutations of N370S and L444P accounted for 36.0% (9/25) of all the GBA mutations in this Eastern Canadian PD cohort. The frequency (6.67%) of E326K and T369M in PD patients is comparable to 7.27% in control individuals (X(2) = 0.042, p = 0.8376), further supporting that these two variants have no pathological effects on PD. Phenotype analysis showed that no significant difference in family history, age at onset and cognitive impairment was identified between the GBA mutation carriers and non-GBA mutation carriers. CONCLUSION: GBA mutations were found to be a common genetic risk factor for PD in Eastern Canadian patients.
Subject(s)
Genetic Predisposition to Disease , Glucosylceramidase/genetics , Mutation , Parkinson Disease/genetics , Aged , Alleles , Canada , Female , Gene Frequency , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Risk FactorsABSTRACT
Pathological mutations in the glucocerebrosidase gene (GBA) have been suggested to be associated with Parkinson's disease (PD) in various ethnic populations. Most studies on Chinese PD patients have only screened the N370S and L444P mutations in the GBA gene. To investigate the GBA mutations in Chinese population, we performed complete sequencing of the GBA gene in 184 Chinese PD patients and 130 Chinese control individuals. As a result, we identified three novel and nine reported GBA mutations. The novel mutations include 5-bp deletion (c.334_338delCAGAA), L264I and L314V and the nine reported GBA mutations are R163Q, F213I, E326K, S364S, F347L, V375L, L444P, RecNciI and Q497R. The novel 5-bp deletion (CAGAA) produces a short truncated GBA protein of 142 amino acids, which loses major function domains of the 536 amino acids. Our data also reveals that the frequency of GBA mutations within this Chinese PD cohort was 8.7%, which is significantly higher than 1.54% observed in the Chinese control cohort (χ(2) = 7.22, P = 0.0072; odds ratio (OR) = 6.095, 95% confidence interval of OR = 1.546-24.030). The most common L444P mutation accounts 2.74%, which confer more genetic risk for PD in this Chinese population. In conclusion, novel and known GBA mutations were identified and were found to be associated to PD in this Chinese population.
Subject(s)
Genetic Predisposition to Disease/genetics , Glucosylceramidase/genetics , Mutation , Parkinson Disease/genetics , Amino Acid Sequence , Asian People/genetics , Base Sequence , China , Cohort Studies , DNA Mutational Analysis , Female , Gene Frequency , Genetic Predisposition to Disease/ethnology , Haplotypes , Humans , Male , Molecular Sequence Data , Parkinson Disease/ethnology , Polymorphism, Single Nucleotide , Risk Factors , Sequence DeletionABSTRACT
BACKGROUND AIMS: Since human embryonic stem cells and human fetal neural stem cells have immune rejection and ethical issues, recent advancements in induced pluripotent stem cells (iPS cells) provide new possibilities to study autologous cell therapy for Parkinson's disease (PD). METHODS: We isolated human skin fibroblasts from normal individuals and patients with PD; we generated iPS cells by transfecting these human skin fibroblasts with retroviral reprogramming factors of OCT4, SOX2, KLF4 and c-MYC and induced iPS cells to differentiate neural stem cells (NSCs) and then into neurons and dopamine neurons in vitro. RESULTS: We found that iPS cell-derived NSC transplant into the striatum of the 6-hydroxydopamine (OHDA)-induced PD rats improved their functional defects of rotational asymmetry at 4, 8, 12 and 16 weeks after transplantation. iPS cell-derived NSCs were found to survive and integrate into the brain of transplanted PD rats and differentiated into neurons, including dopamine neurons in vivo. CONCLUSIONS: Transplantation of iPS cell-derived NSCs has therapeutic potential for PD. Our study provided experimental proof for future clinical application of iPS cells in cell-based treatment of PD.
Subject(s)
Induced Pluripotent Stem Cells/cytology , Motor Neurons/cytology , Parkinson Disease/therapy , Stem Cell Transplantation , Aged , Animals , Cell Differentiation/drug effects , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Female , Fibroblasts/metabolism , Humans , Immunohistochemistry , Kruppel-Like Factor 4 , Male , Mice , Middle Aged , Neural Stem Cells/cytology , Oxidopamine , Parkinson Disease/pathology , Pluripotent Stem Cells/drug effects , Rats, Sprague-Dawley , Skin/pathology , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Objective: This study aimed to investigate the causal relationship between gut microbiota characteristics (207 taxa and 205 pathways) and Alzheimer's disease and determine and quantify the role of immune cells as potential mediators. Methods: Gut microbiota characteristics (207 taxa and 205 pathways) were obtained from the NHGRI-EBI GWAS Catalog project, while Alzheimer's disease data and 731 immune cell characteristics were obtained from the IEU Open GWAS project. Two-sample Mendelian randomization (MR) was conducted to determine whether gut microbiota characteristics (207 taxa and 205 pathways) were causally related to Alzheimer's disease. Furthermore, two-step MR was employed to quantify the proportion of the effect of immune cell characteristics mediated by gut microbiota characteristics (207 taxa and 205 pathways) on Alzheimer's disease. Results: A total of 17 immune cell characteristics were identified as potential mediators for 13 gut microbiota influencing Alzheimer's disease, with Effector Memory CD4+ T-cell Absolute Count accounted for 8.99% of the causal relationship between genus Oscillibacter and Alzheimer's disease. Conclusion: In summary, our research confirms a causal relationship between gut microbiota and Alzheimer's disease, with immune cells contributing to a significant portion of the effect. However, the full mediators of gut microbiota's impact on Alzheimer's disease remain unclear. Further investigation is warranted to explore additional potential risk factors acting as mediators.
ABSTRACT
Parkinson's disease (PD) is a highly prevalent and severe neurodegenerative disease that affects more than 10 million individuals worldwide. Pathogenic mutations in LRP10 have been associated with autosomal dominant PD. Here, we report an induced pluripotent stem cell (iPSC) line generated from a PD patient harboring the LRP10 c.688C > T (p.Arg230Trp) variant. Skin fibroblasts from the PD patient were successfully reprogrammed into iPSCs that expressed pluripotency markers, a normal karyotype, and the capacity to differentiate into the three germ layers in vivo. This iPSC line is a potential resource for studying the pathogenic mechanisms of PD.
Subject(s)
Induced Pluripotent Stem Cells , Mutation , Parkinson Disease , Induced Pluripotent Stem Cells/metabolism , Humans , Parkinson Disease/genetics , Parkinson Disease/pathology , LDL-Receptor Related Proteins/genetics , LDL-Receptor Related Proteins/metabolism , Cell Line , Cell Differentiation , MaleABSTRACT
Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/ß-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.
Subject(s)
Autophagy , Bleomycin , Cellular Senescence , Lysosomes , Reactive Oxygen Species , Bleomycin/pharmacology , Cellular Senescence/drug effects , Reactive Oxygen Species/metabolism , Lysosomes/metabolism , Lysosomes/drug effects , Autophagy/drug effects , Autophagy/physiology , Animals , Humans , Mice , Intracellular Membranes/metabolism , Intracellular Membranes/drug effects , Permeability/drug effects , Mice, Inbred C57BLABSTRACT
Background and Objectives: Chronic periodontitis can lead to alveolar bone resorption and eventually tooth loss. Stem cells from exfoliated deciduous teeth (SHED) are appropriate bone regeneration seed cells. To track the survival, migration, and differentiation of the transplanted SHED, we used super paramagnetic iron oxide particles (SPIO) Molday ION Rhodamine-B (MIRB) to label and monitor the transplanted cells while repairing periodontal bone defects. Methods and Results: We determined an appropriate dose of MIRB for labeling SHED by examining the growth and osteogenic differentiation of labeled SHED. Finally, SHED was labeled with 25 µg Fe/ml MIRB before being transplanted into rats. Magnetic resonance imaging was used to track SHED survival and migration in vivo due to a low-intensity signal artifact caused by MIRB. HE and immunohistochemical analyses revealed that both MIRB-labeled and unlabeled SHED could promote periodontal bone regeneration. The colocalization of hNUC and MIRB demonstrated that SHED transplanted into rats could survive in vivo. Furthermore, some MIRB-positive cells expressed the osteoblast and osteocyte markers OCN and DMP1, respectively. Enzyme-linked immunosorbent assay revealed that SHED could secrete protein factors, such as IGF-1, OCN, ALP, IL-4, VEGF, and bFGF, which promote bone regeneration. Immunofluorescence staining revealed that the transplanted SHED was surrounded by a large number of host-derived Runx2- and Col II-positive cells that played important roles in the bone healing process. Conclusions: SHED could promote periodontal bone regeneration in rats, and the survival of SHED could be tracked in vivo by labeling them with MIRB. SHED are likely to promote bone healing through both direct differentiation and paracrine mechanisms.
ABSTRACT
Astragalus membranaceus Bunge is widely used in Traditional Chinese Medicine to treat various cancers. AstragalosideIV (ASIV) is one of the major compounds isolated from A. membranaceus Bunge and has been demonstrated to have antitumor effects by inhibiting cell proliferation, invasion and metastasis in various cancer types. Numerous studies have used in vitro cell culture and in vivo animal models of cancer to explore the antitumor activities of ASIV. In the present study, the antitumor effects and mechanisms of ASIV reported in studies recorded in the PubMed database were reviewed. First, the antitumor effects of ASIV on proliferation, cell cycle, apoptosis, autophagy, invasion, migration, metastasis and epithelialmesenchymal transition processes in cancer cells and the tumor microenvironment, including angiogenesis, tumor immunity and macrophagerelated immune responses to cancer cells, were comprehensively discussed. Subsequently, the molecular mechanisms and related signaling pathways associated with antitumor effects of ASIV as indicated by in vitro and in vivo studies were summarized, including the Wnt/AKT/GSK-3ß (glycogen synthase kinase3ß)/ßcatenin, TGFß/PI3K/AKT/mTOR, PI3K/MAPK/mTOR, PI3K/AKT/NFκB, Rac family small GTPase 1/RAS/MAPK/ERK, TNFα/protein kinase C/ERK1/2NFκB and Tregs (Tregulatory cells)/IL11/STAT3 signaling pathways. Of note, several novel mechanisms of Tolllike receptor 4 (TLR4)/NFκB/STAT3, pSmad3C/3L, nuclear factor erythroid 2related factor (NrF2)/heme oxygenase 1, circDLST/microRNA4893p/eukaryotic translation initiation factor 4A1 and macrophagerelated highmobility group box 1TLR4 signaling pathways associated with the anticancer activity of ASIV were also included. Finally, the limitations of current studies that must be addressed in future studies were pointed out to facilitate the establishment of ASIV as a potent therapeutic drug in cancer treatment.
Subject(s)
Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Animals , Apoptosis , Cell Line, Tumor , Cell Proliferation , Glycogen Synthase Kinase 3 beta , NF-kappa B , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Toll-Like Receptor 4 , TOR Serine-Threonine Kinases/metabolismABSTRACT
Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic, epigenetic, and environmental factors. Recent advance in genomics and epigenetics have revealed epigenetic mechanisms in PD. These epigenetic modifications include DNA methylation, post-translational histone modifications, chromatin remodeling, and RNA-based mechanisms, which regulate cellular functions in almost all cells. Epigenetic alterations are involved in multiple aspects of neuronal development and neurodegeneration in PD. In this review, we discuss current understanding of the epigenetic mechanisms that regulate gene expression and neural degeneration and then highlight emerging epigenetic targets and diagnostic and therapeutic biomarkers for treating or preventing PD.