ABSTRACT
It remains an obstacle to induce the regeneration of hard dentin tissue in clinical settings. To overcome this, a P(VDF-TrFE) piezoelectric film with 2 wt% SrCl2 addition is designed. The biofilm shows a high flexibility, a harmonious biocompatibility, and a large piezoelectric d33 coefficient of 14 pC N-1, all contributing to building an electric microenvironment that favor the recruitment of dental pulp stem cells (DPSCs) and their differentiation into odontoblasts during normal chewing, speaking, etc. On the other hand, the strontium ions can be gradually released from the film, thus promoting DPSC odonto-differentiation. In vivo experiments also demonstrate that the film induces the release of dentin minerals and regeneration of dentin tissue. In the large animal dentin defect models, this piezoelectric film induces in situ dentin tissue formation effectively over a period of three months. This study illustrates a therapeutic potential of the piezoelectric film to improve dentin tissue repair in clinical settings.
Subject(s)
Biofilms , Dental Pulp , Dentin , Regeneration , Stem Cells , Strontium , Dentin/chemistry , Biofilms/drug effects , Dental Pulp/cytology , Strontium/chemistry , Strontium/pharmacology , Animals , Humans , Regeneration/drug effects , Stem Cells/cytology , Stem Cells/drug effects , Cell Differentiation/drug effects , Odontoblasts/cytology , Odontoblasts/drug effects , Odontoblasts/metabolism , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacologyABSTRACT
Major depressive disorder (MDD) is a common, chronic, recurrent disease. The existing drugs are ineffective for approximately half of patients, so the development of antidepressant drugs with novel mechanisms is urgent. Cumulative evidence has shown neuro-inflammation plays a key role in the etiology of major depressive disorder. Clinical studies implicated that bile acids, an important component of gut-brain axis, inhibit neuro-inflammation and mediate the pathophysiology of the MDD. Here, we found that ganoderic acid A (GAA) modulated bile acid receptor FXR (farnesoid X receptor), inhibited brain inflammatory activity, and showed antidepressant effects in the chronic social defeat stress depression model, tail suspension, forced swimming, and sucrose preference tests. GAA directly inhibited the activity of the NLRP3 inflammasome, and activated the phosphorylation and expression of the AMPA receptor by modulating FXR in the prefrontal cortex of mice. If we knocked out FXR or injected the FXR-specific inhibitor z-gugglesterone (GS), the antidepressant effects induced by GAA were completely abolished. These results suggest that GAA modulates the bile acid receptor FXR and subsequently regulates neuroimmune and antidepressant behaviors. GAA and its receptor FXR have potential as targets for the treatment of MDD.
Subject(s)
Antidepressive Agents/therapeutic use , Depression/metabolism , Heptanoic Acids/therapeutic use , Lanosterol/analogs & derivatives , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Receptors, Cytoplasmic and Nuclear/deficiency , Synapses/metabolism , Animals , Antidepressive Agents/pharmacology , Depression/drug therapy , Depression/psychology , Heptanoic Acids/pharmacology , Lanosterol/pharmacology , Lanosterol/therapeutic use , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Social Defeat , Synapses/drug effects , Synapses/geneticsABSTRACT
Major depressive disorder (MDD) is a prevalent, chronic, and recurrent disease. At least one-third of patients have treatment-resistant depression; therefore, there is an urgent need for novel drug development. Cumulative studies have suggested an inflammatory mechanism for the pathophysiology of MDD. Ganoderma lucidum polysaccharides (GLP) is an anti-inflammatory and immunomodulatory agent. Here, we found that an injection of GLP led to a rapid and robust antidepressant effect after 60 min in the tail suspension test. This antidepressant effect remained after 5 days of treatment with GLP in the forced swim test. Unlike psychostimulants, GLP did not show a hyperactive effect in the open field test. After 60 min or 5 days of treatment, GLP exhibited an antidepressant effect in a chronic social defeat stress (CSDS) depression animal model. Moreover, after 5 days of treatment, GLP attenuated the expression of the proinflammatory cytokines IL-1ß and TNF-α, enhanced the expression of the anti-inflammatory cytokine IL-10 and the neurotrophic factor BDNF, and inhibited the activation of microglia and proliferation of astrocytes in the hippocampus of CSDS mice. In addition, after 5 days of treatment, GLP significantly enhanced GluA1 S845 phosphorylation as well as GluA1 and GluA2 expression levels in the hippocampus of CSDS mice. To determine whether the antidepressant effect was mediated by Dectin-1, we found that GLP treatment enhanced Dectin-1 expression in the hippocampus in CSDS mice, and the Dectin-1-specific inhibitor laminarin almost completely blocked the antidepressant effect of GLP. This study identified GLP, an agonist of Dectin-1, as a novel and rapid antidepressant with clinical potential and multiple beneficial mechanisms, particularly in regulating the neuroimmune system and, subsequently, AMPA receptor function.
Subject(s)
Antidepressive Agents/therapeutic use , Depression/drug therapy , Drugs, Chinese Herbal/therapeutic use , Immunity, Innate/drug effects , Lectins, C-Type/metabolism , Reishi , Social Defeat , Animals , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Cytokines/metabolism , Depression/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Male , Mice , Microglia/drug effects , Microglia/metabolismABSTRACT
Multiple sclerosis (MS), as an inflammatory demyelinating disorder of central nervous system, is the leading cause of non-traumatic neurologic disability in young adults. The pathogenesis of MS remains unknown, however, a dysregulation of glia-neuroimmune signaling plays a key role during progressive disease stage. Most of the existing drugs are aimed at the immune system, but there is no approved drug by promoting remyelination after demyelination so far. There is a great interest in identifying novel agents for treating MS bytargeting to switch the immune imbalance from pro-inflammation and apoptosis to anti-inflammation and regeneration during remyelination phase. Here, we reported that ganoderic acid A (GAA) significantly enhanced the remyelination and rescued motor deficiency in two animal models of MS, including cuprizone-induced demyelination and myelin oligodendrocyte glycoprotein (MOG) 35-55-induced experimental autoimmune encephalomyelitis model. In these two independent MS animal models, GAA modulated neuroimmune to enhance the anti-inflammatory and regeneration markers IL-4 and BDNF, inhibited inflammatory markers IL-1ß and IL-6, followed by down-regulation of microglia activation and astrocyte proliferation. Pharmacological and genetic ablation of farnesoid-X-receptor (FXR) abolished GAA-induced remyelination and restoration of motor deficiency in MS mice. Thus, GAA is a novel and potential therapeutic agent that can rescue MS neuroimmune imbalance and remyelination through an FXR receptor-dependent mechanism. Clinical investigation on the therapeutic effect of GAA in improving remyelination of the MS patients to rescue the motor function is warranted.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Heptanoic Acids/therapeutic use , Lanosterol/analogs & derivatives , Multiple Sclerosis/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Regeneration/physiology , Remyelination/physiology , Animals , Anti-Inflammatory Agents/pharmacology , Female , Heptanoic Acids/pharmacology , Lanosterol/pharmacology , Lanosterol/therapeutic use , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Multiple Sclerosis/drug therapy , Multiple Sclerosis/pathology , Myelin Sheath/drug effects , Myelin Sheath/metabolism , Myelin Sheath/pathology , Regeneration/drug effects , Remyelination/drug effectsABSTRACT
Multiple sclerosis (MS) is an inflammatory demyelination disease characterized by autoimmune damage to the central nervous system. In this disease, failure of remyelination could cause persistent disability. Cordycepin, also known as 3'-deoxyadenosine, exerts anti-inflammatory, anti-oxidic, anti-apoptotic and neuroprotective effects. The cuprizone (CPZ) model has been widely used to study MS as it mimics some characteristics of demyelination disease. To determine whether cordycepin promotes remyelination and functional recovery after CPZ-induced demyelination, we administered cordycepin to the CPZ-induced demyelination mice. Cordycepin reversed CPZ-induced loss of body weight and rescued motor dysfunction in the model mice. Cordycepin effectively promoted remyelination and enhanced MBP expression in the corpus callosum. Cordycepin also inhibited the CPZ-induced increase in the number of Iba1-positive microglia, GFAP-positive astrocytes and Olig2-positive oligodendroglial precursor cells in the corpus callosum and cerebral cortex. Pro-inflammatory cytokine expression (IL-1ß and IL-6) was inhibited while anti-inflammatory cytokine IL-4 and neurotrophic factor BDNF release was elevated in the corpus callosum and hippocampus after cordycepin treatment. In addition, we also found that cordycepin ameliorated CPZ-induced body weight loss, motor dysfunction, demyelination, glial cells activation and pro-inflammatory cytokine expression in the corpus callosum and hippocampus. Our results suggest that cordycepin may represent a useful therapeutic agent in demyelination-related diseases via suppression of neuroinflammation.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Demyelinating Diseases/drug therapy , Deoxyadenosines/therapeutic use , Neuroprotective Agents/therapeutic use , Remyelination/drug effects , Animals , Anti-Inflammatory Agents/pharmacology , Astrocytes/drug effects , Corpus Callosum/drug effects , Corpus Callosum/immunology , Cuprizone , Cytokines/immunology , Demyelinating Diseases/chemically induced , Demyelinating Diseases/immunology , Deoxyadenosines/pharmacology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/immunology , Male , Mice , Mice, Inbred C57BL , Neuroglia/drug effects , Neuroprotective Agents/pharmacologyABSTRACT
The methylcytosine dioxygenases TET proteins (TET1, TET2, and TET3) play important regulatory roles in neural function. In this study, we investigated the role of TET proteins in neuronal differentiation using Neuro2a cells as a model. We observed that knockdown of TET1, TET2 or TET3 promoted neuronal differentiation of Neuro2a cells, and their overexpression inhibited VPA (valproic acid)-induced neuronal differentiation, suggesting all three TET proteins negatively regulate neuronal differentiation of Neuro2a cells. Interestingly, the inducing activity of TET protein is independent of its enzymatic activity. Our previous studies have demonstrated that srGAP3 can negatively regulate neuronal differentiation of Neuro2a cells. Furthermore, we revealed that TET1 could positively regulate srGAP3 expression independent of its catalytic activity, and srGAP3 is required for TET-mediated neuronal differentiation of Neuro2a cells. The results presented here may facilitate better understanding of the role of TET proteins in neuronal differentiation, and provide a possible therapy target for neuroblastoma.
Subject(s)
Cell Differentiation/physiology , DNA-Binding Proteins/metabolism , GTPase-Activating Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Animals , Catalytic Domain , Cell Differentiation/drug effects , Cell Line, Tumor , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/genetics , Enzyme Inhibitors/pharmacology , GTPase-Activating Proteins/genetics , Immunohistochemistry , Mice , Microscopy, Fluorescence , Neuroblastoma/metabolism , Neuroblastoma/pathology , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/genetics , Protein Isoforms/metabolism , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , RNA Interference , RNA, Messenger/metabolism , RNA, Small Interfering/metabolism , Valproic Acid/pharmacologyABSTRACT
Earlier studies with in vitro models have revealed that application of vitamin C can act as a primary NO(2) absorption substrate to contribute to NO(2)-induced cellular injury. In the present study, we showed that the pharmacological application of vitamin C had dual role in lungs of mice exposed to NO(2), with an exacerbated oxidative stress occurring at low concentrations, as indicated by excessive reactive oxygen species production and lipid peroxidation. However, at high concentrations, vitamin C functioned as an antioxidant removing reactive oxygen species and maintaining a reducing status in cells, alleviating NO(2)-induced oxidative toxicity.
Subject(s)
Air Pollutants/toxicity , Antioxidants/metabolism , Ascorbic Acid/metabolism , Lung/drug effects , Nitrogen Dioxide/toxicity , Oxidative Stress/drug effects , Animals , Antioxidants/pharmacology , Ascorbic Acid/pharmacology , Dose-Response Relationship, Drug , Inhalation Exposure , Lung/enzymology , Lung/metabolism , Lung/pathology , Male , Mice , Reactive Oxygen Species/metabolismABSTRACT
Colonization of arbuscular mycorrhizal fungi Glomus mosseae or exogenous salicylic acid (SA) treatment can increase Avena nuda plant tolerance to elevated NO(2) exposure. The combination of the two factors, namely application of SA to the mycorrhizal plants, further promoted NO(2) tolerance, as indicated by an alleviated plant biomass decrease compared to the respective treatment. The analysis of antioxidant capacity, redox status and photon energy utilization showed that the increased NO(2) tolerance in the treated plants may be associated, at least in part, with scavenging reactive oxygen species, maintaining CO(2) assimilated rate and reducing conditions in cells.