•GLP treatment led to a rapid and robust antidepressant effect in the CSDS mice.•GLP attenuated IL-1β and TNF-α, enhanced IL-10 and BDNF expression.•GLP inhibited the activation of microglia and the ...proliferation of astrocytes.•GLP significantly enhanced GluA1 S845 phosphorylation, GluA1, and GluA2 expression.•GLP exerted antidepressant effects on CSDS mice via modulation of Dectin-1.
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-1β 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.
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.
In this study, a strontium‐containing P(VDF‐TrFE) film is fabricated to create the electrical microenvironment in dentin defects. The piezoelectric biofilm provides surface electrical potential to induce DPSC odonto‐differentiation and the release of strontium ions, both effects of which contribute to endogenous dentin tissue regeneration.
Display omitted
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.
Display omitted
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-1β 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.
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-1β 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.
•Cordycepin promoted remyelination and rescued motor dysfunction after cuprizone-induced demyelination.•Cordycepin inhibited the cuprizone-induced increase in the positive number of microglia, astrocytes and OPCs.•Cordycepin inhibited cuprizone-induced pro-inflammatory cytokine expression (IL-1β and IL-6).•Cordycepin promoted anti-inflammatory cytokine IL-4 and neurotrophic factor BDNF release.
Colonization of arbuscular mycorrhizal fungi Glomus mosseae or exogenous salicylic acid (SA) treatment can increase Avena nuda plant tolerance to elevated NO₂ exposure. The combination of the two ...factors, namely application of SA to the mycorrhizal plants, further promoted NO₂ 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 NO₂ tolerance in the treated plants may be associated, at least in part, with scavenging reactive oxygen species, maintaining CO₂ assimilated rate and reducing conditions in cells.
Earlier studies with in vitro models have revealed that application of vitamin C can act as a primary NO₂ absorption substrate to contribute to NO₂-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 NO₂, 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 NO₂-induced oxidative toxicity.
Earlier studies with in vitro models have revealed that application of vitamin C can act as a primary NO sub(2) absorption substrate to contribute to NO sub(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 sub(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 sub(2)-induced oxidative toxicity.