Inhibition of abnormal C/EBPß/α-Syn signaling pathway through activation of Nrf2 ameliorates Parkinson's disease-like pathology.

Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs) in the brain. These LBs are primarily composed of α-Synuclein (α-Syn), which has aggregated. A recent report proposes that CCAAT/enhancer-binding proteins ß (C/EBPß) may act as an age-dependent transcription factor for α-Syn, thereby initiating PD pathologies by regulating its transcription. Potential therapeutic approaches to address PD could involve targeting the regulation of α-Syn by C/EBPß. This study has revealed that Nrf2, also known as nuclear factor (erythroid-derived 2)-like 2 (NFE2L2), suppresses the transcription of C/EBPß in SH-SY5Y cells when treated with MPP+ . To activate Nrf2, sulforaphane, an Nrf2 activator, was administered. Additionally, C/EBPß was silenced using C/EBPß-DNA/RNA heteroduplex oligonucleotide (HDO). Both approaches successfully reduced abnormal α-Syn expression in primary neurons treated with MPP+ . Furthermore, sustained activation of Nrf2 via its activator or inhibition of C/EBPß using C/EBPß-HDO resulted in a reduction of aberrant α-Syn expression, thus leading to an improvement in the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) in mouse models induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and those treated with preformed fibrils (PFFs). The data presented in this study illustrate that the activation of Nrf2 may provide a potential therapeutic strategy for PD by inhibiting the abnormal C/EBPß/α-Syn signaling pathway.

18ß-glycyrrhetinic acid ameliorates MPTP-induced neurotoxicity in mice through activation of microglial anti-inflammatory phenotype.

RATIONALE: 18ß-glycyrrhetinic acid (18ß-GA) has been reported to have anti-inflammatory and neuroprotective effects. However, the therapeutic effect of 18ß-GA in Parkinson's disease (PD) has not been defined. OBJECTIVE: The current study aimed to evaluate the potential therapeutic effects of 18ß-GA in treating PD by mitigating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. RESULTS: The study showed that 18ß-GA has anti-inflammatory effects by upregulating TREM2 expression in BV2 cells, which correlates with the presence of NF-E2-related factor-2 (Nrf2). 18ß-GA reduced inflammation in BV2 cells treated with 1-methyl-4- phenylpyridinium (MPP+) by enhancing TREM2 expression, which promotes an anti-inflammatory microglial phenotype. Repeated administration of 18ß-GA in MPTP-treated mice led to therapeutic effects by enhancing TREM2 expression, resulting in the activation of anti-inflammatory microglia. Moreover, 18ß-GA attenuated the decrease in brain-derived neurotrophic factor (BDNF) levels in both MPP+-induced BV2 cells and MPTP-intoxicated mice, indicating the involvement of BDNF in the beneficial effects of 18ß-GA. CONCLUSIONS: It is probable that activating microglial anti-inflammatory response through TREM2 expression might serve as a novel therapeutic strategy for PD. Additionally, 18ß-GA seems to hold potential as a new therapeutic agent for PD.

Nrf2 regulates the arginase 1+ microglia phenotype through the initiation of TREM2 transcription, ameliorating depression-like behavior in mice.

The expression of the triggering receptor on myeloid cell-2 (TREM2) knockdown in microglia from the lateral habenula (LHb) reportedly induces depression-like behaviors in mice. However, the key molecular mechanism that mediates major depressive disorder (MDD) pathogenesis remains elusive. We herein show that Nrf2 regulates TREM2 transcription and effects TREM2 mRNA and protein expression. The activation of Nrf2 by sulforaphane (Nrf2 activator) increases the microglial arginase 1+ phenotype by initiating TREM2 transcription in the medial prefrontal cortex (mPFC) and ameliorates depression-like behavior in CSDS mice. The knockout of Nrf2 decreases TREM2 and the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice with depression-like behavior. Downregulating TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC, resulting in depression-like behavior in SFN-treated CSDS mice. Finally, the knockout of Nrf2 and downregulation of TREM2 expression decreases the microglial arginase 1+ phenotype in the mPFC of Nrf2 KO mice and SFN-treated CSDS mice were associated with the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway. These data indicate that alterations in the interaction between Nrf2 and TREM2 may play a role in the pathophysiology of depression-like behavior in mice.

First Report of Powdery Mildew on Photinia × fraseri Caused by Podosphaera leucotricha in Guizhou Province, China.

The evergreen shrub Photinia × fraseri is a Photinia glabra × Photinia serrulata hybrid belonging to the family Rosaceae that is widely used in ornamental landscaping. In March 2022, severe powdery mildew symptoms were observed on shrubs of Photinia × fraseri in Huaxi University Town, Guiyang, Guizhou Province, China. All observed Photinia × fraseri plants in the green belts of both roads and parks in University Town showed powdery mildew symptoms. Almost all young branches of each Photinia × fraseri individual was infected. Powdery mildew colonies covered twig tips entirely, including the stems, petioles, and the adaxial and abaxial surfaces of leaves. Infected leaves were rolled up and had irregular, dark red spots. Fungal hyphae were straight to flexuous, branched, septate, 3 to 6 µm in width, and had nipple-shaped appressoria. Conidiophores were erect, straight or somewhat flexuous, and measured 90 to 300 µm × 7 to 10.5 µm (n = 30). Foot-cells were cylindrical or subcylindrical, straight or somewhat flexuous, and measured 25 to 50 × 7 to 9.5 µm (n = 30). Foot-cells were followed by one to two shorter cells, these being 10 to 16 × 7 to 9.5 µm in size (n = 50). Shorter cells were followed by one to six conidia (most often five conidia). Conidia formed in chains, ellipsoid to ovoid in shape, having dimensions of 22.5 to 30 × 12.5 to 16 µm (n = 50), and containing fibrosin bodies. No chasmothecia (fruiting bodies) were observed. Based on these morphological characteristics, the pathogen was identified as Podosphaera leucotricha (Ellis & Everh.) E.S. Salmon (Braun & Cook 2012). To confirm this species-level identification, the ribosomal DNA internal transcribed spacer (ITS) was amplified using the primers ITS1/ITS4 (White et al. 1990). The resulting sequence was deposited in GenBank (Accession No. ON325389). When the query coverage is 100%, the obtained ITS sequence showed 99.8% identity with P. leucotricha (AB027231, MT180425, MZ298746, KX842350, and KY661036) and 100% with P. leucotricha (HM242221, KY661017, KY661028, KY661050, KY661076, KR048110, MW364489, MW364490, MZ343479, OM022112, ON073894, and ON325389), respectively. Based on the ITS sequences of Podosphaera spp., phylogenetic tree was constructed with MEGA7.0 using the Maximum Likelihood method. The ML analysis supported our isolate's putative identification as P. leucotricha. To fulfill Koch's postulates, pathogenicity testing was conducted by gently pressing naturally diseased leaves onto young leaves of three healthy, potted 1-year-old Photinia × fraseri plants; three non-inoculated healthy plants served as control. Powdery mildew symptoms were observed on 100% inoculated Photinia × fraseri plants after 12 days (in a growth chamber at 21°C under a 12 h/12 h light/dark cycle), whereas the control plants remained symptomless. The powdery mildew colonies on inoculated leaves were morphologically identical to those observed on the original diseased leaves. It is known that P. leucotricha causes powdery mildew on Photinia × fraseri in Italy (Garibaldi et al. 2005). Moreover, this fungus reportedly infected Photinia serrulata in New Zealand, Ukraine, Italy, the United States, Japan, and in East China's Shandong Province (Liang et al. 2012). To the best of our knowledge, this is the first report of powdery mildew caused by P. leucotricha on Photinia × fraseri in Southwest China's Guizhou Province. This finding is significant as P. leucotricha is the causal agent of powdery mildew on apple and pear (Strickland et al. 2021). The occurrence of said disease on Photinia × fraseri could pose a potential disease threat to these fruit crops if nearby ornamental shrubs were able to act as reservoirs for the fungus, and a means to escape agricultural management efforts.