Deficiency of p38α-MAPK in myeloid cells ameliorates symptoms and pathology of APP-transgenic Alzheimer's disease mice

Microglial activation is a hall marker of Alzheimer disease (AD); its pathogenic role and regulating mechanisms are unclear. In APP-transgenic mice, we deleted p38α-MAPK in the myeloid cell lineage from birth or specifically in microglia from 9 months, and analysed the AD pathology at the age of 4, 9 and 12 months. In both experimental settings, p38α-MAPK deficiency decreased cerebral Aβ and improved cognitive function in AD mice; however, p38α-MAPK deficiency in whole myeloid cells was more effective than specifically in microglia in preventing AD pathogenesis. Deficiency of p38α-MAPK in whole myeloid cells inhibited the inflammatory activation of individual microglia by 4 months, but enhanced it by 9 months. Inflammatory activation was essential for p38α-MAPK deficiency to promote microglial internalization of Aβ in the brain. In the investigation of mechanisms mediating different effects of p38α-MAPK-deficient myeloid cells and p38α-MAPK-deficient microglia on the pathogenesis of AD mice, we observed that p38α-MAPK deficiency in peripheral myeloid cells reduced il-17a transcription in CD4-positive spleen cells. By cross-breeding APP-transgenic mice and IL-17a knockout mice, we further found that IL-17a deficiency activated microglia and decreased Aβ deposits in AD mouse brain. In summary, our study shows that p38α-MAPK deficiency in myeloid cells attenuates symptoms and pathology of APP-transgenic mice. As a potential mechanism, p38α-MAPK-deficient peripheral myeloid cells reduces IL-17a-expressing T lymphocytes, and subsequently regulates cerebral Aβ clearance in APP-transgenic mice. Together with our previous observations that a deficiency of p38α-MAPK in neurons prevents AD pathogenesis, our study supports p38α-MAPK as a novel target for AD therapy.

LY6G6D is Epigenetically Activated in Classical Colorectal Adenocarcinoma and Hyper-Methylated in Mucinous Subtypes Determining Resistance to FOLFOX Therapeutic Regimens.

Background: Colorectal cancer (CRC) represents a significant and ever-increasing societal threat and burden. Activation of Lymphocyte antigen 6G6D could induce anti-tumor specific immunity unique to CRC, but factors regulating its activation remain obscure.Methods: Transcriptome, epigenome and proteomic data from TCGA and independent database were investigated using in silico approaches. Expression of candidate genes was independently validated by immunohistochemistry in CRC tissues. In vitro RNA mediated gene silencing of putative regulators, treatment with MEK and p38 MAPK inhibitors and Bioinformatic prediction were carried out to unveil LY6G6D regulation.Results: LY6G6D is down-regulated in mucinous CRC regardless its anatomic location, while its activation progresses through the classical adenoma-carcinoma sequence. The lack of LY6G6D expression in mucinous CRC involves alterations of secretome-based immune responses. DNA methylation changes in LY6G6D promoter are intimately related to its transcript regulation, epigenomic and different histological subtypes. RNA-mediated gene silencing and chemical inhibition of p38α MAPK as well as DNA methyltransferase DNMT1 knock-down lead to a decrease in LY6G6D expression, supporting that p38a MAPK and DNA methylases mediated LY6G6D regulation. Cancer cells with an intact p38α MAPK stabilize LY6G6D expression allowing effective responses to trametinib, a MEK inhibitor able to exert anti-inflammatory effects. In a metastatic CRC subset, LY6G6D hypermethylation predicts resistance to FOLFOX first-line therapy, supporting the idea that its cancer-specific hypomethylation and consequent activation may be a tissue-specific mechanism of anti-tumor immunity. Conclusions: LY6G6D has the potentiality to be used as a biomarker for patient stratification and immune therapeutic intervention of mucinous versus non-mucinous CRC.

Opposing roles of p38α phosphorylation and arginine methylation in driving TDP-43 proteinopathy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we demonstrate that inhibition of p38α MAPK reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. We establish that p38α MAPK phosphorylates TDP-43 at pathological serine 409/410 (S409/S410) and serine 292 (S292), which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we show that protein arginine methyltransferase 1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.

Rare Opportunities for Insights Into Serotonergic Contributions to Brain and Bowel Disorders: Studies of the SERT Ala56 Mouse

Altered structure, expression, and regulation of the presynaptic serotonin (5-HT) transporter (SERT) have been associated with multiple neurobehavioral disorders, including mood disorders, obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD). Opportunities to investigate mechanistic links supporting these associations were spurred with the identification of multiple, rare human SERT coding variants in a study that established a male-specific linkage of ASD to a linkage marker on chromosome 17 which encompassed the location of the SERT gene (SLC6A4). We have explored the most common of these variants, SERT Ala56, in vitro and in vivo. Results support a tonic elevation of 5-HT transport activity in transfected cells and human lymphoblasts by the variant in vitro that leads to an increased 5-HT clearance rate in vivo when studied in the SERT Ala56 mouse model, along with altered sensitivity to SERT regulatory signaling pathways. Importantly, hyperserotonemia, or an elevated whole blood 5-HT, level, was found in SERT Ala56 mice, reproducing a well-replicated trait observed in a significant fraction of ASD subjects. Additionally, we found multiple biochemical, physiological, and behavioral alterations in the SERT Ala56 mice that can be analogized to those observed in ASD and its medical comorbidities. The similarity of the functional impact of the SERT Ala56 variant to the consequences of p38α MAPK activation, ascribed to the induction of a biased conformation of the transporter toward an outward-facing conformation, has resulted in successful efforts to restore normal behavioral and bowel function via pharmacological and genetic p38α MAPK targeting. Moreover, the ability of the inflammatory cytokine IL-1β to enhance SERT activity via a p38α MAPK-dependent pathway suggests that the SERT Ala56 conformation mimics that of a chronic inflammatory state, supporting findings in ASD of elevated inflammatory cytokine levels. In this report, we review studies of the SERT Ala56 variant, discussing opportunities for continued insight into how chronically altered synaptic 5-HT homeostasis can drive reversible, functional perturbations in 5-HT sensitive pathways in the brain and periphery, and how targeting the SERT regulome, particularly through activating pathways such as those involving IL-1β/p38α MAPK, may be of benefit for neurobehavioral disorders, including ASD.

Protective Effects of Rutin Against Deltamethrin-Induced Hepatotoxicity and Nephrotoxicity in Rats via Regulation of Oxidative Stress, Inflammation and Apoptosis

Deltamethrin (DLM) is a type-II pyrethroid synthetic insecticide that is extensively used for controlling mosquitoes, flies, pests, insects worldwide. Oxidative stress is one of the DLM toxicity mechanisms. This study was carried out to evaluate the likelihood protective effects of rutin (RUT), a natural antioxidant, against DLM-induced liver and kidney toxicities in rats. Hepatotoxicity and nephrotoxicity were evaluated after the rats were treated orally with DLM (1.28 mg/kg b.w.) alone or with RUT (25 and 50 mg/kg b.w.) for 30 days. DLM administration caused an increase in lipid peroxidation level and a decrease in activities of SOD, CAT, and GPx and GSH levels in the both tissues. DLM also increased serum ALT, AST, ALP, urea, and creatinine levels, while reduced nephrine levels in rats. In addition, DLM increased the activation of inflammatory and apoptotic pathways by decreasing Bcl-2 and increasing TNF-α, NF-κB, IL-1β, p38α MAPK, COX-2, iNOS, beclin-1, Bax, and caspase-3 protein levels and/or activities. Furthermore, DLM increased mRNA expression levels of PARP-1, VEGF and immunohistochemical expressions of c-fos in the tissues. RUT treatment significantly improved all examined parameters and restored the liver and kidney histopathological and immunohistochemical alterations. These findings demonstrate that RUT could be used to ameliorate hepatotoxicity and nephrotoxicity associated with oxidative stress, inflammation, and apoptosis in DLM-induced rats.

The Roles of Epinephelus coioides miR-122 in SGIV Infection and Replication

In mammals, mature miR-122 is 22 nucleotides long and can be involved in regulating a variety of physiological and biological pathways. In this study, the expression profile and effects of grouper Epinephelus coioides miR-122 response to Singapore grouper iridovirus (SGIV) infection were investigated. The sequences of mature microRNAs (miRNAs) from different organisms are highly conserved, and miR-122 from E. coioides exhibits high similarity to that from mammals and other fish. The expression of miR-122 was up-regulated during SGIV infection. Up-regulation of miR-122 could significantly enhance the cytopathic effects (CPE) induced by SGIV, the transcription levels of viral genes (MCP, VP19, LITAF and ICP18), and viral replication; reduce the expression of inflammatory factors (TNF-a, IL-6, and IL-8), and the activity of AP-1 and NF-κB, and miR-122 can bind the target gene p38α MAPK to regulate the SGIV-induced cell apoptosis and the protease activity of caspase-3. The results indicated that SGIV infection can up-regulate the expression of E. coioides miR-122, and up-regulation of miR-122 can affect the activation of inflammatory factors, the activity of AP-1 and NF-κB, and cell apoptosis to regulate viral replication and proliferation.