PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking, and LRRK2-activating mutations are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including protein phosphatase, Mg2/Mn2 dependent 1H (PPM1H), which acts on phosphorylated Rab 8A (phosphoRab8A) and phosphoRab10. Here, we report a phosphatome-wide small interfering RNA (siRNA) screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10.

Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson's disease-linked -mutant mice.

Parkinson's disease is associated with activating mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which suppresses primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum. As a result, there is a decrease in the production of neuroprotective glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN), which normally support the viability of dopaminergic neurons. MLi-2 is a brain-penetrant, selective, and now experimental inhibitor of LRRK2.

Phylogenomic Inference Suggests Differential Deep Time Phylogenetic Signals from Nuclear and Organellar Genomes in Gymnosperms.

The living gymnosperms include about 1200 species in five major groups: cycads, ginkgo, gnetophytes, Pinaceae (conifers I), and cupressophytes (conifers II). Molecular phylogenetic studies have yet to reach a unanimously agreed-upon relationship among them. Moreover, cytonuclear phylogenetic incongruence has been repeatedly observed in gymnosperms.

PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; activating mutations in are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including PPM1H, that acts on phosphoRab8A and phosphoRab10. Here we report a phosphatome-wide siRNA screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10.

Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1) are associated with familial Parkinson's disease (PD). LRRK2 phosphorylates Rab guanosine triphosphatase (GTPases) within the Switch II domain while PINK1 directly phosphorylates Parkin and ubiquitin (Ub) and indirectly induces phosphorylation of a subset of Rab GTPases. Herein we have crossed LRRK2 [R1441C] mutant knock-in mice with PINK1 knock-out (KO) mice and report that loss of PINK1 does not impact endogenous LRRK2-mediated Rab phosphorylation nor do we see significant effect of mutant LRRK2 on PINK1-mediated Rab and Ub phosphorylation.

and formula alleviates depressive behaviors microglia regulation in an unpredictable chronic mild stress animal model.

Background And Aim: (CM) and (AM) are medicinal mushrooms with potential applications in the treatment of mood disorders, including depression and anxiety. While research suggests that both CM and AM possess anti-inflammatory properties and hold potential for treating depression when administered separately, there is limited knowledge about their efficacy when combined in a formula, as well as the underlying mechanism involving the modulation of microglia.

Experimental Procedure: Rats received oral administrations of the low-dose formulation, medium-dose formulation, and high-dose formulation over 28 consecutive days as part of the UCMS protocols.

Pathogenic mutations cause loss of primary cilia and Neurturin in striatal parvalbumin interneurons.

Parkinson's disease-associated, activating mutations in the LRRK2 kinase block primary cilium formation in cell culture and in specific cell types in the brain. In the striatum that is important for movement control, about half of astrocytes and cholinergic interneurons, but not the predominant medium spiny neurons, lose their primary cilia. Here, we show that mouse and human striatal parvalbumin interneurons that are inhibitory regulators of movement also lose primary cilia.

Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson's disease.

Activating leucine-rich repeat kinase 2 (LRRK2) mutations cause Parkinson's and phosphorylation of Rab10 by pathogenic LRRK2 blocks primary ciliogenesis in cultured cells. In the mouse brain, LRRK2 blockade of primary cilia is highly cell type specific: For example, cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2-pathway mutant mice. We show here that the cell type specificity of LRRK2-mediated cilia loss is also seen in human postmortem striatum from patients with LRRK2 pathway mutations and idiopathic Parkinson's.

Phylogenomics identifies parents of naturally occurring tetraploid bananas.

Background: Triploid bananas are almost sterile. However, we succeeded in harvesting seeds from two edible triploid banana individuals (Genotype: ABB) in our conservation repository where various wild diploid bananas were also grown. The resulting rare offspring survived to seedling stages.

A formulation of combined and rice ameliorates depressive-like effects by downregulating p38 MAPK signaling pathways.

Background And Aim: (PC) is traditional Chinese medicine with sedative, diuretic, and tonic properties. rice (CMR) is a matrix used for the solid-state culture of C. militaris, which has been used for anti-angiogenetic and anti-inflammation effects.

Study on pulse current auxiliary heating process of submerged arc welding.

During the welding process, temperature filed distribution of weldment is one of the key factors which influence welding quality. In order to improve the mechanical properties of welding joint, a technology for heating process of weldment using auxiliary pulse current was proposed in this article. Firstly, through metallographic experiment, strength experiment and hardness experiment, it was proved that the auxiliary pulse current not only can refine grain size but also improves the mechanical property of the welding joint.

Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinson's disease.

Activating LRRK2 mutations cause Parkinson's disease. Previously, we showed that cholinergic interneurons and astrocytes but not medium spiny neurons of the dorsal striatum lose primary cilia in LRRK2 mutant mice. Single nucleus RNA sequencing shows that cilia loss in cholinergic interneurons correlates with higher LRRK2 expression and decreased glial derived neurotrophic factor transcription.

Anti-depressive-like and cognitive impairment alleviation effects of Gastrodia elata Blume water extract is related to gut microbiome remodeling in ApoE mice exposed to unpredictable chronic mild stress.

Ethnopharmacology Relevance: Gastrodia elata Blume (GE) is a traditional Chinese dietary therapy used to treat neurological disorders. Gastrodia elata Blume water extract (WGE) has been shown to ameliorate inflammation and improve social frustration in mice in a chronic social defeat model. However, studies on the anti-depressive-like effects and cognitive impairment alleviation related to the impact of WGE on the gut microbiome of ApoE mice remain elusive.

Genotoxicity and 28-day repeated dose oral toxicity study of garlic essential oil in mice.

Background And Aim: Garlic essential oil (GEO) isolated from Garlic ( L.) exerts biological activities in disease prevention, particularly in metabolic and liver diseases, and is used for a dietary therapy for centuries. However, due to the side effects associated with the excessive consumption of GEO, there is a need to evaluate the safety of the GEO.

Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.

Parkinson's disease is one of the most common neurodegenerative diseases affecting the ageing population, with a prevalence that has doubled over the last 30 years. As the mechanism of the disease is not fully elucidated, the current treatments are unable to effectively prevent neurodegeneration. Studies have found that mutations in Leucine-rich-repeat-kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD).

Dietary Exposure to Antibiotic Residues Facilitates Metabolic Disorder by Altering the Gut Microbiota and Bile Acid Composition.

Antibiotics used as growth promoters in livestock and animal husbandry can be detected in animal-derived food. Epidemiological studies have indicated that exposure to these antibiotic residues in food may be associated with childhood obesity. Herein, the effect of exposure to a residual dose of tylosin-an antibiotic growth promoter-on host metabolism and gut microbiota was explored .

The Effects of Behavioral Foundations and Business Strategy on Corporate Dividend Policy.

This study analyzes the influence of behavioral foundation factors and corporate strategic behavior on the formulation of corporate dividend policy. We use the Logit model and the OLS model for estimating the empirical model. The year- and industry-fixed effects are controlled in the model.

Glial Nrf2 signaling mediates the neuroprotection exerted by Blume in Lrrk2-G2019S Parkinson's disease.

The most frequent missense mutations in familial Parkinson's disease (PD) occur in the highly conserved gene with G2019S mutation. We previously established a fly model of PD carrying the mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models.

Gastrodia elata Blume water extract modulates neurotransmitters and alters the gut microbiota in a mild social defeat stress-induced depression mouse model.

Gastrodia elata Blume has multiple bioactive functions, such as antioxidant and antidepressant activities, immune modulation, neuroplasticity, and neuroprotection. We previously found that the water extract of G. elata exerts antidepressant-like effects in unpredictable chronic mild stress models and animals exposed to the forced swimming test.

Antidepressant-like effects of water extract of Cordyceps militaris (Linn.) Link by modulation of ROCK2/PTEN/Akt signaling in an unpredictable chronic mild stress-induced animal model.

Ethnopharmacology Relevance: Cordyceps militaris (Linn.) Link (CM) is a medicinal mushroom traditionally used in tonics for treating several neurological disorders, including epilepsy and anxiety, in Asia. Reports have shown that CM has anti-inflammatory and anti-oxidative effects and may be beneficial for depression management.

Water extract of Armillaria mellea (Vahl) P. Kumm. Alleviates the depression-like behaviors in acute- and chronic mild stress-induced rodent models via anti-inflammatory action.

Ethnopharmacology Relevance: Armillaria mellea (Vahl) P. Kumm. (AM) is an edible mushroom that has been reported as treatment for several neurological disorders, such as dizziness and epilepsy in Asia.

Allicin Modifies the Composition and Function of the Gut Microbiota in Alcoholic Hepatic Steatosis Mice.

The intestinal microbiome plays an important role in the pathogenesis of liver diseases. Alcohol intake induces gut microbiota dysbiosis and alters its function. This study investigated the antibiotic effect of allicin in mice with hepatic steatosis.

Poria cocos water extract ameliorates the behavioral deficits induced by unpredictable chronic mild stress in rats by down-regulating inflammation.

Ethnopharmacological Relevance: Poria cocos is a medicinal mushroom of the Polyporaceae family with antioxidant and anti-inflammatory activities, which has been used for its sedative, diuretic and tonic effects in traditional medicine for several hundred years.

Aim Of Study: Considering that depression is an inflammatory related mental disease, this study investigated the antidepressant-like effects of water extract of P. cocos in a rodent animal model.

Garlic essential oil mediates acute and chronic mild stress-induced depression in rats via modulation of monoaminergic neurotransmission and brain-derived neurotrophic factor levels.

Garlic essential oil (GEO) and its major organosulfur component (diallyl disulfide, DADS) possess diverse biological properties; however, limited information on their antidepressant-like effects is available. This study is the first to investigate these effects of GEO using the forced swimming test (FST) and unpredictable chronic mild stress (UCMS) induced depression in rats. After oral administration for 28 consecutive days, GEO (25 and 50 mg per kg bw) significantly reduced the immobility time in the FST.