RESUMEN
BACKGROUND: The continuously developing pesticide resistance is a great threat to agriculture and human health. Understanding the mechanisms of insecticide resistance is a key step in dealing with the phenomenon. Insect cuticle is recently documented to delay xenobiotic penetration which breaks the previous stereotype that cuticle is useless in insecticide resistance, while the underlying mechanism remains scarce. RESULTS: Here, we find the integument contributes over 40.0% to insecticide resistance via different insecticide delivery strategies in oriental fruit fly. A negative relationship exists between cuticle thickening and insecticide penetration in resistant/susceptible, also in field strains of oriental fruit fly which is a reason for integument-mediated resistance. Our investigations uncover a regulator of insecticide penetration that miR-994 mimic treatment causes cuticle thinning and increases susceptibility to malathion, whereas miR-994 inhibitor results in opposite phenotypes. The target of miR-994 is a most abundant cuticle protein (CPCFC) in resistant/susceptible integument expression profile, which possesses capability of chitin-binding and influences the cuticle thickness-mediated insecticide penetration. Our analyses find an upstream transcriptional regulatory signal of miR-994 cascade, long noncoding RNA (lnc19419), that indirectly upregulates CPCFC in cuticle of the resistant strain by sponging miR-994. Thus, we elucidate the mechanism of cuticular competing endogenous RNAs for regulating insecticide penetration and demonstrate it also exists in field strain of oriental fruit fly. CONCLUSIONS: We unveil a regulatory axis of lnc19419 ~ miR-994 ~ CPCFC on the cuticle thickness that leads to insecticide penetration resistance. These findings indicate that competing endogenous RNAs regulate insecticide resistance by modulating the cuticle thickness and provide insight into the resistance mechanism in insects.
Asunto(s)
Insecticidas , MicroARNs , Humanos , Animales , Insecticidas/farmacología , Malatión/farmacología , Piel , Agricultura , Drosophila , MicroARNs/genéticaRESUMEN
Essential Tremor (ET) is a prevalent neurological disease characterized by an 8-10 Hz action tremor. Molecular mechanisms of ET remain poorly understood. Clinical data suggest the importance of the cerebellum in disease pathophysiology, and pathological studies indicate Purkinje Cells (PCs) incur damage. Our recent cerebellar cortex and PC-specific transcriptome studies identified alterations in calcium (Ca2+) signaling pathways that included ryanodine receptor type 1 (RyR1) in ET. RyR1 is an intracellular Ca2+ release channel located on the Endoplasmic Reticulum (ER), and in cerebellum is predominantly expressed in PCs. Under stress conditions, RyR1 undergoes several post-translational modifications (protein kinase A [PKA] phosphorylation, oxidation, nitrosylation), coupled with depletion of the channel-stabilizing binding partner calstabin1, which collectively characterize a "leaky channel" biochemical signature. In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correlated with loss of PCs and climbing fiber-PC synapses in ET. This 'leaky' RyR1 signature was not seen in control or Parkinson's disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca2+ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 point mutation that mimics constitutive site-specific PKA phosphorylation (RyR1-S2844D). RyR1-S2844D homozygous mice develop a 10 Hz action tremor and robust abnormal oscillatory activity in cerebellar physiological recordings. Intra-cerebellar microinfusion of RyR1 agonist or antagonist, respectively, increased or decreased tremor amplitude in RyR1-S2844D mice, supporting a direct role of cerebellar RyR1 leakiness for tremor generation. Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca2+ leak via RyR1 may contribute to tremor pathophysiology.
Asunto(s)
Calcio , Canal Liberador de Calcio Receptor de Rianodina , Humanos , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Calcio/metabolismo , Temblor/metabolismo , Cerebelo/metabolismo , Retículo Endoplásmico/metabolismo , Músculo Esquelético/metabolismoRESUMEN
BACKGROUND: Parkinson's disease (PD) is one of the most important neurodegenerative disorders in elderly people. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are found in a large proportion of the patients with sporadic and familial PD. Mutations can occur at different locations in the LRRK2. Patients with LRRK2 ROC-COR mutations face an increased risk of typical motor symptoms of PD, along with cognitive decline. An animal model with a monogenic LRRK2 gene mutation is a suitable model for exploring the pathophysiology of PD and identifying potential drug therapies. However, the effect of homozygous (HOM) LRRK2 in PD pathophysiology is unclear. METHODS: We established human LRRK2 (hLRRK2) R1441G HOM transgenic (Tg) mice to explore the phenotype and pathological features that are associated with hLRRK2 R1441G Tg mouse models and discuss the potential clinical relevance. The open field test (OFT) was performed to examine motor and nonmotor behaviors. A CatWalk analysis system was used to study gait function. [18F]FDOPA PET was used to investigate functional changes in the nigrostriatal pathway in vivo. Transmission electron microscopy was used to examine the morphological changes in mitochondria and lysosomes in the substantia nigra. RESULTS: The R1441G HOM Tg mice demonstrated gait disturbance and exhibited less anxiety-related behavior and exploratory behavior than mice with hLRRK2 at 12 months old. Additionally, [18F]FDOPA PET showed a reduction in FDOPA uptake in the striatum of the HOM Tg mice. Notably, there was significant lysosome and autophagosome accumulation in the cytoplasm of dopaminergic neurons in R1441G hemizygous (HEM) and HOM mice. Moreover, it was observed using transmission electron microscopy (TEM) that the mitochondria of R1441G Tg mice were smaller than those of hLRRK2 mice. CONCLUSION: This animal provides a novel HOM hLRRK2 R1441G Tg mouse model that reproduces some phenotype of Parkinsonism in terms of both motor and behavioral dysfunction. There is an increased level of mitochondrial fission and no change in the fusion process in the group of HOM hLRRK2 R1441G Tg mouse. This mutant animal model of PD might be used to study the mechanisms of mitochondrial dysfunction and explore potential new drug targets.
Asunto(s)
Enfermedad de Parkinson , Trastornos Parkinsonianos , Anciano , Animales , Modelos Animales de Enfermedad , Humanos , Lactante , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Ratones , Ratones Transgénicos , Modelos Genéticos , Mutación , Trastornos Parkinsonianos/genética , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) has no definitive genetic or environmental (G-E) risk factors, and the integrated effect of these factors on MSA etiology remains unknown. This study was undertaken to investigate the integrated effect of G-E factors associated with MSA and its subtypes, MSA-P and MSA-C. METHODS: A consecutive case-control study was conducted at two medical centers, and the interactions between genotypes of five previously reported susceptible single nucleotide polymorphisms (SNPs; SNCA_rs3857059, SNCA_rs11931074, COQ2_rs148156462, EDN1_rs16872704, MAPT_rs9303521) and graded exposure (never, ever, current) of four environmental factors (smoking, alcohol, drinking well water, pesticide exposure) were analyzed by a stepwise logistic regression model. RESULTS: A total of 207 MSA patients and 136 healthy controls were enrolled. In addition to SNP COQ2_rs148156462 (TT), MSA risk was correlated with G-E interactions, including COQ2_rs148156462 (Tc) × pesticide nonexposure, COQ2_rs148156462 (TT) × current smokers, SNCA_rs11931074 (tt) × alcohol nonusers, and SNCA_rs11931074 (GG) × well water nondrinkers (all p < 0.01), with an area under the receiver operating characteristic curve (AUC) of 0.804 (95% confidence interval [CI] = 0.671-0.847). Modulated risk of MSA-C, with MSA-P as a control, correlated with COQ2_rs148156462 (TT) × alcohol nondrinkers, SNCA_rs11931074 (GG) × well water ever drinkers, SNCA_rs11931074 (Gt) × well water never drinkers, and SNCA_rs3857059 (gg) × pesticide nonexposure (all p < 0.05), with an AUC of 0.749 (95% CI = 0.683-0.815). CONCLUSIONS: Certain COQ2 and SNCA SNPs interact with common environmental factors to modulate MSA etiology and subtype disposition. The mechanisms underlying the observed correlation between G-E interactions and MSA etiopathogenesis warrant further investigation.
Asunto(s)
Transferasas Alquil y Aril/genética , Atrofia de Múltiples Sistemas , Plaguicidas , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patología , Agua , alfa-Sinucleína/genéticaRESUMEN
Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.
Asunto(s)
Mitocondrias/genética , Trastornos Parkinsonianos/genética , Polineuropatías/genética , Edad de Inicio , Anciano , Animales , Antiparkinsonianos/uso terapéutico , Línea Celular , Aberraciones Cromosómicas , Drosophila , Complejo III de Transporte de Electrones/genética , Femenino , Mutación del Sistema de Lectura , Técnicas de Sustitución del Gen , Genes Dominantes , Humanos , Levodopa/uso terapéutico , Masculino , Ratones , Persona de Mediana Edad , Mutación/genética , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/tratamiento farmacológico , Linaje , Polineuropatías/etiología , Secuenciación del ExomaRESUMEN
BACKGROUND: Recent genetic progress has allowed for the molecular diagnosis of Parkinson's disease. However, genetic causes of PD vary widely in different ethnicities. Mutational frequencies and clinical phenotypes of genes associated with PD in Asian populations are largely unknown. The objective of this study was to identify the mutational frequencies and clinical spectrums of multiple PD-causative genes in a Taiwanese PD cohort. METHODS: A total of 571 participants including 324 patients with early-onset parkinsonism (onset age, <50 years) and 247 parkinsonism pedigrees were recruited at a tertiary referral center in Taiwan from 2002 to 2017. Genetic causes were identified by an integrated approach including gene dosage analysis, a targeted next-generation sequencing panel containing 40 known PD-causative genes, repeat-primed polymerase chain reaction, and whole-exome sequencing analysis. RESULTS: Thirty of the 324 patients with early-onset parkinsonism (9.3%) were found to carry mutations in Parkin, PINK1, or PLA2G6 or had increased trinucleotide repeats in SCA8. Twenty-nine of 109 probands with autosomal-recessive inheritance of parkinsonism (26.6%) were found to carry mutations in Parkin, PINK1, GBA, or HTRA2. The genetic causes for the 138 probands with an autosomal-dominant inheritance pattern of parkinsonism were more heterogeneous. Seventeen probands (12.3%) carried pathogenic mutations in LRRK2, VPS35, MAPT, GBA, DNAJC13, C9orf72, SCA3, or SCA17. A novel missense mutation in the UQCRC1 gene was found in a family with autosomal-dominant inheritance parkinsonism via whole-exome sequencing analysis. CONCLUSIONS: Our findings provide a better understanding of the genetic architecture of PD in eastern Asia and broaden the clinical spectrum of PD-causing mutations. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Dosificación de Gen , Trastornos Parkinsonianos/genética , Proteínas Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Edad de Inicio , Anciano , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , TaiwánRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder that lacks a disease-modifying therapy. Leucine-rich repeat kinase 2 (LRRK2) was implicated as the most common genetic cause of PD. We previously established a LRRK2-G2019S Drosophila model that displayed the crucial phenotypes of LRRK2 parkinsonism. Here, we used a two-step approach to identify compounds from the FDA-approved licensed drug library that could suppress neurite degeneration in LRRK2-G2019S parkinsonism. Of 640 compounds, 29 rescued neurite degeneration phenotypes and 3 restored motor disability and dopaminergic neuron loss in aged LRRK2-G2019S flies. Of these three drugs, lovastatin had the highest lipophilicity, which facilitated crossing the blood-brain barrier. In LRRK2-G2019S knock-in mice and stably transfected human dopaminergic cells, lovastatin significantly rescued neurite degeneration in a dose-dependent manner, within a range of 0.05-0.1 µm The beneficial effect of lovastatin was exerted by activating anti-apoptotic Akt/Nrf signaling and decreasing caspase 3 levels. We also observed that lovastatin inhibited GSK3ß activity, a kinase downstream of Akt, by up-regulating GSK3ß (Ser9) phosphorylation. This inhibition subsequently decreased tau phosphorylation, which was linked to neuronal cytoskeleton instability. Conversely, pre-treatment with the Akt inhibitor, A6730, blocked the lovastatin-induced neuroprotective effect. The rescuing effects of lovastatin in dendritic arborization of LRRK2-G2019S neurons were abolished by co-expressing either a mutant allele of Akt (Akt104226) or a constitutively active form of GSK3ß (sggS9A). Our findings demonstrated that lovastatin restored LRRK2-G2019S neurite degeneration by augmenting Akt/NRF2 pathway and inhibiting downstream GSK3ß activity, which decreased phospho-tau levels. We suggested that lovastatin is a potential disease-modifying agent for LRRK2-G2019S parkinsonism.
Asunto(s)
Glucógeno Sintasa Quinasa 3 beta/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Degeneración Nerviosa/tratamiento farmacológico , Enfermedad de Parkinson/genética , Proteínas Proto-Oncogénicas c-akt/genética , Serina Endopeptidasas/genética , Animales , Animales Modificados Genéticamente , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Drosophila melanogaster/genética , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/biosíntesis , Humanos , Lovastatina/administración & dosificación , Ratones , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/patología , Mutación , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Neuritas/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/fisiopatología , Transducción de Señal/efectos de los fármacosRESUMEN
Lung squamous cell carcinoma (LSCC) is a common type of non-small-cell lung cancer (NSCLC) and lacks effective treatment. Regorafenib, an oral multikinase inhibitor, has demonstrated promising anti-tumor activity in various solid tumors. To study whether regorafenib inhibits LSCC cells, we investigate the compound in several LSCC cell lines and explore the possible mechanism. In this study, we confirmed that regorafenib had anti-proliferation effect on LSCC cell lines by inducing G0/G1 arrest. In addition, glycogen synthase kinase 3ß (GSK3ß) remained at the same level and Ser9 phosphorylation of GSK3ß decreased with increasing incubation time and increasing regorafenib concentration in LSCC cells. GSK3ß inhibition enhanced the anti-tumor activity of regorafenib. Thus, GSK3ß activation restricted the anti-cancer effect of regorafenib on LSCC. In conclusion, regorafenib might be a promising drug for LSCC therapy. GSK3ß might be a potential target to increase the anti-tumor effect of regorafenib in LSCC cells.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Piridinas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Fosforilación/efectos de los fármacosRESUMEN
Parkinson's disease (PD) is the most common movement disorder and manifests as resting tremor, rigidity, bradykinesia, and postural instability. Pathologically, PD is characterized by selective loss of dopaminergic neurons in the substantia nigra and the formation of intracellular inclusions containing α-synuclein and ubiquitin called Lewy bodies. Consequently, a remarkable deficiency of dopamine in the striatum causes progressive disability of motor function. The etiology of PD remains uncertain. Genetic variability in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of sporadic and familial PD. LRRK2 encodes a large protein containing three catalytic and four protein-protein interaction domains. Patients with LRRK2 mutations exhibit a clinical and pathological phenotype indistinguishable from sporadic PD. Recent studies have shown that pathological mutations of LRRK2 can reduce the rate of guanosine triphosphate (GTP) hydrolysis, increase kinase activity and GTP binding activity, and subsequently cause cell death. The process of cell death involves several signaling pathways, including the autophagic-lysosomal pathway, intracellular trafficking, mitochondrial dysfunction, and the ubiquitin-proteasome system. This review summarizes the cellular function and pathophysiology of LRRK2 ROCO domain mutations in PD and the perspective of therapeutic approaches.
Asunto(s)
Dopamina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Enfermedad de Parkinson/genética , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Humanos , Mutación , Enfermedad de Parkinson/patología , Dominios Proteicos/genética , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
Mutations in transmembrane protein 230 (TMEM230) have recently been reported to be associated with Parkinson's disease (PD) in a North American population. A highly prevalent mutation, c.550_552delTAGinsCCCGGG (p.*184ProGlyext*5) was found in 3.1% of Chinese familial PD patients. However, subsequent studies failed to replicate these findings in different populations. Our objective was to confirm the role of this gene in a large number of PD patients and controls in a Taiwanese population. Among 1,672 participants, we sequenced all coding exons and exon-intron boundary junctions of the TMEM230 gene in 180 probands with familial PD. We also genotyped the potential pathogenic variants identified and the previously reported mutations (p.Arg141Leu, p.Tyr92Cys, p.*184Trpext*5, and p.*184ProGlyext*5) in an additional cohort of 500 patients with sporadic PD, and 992 age and gender-matched neurologically normal control subjects. We did not find any of the previously reported mutations, but we observed one novel missense exonic variant, c.G68A (p.Arg23Gln), in one patient with familial PD, and two patients with sporadic PD in a heterozygous state. However, subsequent analysis of this variant in 992 controls did not find any significant associations between p.Arg23Gln and the risk of PD (0.44% vs. 0.30%, p = 0.22). Our findings suggest that genetic variants of TMEM230 do not play a major role in PD in our Taiwanese population. Further experimental studies are warranted to confirm the pathogenicity of this gene in PD disease process.
Asunto(s)
Exones , Proteínas de la Membrana/genética , Mutación , Enfermedad de Parkinson/genética , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Pronóstico , Taiwán/epidemiologíaRESUMEN
The activation of G-protein-coupled olfactory receptors on the olfactory sensory neurons (OSNs) triggers a signaling cascade, which is mediated by a heterotrimeric G-protein consisting of α, ß, and γ subunits. Although its α subunit, Gαolf, has been identified and well characterized, the identities of its ß and γ subunits and their function in olfactory signal transduction, however, have not been well established yet. We, and others, have found the expression of Gγ13 in the olfactory epithelium, particularly in the cilia of the OSNs. In this study, we generated a conditional gene knock-out mouse line to specifically nullify Gγ13 expression in the olfactory marker protein-expressing OSNs. Immunohistochemical and Western blot results showed that Gγ13 subunit was indeed eliminated in the mutant mice's olfactory epithelium. Intriguingly, Gαolf, ß1 subunits, Ric-8B and CEP290 proteins, were also absent in the epithelium whereas the presence of the effector enzyme adenylyl cyclase III remained largely unaltered. Electro-olfactogram studies showed that the mutant animals had greatly reduced responses to a battery of odorants including three presumable pheromones. Behavioral tests indicated that the mutant mice had a remarkably reduced ability to perform an odor-guided search task although their motivation and agility seemed normal. Our results indicate that Gαolf exclusively forms a functional heterotrimeric G-protein with Gß1 and Gγ13 in OSNs, mediating olfactory signal transduction. The identification of the olfactory G-protein's ßγ moiety has provided a novel approach to understanding the feedback regulation of olfactory signal transduction pathways as well as the control of subcellular structures of OSNs.
Asunto(s)
Proteínas de Unión al GTP Heterotriméricas/fisiología , Olfato/fisiología , Animales , Animales Recién Nacidos , Electrooculografía/métodos , Embrión de Mamíferos , Potenciales Evocados/genética , Conducta Alimentaria/fisiología , Femenino , Subunidades alfa de la Proteína de Unión al GTP , Subunidades beta de la Proteína de Unión al GTP/genética , Subunidades gamma de la Proteína de Unión al GTP/genética , Regulación del Desarrollo de la Expresión Génica/genética , Proteínas de Unión al GTP Heterotriméricas/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Odorantes , Proteína Marcadora Olfativa/metabolismo , Mucosa Olfatoria/metabolismo , Vías Olfatorias/citología , Neuronas Receptoras Olfatorias/fisiología , Tiempo de Reacción/genética , Transducción de Señal/genética , Olfato/genéticaRESUMEN
Polymorphisms in the PSAP gene, which encodes prosaposin and is involved in the lysosomal function, yielded conflicting results regarding the association with Parkinson's disease (PD). Therefore, this study aims to investigate the role of PSAP in familial PD (FPD), early onset PD (EOPD) with age at onset before 50 years old, and sporadic PD (SPD) among Taiwanese population, and summarize relevant studies via meta-analysis. By sequencing exon 1 to 14 in 183 FPD and 219 EOPD, two novel exonic variants were found in EOPD, including p.A146E (c.437C > A) on exon 5 and p.Y248C (c.743A > G) on exon 7. Furthermore, four previously reported intronic variants (rs142614739/rs74733861), rs749823, rs4747203 and rs885828) in intron 11 and 12 were analyzed in 485 SPD and 712 in-hospital controls, in addition to the aforementioned FPD and EOPD groups. The adjusted odd ratios (ORs) by age and sex, only rs142614739 was significantly associated with higher risk of EOPD (OR = 1.85, 95% CI = 1.33-2.58). The risk effect was further confirmed by the meta-analysis of the association between rs142614739 and the risk of PD in both common effect (OR = 1.29, 95% CI = 1.11-1.50) and random effect (OR = 1.29, 95% CI = 1.11-1.50). Our findings suggest that the PSAP rs142614739 variant is associated with the risk of EOPD. Further functional studies are warranted to elucidate the biochemical mechanisms.
Asunto(s)
Enfermedad de Parkinson , Humanos , Persona de Mediana Edad , Edad de Inicio , Estudios de Casos y Controles , Mutación , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/epidemiología , Saposinas/genética , Pueblos del Este de AsiaRESUMEN
OBJECTIVE: Explore the preliminary effects of a breathing exercise (BE) intervention on chronic pain among breast cancer survivors. METHODS: This two-parallel-arm, open-label pilot randomized controlled trial recruited 72 breast cancer survivors who were randomly allocated to either the control or intervention group (n = 36 each). Both groups received usual care and a pain information booklet, while the intervention group received 4 weeks of additional BE. The primary clinical outcome was measured using the Brief Pain Inventory (BPI), with secondary clinical outcomes measured by the Hospital Anxiety and Depression Scale (HADS), Quality of Life Patient/Cancer Survivor Version in Chinese (QOLCSV-C), and Functional Assessment of Cancer Therapy- Breast (FACT-B) immediately post-intervention and at 4-week follow-up. Both adjusted and unadjusted Generalized Estimating Equation models were utilized to assess the BE's potential effects, with safety assessed through participant self-report. RESULTS: Sixty-eight participants completed the study. Statistical significance was observed in BPI in both adjusted and unadjusted models at post-intervention and follow-up (p < 0.05). BE demonstrated positive effects on anxiety, depression and quality of life improvement across all measures and timepoints in both adjusted and unadjusted models (p < 0.05). The effect sizes were smaller in the adjusted model. Three mild transient discomforts were reported associated with BE practice including dizziness, tiredness and yawning, without requirement of medical treatment. No severe adverse events occurred. CONCLUSION: This BE intervention appears effective in alleviating chronic pain, anxiety and depression, and improving quality of life for breast cancer survivors. Fully powered large-scale studies are required to confirm its effects.
Asunto(s)
Neoplasias de la Mama , Ejercicios Respiratorios , Supervivientes de Cáncer , Dolor Crónico , Calidad de Vida , Humanos , Femenino , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/terapia , Persona de Mediana Edad , Supervivientes de Cáncer/psicología , Dolor Crónico/terapia , Ejercicios Respiratorios/métodos , Adulto , Manejo del Dolor/métodos , Proyectos Piloto , Resultado del Tratamiento , Anciano , Dimensión del DolorRESUMEN
Exposure to artificial sweetener acesulfame-K (AK) at early development stages may influence the adult sweet preference and the periphery gustatory system. We observed that the intraoral AK stimulation to mice from postnatal day 4 (P4) to weaning decreased the preference thresholds for AK and sucrose solutions in adulthood, with the preference pattern unchanged. The preference scores were increased in the exposure group significantly when compared with the control group at a range of concentrations for AK or sucrose solution. Meanwhile, more α-Gustducin-labeled fungiform taste buds and cells in a single taste bud were induced from week 7 by the early intraoral AK stimulation. However, the growth in the number of α-Gustducin-positive taste bud or positive cell number per taste bud occurred only in the anterior region, the rostral 1-mm part, but not in the intermediate region, the caudal 4-mm part, of the anterior two-third of the tongue containing fungiform papillae. This work extends our previous observations and provides new information about the developmental and regional expression pattern of α-Gustducin in mouse fungiform taste bud under early AK-stimulated conditions.
Asunto(s)
Preferencias Alimentarias/efectos de los fármacos , Edulcorantes/administración & dosificación , Edulcorantes/farmacología , Papilas Gustativas/efectos de los fármacos , Tiazinas/administración & dosificación , Tiazinas/farmacología , Transducina/biosíntesis , Administración Oral , Animales , Femenino , Ratones , Ratones Endogámicos ICR , Papilas Gustativas/metabolismoRESUMEN
Crystals of a uranyl-europium germanate, K4[(UO2)Eu2(Ge2O7)2], have been grown at high temperature from a KF-MoO3 flux and structurally characterized by single-crystal X-ray diffraction. The structure contains PaCl5-type chains formed of edge-sharing EuO7 pentagonal bipyramids that are connected by digermanate groups such that layers of europium germanate are formed. Neighboring layers are further linked by UO6 tetragonal bipyramids through uranyl ion oxygen atoms to generate a 3D framework with 6-ring channels where the K(+) cations are located. The structure contains an unusual heterometallic UâO-Eu linkage. Photoluminescence studies show strong red emission at room temperature. The relative intensities of the (5)D0 â (7)F1 and (5)D0 â (7)F2 transitions confirm that the europium site lacks an inversion center. All of the emission lines show similar decay curves, which can be well-fitted by a single exponential decay function with radiative lifetimes of 0.53 ± 0.03 ms. No emission is observed in the region from 450 to 550 nm typical of the uranyl cation, indicating that, upon uranyl excitation, the energy is either transferred to the Eu(3+) centers or lost to nonradiative processes.
RESUMEN
Recent genome-wide association studies of Parkinson's disease (PD) in Caucasian populations have identified two new susceptibility loci, GAK and HLA-DRA; however, only limited information exists regarding the involvement of these genes in PD risk in other ethnic groups. Here, we examined whether these genetic effects were consistent in a Taiwanese PD population. In a total 900 participants, including 448 PD patients and 452 control subjects, we genotyped the rs11248051 and rs1564282 variants of GAK, and the rs3129882 variant of HLA-DRA. Logistic regression analysis was used to test for associations between genotype and PD under an additive model, adjusting for age and gender. Subjects with CT/TT genotypes of GAK rs11248051 had a modestly increased association with PD compared to those with CC genotype (OR = 1.37; 95% CI = 1.09, 1.87; P = 0.03). Carriers and non-carriers exhibited indistinguishable phenotypes in regards to clinical presentation and onset age. We observed no association between PD risk and GAK rs1564282 or HLA-DRA rs3129882 variant. The different genetic effects between Taiwanese and Caucasian populations may come from differences in population structure and geographic region-specific genetic-environmental interactions. In conclusion, our results supported the association between the rs11248051 variant in GAK and PD risk in a Taiwanese population. Future functional studies of GAK in neuronal degeneration are warranted to unravel its role in the pathogenetic mechanism of PD.
Asunto(s)
Predisposición Genética a la Enfermedad , Cadenas alfa de HLA-DR/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Taiwán , Adulto JovenRESUMEN
BACKGROUND: The oriental fruit fly, Bactrocera dorsalis (Hendel) is a worldwide pest damaging a wide range of hosts. Due to the long-term indiscriminate use of insecticides, B. dorsalis has developed serious resistance to several insecticides. UDP-glycosyltransferases (UGTs) are secondary metabolic enzymes involved in biotransformation and play an important role in the metabolism of plant secondary metabolites and synthetic insecticides in insects. Thus, we suspect that UGTs in B. dorsalis play an important role in insecticide tolerance. RESULTS: In this study, 31 UGT genes were identified in the genome of B. dorsalis, belonging to 13 subfamilies. Real-time quantitative polymerase chain reaction (RT-qPCR) results revealed that 12 UGT genes were highly expressed in the antennae, midgut, Malpighian tubule and fat body. The mRNA expressions of 17 UGT genes were up-regulated upon exposure to λ-cyhalothrin, imidacloprid, abamectin and chlorpyrifos. Knockdown of the selected five UGT genes (BdUGT301D2, BdUGT35F2, BdUGT36K2, BdUGT49D2, BdUGT50B5) by RNA interference increased the mortality of B. dorsalis from 9.29% to 27.22% upon exposure to four insecticides. CONCLUSION: The abundance of UGTs in B. dorsalis is similar to other insect species, and 12 out of 31 UGTs were specifically expressed in metabolic tissues, suggesting a key role in detoxification. Down-regulation of five selected UGT genes increased the susceptibility of B. dorsalis to various insecticides, indicating that UGTs may play an important role in tolerance of B. dorsalis to multiple insecticides. © 2022 Society of Chemical Industry.
Asunto(s)
Insecticidas , Tephritidae , Animales , Insecticidas/farmacología , Uridina Difosfato , Insectos/metabolismo , Drosophila , Glicosiltransferasas/genéticaRESUMEN
The oriental fruit fly, Bactrocera dorsalis, is a damaging insect pest for many vegetable and fruit crops that has evolved severe chemical insecticide resistance, including organophosphorus, neonicotinoid, pyrethroid, and macrolides. Hence, it is important to elucidate its detoxification mechanism to improve its management and mitigate resource destruction. Glutathione S-transferase (GST) is a critical secondary phase enzyme that plays multiple detoxification functions against xenobiotics. In this study, we identified several BdGSTs by characterizing their potential relationships with five insecticides using inducible and tissue-specific expression pattern analyses. We found that an antenna-abundant BdGSTd8 responded to four different classes of insecticides. Subsequently, our immunohistochemical and immunogold staining analysis further confirmed that BdGSTd8 was primarily located in the antenna. Our investigations also confirmed that BdGSTd8 possesses the capability to enhance cell viability by directly interacting with malathion and chlorpyrifos, which clarified the function of antenna-abundant GST in B. dorsalis. Altogether, these findings enrich our understanding of GST molecular characteristics in B. dorsalis and provide new insights into the detoxification of superfluous xenobiotics in the insect antenna.
Asunto(s)
Insecticidas , Tephritidae , Animales , Insecticidas/farmacología , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Xenobióticos , Compuestos Organofosforados , Tephritidae/genética , Tephritidae/metabolismoRESUMEN
The previous study indicated that aquaporin 4 (AQP4) deficiency attenuated opioid physical dependence. However, the underlying mechanism remains unknown. In the present study, the effects of AQP4 deficiency on the expression of three factors, protein kinase C (PKC) α, PKCγ and c-Fos in the spinal cord, which are known to be concerned with spinal neuronal sensitization and opiate dependence, were investigated in AQP4 knockout mice using Western blotting analysis. It was observed that AQP4 deficiency reduced the score of naloxone-precipitated abstinent jumping after repeated morphine administration compared with wild-type (P < 0.001). Meanwhile, the protein levels of PKCα and c-Fos in the spinal cord of AQP4 knockout mice were significantly higher than those in the wild-type mice; while the expression of PKCγ was decreased remarkably by AQP4 knockout during the withdrawal (P < 0.01). These data suggest that AQP4 deficiency-attenuated morphine withdrawal responses may be partially attributed to the changes in the spinal expression of PKCα, PKCγ or c-Fos.
Asunto(s)
Acuaporina 4/genética , Naloxona/farmacología , Proteína Quinasa C-alfa/metabolismo , Proteína Quinasa C/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Analgésicos Opioides/farmacología , Animales , Acuaporina 4/deficiencia , Ratones , Ratones Noqueados , Morfina/farmacología , Médula Espinal/metabolismoRESUMEN
Aphids feed on plant phloem sap that contains massive amounts of sucrose; this not only provides vital nutrition for the aphids but also produces high osmotic pressure. To utilize this carbon source and overcome the osmotic pressure, sucrose is hydrolyzed into the monosaccharides, glucose and fructose. In the green peach aphid (Myzus persicae), we show that this process is facilitated by a key α-glucosidase (MpAgC2-2), which is abundant in the aphid salivary gland and is secreted into leaves during feeding. MpAgC2-2 has a pH optimum of 8.0 in vitro, suggesting it has adapted to the environment of plant cells. Silencing MpAgC2-2 (but not the gut-specific MpAgC3-4) significantly increased the amount of sucrose ingested and hindered aphid feeding on the phloem of tobacco seedlings, resulting in a smaller body size, as well as lower α-glucosidase activity and glucose levels. These effects could be rescued by feeding aphids on tobacco plants transiently expressing MpAgC2-2. The transient expression of MpAgC2-2 also led to the hydrolysis of sucrose in tobacco leaves. Taken together, these results demonstrate that MpAgC2-2 is a salivary protein that facilitates extra-intestinal feeding via sucrose hydrolysis. Our findings provide insight into the ability of aphids to digest the high concentration of sucrose in phloem, and the underlying mechanism of extra-intestinal digestion.