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1.
Proc Natl Acad Sci U S A ; 119(41): e2122099119, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36191206

RESUMO

Viruses pose a great threat to animal and plant health worldwide, with many being dependent on insect vectors for transmission between hosts. While the virus-host arms race has been well established, how viruses and insect vectors adapt to each other remains poorly understood. Begomoviruses comprise the largest genus of plant-infecting DNA viruses and are exclusively transmitted by the whitefly Bemisia tabaci. Here, we show that the vector Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway plays an important role in mediating the adaptation between the begomovirus tomato yellow leaf curl virus (TYLCV) and whiteflies. We found that the JAK/STAT pathway in B. tabaci functions as an antiviral mechanism against TYLCV infection in whiteflies as evidenced by the increase in viral DNA and coat protein (CP) levels after inhibiting JAK/STAT signaling. Two STAT-activated effector genes, BtCD109-2 and BtCD109-3, mediate this anti-TYLCV activity. To counteract this vector immunity, TYLCV has evolved strategies that impair the whitefly JAK/STAT pathway. Infection of TYLCV is associated with a reduction of JAK/STAT pathway activity in whiteflies. Moreover, TYLCV CP binds to STAT and blocks its nuclear translocation, thus, abrogating the STAT-dependent transactivation of target genes. We further show that inhibition of the whitefly JAK/STAT pathway facilitates TYLCV transmission but reduces whitefly survival and fecundity, indicating that this JAK/STAT-dependent TYLCV-whitefly interaction plays an important role in keeping a balance between whitefly fitness and TYLCV transmission. This study reveals a mechanism of plant virus-insect vector coadaptation in relation to vector survival and virus transmission.


Assuntos
Begomovirus , Hemípteros , Vírus de Plantas , Solanum lycopersicum , Animais , Antivirais , Begomovirus/genética , DNA Viral , Hemípteros/fisiologia , Janus Quinases/genética , Solanum lycopersicum/genética , Doenças das Plantas , Vírus de Plantas/genética , Fatores de Transcrição STAT/genética , Transdução de Sinais
2.
Acta Pharmacol Sin ; 44(4): 766-779, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36229601

RESUMO

The transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel that is activated by capsaicin (CAP), the main component of chili pepper. Despite studies in several neurological diseases, the role of TRPV1 in demyelinating diseases remains unknown. Herein, we reported that TRPV1 expression was increased within the corpus callosum during demyelination in a cuprizone (CPZ)-induced demyelination mouse model. TRPV1 deficiency exacerbated motor coordinative dysfunction and demyelination in CPZ-treated mice, whereas the TRPV1 agonist CAP improved the behavioral performance and facilitated remyelination. TRPV1 was predominantly expressed in Iba1+ microglia/macrophages in human brain sections of multiple sclerosis patients and mouse corpus callosum under demyelinating conditions. TRPV1 deficiency decreased microglial recruitment to the corpus callosum, with an associated increase in the accumulation of myelin debris. Conversely, the activation of TRPV1 by CAP enhanced the recruitment of microglia to the corpus callosum and potentiated myelin debris clearance. Using real-time live imaging we confirmed an increased phagocytic function of microglia following CAP treatment. In addition, the expression of the scavenger receptor CD36 was increased, and that of the glycolysis regulators Hif1a and Hk2 was decreased. We conclude that TRPV1 is an important regulator of microglial function in the context of demyelination and may serve as a promising therapeutic target for demyelinating diseases such as multiple sclerosis.


Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Animais , Humanos , Camundongos , Cuprizona , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Bainha de Mielina/metabolismo , Canais de Cátion TRPV , Capsaicina/farmacologia
3.
Proc Natl Acad Sci U S A ; 117(29): 16928-16937, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32636269

RESUMO

Whereas most of the arthropod-borne animal viruses replicate in their vectors, this is less common for plant viruses. So far, only some plant RNA viruses have been demonstrated to replicate in insect vectors and plant hosts. How plant viruses evolved to replicate in the animal kingdom remains largely unknown. Geminiviruses comprise a large family of plant-infecting, single-stranded DNA viruses that cause serious crop losses worldwide. Here, we report evidence and insight into the replication of the geminivirus tomato yellow leaf curl virus (TYLCV) in the whitefly (Bemisia tabaci) vector and that replication is mainly in the salivary glands. We found that TYLCV induces DNA synthesis machinery, proliferating cell nuclear antigen (PCNA) and DNA polymerase δ (Polδ), to establish a replication-competent environment in whiteflies. TYLCV replication-associated protein (Rep) interacts with whitefly PCNA, which recruits DNA Polδ for virus replication. In contrast, another geminivirus, papaya leaf curl China virus (PaLCuCNV), does not replicate in the whitefly vector. PaLCuCNV does not induce DNA-synthesis machinery, and the Rep does not interact with whitefly PCNA. Our findings reveal important mechanisms by which a plant DNA virus replicates across the kingdom barrier in an insect and may help to explain the global spread of this devastating pathogen.


Assuntos
Begomovirus/fisiologia , DNA Polimerase III/metabolismo , Hemípteros/virologia , Proteínas de Insetos/metabolismo , Insetos Vetores/virologia , Replicação Viral , Animais , Begomovirus/genética , DNA Polimerase III/genética , Gossypium/parasitologia , Gossypium/virologia , Hemípteros/patogenicidade , Interações Hospedeiro-Patógeno , Proteínas de Insetos/genética , Insetos Vetores/patogenicidade , Glândulas Salivares/metabolismo , Glândulas Salivares/virologia
4.
Pestic Biochem Physiol ; 197: 105651, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38072526

RESUMO

Solenopsis invicta is a main issue in southern China and is causing significant damage to the local ecological environment. The extensive use of insecticides has resulted in the development of tolerance in S. invicta. In our study, ten S. invicta colonies from Sichuan Province exhibited varying degrees of tolerance against flonicamid, with LC50 values from 0.49 mg/L to 8.54 mg/L. The sensitivity of S. invicta to flonicamid significantly increased after treatment with the P450 enzyme inhibitor piperonyl butoxide (PBO). Additionally, the activity of P450 in S. invicta was significantly enhanced after being treated with flonicamid. Flonicamid induced the expression levels of CYP4aa1, CYP9e2, CYP4C1, and CYP6A14. The expression levels of these P450 genes were significantly higher in the tolerant colonies compared to the sensitive colonies, and the relative copy numbers of CYP6A14 in the tolerant colonies were 2.01-2.15 fold. RNAi feeding treatment effectively inhibited the expression of P450 genes, thereby reducing the tolerance of S. invicta against flonicamid. In addition, the overexpression of CYP6A14 in D. melanogaster resulted in reduced sensitivity to flonicamid. Our investigations revealed hydrophobic interactions between flonicamid and seven amino acid residues of CYP6A14, along with the formation of a hydrogen bond between Glu306 and flonicamid. Our findings suggest that flonicamid can effectively control S. invicta and P450 plays a pivotal role in the tolerance of S. invicta against flonicamid. The overexpression of CYP6A14 also increased tolerance to flonicamid.


Assuntos
Formigas , Inseticidas , Animais , Formigas Lava-Pés , Drosophila melanogaster , Inseticidas/toxicidade
5.
Ophthalmology ; 129(3): 308-321, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34627809

RESUMO

PURPOSE: (1) To compare the efficacy of continued and stopping treatment for 0.05%, 0.025%, and 0.01% atropine during the third year. (2) To evaluate the efficacy of continued treatment over 3 years. (3) To investigate the rebound phenomenon and its determinants after cessation of treatment. DESIGN: A randomized, double-masked extended trial. PARTICIPANTS: A total of 350 of 438 children aged 4 to 12 years originally recruited into the Low-Concentration Atropine for Myopia Progression (LAMP) study. METHODS: At the beginning of the third year, children in each group were randomized at a 1:1 ratio to continued treatment and washout subgroups. Cycloplegic spherical equivalent (SE) refraction and axial length (AL) were measured at 4-month intervals. MAIN OUTCOME MEASURES: Changes in SE and AL between groups. RESULTS: A total of 326 children completed 3 years of follow-up. During the third year, SE progression and AL elongation were faster in the washout subgroups than in the continued treatment groups across all concentrations: -0.68 ± 0.49 diopters (D) versus -0.28 ± 0.42 D (P < 0.001) and 0.33 ± 0.17 mm versus 0.17 ± 0.14 mm (P < 0.001) for the 0.05%; -0.57 ± 0.38 D versus -0.35 ± 0.37 D (P = 0.004) and 0.29 ± 0.14 mm versus 0.20 ± 0.15 mm (P = 0.001) for the 0.025%; -0.56 ± 0.40 D versus -0.38 ± 0.49 D (P = 0.04) and 0.29 ± 0.15 mm versus 0.24 ± 0.18 mm (P = 0.13) for the 0.01%. Over the 3-year period, SE progressions were -0.73 ± 1.04 D, -1.31 ± 0.92 D, and -1.60 ± 1.32 D (P = 0.001) for the 0.05%, 0.025%, and 0.01% groups in the continued treatment subgroups, respectively, and -1.15 ± 1.13 D, -1.47 ± 0.77 D, and -1.81 ± 1.10 D (P = 0.03), respectively, in the washout subgroup. The respective AL elongations were 0.50 ± 0.40 mm, 0.74 ± 0.41 mm, and 0.89 ± 0.53 mm (P < 0.001) for the continued treatment subgroups and 0.70 ± 0.47 mm, 0.82 ± 0.37 mm, and 0.98 ± 0.48 mm (P = 0.04) for the washout subgroup. The rebound SE progressions during washout were concentration dependent, but their differences were clinically small (P = 0.15). Older age and lower concentration were associated with smaller rebound effects in both SE progression (P < 0.001) and AL elongation (P < 0.001). CONCLUSIONS: During the third year, continued atropine treatment achieved a better effect across all concentrations compared with the washout regimen. 0.05% atropine remained the optimal concentration over 3 years in Chinese children. The differences in rebound effects were clinically small across all 3 studied atropine concentrations. Stopping treatment at an older age and lower concentration are associated with a smaller rebound.


Assuntos
Atropina/administração & dosagem , Midriáticos/administração & dosagem , Miopia Degenerativa/tratamento farmacológico , Comprimento Axial do Olho/fisiologia , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Miopia Degenerativa/fisiopatologia , Refração Ocular/fisiologia , Perfil de Impacto da Doença , Resultado do Tratamento , Acuidade Visual/fisiologia
6.
Int J Mol Sci ; 23(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35457041

RESUMO

The contributory roles of vitamin D in ocular and visual health have long been discussed, with numerous studies pointing to the adverse effects of vitamin D deficiency. In this paper, we provide a systematic review of recent findings on the association between vitamin D and different ocular diseases, including myopia, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), dry eye syndrome (DES), thyroid eye disease (TED), uveitis, retinoblastoma (RB), cataract, and others, from epidemiological, clinical and basic studies, and briefly discuss vitamin D metabolism in the eye. We searched two research databases for articles examining the association between vitamin D deficiency and different ocular diseases. One hundred and sixty-two studies were found. There is evidence on the association between vitamin D and myopia, AMD, DR, and DES. Overall, 17 out of 27 studies reported an association between vitamin D and AMD, while 48 out of 54 studies reported that vitamin D was associated with DR, and 25 out of 27 studies reported an association between vitamin D and DES. However, the available evidence for the association with other ocular diseases, such as glaucoma, TED, and RB, remains limited.


Assuntos
Retinopatia Diabética , Glaucoma , Degeneração Macular , Miopia , Deficiência de Vitamina D , Retinopatia Diabética/complicações , Olho , Glaucoma/complicações , Glaucoma/etiologia , Humanos , Degeneração Macular/complicações , Degeneração Macular/etiologia , Vitamina D , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Vitaminas
7.
Planta Med ; 87(3): 225-235, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33348408

RESUMO

Four new ß-resorcylic acid lactones, including penochrochlactone A (2: ), 4-O-desmethyl-aigialomycin B (4: ), and penochrochlactones C and D (5: and 6: ), two compounds isolated from a natural source for the first time, 5α, 6ß-acetonide-aigialomycin B (1: ) and penochrochlactone B (3: ), together with six known compounds, aigialomycin F (7: ), aigialomycins A, B, and D (8: -10: ), zeaenol (11: ), and oxozeaenol (12: ), were isolated from a mycelial solid culture of the endophytic fungus Penicillium ochrochloron SWUKD4.1850 from the medicinal plant Kadsura angustifolia by sequential purification over silica gel, Sephadex LH-20 column chromatography, and preparative HPLC. Their structures were elucidated by extensive spectroscopic analysis and chemical conversions. In addition, all the new compounds were evaluated for their cytotoxic and antibacterial activities in vitro. Penochrochlactone C (5: ) displayed moderate cytotoxicity against the HeLa tumor cell line with an IC50 value of 9.70 µM. In the antibacterial assays, compounds 4:  - 6: exhibited moderate activities against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa with MIC values between 9.7 and 32.0 µg/mL.


Assuntos
Kadsura , Penicillium , Antibacterianos/farmacologia , Lactonas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular
8.
Bioorg Chem ; 95: 103489, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862456

RESUMO

Five new isoquinolines (1-5) were isolated from national herb Corydalis tomentella. Their structures were elucidated by extensive analysis of the 1D and 2D NMR spectra and from the HRESIMS. Absolute configurations of 1-3 were determined by comparing their experimental and computed ECD data. Since plants from Corydalis have been reported to protect against Alzheimer's disease, all compounds were evaluated for their neuroprotective effect against lipopolysaccharide-induced BV2 microglia cells. Compound 2 and 3 showed well anti-neuroinflammatory activity at low concentration (25 µM).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Corydalis/química , Isoquinolinas/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Relação Estrutura-Atividade
9.
Eye Contact Lens ; 46(5): 306-309, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31425353

RESUMO

PURPOSE: To assess corneal biomechanical changes after conventional corneal crosslinking (CXL), with and without oxygen enrichment. METHODS: Sixty fresh porcine corneas were randomly divided into group 1 (control), group 2 (conventional CXL), and group 3 (conventional CXL in a high-oxygen environment during ultraviolet A [UVA] irradiation). After crosslinking, a 5-mm wide corneal strip was extracted using a double-bladed knife from 12 to 6'o clock. The Young's modulus of each strip was determined by stress-strain measurements. A comparison between the three groups was performed with a one-way analysis of variance. RESULTS: At 4% strain, the Young's modulus of the corneas in groups 1, 2, and 3 were: 0.68±0.20 megapascal (MPa), 1.01±0.23 MPa, and 1.12±0.24 MPa, respectively. The Young's modulus values for groups 2 and 3 showed no statistical significance (P>0.05), However, both groups 2 and 3 were significantly higher than group 1 (P<0.05). At 6% strain, the Young's modulus of the corneas in groups 1, 2, and 3 were: 0.97±0.21, 1.35±0.25, and 1.64±0.44 MPa, respectively, and at 8% strain, the Young's modulus was: 1.29±0.26, 1.72±0.45, 2.20±0.74 MPa, respectively. At 6% and 8% strain, the Young's modulus for the corneas in group 3 was significantly higher than those in both group 1 and group 2 (P<0.05). CONCLUSIONS: Increasing oxygen concentration during UVA irradiation may improve the efficacy of conventional CXL.


Assuntos
Oxigênio , Riboflavina , Animais , Fenômenos Biomecânicos , Córnea , Reagentes de Ligações Cruzadas , Elasticidade , Fármacos Fotossensibilizantes , Suínos , Raios Ultravioleta
10.
Eye Contact Lens ; 46(1): 35-45, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30985487

RESUMO

PURPOSE: To compare the repeatability and agreement between a swept-source biometer and a Scheimpflug biometer in cataract patients. METHODS: Three consecutive measurements were obtained using a swept-source biometer (IOLMaster 700) and a Scheimpflug biometer (AL-Scan) in 52 eyes of 52 patients. Keratometry, central corneal thickness (CCT), anterior chamber depth (ACD), axial length, and white-to-white (WTW) distance were recorded. Astigmatism values were transformed into vector components of J0 and J45. Intraoperator repeatability was analyzed using intraclass correlation coefficients (ICCs) and reproducibility coefficients (RCs). Agreement of measurements between the two devices was evaluated using the Bland-Altman method. RESULTS: The IOLMaster 700 showed higher ICCs and lower RCs for the mean keratometry (Km) (P≤0.018), CCT (P≤0.027), and ACD (P≤0.001) measurements, whereas the AL-Scan showed higher ICC and lower RC for the J45 vector component of astigmatism at the 2.4-mm zone (P≤0.034). Both the devices had excellent repeatability (ICC=0.999) in axial length measurement. Systematic differences were found in Km, CCT, ACD, and WTW (P≤0.018) between the devices. The mean difference for Km was -0.196 and -0.144 D measured at the 2.4-mm zone and 3.3-mm zone, respectively. The corresponding mean difference for CCT, ACD, and WTW distance was 14.92 µm, -0.017 mm, and 0.283 mm, respectively. These differences led to a statistically significant but clinically insignificant difference in the prediction of intraocular lens power. CONCLUSIONS: This study showed significant differences in anterior segment measurement repeatability and agreement between a swept-source biometer and a Scheimpflug biometer in eyes with cataract.


Assuntos
Comprimento Axial do Olho/diagnóstico por imagem , Biometria/instrumentação , Catarata/diagnóstico , Córnea/diagnóstico por imagem , Interferometria/métodos , Tomografia de Coerência Óptica/métodos , Idoso , Desenho de Equipamento , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Curva ROC , Reprodutibilidade dos Testes
11.
Bioorg Chem ; 88: 102924, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31005783

RESUMO

Artemisia argyi (AA) is one of the renowned herbs in China often used in the treatment of gastric ulcer (GU). Aiming to predict the active compounds and systematically investigate the mechanisms of Artemisia argyi for GU treatment, the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, respectively, in present study. A total of 13 predicted targets of the 103 compounds in Artemisia argyi were obtained. Sorted by pathogenic mechanisms of targets and structure types of compounds, it was revealed that flavonoids and sesquiterpenes had better performance than monoterpenes. The network analysis showed that Phospholipase a2 (PA21B), Sulfotransferase family cytosolic 2b member 1 (ST2B1), Nitric-oxide synthase, endothelial (NOS3), Gastrin (GAST), neutrophil collagenase (MMP-8), Leukotriene A-4 hydrolase (LKHA4), Urease maturation factor HypB (HYPB), and Periplasmic serine endoprotease DegP (HtrA) were the key targets with intensely interaction. The functional enrichment analysis indicated that AA probably produced the gastric mucosa protection effects by synergistically regulating many biological pathways, such as NF-κB signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, and Toll-like receptor signaling pathway, etc. In addition, C73 and C15 might be promising leading compounds with good molecular docking score. As a consequence, this study holistically illuminates the active constituents and mechanisms based on data analysis, which contributes to searching for leading compounds and the development of new drugs for gastric ulcer.


Assuntos
Antiulcerosos/metabolismo , Artemisia/química , Farmacologia/métodos , Proteínas/metabolismo , Antiulcerosos/química , Simulação de Acoplamento Molecular , Ligação Proteica , Proteínas/química , Transdução de Sinais
12.
Molecules ; 24(21)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31671631

RESUMO

Tagetespatula L. is a widely cultivated herbal medicinal plant in China and other countries. In this study, two new 2, 3-dihydrobenzofuran glucosides (1, 2) and fourteen known metabolites (3-16) were isolated from the stems and leaves of T. patula (SLT). The chemical structures of the isolated compounds were characterized comprehensively based on one- and two-dimensional NMR spectroscopy and high resolution mass spectrometry. Absolute configurations of compounds 1 and 2 were determined by ECD calculations. Compounds 1 and 2 exhibited moderate in vitro inhibitory activities against human gastric cancer cell lines (AGS) with IC50 values of 41.20 µmol/L and 30.43 µmol/L, respectively. The fingerprint profiles of stems and leaves of T. patula with three color types of flowers (Janie Yellow Bright, Jinmen Orange, Shouyao Red and Yellow color) were established by high-performance liquid chromatography (HPLC). Ten different batches of stems and leaves were examined as follow: Shouyao Red and Yellow color (1, 2, 3), Janie Yellow Bright (4, 5, 6, 7) and Jinmen Orange (8, 9, 10). Twenty-two common peaks were identified with similarity values ranging from 0.910 to 0.977. Meanwhile, the average peak area of SLT in the three types of flowers was different and it was the highest in Janie Yellow Bright.


Assuntos
Compostos Fitoquímicos/análise , Folhas de Planta/química , Caules de Planta/química , Tagetes/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
15.
Cell Rep Med ; 5(2): 101413, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38325382

RESUMO

Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1G93A ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy. FP802 also effectively blocks NMDA-induced death of neurons in ALS patient-derived forebrain organoids. These results establish eNMDAR toxicity as a key player in ALS pathogenesis. TI inhibitors may provide an effective treatment option for ALS patients.


Assuntos
Esclerose Lateral Amiotrófica , Canais de Cátion TRPM , Camundongos , Animais , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia , Superóxido Dismutase/uso terapêutico , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Modelos Animais de Doenças , Progressão da Doença
16.
Chin J Dent Res ; 27(1): 89-99, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38546524

RESUMO

OBJECTIVE: To explore the genetic background and clinical phenotypes of multiple idiopathic cervical root resorption (MICRR) in a Chinese family. METHODS: The proband and his three family members were clinically examined and had radiographs taken with a radiovisiography (RVG) system and CBCT to define the diagnosis of MICRR. Genomic DNA (gDNA) was extracted from peripheral blood samples of the patient, his father, mother and younger sister for whole exome sequencing (WES). The pathogenicity of rare variants with minor allele frequency (MAF) less than 0.005 were analysed following possible inheritance patterns, predicted results from 12 software programs, the American College of Medical Genetics (ACMG) 2015 criteria, and information from ClinVar, OMIM and HGMD databases as well as gene function. RESULTS: The proband presented the typical MICRR phenotypes such as thin cervical pulp wall and apple core-like lesions in radiographs. Following the recessive inheritance pattern, WES analysis identified SHROOM2, SYTL5, MAGED1 and FLNA with a higher chance of causing MICRR. Four genes with compound heterozygous variants and another 27 genes with de novo variants either in autosomal-dominant or autosomal-recessive pattern were also found to have the potential pathogenicity. CONCLUSION: A total of 35 novel potential pathogenic genes were found to be associated with MICRR from a Chinese family through WES. The new genetic background of MICRR may be helpful for clinical and molecular diagnosis.


Assuntos
Reabsorção da Raiz , Reabsorção de Dente , Feminino , Humanos , Proteínas de Transporte , Genes Reguladores , Proteínas de Membrana , Reabsorção da Raiz/diagnóstico por imagem , Reabsorção da Raiz/genética , Masculino , População do Leste Asiático
17.
J Am Soc Mass Spectrom ; 35(4): 746-755, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38422384

RESUMO

Hops (Humulus lupulus L.) are essential raw materials for beer brewing, and the major contributors to beer bitterness are isohumulones (iso-α-acids) and humulinones. In recent years, many breweries have focused on the production of hop-forward beer styles by adding hops after or during the cold fermentation stage, which will tend to release humulinones or other hop-derived bitter compounds. In this study, a LC-MS/MS method was developed for quantification of 60 hop-derived bitter compounds in 25 min. Reverse-phase chromatography with an alkaline methanol/acetonitrile (70:30) mobile phase was used for the separation. The quantitative range was 0.053-3912 ng/mL with correlation coefficient r > 0.99, and the LOQ were 0.26 and 0.053 ng/mL for iso-α-acids and humulinones. Precision (RSD < 5.0%) and accuracy (recovery 86.3%-118.1%) were both satisfactory. The abundance of hop-derived bitter compounds in the dry-hopped beer (Double-India Pale Ale) and the nondry-hopped beer (Vienna Lager) were monitored throughout the fermentation and storage stages, and the formation of oxidation and cyclization products showed difference profiles between these two beers. The quantification results reveal how hop-derived bitter compounds change throughout the brewing process, as well as the influence of hops and brewing techniques on beer bitterness.


Assuntos
Cerveja , Humulus , Cromatografia Líquida , Cerveja/análise , Humulus/química , Espectrometria de Massa com Cromatografia Líquida , Espectrometria de Massas em Tandem , Ácidos/química
18.
Artigo em Inglês | MEDLINE | ID: mdl-38154657

RESUMO

Microcystins (MCs) are the most widespread, frequently found, and seriously toxic cyanobacterial toxins in aquatic environments. Microcystin-leucine-arginine (MCLR) and microcystin-arginine-arginine (MCRR) are the most studied MCs. Normally, their levels are low and they coexist in the environment; however, they may also interact with each other. The developmental toxicity of MCLR in the presence of MCRR in the early life stage of zebrafish (from 2 to 120 h post fertilization) was investigated for the first time in this study. Our findings revealed that MCRR treatment marginally elevated thyroxine (T4) and 3,5,3'-triiodothyronine (T3) levels, whereas MCLR treatment alone resulted in a significant increase in T3 and T4 levels, indicating a cooperative effect. Furthermore, clear changes in the expression levels of genes involved in growth and development, accompanied by growth inhibition, were observed after co-treatment with MCRR and MCLR. In addition, zebrafish larvae subjected to MCRR and/or MCLR treatment showed increased levels of superoxide dismutase, glutathione, and malondialdehyde, and decreased levels of catalase in the MCRR + MCLR group, indicating oxidative stress and lipid peroxidation. Thus, we investigated the synergistic developmental toxicity of MCRR and MCLR during the early life stages of zebrafish development.


Assuntos
Toxinas Marinhas , Microcistinas , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Microcistinas/toxicidade , Larva , Arginina/metabolismo
19.
Biomed Pharmacother ; 175: 116705, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38713949

RESUMO

Currently, the drugs used in clinical to treat psoriasis mainly broadly suppress cellular immunity. However, these drugs can only provide temporary and partial symptom relief, they do not cure the condition and may lead to recurrence or even serious toxic side effects. In this study, we describe the discovery of a novel potent CDK8 inhibitor as a treatment for psoriasis. Through structure-based design, compound 46 was identified as the most promising candidate, exhibiting a strong inhibitory effect on CDK8 (IC50 value of 57 nM) along with favourable inhibition against NF-κB. Additionally, it demonstrated a positive effect in an in vitro psoriasis model induced by TNF-α. Furthermore, this compound enhanced the thermal stability of CDK8 and exerted evident effects on the biological function of CDK8, and it had favourable selectivity across the CDK family and tyrosine kinase. This compound showed no obvious inhibitory effect on CYP450 enzyme. Further studies confirmed that compound 46 exhibited therapeutic effect on IMQ-induced psoriasis, alleviated the inflammatory response in mice, and enhanced the expression of Foxp3 and IL-10 in the dorsal skin in vivo. This discovery provides a new strategy for developing selective CDK8 inhibitors with anti-inflammatory activity for the treatment of psoriasis.


Assuntos
Quinase 8 Dependente de Ciclina , Inibidores de Proteínas Quinases , Psoríase , Animais , Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Quinase 8 Dependente de Ciclina/metabolismo , Psoríase/tratamento farmacológico , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Camundongos , NF-kappa B/metabolismo , NF-kappa B/antagonistas & inibidores , Piridinas/farmacologia , Piridinas/química , Camundongos Endogâmicos BALB C , Interleucina-10/metabolismo , Masculino , Pirróis/farmacologia , Pirróis/química , Fatores de Transcrição Forkhead/metabolismo , Descoberta de Drogas/métodos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Modelos Animais de Doenças , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo
20.
Pest Manag Sci ; 80(4): 1751-1760, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38009258

RESUMO

BACKGROUND: Migration is a strategy that shifts insects to more favorable habitats in response to deteriorating local environmental conditions. The ecological factors that govern insect migration are poorly understood for many species. Plutella xylostella causes great losses in Brassica vegetable and oilseed crops, and undergoes mass migration. However, the physiological and behavioral basis for distinguishing migratory individuals and the factors driving its migration remain unclear. RESULTS: Daily light trap catches conducted from April to July in a field population of P. xylostella in central China revealed a sharp decline in abundance from late-May. Analysis of ovarian development levels showed that the proportion of sexually immature females gradually increased, while the mating rate decreased, indicating that generations occurring in May mainly resulted from local breeding and that emigration began in late-May. Physiological and behavioral analyses revealed that emigrant populations had a higher take-off proportion, stronger flight capacity and greater energy reserves of triglyceride compared to residents. Furthermore, a gradual increase in temperature from 24 °C to >30 °C during larval development resulted in a significant delay in oogenesis and increased take-off propensity of adults compared with the control treatment reared at a constant temperature of 24 °C. CONCLUSION: Our results provide the physiological and behavioral factors that underpin mass migration in P. xylostella, and demonstrate that exposure to increased temperature increases their migration propensity at the cost of reproductive output. This study sheds light on understanding the factors that influence population dynamics, migratory propensity and reproductive tradeoffs in migratory insects. © 2023 Society of Chemical Industry.


Assuntos
Brassica , Mariposas , Humanos , Animais , Feminino , Melhoramento Vegetal , Temperatura , Resposta ao Choque Térmico , Larva
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