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

RESUMEN

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.


Asunto(s)
Begomovirus , Hemípteros , Virus de Plantas , Solanum lycopersicum , Animales , Antivirales , Begomovirus/genética , ADN Viral , Hemípteros/fisiología , Quinasas Janus/genética , Solanum lycopersicum/genética , Enfermedades de las Plantas , Virus de Plantas/genética , Factores de Transcripción STAT/genética , Transducción de Señal
2.
J Asian Nat Prod Res ; : 1-11, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39082687

RESUMEN

Four new lycoctonine-type C19-diterpenoid alkaloids kamaonensines H-K (1-4) have been isolated from the whole plants of Delphinium kamaonense, together with 12 known compounds (5-16). Interestingly, kamaonensines 1-3 contained a rare nitrone (immine N-oxide) moiety, respectively. Their structures were established by spectroscopic analyses. The active evaluation of compounds (1-16) by LPS induced RAW 264.7 macrophages showed that compounds 4 and 8 displayed strong anti-inflammatory activities. While compounds 11 and 12 also showed strong cytotoxicities by the RAW 264.7 cell viability assay.

3.
Acta Pharmacol Sin ; 44(4): 766-779, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36229601

RESUMEN

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.


Asunto(s)
Enfermedades Desmielinizantes , Esclerosis Múltiple , Animales , Humanos , Ratones , Cuprizona , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Microglía/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Vaina de Mielina/metabolismo , Canales Catiónicos TRPV , Capsaicina/farmacología
4.
Proc Natl Acad Sci U S A ; 117(29): 16928-16937, 2020 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-32636269

RESUMEN

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.


Asunto(s)
Begomovirus/fisiología , ADN Polimerasa III/metabolismo , Hemípteros/virología , Proteínas de Insectos/metabolismo , Insectos Vectores/virología , Replicación Viral , Animales , Begomovirus/genética , ADN Polimerasa III/genética , Gossypium/parasitología , Gossypium/virología , Hemípteros/patogenicidad , Interacciones Huésped-Patógeno , Proteínas de Insectos/genética , Insectos Vectores/patogenicidad , Glándulas Salivales/metabolismo , Glándulas Salivales/virología
5.
Pestic Biochem Physiol ; 197: 105651, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38072526

RESUMEN

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.


Asunto(s)
Hormigas , Insecticidas , Animales , Hormigas de Fuego , Drosophila melanogaster , Insecticidas/toxicidad
6.
Ophthalmology ; 129(3): 308-321, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34627809

RESUMEN

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.


Asunto(s)
Atropina/administración & dosificación , Midriáticos/administración & dosificación , Miopía Degenerativa/tratamiento farmacológico , Longitud Axial del Ojo/fisiología , Niño , Preescolar , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Miopía Degenerativa/fisiopatología , Refracción Ocular/fisiología , Perfil de Impacto de Enfermedad , Resultado del Tratamiento , Agudeza Visual/fisiología
7.
Int J Mol Sci ; 23(8)2022 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-35457041

RESUMEN

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.


Asunto(s)
Retinopatía Diabética , Glaucoma , Degeneración Macular , Miopía , Deficiencia de Vitamina D , Retinopatía Diabética/complicaciones , Ojo , Glaucoma/complicaciones , Glaucoma/etiología , Humanos , Degeneración Macular/complicaciones , Degeneración Macular/etiología , Vitamina D , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/epidemiología , Vitaminas
8.
Planta Med ; 87(3): 225-235, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33348408

RESUMEN

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.


Asunto(s)
Kadsura , Penicillium , Antibacterianos/farmacología , Lactonas/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular
9.
Bioorg Chem ; 95: 103489, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31862456

RESUMEN

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).


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Corydalis/química , Isoquinolinas/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Isoquinolinas/química , Isoquinolinas/aislamiento & purificación , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Relación Estructura-Actividad
10.
Eye Contact Lens ; 46(5): 306-309, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31425353

RESUMEN

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.


Asunto(s)
Oxígeno , Riboflavina , Animales , Fenómenos Biomecánicos , Córnea , Reactivos de Enlaces Cruzados , Elasticidad , Fármacos Fotosensibilizantes , Porcinos , Rayos Ultravioleta
11.
Eye Contact Lens ; 46(1): 35-45, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30985487

RESUMEN

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.


Asunto(s)
Longitud Axial del Ojo/diagnóstico por imagen , Biometría/instrumentación , Catarata/diagnóstico , Córnea/diagnóstico por imagen , Interferometría/métodos , Tomografía de Coherencia Óptica/métodos , Anciano , Diseño de Equipo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Prospectivos , Curva ROC , Reproducibilidad de los Resultados
12.
Bioorg Chem ; 88: 102924, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31005783

RESUMEN

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.


Asunto(s)
Antiulcerosos/metabolismo , Artemisia/química , Farmacología/métodos , Proteínas/metabolismo , Antiulcerosos/química , Simulación del Acoplamiento Molecular , Unión Proteica , Proteínas/química , Transducción de Señal
13.
Molecules ; 24(21)2019 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-31671631

RESUMEN

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.


Asunto(s)
Fitoquímicos/análisis , Hojas de la Planta/química , Tallos de la Planta/química , Tagetes/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión/métodos , Humanos , Fitoquímicos/química , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología
16.
Cell Rep Med ; 5(2): 101413, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38325382

RESUMEN

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.


Asunto(s)
Esclerosis Amiotrófica Lateral , Canales Catiónicos TRPM , Ratones , Animales , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/patología , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/farmacología , Superóxido Dismutasa/uso terapéutico , Ratones Transgénicos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad
17.
J Am Soc Mass Spectrom ; 35(4): 746-755, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38422384

RESUMEN

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.


Asunto(s)
Cerveza , Humulus , Cromatografía Liquida , Cerveza/análisis , Humulus/química , Cromatografía Líquida con Espectrometría de Masas , Espectrometría de Masas en Tándem , Ácidos/química
18.
Chin J Dent Res ; 27(1): 89-99, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38546524

RESUMEN

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.


Asunto(s)
Resorción Radicular , Resorción Dentaria , Femenino , Humanos , Proteínas Portadoras , Genes Reguladores , Proteínas de la Membrana , Resorción Radicular/diagnóstico por imagen , Resorción Radicular/genética , Masculino , Pueblos del Este de Asia
19.
Acta Neuropathol Commun ; 12(1): 149, 2024 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-39267142

RESUMEN

Motor neuron loss is well recognized in amyotrophic lateral sclerosis (ALS), but research on retinal ganglion cells (RGCs) is limited. Ocular symptoms are generally not considered classic ALS symptoms, although RGCs and spinal motor neurons share certain cell pathologies, including hallmark signs of glutamate neurotoxicity, which may be triggered by activation of extrasynaptic NMDA receptors (NMDARs). To explore potential novel strategies to prevent ALS-associated death of RGCs, we utilized inhibition of the TwinF interface, a new pharmacological principle that detoxifies extrasynaptic NMDARs by disrupting the NMDAR/TRPM4 death signaling complex. Using the ALS mouse model SOD1G93A, we found that the small molecule TwinF interface inhibitor FP802 prevents the loss of RGCs, improves pattern electroretinogram (pERG) performance, increases the retinal expression of Bdnf, and restores the retinal expression of the immediate early genes, Inhibin beta A and Npas4. Thus, FP802 not only prevents, as recently described, death of spinal motor neurons in SOD1G93A mice, but it also mitigates ALS-associated retinal damage. TwinF interface inhibitors have great potential for alleviating neuro-ophthalmologic symptoms in ALS patients and offer a promising new avenue for therapeutic intervention.


Asunto(s)
Esclerosis Amiotrófica Lateral , Modelos Animales de Enfermedad , Ratones Transgénicos , Células Ganglionares de la Retina , Animales , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Ratones , Electrorretinografía , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Humanos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo
20.
Insects ; 15(10)2024 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-39452385

RESUMEN

Striking a trade-off between migration and reproduction becomes imperative during long-range migration to ensure proper energy allocation. However, the mechanisms involved in this trade-off remain poorly understood. Here, we used a takeoff assay to distinguish migratory from non-migratory individuals in the fall armyworm, which is a major migratory insect worldwide. Migratory females displayed delayed ovarian development and flew further and faster than non-migratory females during tethered flight. Transcriptome analyses demonstrated an enrichment of fatty acid genes across successive levels of ovarian development and different migratory behaviors. Additionally, genes with roles in phototransduction and carbohydrate digestion along with absorption function were enriched in migratory females. Consistent with this, we identified increased abdominal lipids in migratory females that were mobilized to supply energy to the flight muscles in the thorax. Our study reveals that the fall armyworm faces a trade-off in allocating abdominal triglycerides between migration and reproduction during flight. The findings provide valuable insights for future research on this trade-off and highlight the key energy components involved in this strategic balance.

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