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1.
Mol Cancer ; 23(1): 40, 2024 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-38383439

RESUMO

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.


Assuntos
Melanoma , RNA Longo não Codificante , Humanos , Camundongos , Animais , Melanoma/patologia , RNA Longo não Codificante/genética , Apoptose/genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Linhagem Celular Tumoral , Proteínas de Membrana/genética , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo
2.
Molecules ; 22(5)2017 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-28468284

RESUMO

Nine monoterpenoids from Radix Paeoniae Alba, including paeoniflorin derivatives, paeoniflorin (PF), 4-O-methylpaeoniflorin (MPF), 4-O-methylbenzoylpaeoniflorin (MBPF); paeonidanin derivatives, paeonidanin (PD), paeonidanin A (PDA), albiflorin derivatives, albiflorin (AF), benzoylalbiflorin (BAF), galloylalbiflorin (GAF), and debenzoylalbiflorin (DAF), were obtained in our previous phytochemistry investigations. Their anti-inflammatory effects were determined in the present study. The expression and production of pro-inflammatory cytokines in lipopolysaccharides (LPS)-stimulated RAW 264.7 cells were measured using an Elisa assay and nitric oxide (NO) release was determined using the Griess method. The results demonstrated that the most of the monoterpenoids suppressed the LPS-induced production of NO, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). The anti-inflammatory activities of these monoterpenoids were closely related to their structural characteristics. Paeoniflorins and paeonidanins presented stronger anti-inflammatory activities than those of albiflorin derivatives. Furthermore, the action mechanisms of MBPF, having a strong anti-inflammatory effect, were investigated using quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot methods. The results indicated that MBPF could down-regulate the mRNA and protein expression level of inducible nitric oxide synthase (iNOS) in LPS-stimulated RAW 264.7 cells. The mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT and nuclear factor κB (NF-κB) signaling pathways are involved in mediating the role of MBPF in suppressing the expression and production of pro-inflammatory cytokines in RAW 264.7 cells.


Assuntos
Anti-Inflamatórios/farmacologia , Monoterpenos/farmacologia , Paeonia/química , Animais , Avaliação Pré-Clínica de Medicamentos , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/imunologia , Mesotelina , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade
3.
Apoptosis ; 21(5): 517-31, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27007273

RESUMO

Macroautophagy (Autophagy), an evolutionarily conserved cellular self-digesting process implicated in various physiological and pathological processes, is activated by different stimuli including oxidative stress. Reactive oxygen species (ROS) are involved in autophagy modulation through multiple signaling pathways and transcription regulators. Accumulating data support both a positive and negative role of ROS-modulated autophagy in cancer. As a tumor suppressive mechanism, autophagy induces autophagic cell death and maintains genome stability. Conversely, autophagy may promote cancer development by limiting metabolic stress and supplying high-energetic nutrients. Mitochondrial ROS (mitoROS), the main source of endogenous ROS, serve as essential signal transducers that mediate autophagy, while autophagy can also regulate mitochondrial ROS generation in turn. Here, we untangle the knot between mitochondrial ROS and autophagy, which may be of great significance to solve the conundrum of the inter-conversion between cytoprotective and cytotoxic roles of autophagy; thus providing new insights for current cancer therapies. Whilst, we focus on anti-tumor agents that target mitoROS-regulated autophagy, in the hope of fueling the exploration of more potential novel anti-cancer drugs in the future.


Assuntos
Antineoplásicos/uso terapêutico , Autofagia , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Autofagia/efeitos dos fármacos , Carcinogênese , Humanos , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Transdução de Sinais
4.
Neuroimage ; 90: 33-42, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24373882

RESUMO

We exploit the morphological stereotypy and relative simplicity of the Drosophila nervous system to model the diverse neuronal morphologies of individual motor neurons and understand underlying principles of synaptic connectivity in a motor circuit. In our analysis, we use images depicting single neurons labeled with green fluorescent protein (GFP) and serially imaged with laser scanning confocal microscopy. We model morphology with a novel formulation of Conditional Random Fields, a hierarchical latent-state CRF, to capture the highly varying compartment-based structure of the neurons (soma-axon-dendrites). In the training phase, we follow two approaches: (i) hierarchical learning, where compartment labels are given, and (ii) latent-state learning, where compartment labels are not given in the samples. We demonstrate the accuracy of our approach using wild-type motor neurons in the larval ventral nerve cord. However, our method can also be used for the identification of motor neuron mutations, as well as the automated annotation of the motor circuitry in wild type and mutant animals. Our method is directly applicable to the recognition of compartment-defined structures.


Assuntos
Sistema Nervoso Central/embriologia , Drosophila melanogaster/embriologia , Modelos Neurológicos , Neurônios Motores/citologia , Neurogênese/fisiologia , Animais , Padronização Corporal/fisiologia , Sistema Nervoso Central/citologia , Microscopia Confocal
5.
Cell Death Discov ; 10(1): 150, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514643

RESUMO

Close correlation between vitamin D (VitD) deficiency and Parkinson's Disease (PD) risk, VitD as an adjuvant treatment promising to improve PD progression. However, VitD excessive intake could induce hypercalcemia and renal damage. Therefore, upregulation of vitD receptor (VDR) is considered a compensatory strategy to overcome VitD insufficiency and alleviate PD symptoms. In this study, we discovered that VDR played antioxidative roles in dopaminergic neurons by decreasing reactive oxygen species (ROS) and maintaining mitochondrial membrane potential. Further, we newly identified VDR downstream events in C. elegans, including glutathione S-transferase (gst) and forkhead box transcription factor class O (daf-16) mediated oxidative stress resistance. VDR upregulation also mitigated microglial activation through inhibition of NLRP3/caspase-1-mediated inflammation and membrane permeabilization. These findings highlight the multifaceted protective effects of VDR in both neurons and microglia against the development of PD. Importantly, we discovered a novel deubiquitinase DUB3, whose N-terminal catalytic domain interacted with the C-terminal ligand-binding domain of VDR to reduce VDR ubiquitination. Identification of DUB3 as an essential player in the deubiquitinating mechanism of VDR provides valuable insights into VDR regulation and its potential as a therapeutic target for PD.

6.
Front Public Health ; 11: 1133340, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36908457

RESUMO

Background: Anxiety and the physical environment are critical factors influencing frailty among older adults; however, the interaction effect of anxiety and the physical environment, such as outdoor activity spaces, on frailty has not been examined. This study aimed to investigate the interaction effect of anxiety and outdoor activity spaces on frailty and to identify differences by gender. Methods: A total of 353 nursing home residents (197 women; 156 men; age ≥ 60 years) from 27 Chinese nursing homes were included in the analysis. Anxiety and frailty were analyzed using the Generalized Anxiety Disorder Scale and the FRAIL-NH Scale, respectively. Outdoor activity spaces were assessed through on-site observations using self-designed items. Demographic and socioeconomic information and health-related covariates were also collected. Interaction effect analyses were conducted using multilevel mixed-effects linear models. Results: Anxiety and outdoor activity spaces had an interaction effect on frailty among nursing home residents (ß = -1.32, 95% CI: -2.44, -0.20). However, further analysis demonstrated that this interaction effect was only significant in older women (ß = -1.60, 95% CI: -2.93, -0.27) but not in older men (ß = -0.23, 95% CI: -2.29, 1.82). Conclusions: This study highlighted that gender differences should be considered when preventing frailty in older adults with anxiety. Furthermore, it may be beneficial for nursing homes to provide outdoor activity spaces and create a supportive living environment to help delay or reverse frailty among female nursing home residents.


Assuntos
Fragilidade , Masculino , Idoso , Humanos , Feminino , Pessoa de Meia-Idade , Idoso Fragilizado , Fatores Sexuais , Avaliação Geriátrica , Casas de Saúde , China , Ansiedade
7.
J Ovarian Res ; 16(1): 227, 2023 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-37996919

RESUMO

BACKGROUNDS: Existing studies have investigated the relationship between the levels of serum inhibin B (INHB), anti-müllerian hormone (AMH) and precocious puberty in girls, but the results are inconsistent. OBJECTIVE: The aim of this meta-analysis was to assess whether the INHB and AMH levels changed in girls with precocious puberty relative to healthy controls. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched through June 2022. We included observational clinical studies reporting the serum levels INHB and AMH in girls with precocious puberty. Conference articles and observational study abstracts were included if they contained enough information regarding study design and outcome data. Case series and reports were excluded. An overall standard mean difference (SMD) between precocious puberty and healthy controls was estimated using a DerSimonian-Laird random-effects model. RESULTS: A total of 11 studies featuring 552 girls with precocious puberty and 405 healthy girls were selected for analysis. The meta-analysis showed that the INHB level of precocious puberty [including central precocious puberty (CPP) and premature the larche (PT)] were significantly increased. While there was no significant association between precocious puberty [including CPP, PT, premature pubarche (PP) and premature adrenarche (PA)] and the level of serum AMH. CONCLUSION: Scientific evidence suggested that the INHB level, but not the AMH level, altered in girls with precocious puberty compared with healthy controls. Through our results we think that INHB level might be a marker for the auxiliary diagnosis of precocious puberty (especially CPP and PT). Therefore, it is important to evaluate and thoroughly investigate the clinical indicators (e.g., INHB) in order to ensure early diagnosis and medical intervention, and the risk of physical, psychological and social disorders in immature girls with precocious puberty is minimized.


Assuntos
Puberdade Precoce , Feminino , Humanos , Hormônio Antimülleriano , Hormônio Foliculoestimulante , Inibinas , Estudos Observacionais como Assunto , Puberdade Precoce/diagnóstico
8.
Res Sq ; 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38077055

RESUMO

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impacton normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

9.
Elife ; 112022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35666955

RESUMO

Precise developmental control of jaw length is critical for survival, but underlying molecular mechanisms remain poorly understood. The jaw skeleton arises from neural crest mesenchyme (NCM), and we previously demonstrated that these progenitor cells express more bone-resorbing enzymes including Matrix metalloproteinase 13 (Mmp13) when they generate shorter jaws in quail embryos versus longer jaws in duck. Moreover, if we inhibit bone resorption or Mmp13, we can increase jaw length. In the current study, we uncover mechanisms establishing species-specific levels of Mmp13 and bone resorption. Quail show greater activation of and sensitivity to transforming growth factor beta (TGFß) signaling than duck; where intracellular mediators like SMADs and targets like Runt-related transcription factor 2 (Runx2), which bind Mmp13, become elevated. Inhibiting TGFß signaling decreases bone resorption, and overexpressing Mmp13 in NCM shortens the duck lower jaw. To elucidate the basis for this differential regulation, we examine the Mmp13 promoter. We discover a SMAD-binding element and single nucleotide polymorphisms (SNPs) near a RUNX2-binding element that distinguish quail from duck. Altering the SMAD site and switching the SNPs abolish TGFß sensitivity in the quail Mmp13 promoter but make the duck promoter responsive. Thus, differential regulation of TGFß signaling and Mmp13 promoter structure underlie avian jaw development and evolution.


Assuntos
Reabsorção Óssea , Fator de Crescimento Transformador beta , Animais , Subunidade alfa 1 de Fator de Ligação ao Core , Patos , Arcada Osseodentária/fisiologia , Metaloproteinase 13 da Matriz/genética , Crista Neural/fisiologia , Codorniz
10.
J Tradit Chin Med ; 40(5): 863-869, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33000588

RESUMO

OBJECTIVE: To evaluate the effectiveness of Xiaoyin Jiedu (XYJD) granules in the treatment of psoriasis vulgaris (PSV) in patients with a blood-heat pattern (BHP) in terms of Traditional Chinese Medicine (TCM). We also aimed to identify the possible underlying immunological mechanism. METHODS: Twenty-five PSV patients with BHP and ten normal controls were enrolled from January 1, 2015 to December 31, 2016. Patients were randomly assigned to either the XYJD group (15 cases) or the placebo group (10 cases), in which patients were treated with XYJD granules or a placebo, respectively. Additionally, albolene was used to relieve skin dryness in these two groups. The psoriasis area and severity indexes, dermatology life quality indexes and itching scores were assessed at the end of the 2nd, 4th and 8th week of treatment. The number of peripheral blood T helper (Th) 9, Th17 and regulatory T cells (Tregs) and the mRNA and protein expression levels of PU.1, RAR-related orphan receptor (ROR)-γt, forkhead box protein 3 (Foxp3), interleukin (IL)-9, IL-17, IL-23 and IL-10 in the control and experimental groups were compared before and after treatment. RESULTS: Psoriasis area and severity indexes and itching scores of patients in the XYJD group were significantly lower than those in the placebo group, whereas dermatology life quality indexes were significantly higher. In comparison with the placebo group, XYJD granules significantly reduced the number of Th17 cells and the mRNA and protein expression levels of Th17-related ROR-γt, IL-17, IL-22 and IL-23 in the peripheral blood and reduced the number of Th9 cells and the mRNA and protein expression levels of Th9-related PU.1 and IL-9. CONCLUSION: XYJD granules were effective against PSV in patients with BHP by reducing the number of Th9 and Th17 cells and the levels of their related cytokines.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Psoríase/tratamento farmacológico , Adulto , Feminino , Temperatura Alta , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-23/genética , Interleucina-23/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Psoríase/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
11.
Neuropharmacology ; 170: 108041, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32213357

RESUMO

Our previous studies have shown that ginsenoside Rg1 (Rg1) exerts antidepressant-like effects in animal models of depression, accompanied by an improvement of astrocytic gap junction functions. However, whether connexin 43 (Cx43), the major connexin forming gap junctions between astrocytes, is the key regulator of Rg1-induced antidepressant-like effects is still unknown. In this study, we examine in vitro and in vivo the involvement of Cx43 in the antidepressant effects of Rg1. Corticosterone was used to establish an in vitro rat model of depression. Treatment with Rg1 1 h prior to corticosterone significantly improved the cell viability of astrocytes, which was significantly inhibited by carbenoxolone, a widely used gap junction inhibitor. Moreover, Rg1 treatment significantly ameliorated antidepressant-sensitive behaviours induced by infusion of carbenoxolone or Gap26, a selective inhibitor of Cx43, into the prefrontal cortex of the animals. Rg1 treatment increased the expression of Cx43 compared with Gap26 group. According to these results, the antidepressant-like effects of Rg1 were mainly mediated by Cx43-formed gap junctions.


Assuntos
Conexina 43/biossíntese , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Ginsenosídeos/administração & dosagem , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Carbenoxolona/administração & dosagem , Carbenoxolona/toxicidade , Células Cultivadas , Fármacos do Sistema Nervoso Central/administração & dosagem , Conexina 43/antagonistas & inibidores , Depressão/induzido quimicamente , Relação Dose-Resposta a Droga , Masculino , Peptídeos/administração & dosagem , Peptídeos/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley
12.
J Tradit Chin Med ; 39(5): 700-706, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-32186120

RESUMO

OBJECTIVE: To investigate potential differences in circulating levels of T regulatory (Treg)/T helper 17 (Th17) cells, related inflammatory cytokines and specific transcription factors in healthy individuals and patients with psoriasis conforming to one of three Traditional Chinese Medicine (TCM) syndromes: blood-heat syndrome (BHS), blood-stasis syndrome (BSS) and blood-dryness syndrome (BDS). METHODS: Sixty-seven patients with psoriasis were recruited and assigned to one of three corresponding TCM syndrome groups: BHS (n = 40), BSS (n = 14) and BDS (n = 13 patients). The control group comprised 21 healthy individuals. The circulating levels of Treg/Th17 cells in peripheral blood were assessed using flow cytometry; the levels of inflammatory cytokines interleukin (IL)-10 and tumor necrosis factor (TNF)-α by enzyme-linked immunosorbent assay; and the mRNA expression of T cell-specific transcription factors retinoic acid-related orphan receptor γt (RORγt) and forkhead box P3 (Foxp3) by quantitative real-time PCR. RESULTS: The ratio of Th17 cells and the levels of TNF-α and RORγt were all significantly higher in the BHS and BSS groups than the control group (P < 0.05), while the ratio of Treg cells and the levels of IL-10 and Foxp3 mRNA in the BHS group were significantly lower compared with the control group (P < 0.05). No significant differences were seen between the BSS group and the control group. The ratio of Th17 cells and the levels of TNF-α and RORγt in the BDS group were not significantly different from those of the control group; however, the ratio of Treg cells and the levels of IL-10 and Foxp3 were all lower than those in the healthy controls (P < 0.05). CONCLUSION: Compared with healthy individuals, the ratio of Th17 cells and the levels of related cytokines were higher, while the ratio of Treg cells and the levels of related cytokines were lower, in the peripheral blood of psoriasis/BHS patients; corresponding results for the BSS and BDS groups also showed differences. We propose that patterns of differentiation of immunological cells in psoriasis patients are reflected in corresponding TCM blood syndromes.


Assuntos
Citocinas/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Adulto , Estudos de Casos e Controles , Contagem de Células , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Humanos , Interleucina-10/metabolismo , Masculino , Medicina Tradicional Chinesa , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Psoríase/genética , Psoríase/terapia , RNA Mensageiro/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
J Tradit Chin Med ; 39(1): 118-126, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-32186032

RESUMO

OBJECTIVE: To establish a method to analyze the commonalities and characteristics of the aqueous extracts from three Uighur medicines. METHODS: In this study, a combination method of three-stage infrared spectroscopy and ultra-performance liquid chromatography-time of flight-mass spectra (UPLC-TOF-MS) method was used to analyze the commonalities and characteristics of the aqueous extracts from Hezi (Fructus Chebulae), Maohezi (Terminalia Belliricae Fructus) and Xiqingguo (Chebulae Fructus Immaturus). RESULTS: In Fourier transform-infrared spectroscopy spectra, all three samples showed the characteristic absorption peaks of tannins similarly. According to UPLC-TOF-MS data analysis, the difference of the position and intensity of the peaks at 1713- 1707 cm-1 in the three samples were related to the difference in the relative content of tannin and pentacyclic triterpenoids. In second derivative infrared spectroscopy spectra, further analysis of the differences in the infrared spectra of the three samples was performed by increasing the apparent resolution. In combination with UPLC-TOF-MS data, some features infrared absorption peaks were assigned. The absorption peaks at 1032-1030 cm-1 assigned to the stretching vibration of C-O-C (ether bond) groups of tannins; 1164-1163, 1063-1062, 1009- 1005, 904 cm-1 attributed to the stretching vibration of C-O (ether bond) and C-O-C groups of glycosidic compounds. 1385-1383 cm-1 attributed to the bending vibration of C-H (alkyl hydrogen) of methoxyl group of pentacyclic triterpenoids. Peak 835 cm-1 was assigned to the characteristic absorption peak of bending vibration of = C-H groups of pentacyclic triterpenoids. The two dimensional correlation infrared spectroscopy could further quickly distinguish three samples through the dynamic structural information of their chemical components and discrepancy of auto-peaks and cross- peaks intuitively in the range of 1720-419 cm-1. CONCLUSION: By comparing the intensity of the infrared characteristic absorption peaks, the main chemical components were assigned, which significantly enriched and perfected the data analysis of the infrared spectra of three Uighur Medicines. It provided a rationale for the identification of medicinal materials with complex and similar chemical components using the three-stage infrared spectroscopy and UPLC-TOF-MS.


Assuntos
Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/química , Extratos Vegetais/química , Espectrofotometria Infravermelho/métodos , Espectroscopia de Infravermelho com Transformada de Fourier
14.
Artigo em Inglês | MEDLINE | ID: mdl-30305831

RESUMO

Mycoplasma pneumoniae (MP) infection is a major pathogen of community-acquired pneumonia (CAP) in children worldwide. Infantile Feire Kechuan Oral Solution (IFKOS) has been used for the treatment of MP pneumonia clinically in China for many years. The present study was designed to investigate the therapeutic effect of IFKOS on MP pneumonia and explore the potential mechanism of the actions. The infant BALB/c mouse and Wistar rat models of MP infection were successfully established to confirm the therapeutic effects of IFKOS, followed by assays for related cytokines and investigations of the IgM response involved. The results showed that IFKOS exhibited an inhibitory effect on pulmonary index (PI) and effectively reduced the degree of lesions in the lungs. The lethal rate of mice was significantly decreased while survival time of mice was dramatically increased by IFKOS treatment in comparison to infection control, respectively. IFKOS treatment (40, 20, and 10ml/kg) significantly decreased the level of MP-IgM in a dose-dependent manner, whereas IFKOS showed no obvious inhibitory effect on the increase of relative expression of MP-DNA. In addition, the elevated IL-2 and TNF-α levels were significantly reduced and the decreased IL-6 level was significantly enhanced by IFKOS treatment. Our study demonstrates that IFKOS has inhibitory effect on MP infection in infant mouse and rat models of MP pneumonia and protective effect from lethal MP challenge in infant murine model. These anti-MP effects might be related to suppression of the IgM response and a reversal the imbalance of Th1/Th2 cytokines induced by MP infection.

15.
eNeuro ; 4(4)2017.
Artigo em Inglês | MEDLINE | ID: mdl-28812061

RESUMO

Loss-of-function mutations in SCN1A cause Dravet syndrome (DS), a catastrophic childhood epilepsy in which patients experience comorbid behavioral conditions, including movement disorders, sleep abnormalities, anxiety, and intellectual disability. To study the functional consequences of voltage-gated sodium channel mutations, we use zebrafish with a loss-of-function mutation in scn1lab, a zebrafish homolog of human SCN1A. Homozygous scn1labs552/s552 mutants exhibit early-life seizures, metabolic deficits, and early death. Here, we developed in vivo assays using scn1labs552 mutants between 3 and 6 d postfertilization (dpf). To evaluate sleep disturbances, we monitored larvae for 24 h with locomotion tracking software. Locomotor activity during dark (night phase) was significantly higher in mutants than in controls. Among anticonvulsant drugs, clemizole and diazepam, but not trazodone or valproic acid, decreased distance moved at night for scn1labs552 mutant larvae. To monitor exploratory behavior in an open field, we tracked larvae in a novel arena. Mutant larvae exhibited impaired exploratory behavior, with increased time spent near the edge of the arena and decreased mobility, suggesting greater anxiety. Both clemizole and diazepam, but not trazodone or valproic acid, decreased distance moved and increased time spent in the center of the arena. Counting inhibitory neurons in vivo revealed no differences between scn1labs552 mutants and siblings. Taken together, our results demonstrate conserved features of sleep, anxiety, and movement disorders in scn1lab mutant zebrafish, and provide evidence that a zebrafish model allows effective tests of treatments for behavioral comorbidities associated with DS.


Assuntos
Anticonvulsivantes/uso terapêutico , Terapia Cognitivo-Comportamental/métodos , Epilepsias Mioclônicas , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Animais , Animais Geneticamente Modificados , Contagem de Células , Ritmo Circadiano/genética , Modelos Animais de Doenças , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/reabilitação , Comportamento Exploratório/efeitos dos fármacos , Feminino , Genótipo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Interneurônios/metabolismo , Interneurônios/patologia , Larva , Locomoção/efeitos dos fármacos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Transtornos do Sono-Vigília/etiologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
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