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Nigrograna sp. LY66, an endophytic fungus associated with the herbal medicinal plant Clematis shensiensis, produced four undescribed steroids, nigergostanes A-D (1-4), including an unusual ketal-containing nigergostane (1), and four undescribed sesquiterpenoids decorated with cyclohexanone motifs, nigbisabolanes A-D (7-10), along with three known compounds, 23R-hydroxy-(20Z,24R)-ergosta-4,6,8(14),20(22)-tetraen-3-one (5), ergosta-5,7,22-trien-3ß-ol (6), and curculonone A (11). The structures and absolute configurations of these undescribed compounds were confirmed using spectroscopic data (NMR and HRESIMS), modified Mosher's method, and ECD experiments. Additionally, compounds 5 and 8 displayed significant inhibition of nitric oxide generation in lipopolysaccharide-induced BV-2 microglial cells with IC50 values of 2.8 and 2.7 µM, respectively, and is thus more potent than that of the positive control, quercetin (IC50 = 8.77 µM). A molecular docking study revealed that 23-OH of 5 binds to the Y347 residue of inducible nitric oxide synthase (iNOS), whereas the 2-OH and 9,10-diol moieties of 8 bind to R381 and W463 and haeme residues of iNOS, respectively, which has rarely been reported in previous studies. These findings provide a set of undescribed lead compounds that can be developed into anti-neuroinflammatory agents.
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Ascomicetos , Clematis , Fitosteroles , Sesquiterpenos , Esteroles , Clematis/metabolismo , Simulación del Acoplamiento Molecular , Ascomicetos/metabolismo , Sesquiterpenos/farmacología , Sesquiterpenos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Óxido NítricoRESUMEN
Background: Sleep disturbance is one of the most prominent complaints of patients with alcohol use disorder (AUD), with more than 70% of patients with AUD reporting an inability to resolve sleep problems during abstinence. Mindfulness-based stress reduction (MBSR) has been shown to improve sleep quality and as an alternative therapy to hypnotics for sleep disorders. Objective: The aim of the present study was to evaluate the effect of short-term MBSR on sleep quality in male patients with AUD after withdrawal. Methods: A total of 91 male patients with AUD after 2 weeks of routine withdrawal therapy were randomly divided into two groups using a coin toss: the treatment group (n = 50) and the control group (n = 41). The control group was received supportive therapy, and the intervention group added with MBSR for 2 weeks on the basis of supportive therapy. Objective sleep quality was measured at baseline and 2 weeks after treatment using the cardiopulmonary coupling (CPC). Indicators related to sleep quality include total sleep time, stable sleep time, unstable sleep time, rapid eye movement (REM) sleep time, wake-up time, stable sleep latency, sleep efficiency, and apnea index. These indicators were compared by an analysis of covariance (ANCOVA) between the two groups, controlling for individual differences in the respective measures at baseline. Results: The results showed that there were no significant differences in the age [t (89) = -0.541, P = 0.590), BMI [t (89) = -0.925, P = 0.357], educational status [t (89) = 1.802, P = 0.076], years of drinking [t (89) = -0.472, P = 0.638), daily intake [t (89) = 0.892, P = 0.376], types of alcohol [χ2 (1) = 0.071, P = 0.789], scores of CIWA-AR [t (89) = 0.595, P = 0.554], scores of SDS [t (89) = -1.151, P = 0.253), or scores of SAS [t (89) = -1.209, P = 0.230] between the two groups. Moreover, compared with the control group, the total sleep time [F (1.88) = 4.788, P = 0.031) and stable sleep time [F (1.88) = 6.975, P = 0.010] were significantly increased in the treatment group. Furthermore, the average apnea index in the patients who received MBSR was significantly decreased than in the control group [F (1.88) = 5.284, P = 0.024]. Conclusion: These results suggest that short-term MBSR could improve sleep quality and may serve as an alternative treatment to hypnotics for sleep disturbance in patients with AUD after withdrawal.
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Polycystic ovary syndrome (PCOS) is a common endocrine/reproductive/metabolic disorder. The etiology of PCOS is complex and has been linked to low-grade chronic inflammation. Local inflammation of the ovary affects ovulation and induces or aggravates systemic inflammation. PCOS patients demonstrated significantly higher concentrations of circulating inflammatory cells, such as lymphocytes, neutrophils, eosinophilic granulocytes, monocytes and Th17 cells than women without PCOS, while the percentage of Treg cells was lower. Inflammatory factors, such as serum CRP, hs-CRP, IL-1Ra, IL-6, IL-17A, IL-17F, IL-18, IL-23, TNF-α, α-1 acid glycoprotein,monocyte chemoattractant protein-1 (MCP-1) and adipokines and their paralogs, including chemerin, C1q and TNF-related 6 (C1QTNF6), were also found to be significantly increased in the peripheral blood of PCOS patients. Levels of anti-inflammatory cytokines, such as IL-10, IL-17E, IL-27, IL-35 and IL-37, TGF-ß, omentin-1, Secreted frizzled-related protein5 (SFRP5) were significantly lower. An analogous situation occurs locally in the ovary. Some vital inflammatory cells and cytokines may initially be released from the ovary and then enter the circulation. The systemic inflammation underlying PCOS is thought to interact with obesity, insulin resistance (IR) and hyperandrogenism. Traditional Chinese medicine, multitargeted treatment, anti-inflammatory and antioxidant medicine, and lifestyle modification can benefit PCOS women by alleviating inflammatory responses.
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Hiperandrogenismo , Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Antiinflamatorios/uso terapéutico , Colágeno/uso terapéutico , Citocinas , Femenino , Humanos , InflamaciónRESUMEN
The aim of this study was to elucidate the mechanism of nuciferine on alleviating obesity based on modulating gut microbiota, ameliorating chronic inflammation, and improving gut permeability. In this study, the obese model mice were induced by high-fat diet and then randomly divided into model group, and nuciferine group; some other mice of the same week age were fed with normal diet as normal group. In the modeling process, the mice were administered intragastrically(ig) for 12 weeks. In the course of both modeling and treatment, the body weight and food intake of mice in each group were measured weekly. After modeling and treatment, the Lee's index, weight percentage of inguinal subcutaneous fat, and the level of blood lipid in each group were measured. The pathological changes of adipocytes were observed by HE staining to evaluate the efficacy of nuciferine treatment in obese model mice. 16 S rRNA sequencing analysis was conducted to study the changes in diversity and abundance of gut microbiota after nuciferine treatment. Enzyme-linked immunosorbent assay(ELISA) and quantitative Real-time polymerase chain reaction(qPCR) were used to detect the levels of inflammatory factors interleukin-6(IL-6), interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α) and the expression of related genes in adipose tissue of mice in each group, so as to evaluate the effect of nuciferine on chronic inflammation of mice in obese model group. qPCR was used to detect the expression of occludin and tight junction protein 1(ZO-1)gene in colon tissure, so as to evaluate the effect of nuciferine on intestinal permeability of mice in obese group. Nuciferine decreased the body weight of obese mice, Lee's index, weight percentage of inguinal subcutaneous fat(P<0.05), and reduced the volume of adipocytes, decreased the level of total cholesterol(TC), triglyceride(TG), and low density lipoprotein cholesterol(LDL-C)(P<0.05) in serum, improved dysbacteriosis, increased the relative abundance of Alloprevotella, Turicibacter, and Lactobacillus, lowered the relative abundance of Helicobac-ter, decreased the expression of inflammatory cytokines IL-6, IL-1ß, and TNF-α genes in adipose tissue(P<0.01), decreased the levels of inflammatory cytokines IL-6, IL-1ß, and TNF-α in serum(P<0.05), and increased the expression of occludin and ZO-1 genes related to tight junction in colon tissue(P<0.01). Nuciferine could treat obesity through modulating gut microbiota, decreasing gut permeability and ameliorating inflammation.
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Microbioma Gastrointestinal , Animales , Aporfinas , Dieta Alta en Grasa/efectos adversos , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/genéticaRESUMEN
Gonadotropin-inhibitory hormone (GnIH) plays a critical role in regulating gonadotropin-releasing hormone (GnRH), gonadotropin hormone (GtH), and steroidogenesis. The Lpxrfa (the piscine ortholog of GnIH) system has been found to regulate fish reproduction. To gain insight into the role of Lpxrfa in the regulation of spotted scat (Scatophagus argus) reproduction, spotted scat Lpxrfa (ssLpxrfa), and its receptor (ssLpxrfa-r) were cloned and analyzed. Tissue distribution and expression patterns at the hypothalamo-pituitary-gonadal axis (HPG axis) of sslpxrfa and sslpxrfa-r mRNA were also investigated during gonadal development of spotted scat. The open reading frame (ORF) of the sslpxrfa was 606 bp encoding 201 amino acids and includes a putative signal peptide and two mature ssLpxrfa peptides with LPXRFamide motif at their C-terminus. The sslpxrfa-r ORF was 1449 bp encoding 482 amino acids and contracted a seven-hydrophobic transmembrane (TM) domain structure. The tissue distribution showe d that the sslpxrfa was highly expressed in hypothalami, gill, and the gonads. In addition, sslpxrfa-r was highly expressed in hypothalami, pituitaries, and the gonads. Quantitative real-time polymerase chain reaction (qPCR) revealed that sslpxrfa had the highest expression in the hypothalami and pituitaries, and the lowest expression in the gonads in stage V. During gonadal development, the expression of sslpxrfa-r was gradually increased in the hypothalami but reduced in the gonads. However, no obvious trend was observed in the pituitaries. The expression of sslpxrfa and sslpxrfa-r decreased significantly after injection with 17ß-estradiol (E2). However, the expression of both sslpxrfa and sslpxrfa-r was not changed after injection with 17α-methyltestosterone(17α-MT) in the hypothalami. In addition, no changes were observed in the expression of fshß and lhß in the pituitaries after injecting ssLpxrfa-1. However, ssLpxrfa-2 could downregulate the expression of sbgnrh and fshß in the hypothalami and pituitaries, respectively. Taken together, these findings suggested that ssLpxrfa may participate in E2 feedback in reproduction and regulate the reproductive axis of spotted scat.
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Proteínas de Peces/genética , Peces/genética , Neuropéptidos/genética , Receptores de Neuropéptido/genética , Reproducción/genética , Secuencia de Aminoácidos , Animales , Estradiol/farmacología , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Gónadas/metabolismo , Sistema Hipotálamo-Hipofisario , Hipotálamo/metabolismo , Masculino , Metiltestosterona/farmacología , Filogenia , Hipófisis/metabolismoRESUMEN
BACKGROUND: Alisma orientalis beverage (AOB) is a Chinese traditional medicine formulated with a diversity of medicinal plants and used for treating metabolic syndrome and atherosclerosis (AS) since time ago. Given the current limited biological research on AOB, the mechanism by which AOB treats AS is unknown. This study investigats the role of AOB-induced gut microbiota regulation in the expansion of AS. METHODS: We established an AS model in male apolipoprotein E-deficient (ApoE-/-) mice that are fed with a high-fat diet (HFD), treated with numerous interventions, and evaluated the inflammatory cytokines and serum biochemical indices. The root of the aorta was stained with oil red O, and the proportion of the lesion area was quantified. Trimethylamine N-oxide (TMAO) and trimethylamine (TMA) levels in serum were evaluated through liquid chromatography with mass spectrometry. Flavin-containing monooxygenase 3 (FMO3) liver protein expression was assessed by Western blotting. 16S rDNA sequencing technique was adopted to establish the changes in the microbiota structure. RESULTS: After 8 weeks of HFD feeding, an inflammatory cytokine, and AS development expression were significantly decreased in mice treated with AOB; the same parameters in the mice treated with the antibiotics cocktail did not change. In the gut microbiota study, mice treated with AOB had a markedly different gut microbiota than the HFD-fed mice. Additionally, AOB also decreased serum TMAO and hepatic FMO3 expression. CONCLUSION: The antiatherosclerotic effects of AOB were found associated with changes in the content of gut microbiota and a reduction in TMAO, a gut microbiota metabolite, suggesting that AOB has potential therapeutic value in the treatment of AS.
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The epithelial-mesenchymal transition (EMT) serves vital roles in the angiogenesis, cell invasion and metastasis of various malignant tumors, including bladder cancer. Traditional Chinese medicinal herbs have been demonstrated to exhibit anticancer properties. The present study aimed to screen the sensitivity of bladder cancer to natural compounds by using six classic anti-inflammatory and detoxifying herbs, including the ethanol extract of Paris polyphylla (PPE), Scutellaria barbata, Pulsatillae decoction, Dahuang Huanglian Xiexin decoction, Bazhengsan and Hedyotis diffusa combined with S. barbata, were used to treat bladder cancer cells in vitro. Bladder cancer was more sensitive to PPE compared with the other tested herbs, and PPE significantly suppressed bladder cancer cell migration and invasion. Thus, the present study focused on PPE. Bladder cancer cells were treated with monomer components of PPE, including polyphyllin (PP) I, PPII, PPVI and PPVII. The results demonstrated that PPII treatment significantly inhibited cancer cell migration and invasion, increased the expression level of E-cadherin and decreased the levels of N-cadherin, snail family transcriptional repressor 2, twist family bHLH transcription factor 1, matrix metallopeptidase (MMP) 2 and MMP9 compared with those in the control group (untreated cells). These results suggested that PPII treatment may suppress bladder cancer cell migration and invasion by regulating the expression of EMT-associated genes and MMPs. Therefore, PPE and PPII may have antimetastatic effects and PPII may serve as a potential therapeutic option for inhibiting bladder cancer metastasis.
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BACKGROUND AND OBJECTIVES: During the coronavirus disease 2019 outbreak, the treatment of families with children on long-term KRT is challenging. This study was conducted to identify the current difficulties, worries regarding the next 2 months, and mental distress experienced by families with children on long-term KRT during the coronavirus disease 2019 outbreak and to deliver possible management approaches to ensure uninterrupted treatment for children on long-term KRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A multicenter online survey was conducted between February 10 and 15, 2020, among the families with children on long-term KRT from five major pediatric dialysis centers in mainland China. The primary caregivers of children currently on long-term KRT were eligible and included. Demographic information, severe acute respiratory syndrome coronavirus 2 infection status, current difficulties, and worries regarding the next 2 months were surveyed using a self-developed questionnaire. The Patient Health Questionnaire-9 and the General Anxiety Disorder Scale-7 were used to screen for depressive symptoms and anxiety, respectively. RESULTS: Among the children in the 220 families included in data analysis, 113 (51%) children were on dialysis, and the other 107 (49%) had kidney transplants. No families reported confirmed or suspected cases of coronavirus disease 2019. Overall, 135 (61%) and 173 (79%) caregivers reported having difficulties now and having worries regarding the next 2 months, respectively. Dialysis supply shortage (dialysis group) and hard to have blood tests (kidney transplantation group) were most commonly reported. A total of 29 (13%) caregivers had depressive symptoms, and 24 (11%) had anxiety. After the survey, we offered online and offline interventions to address their problems. At the time of the submission of this paper, no treatment interruption had been reported. CONCLUSIONS: The coronavirus disease 2019 outbreak has had physical, mental, logistical, and financial effects on families with children on long-term KRT.
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Betacoronavirus/patogenicidad , Infecciones por Coronavirus/prevención & control , Familia/psicología , Enfermedades Renales/terapia , Pandemias/prevención & control , Neumonía Viral/prevención & control , Terapia de Reemplazo Renal , Adaptación Psicológica , Adolescente , Adulto , Factores de Edad , COVID-19 , Cuidadores/psicología , Niño , China/epidemiología , Infecciones por Coronavirus/psicología , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virología , Costo de Enfermedad , Relaciones Familiares , Femenino , Encuestas de Atención de la Salud , Conocimientos, Actitudes y Práctica en Salud , Accesibilidad a los Servicios de Salud , Interacciones Microbiota-Huesped , Humanos , Enfermedades Renales/psicología , Masculino , Salud Mental , Persona de Mediana Edad , Seguridad del Paciente , Neumonía Viral/psicología , Neumonía Viral/transmisión , Neumonía Viral/virología , Terapia de Reemplazo Renal/efectos adversos , Medición de Riesgo , Factores de Riesgo , SARS-CoV-2 , Factores de Tiempo , Resultado del TratamientoRESUMEN
Phaeosphaeria fuckelii, an endophytic fungus associated with the herbal medicine Phlomis umbrosa, produced four new thiodiketopiperazine alkaloids, phaeosphaones A-D (1-4), featuring an unusual ß-(oxy)thiotryptophan motif, along with four known analogues, phaeosphaone E (5), chetoseminudin B (6), polanrazine B (7), and leptosin D (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. Compounds 4, 6, and 8 were found to display mushroom tyrosinase inhibitory activity with IC50 values of 33.2 ± 0.2, 31.7 ± 0.2, and 28.4 ± 0.2 µM, respectively, more potent than that of the positive control, kojic acid (IC50 = 40.4 ± 0.1 µM). A molecular-docking study disclosed the π-π stacking interaction between the indole moiety of 8 and the His243 residue of tyrosinase.
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Alcaloides/química , Ascomicetos/química , Monofenol Monooxigenasa/antagonistas & inhibidores , Agaricales , Cristalografía por Rayos X , Estructura MolecularRESUMEN
BACKGROUND: Sympathetic overactivation and inflammation are two major mediators to post-myocardial ischemia-reperfusion (I/R)-induced ventricular arrhythmia (VA). The vicious cycle between microglia and sympathetic activation plays an important role in sympathetic hyperactivity related to cardiovascular diseases. Recently, studies have shown that microglial activation might be attenuated by light-emitting diode (LED) therapy. Therefore, we hypothesized that LED therapy might protect against myocardial I/R-induced VAs by attenuating microglial and sympathetic activation. METHODS: Thirty-six male anesthetized rats were randomized into four groups: control group (n = 6), LED group (n = 6), I/R group (n = 12), and LED+I/R group (n = 12). I/R was generated by left anterior descending artery occlusion for 30 min followed by 3 h reperfusion. ECG and left stellate ganglion (LSG) neural activity were recorded continuously. After 3 h reperfusion, a programmed stimulation protocol was conducted to test the inducibility of VA. Furthermore, we extracted the brain tissue to examine the microglial activation, and the peri-ischemic myocardium to examine the expression of NGF and inflammatory cytokines (IL-1ß, IL-18, IL-6, and TNF-α). RESULTS: As compared to the I/R group, LED illumination significantly inhibited the LSG neural activity (P < 0.01) and reduced the inducibility of VAs (arrhythmia score 4.417 ± 0.358 vs. 3 ± 0.3257, P < 0.01) in the LED+I/R group. Furthermore, LED significantly attenuated microglial activation and downregulated the expression of inflammatory cytokines and NGF in the peri-infarct myocardium. CONCLUSIONS: LED therapy may protect against myocardial I/R-induced VAs by central and peripheral neuro-immune regulation.
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Daño por Reperfusión Miocárdica/inmunología , Daño por Reperfusión Miocárdica/terapia , Neuroinmunomodulación/fisiología , Fototerapia/métodos , Fibrilación Ventricular/inmunología , Fibrilación Ventricular/terapia , Animales , Masculino , Daño por Reperfusión Miocárdica/metabolismo , Neuroinmunomodulación/efectos de la radiación , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Fibrilación Ventricular/metabolismoRESUMEN
BACKGROUND: Sympathetic neural activation plays a key role in the incidence and maintenance of acute myocardial infarction (AMI) induced ventricular arrhythmia (VA). Furthermore, previous studies showed that AMI might induce microglia and sympathetic activation and that microglial activation might contribute to sympathetic activation. Recently, studies showed that light emitting diode (LED) therapy might attenuate microglial activation. Therefore, we hypothesized that LED therapy might reduce AMI-induced VA by attenuating microglia and sympathetic activation. METHODS: Thirty anesthetized rats were randomly divided into three groups: the Control group (n = 6), AMI group (n = 12), and AMI + LED group (n = 12). Electrocardiogram (ECG) and left stellate ganglion (LSG) neural activity were continuously recorded. The incidence of VAs was recorded during the first hour after AMI. Furthermore, we sampled the brain and myocardium tissue of the different groups to examine the microglial activation and expression of nerve growth factor (NGF), interleukin-18 (IL-18), and IL-1ß, respectively. RESULTS: Compared to the AMI group, LED therapy significantly reduced the incidence of AMI-induced VAs (ventricular premature beats [VPB] number: 85.08 ± 13.91 vs 27.5 ± 9.168, P < .01; nonsustained ventricular tachycardia (nSVT) duration: 34.39 ± 8.562 vs 9.005 ± 3.442, P < .05; nSVT number: 18.92 ± 4.52 vs 7.583 ± 3.019, P < .05; incidence rate of SVT/VF: 58.33% vs. 8.33%, P < .05) and reduced the LSG neural activity (P < .01) in the AMI + LED group. Furthermore, LED significantly attenuated microglial activation and reduced IL-18, IL-1ß, and NGF expression in the peri-infarct myocardium. CONCLUSION: LED therapy may protect against AMI-induced VAs by suppressing sympathetic neural activity and the inflammatory response.
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Corazón/inervación , Láseres de Semiconductores , Terapia por Luz de Baja Intensidad/instrumentación , Infarto del Miocardio/radioterapia , Neuroinmunomodulación , Núcleo Hipotalámico Paraventricular/fisiopatología , Ganglio Estrellado/fisiopatología , Taquicardia Supraventricular/prevención & control , Taquicardia Ventricular/prevención & control , Complejos Prematuros Ventriculares/prevención & control , Potenciales de Acción , Animales , Modelos Animales de Enfermedad , Frecuencia Cardíaca , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Masculino , Microglía/metabolismo , Infarto del Miocardio/complicaciones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas Sprague-Dawley , Taquicardia Supraventricular/etiología , Taquicardia Supraventricular/metabolismo , Taquicardia Supraventricular/fisiopatología , Taquicardia Ventricular/etiología , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatología , Factores de Tiempo , Complejos Prematuros Ventriculares/etiología , Complejos Prematuros Ventriculares/metabolismo , Complejos Prematuros Ventriculares/fisiopatologíaRESUMEN
Spexin (Spx), a novel neuropeptide, composed of 14 amino acid residues, is evolutionally conserved from fish to mammals. It has been suggested that Spx has pleiotropic functions in mammals. However, reports about Spx are very limited. To clarify the roles of Spx in the regulation of reproduction and food-intake in the spotted scat, the spx (ssspx) gene was cloned and analyzed. Analysis of the tissue distribution by RT-PCR showed that ssspx expression was widespread. During ovary development, expression of ssspx was found to be highest in phase II, moderate in phase III, and at its lowest level in phase IV. Ssspx expression was significantly down-regulated in the hypothalamus after treatment with E2 both in vitro and in vivo. A significant increase of ssspx was observed after 2 and 7â¯days of food deprivation. However, the ssspx transcript levels in the 7â¯day fasting group decreased significantly after refeeding 3â¯h after the scheduled feeding time. This suggests that ssSpx may be involved in the regulation of reproduction and food-intake in the spotted scat.
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Perfilación de la Expresión Génica , Hormonas Peptídicas/genética , Perciformes/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Estradiol/farmacología , Ayuno , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ovario/efectos de los fármacos , Ovario/embriología , Ovario/metabolismo , Hormonas Peptídicas/química , Hormonas Peptídicas/metabolismo , Perciformes/metabolismo , Filogenia , Reproducción , Alineación de Secuencia , Distribución Tisular/efectos de los fármacosRESUMEN
1. Rutaecarpine, a quinolone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is one of the main active components used in a variety of clinical applications, including the treatment of hypertension and arrhythmia. However, its hepatotoxicity has also been reported in recent years. 2. Reactive metabolites (RMs) play a vital role in drug-induced liver injury. Rutaecarpine has a secondary amine structure that may be activated to RMs. The aim of the study was to investigate the inhibition of rutaecarpine on CYPs and explore the possible relationship between RMs and potential hepatotoxicity. 3. A cell counting kit-8 cytotoxicity assay indicated that rutaecarpine can decrease the primary rat hepatocyte viability, increase lactate dehydrogenase and reactive oxygen species, reduce JC-1, and cause cell stress and membrane damage. The indexes were significantly restored by adding ABT, an inhibitor of CYPs. A cocktail assay showed that CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 can be inhibited by rutaecarpine in human liver microsomes. The IC50 values of CYP1A2 with and without NADPH were 2.2 and 7.4 µM, respectively, which presented a 3.3 shift. The results from a metabolic assay indicated that three mono-hydroxylated metabolites and two di-hydroxylated metabolites were identified and two GSH conjugates were also trapped. 4. Rutaecarpine can inhibit the activities of CYPs and exhibit a potential mechanism-based inhibition on CYP1A2. RMs may cause herb-drug interactions, providing important information for predicting drug-induced hepatotoxicity.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Alcaloides Indólicos , Quinazolinas , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Inhibidores Enzimáticos del Citocromo P-450/efectos adversos , Inhibidores Enzimáticos del Citocromo P-450/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Humanos , Alcaloides Indólicos/efectos adversos , Alcaloides Indólicos/farmacocinética , Alcaloides Indólicos/farmacología , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Quinazolinas/farmacología , RatasRESUMEN
OBJECTIVE: To investigate the levels and differences of plasma selenium, manganese, iron, copper, zinc among oldest elderly in longevity areas in China. METHODS: 446 oldest elderly including 208 centenarians, 238 aged 90 and over, who lived in Xiayi county of Henan province (110 persons), Zhongxiang city of Hubei province (111 persons), Mayang county of Hunan province (60 persons), Sanshui district of Guangdong province (113 persons), Yongfu county of Guangxi Zhuang autonomous region (52 persons) in China, were selected. The contents of plasma selenium, manganese, iron, copper, zinc were detected and compared among these elderly who were classified into different genders, different regions and different age groups. RESULTS: In oldest elderly, the median (inter-quartile range) of content of plasma selenium was 1.44 (0.91) micromol/L, content of manganese was 0.54 (0.94) micromol/L, content of iron was 69.17 (102.85) micromol/L, content of copper was 20.19 (8.73) micromol/L, content of zinc was 31.66 (32.51) micromol/L. Contents of plasma selenium of oldest elderly in Xiayi, Zhongxiang, Mayang, Sanshui, Yongfu region were 1.46 (0.66), 1.30 (0.80), 1.06 (0.51), 2.39 (1.53) and 1.35(0.55) micromol/L; contents of plasma manganese were 0.56 (0.51), 1.40 (1.11), 0.35 (0.71), 0.44 (0.55) and 0.15 (0.21) micromol/L; contents of plasma iron were 86.77 (86.87), 141.42 (101.83), 38.88 (36.28), 31.38 (46.19) and 79.64 (75.34) micromol/L; contents of plasma copper were 22.16 (8.11), 19.46 (9.26), 21.36 (12.38), 18.12 (6.74) and 21.47 (7.85) micromol/L; contents of plasma zinc were 36.85 (26.18), 36.59 (35.94), 39.98 (56.91), 25.05 (24.92) and 16.74 (16.81) micromol/L. Contents of plasma trace elements among oldest elderly in different longevity areas were significantly different (F values were 29.76, 38.75, 47.18, 11.51 and 13.47, P values were all less than 0.05). Contents of plasma trace elements in different gender groups (contents of plasma selenium were 1.38 (0.83) micromol/L in male and 1.45 (0.91) micromol/L in female; contents of plasma manganese were 0.52 (0.95) and 0.54 (0.91) micromol/L; contents of plasma iron were 69.23 (104.06) and 69.11 (101.05) micromol/L; contents of plasma copper were 20.28 (8.72) and 20.06 (8.76) micromol/L; contents of plasma zinc were 28.39 (32.58) and 31.85 (34.26) micromol/L) were not significantly different (t(Se) = -1.82, P = 0.07; t(Mn) = 0.64, P = 0.52; t(Fe) = 0.65, P = 0.52; t(Cu) = -1.90, P = 0.06; t(Zn) = -0.96, P = 0.34). The contents of plasma selenium, iron, copper in centenarians were higher than those aged 90 and over (contents of plasma selenium were 1.63 (0.94) micromol/L and 1.30 (0.82) micromol/L, contents of plasma iron were 112.63 (119.78) and 60.13 (58.43) micromol/L, contents of plasma copper were 21.07 (9.03) and 18.81 (8.86) micromol/L, F value were 41.99, 27.32, 24.45, P values were less than 0.01). Content of plasma manganese in centenarians was lower than those aged 90 and over (0.44 (0.76) and 0.64 (0.93) micromol/L, F = 10.76, P < 0.01). No significant differences were detected in plasma zinc between concentration and those aged 90 and over (31.78 (34.06) and 31.11 (33.85) micromol/L; F = 1.32, P = 0.25). CONCLUSION: The concentrations of plasma selenium, manganese, iron, copper and zinc were high in oldest elderly in the longevity areas. The contents of plasma selenium, iron, copper increased with age.