RESUMEN
The benefits of physical exercise on human health make it desirable to identify new approaches that would mimic or potentiate the effects of exercise to treat metabolic diseases. However, whether far-infrared (FIR) hyperthermia therapy could be used as exercise mimetic to realize wide-ranging metabolic regulation, and its underling mechanisms remain unclear. Here, a specific far-infrared (FIR) rays generated from graphene-based hyperthermia devices might promote exercise capacity and metabolisms. The material characterization showed that the graphene synthesized by chemical vapour deposition (CVD) was different from carbon fiber, with single-layer structure and high electrothermal transform efficiency. The emission spectra generated by graphene-FIR device would maximize matching those adsorbed by tissues. Graphene-FIR enhanced both core and epidermal temperatures, leading to increased blood flow in the femoral muscle and the abdominal region. The combination of microbiomic and metabolomic analysis revealed that graphene-FIR modulates the metabolism of the gut-muscle axis. This modulation was characterized by an increased abundance of short-chain fatty acids (SCFA)-producing bacteria and AMP, while lactic acid levels decreased. Furthermore, the principal routes involved in glucose metabolism, such as glycolysis and gluconeogenesis, were found to be altered. Graphene-FIR managed to stimulate AMPK activity by activating GPR43, thus enhancing muscle glucose uptake. Furthermore, a microbiota disorder model also demonstrated that the graphene-FIR effectively restore the exercise endurance with enhanced p-AMPK and GLUT4. Our results provided convincing evidence that graphene-based FIR therapy promoted exercise capacity and glucose metabolism via AMPK in gut-muscle axis. These novel findings regarding the therapeutic effects of graphene-FIR suggested its potential utility as a mimetic agent in clinical management of metabolic disorders.
Asunto(s)
Glucosa , Grafito , Homeostasis , Rayos Infrarrojos , Condicionamiento Físico Animal , Animales , Ratones , Glucosa/metabolismo , Grafito/farmacología , Grafito/química , Proteínas Quinasas Activadas por AMP/metabolismo , Masculino , Microbioma Gastrointestinal , Músculo Esquelético/metabolismo , Ratones Endogámicos C57BL , Hipertermia Inducida/métodos , Tolerancia al Ejercicio , MicrobiotaRESUMEN
OBJECTIVE: To investigate the relationship between clinical indicators of CRAB symptoms and antioxidant enzyme activity in patients with multiple myeloma (MM). METHODS: The activity of catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD) in the bone marrow supernatants of 44 patients with MM and 12 patients with non-malignant hematological diseases was detected by colorimetric assay, and then the differences in the activity of antioxidant enzymes between the two groups were compared. Furthermore, the relationship between the activity of antioxidant enzymes in the MM group and the levels of serum calcium, serum creatinine (Scr), hemoglobin (Hb), alkaline phosphatase (ALP) as well as bone lesions were analyzed. RESULTS: The antioxidant enzyme activity was lower in MM patients compared with the control group (P < 0.05). When the concentrations of serum calcium and ALP were higher than the normal levels, Hb was lower than 85 g/L, and there were multiple bone lesions, the activity of CAT, SOD and GPX was significantly declined (P < 0.05); When the concentration of Scr≥177 µmol/L, the activity of GPX was significantly declined (P < 0.05). Regression analyses showed that CAT, SOD and GPX were negatively correlated with serum calcium (r =-0.538, r =-0.456, r =-0.431), Scr (r =-0.342, r =-0.384, r =-0.463), and ALP (r =-0.551, r =-0.572, r =-0.482). CONCLUSION: The activity of antioxidant enzymes, including CAT, SOD and GPX, were decreased in patients with MM and they were negatively correlated with some clinical indicators of CRAB symptoms (such as serum calcium, Scr, and ALP), which suggests that promoting the activity of antioxidant enzymes may be beneficial to treat the CRAB symptoms of the patients with MM.
Asunto(s)
Antioxidantes , Mieloma Múltiple , Humanos , Fosfatasa Alcalina/sangre , Fosfatasa Alcalina/metabolismo , Antioxidantes/metabolismo , Médula Ósea , Braquiuros , Calcio/sangre , Calcio/metabolismo , Catalasa/sangre , Catalasa/metabolismo , Creatinina/sangre , Glutatión Peroxidasa/sangre , Glutatión Peroxidasa/metabolismo , Mieloma Múltiple/sangre , Mieloma Múltiple/complicaciones , Mieloma Múltiple/enzimología , Mieloma Múltiple/metabolismo , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismoRESUMEN
The consumption of a high-fat diet (HFD) has been implicated in the etiology of obesity and various neuropsychiatric disturbances, including anxiety and depression. Compelling evidence suggests that far-infrared ray (FIR) possesses beneficial effects on emotional disorders. However, the efficacy of FIR therapy in addressing HFD-induced anxiety and the underlying mechanisms remain to be elucidated. Here, we postulate that FIR emitted from a graphene-based therapeutic device may mitigate HFD-induced anxiety behaviors. The graphene-FIR modify the gut microbiota in HFD-mice, particularly by an enriched abundance of beneficial bacteria Clostridiaceae and Erysipelotrichaceae, coupled with a diminution of harmful bacteria Lachnospiraceae, Anaerovoracaceae, Holdemania and Marvinbryantia. Graphene-FIR also improved intestinal barrier function, as evidenced by the augmented expression of the tight junction protein occludin and G protein-coupled receptor 43 (GPR43). In serum level, we observed the decreased free fatty acids (FFA), lipopolysaccharides (LPS), diamine oxidase (DAO) and D-lactate, and increased the glucagon-like peptide-2 (GLP-2) levels in graphene-FIR mice. Simultaneously, inflammatory cytokines IL-6, IL-1ß, and TNF-α manifested a decrease subsequent to graphene-FIR treatment in both peripheral and central system. Notably, graphene-FIR inhibited over expression of astrocytes and microglia. We further noticed that the elevated the BDNF and decreased TLR4 and NF-κB expression in graphene-FIR group. Overall, our study reveals that graphene-FIR rescued HFD-induced anxiety via improving the intestine permeability and the integrity of blood-brain barrier, and reduced inflammatory response by down regulating TLR4/NF-κB inflammatory pathway.
Asunto(s)
Ansiedad , Dieta Alta en Grasa , Microbioma Gastrointestinal , Grafito , Ratones Endogámicos C57BL , Animales , Dieta Alta en Grasa/efectos adversos , Masculino , Grafito/uso terapéutico , Grafito/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Ansiedad/etiología , Ansiedad/metabolismo , Rayos Infrarrojos/uso terapéutico , Obesidad/metabolismo , Ratones , Enfermedades Neuroinflamatorias/metabolismo , Ratones Obesos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacosRESUMEN
This study established an HPLC fingerprint and multi-component content determination method for salt-fired Eucommiae Cortex, and evaluated the quality of salt-fired Eucommiae Cortex from different sources using fingerprint similarity evaluation, cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least square discriminate analysis(OPLS-DA). HPLC was launched on a Cosmosil 5C_(18)-MS-â ¡ column(4.6 mm×250 mm, 5 µm) by gradient elution with a mobile phase of methanol-0.2% phosphoric acid aqueous solution at a flow rate of 1.0 mL·min~(-1), detection wavelength of 238 nm, column temperature of 30 â, and an injection volume of 10 µL. The results of fingerprint similarity evaluation for 20 batches of salt-fired Eucommiae Cortex indicated that, except for batch S3 with a similarity of 0.893, the similarity of the other 19 batches was of ≥ 0.919, suggesting good similarity. Fourteen common peaks were calibrated and seven common peaks were identified including geniposidic acid. The mass fractions of geniposidic acid, chlorogenic acid, geniposide, genipin, pinoresinol diglucoside, liriodendrin, and pinoresinol-4-O-ß-D-glucopyranoside were 0.062 0%-0.426 9%, 0.024 9%-0.116 5%, 0.009 5%-0.052 9%, 0.005 5%-0.034 8%, 0.115 9%-0.317 8%, 0.016 4%-0.108 8%, and 0.026 4%-0.039 8%, respectively. Using CA, PCA, and OPLS-DA, the 20 batches of salt-fired Eucommiae Cortex were classified into three categories. Additionally, through the analysis of variable importance in projection(VIP) under OPLS-DA, two differential quality markers, geniposidic acid and chlorogenic acid, were identified. The established HPLC fingerprint and multi-component content determination method is stable and reliable, providing a reference for quality control of salt-fired Eucommiae Cortex.
Asunto(s)
Quimiometría , Medicamentos Herbarios Chinos , Cromatografía Líquida de Alta Presión/métodos , Medicamentos Herbarios Chinos/análisis , Glucósidos Iridoides/análisis , Cloruro de SodioRESUMEN
Cannabis sativa has been used for improving sleep for long history. Cannabidiol (CBD) has drown much attention as a non-addictive psychoactive component in Cannabis sativa extract. However, the effects of CBD on sleep architecture and it's acting mechanism remains unclear. In the present study, we evaluated the sedative-hypnotic effect of cannabidiol (CBD), assessed the effects of CBD on sleep using a wireless physiological telemetry system. We further explored the therapeutic effects of CBD using 4-chloro-dl-phenylalanine (PCPA) induced insomnia model and changes in sleep latency, sleep duration and intestinal flora were evaluated. CBD shortened sleep latency and increases sleep duration in both normal and insomnia mice, and those effects were blocked by 5-HT1A receptor antagonist WAY100635. We determined that CBD increases 5-HT1A receptors expression and 5-HT content in the hypothalamus of PCPA-pretreated mice and affects tryptophan metabolism in the intestinal flora. These results showed that activation of 5-HT1A receptors is one of the potential mechanisms underlying the sedative-hypnotic effect of CBD. This study validated the effects of CBD on sleep and evaluated its potential therapeutic effects on insomnia.
Asunto(s)
Cannabidiol , Trastornos del Inicio y del Mantenimiento del Sueño , Ratones , Animales , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/uso terapéutico , Serotonina/metabolismo , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Receptor de Serotonina 5-HT1A , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Antagonistas de la SerotoninaAsunto(s)
Factor Neurotrófico Derivado del Encéfalo , Lipopolisacáridos , Ratones , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/metabolismo , Mentol/farmacología , Enfermedades Neuroinflamatorias , Antidepresivos/farmacología , Antidepresivos/metabolismo , Transducción de Señal , Receptor trkB/metabolismo , Hipocampo/metabolismoRESUMEN
BACKGROUND: Insomnia is the most frequent sleep disorder worldwide and is a prominent risk factor for mental and physical health deterioration. The clinical application of common pharmacological treatments for insomnia is far from satisfactory due to their various adverse effects. In recent years, drugs developed from natural herbs have become potential alternative therapies for insomnia. Sishen Wan (SSW), a traditional Chinese medicine (TCM) used for centuries to treat diarrheal disease, consists of multiple neurologically active herbs with sleep-regulating potential that may have therapeutic effects on insomnia. However, its hypnotic and sleep-regulating effects have not been evaluated in clinical practice or laboratory experiments. PURPOSE: To investigate the anti-insomnia effects of SSW and explore its possible mechanisms using preclinical models. STUDY DESIGN AND METHODS: The sedative effect of the SSW formula was investigated using network pharmacology analysis that was validated using various pharmacological approaches, including the evaluation of locomotor activity (LMA), pentobarbital-induced sleep time, and electroencephalography/electromyogram (EEG/EMG)-based sleep profiling in normal rats. Several animal models of insomnia, including sleep deprivation, serotonin depletion, and cage-changing models, have been used to further assess the anti-insomnia effects of SSW. Furthermore, the potential underlying mechanisms of action of SSW were predicted using bioinformatics methods and verified using in vivo and in silico experiments. RESULTS: The results showed that SSW reduced LMA and prolonged pentobarbital-induced sleep time in a dose-dependent manner, which was consistent with the increase in non-rapid eye movement (NREM) sleep in normal rats, indicating a solid sedative effect. In animal models of insomnia, SSW alleviated sleep disturbance by increasing NREM sleep time, shortening NREM sleep latency, and inhibiting sleep fragmentation, suggesting a possible curative effect of SSW on insomnia. Finally, through functional enrichment analysis and in vivo and in silico experiments, 5-HT1A was identified as the key target of the anti-insomnia effect of SSW. Moreover, (S)-propranolol, nuciferine, zizyphusine, and N,N-dimethyl-5-methoxytryptamine may be the active compounds of SSW responsible for its anti-insomnia effect. CONCLUSION: This study extended the possible indication scope for SSW, which provides a potential therapeutic TCM that may be used for insomnia treatment, as well as a reference scheme for the discovery of novel indications of TCM.
Asunto(s)
Pentobarbital , Trastornos del Inicio y del Mantenimiento del Sueño , Animales , Ratas , Pentobarbital/farmacología , Farmacología en Red , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/uso terapéutico , SerotoninaRESUMEN
BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is one of the fatal pathologies developed under hypobaric hypoxia and eventually leads to right ventricular (RV) remodeling and RV failure. Clinically, the mortality rate of RV failure caused by HPH is high and lacks effective drugs. Xinyang Tablet (XYT), a traditional Chinese medicine exhibits significant efficacy in the treatment of congestive heart failure and cardiac dysfunction. However, the effects of XYT on chronic hypoxia-induced RV failure are not clear. METHODS: The content of XYT was analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Sprague-Dawley (SD) rats were housed in a hypobaric chamber (equal to the parameter in altitude 5500 m) for 21 days to obtain the RV remodeling model. Electrocardiogram (ECG) and hemodynamic parameters were measured by iWorx Acquisition & Analysis System. Pathological morphological changes in the RV and pulmonary vessels were observed by H&E staining and Masson's trichrome staining. Myocardial apoptosis was tested by TUNEL assay. Protein expression levels of TNF-α, IL-6, Bax, Bcl-2, and caspase-3 in the RV and H9c2 cells were detected by western blot. Meanwhile, H9c2 cells were induced by CoCl2 to establish a hypoxia injury model to verify the protective effect and mechanisms of XYT. A CCK-8 assay was performed to determine the viability of H9c2 cells. CoCl2-induced apoptosis was detected by Annexin-FITC/PI flow cytometry and Hoechst 33,258 staining. RESULTS: XYT remarkably improved RV hemodynamic disorder and ECG parameters. XYT attenuated hypoxia-induced pathological injury in RV and pulmonary vessels. We also observed that XYT treatment decreased the expression levels of TNF-α, IL-6, Bax/Bcl-2 ratio, and the numbers of myocardial apoptosis in RV. In H9c2 myocardial hypoxia model, XYT protected H9c2 cells against Cobalt chloride (CoCl2)-induced apoptosis. We also found that XYT could antagonize CoCl2-induced apoptosis through upregulating Bcl-2, inhibiting Bax and caspase-3 expression. CONCLUSIONS: We concluded that XYT improved hypoxia-induced RV remodeling and protected against cardiac injury by inhibiting apoptosis pathway in vivo and vitro models, which may be a promising therapeutic strategy for clinical management of hypoxia-induced cardiac injury.
RESUMEN
Postoperative sleep disorder frequently occurs in patients after surgery. Sleep disturbance aggravates pain, anxiety, and delirium, which is an important risk factor for poor recovery. Circadian rhythm disorder induced by general anesthesia plays important role in postoperative sleep disorders. A large number of clinical studies have shown that various forms and duration of general anesthesia can lead to postoperative sleep disorders. In this study, the effect of prolonged propofol anesthesia on biological rhythm was comprehensively evaluated by wireless physiological telemetry system, and the therapeutic effect of exogenous melatonin pretreatment was further investigated. The results showed that prolonged propofol anesthesia had significant impacts on the circadian rhythm of sleep, body temperature, locomotor activity and endogenous melatonin secretion within 24 h following anesthesia, resulting in diminished oscillation amplitude. In hypothalamus, the expression of circadian factor PER and CRY were inhibited by propofol, possibly through activation of CAMK-CREB signaling pathway. Post-translational factors GSK-3ß, SIRT1, AMPK were also involved in the regulation of circadian factors after propofol anesthesia. Melatonin pretreatment could restore circadian rhythm process by regulating circadian factor expression through post-translational modulation and prohibit the over-synthesis of melatonin in pineal gland. This study verified the effects of anesthetics on circadian rhythm and further evaluated the potential therapeutic effect of melatonin on postoperative circadian rhythm and sleep disorders.
Asunto(s)
Ritmo Circadiano , Melatonina , Propofol , Trastornos del Sueño-Vigilia , Animales , Ritmo Circadiano/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta , Humanos , Melatonina/farmacología , Propofol/farmacología , Ratas , Sueño , Trastornos del Sueño-Vigilia/inducido químicamente , Trastornos del Sueño-Vigilia/prevención & controlRESUMEN
This study aimed to investigate the effects of geniposide(GP) on the expression of prokineticin(PK2) and prokineticin receptor 1(PKR1) in db/db mice with diabetic nephropathy(DN), so as to explore how the PK2 signaling pathway participated in the pathological changes of DN and whether GP exerted the therapeutic effect through this signaling pathway. Male mice were randomly divided into four groups, namely db/m, db/db, db/db+GP, and db/m+GP groups, with five in each group. The mice in the db/db+GP and db/m+GP groups were gavaged with 150 mg·kg~(-1) GP for eight successive weeks. Afterwards, all the mice were sacrificed and the renal tissues were embedded. The morphological changes in glomerulus and renal tubules were observed by Masson and PAS staining. The expression levels of PK2, PKR1, and Wilm's Tumor Protein 1(WT_1) in podocytes were detected by immunohistochemistry, and the protein expression levels of PK2 and PKR1 in mouse kidney by Western blot. The morphological results showed serious glomerular and tubular fibrosis(Masson), high glomerular and tubular injury score(PAS), increased glomerular mesangial matrix, thickened basement membrane, exfoliated brush border of renal tubules, decreased WT_1 in glomerular podocytes, and massive loss of podocytes in the db/db group. After administration with GP, the glomerular and tubular fibrosis was alleviated, accompanied by improved glomerular basement membrane and renal tubule brush edge, and up-regulated WT_1. As revealed by further protein detection, in the db/db group, the expression levels of PK2 and PKR1 and p-Akt/Akt ratio declined, whereas the ratio of Bax/Bcl-2 rose. Ho-wever, PKR2 and p-ERK/ERK ratio did not change significantly. After administration with GP, the PK2 and PKR1 expression was elevated, and p-Akt/Akt ratio was increased. There was no obvious change in PKR2, Bax/Bcl-2 ratio, or p-ERK/ERK ratio. All these have demonstrated that GP improves the renal damage in DN mice, and PK2/PKR1 signaling pathway may be involved in such protection, which has provided reference for clinical treatment of DN with GP.
Asunto(s)
Diabetes Mellitus , Nefropatías Diabéticas , Animales , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/genética , Iridoides , Riñón , Masculino , Ratones , Transducción de SeñalRESUMEN
Epithelial-mesenchymal transition (EMT) enables dissemination of neoplastic cells and onset of distal metastasis of primary tumors. However, the regulatory mechanisms of EMT by microenvironmental factors such as transforming growth factor-ß (TGF-ß) remain largely unresolved. Protein tyrosine phosphatase L1 (PTPL1) is a non-receptor protein tyrosine phosphatase that plays a suppressive role in tumorigenesis of diverse tissues. In this study we investigated the role of PTPL1/PTPN13 in metastasis of lung cancer and the signaling pathways regulated by PTPL1 in terms of EMT of non-small cell lung cancer (NSCLC) cells. We showed that the expression of PTPL1 was significantly downregulated in cancerous tissues of 23 patients with NSCLC compared with adjacent normal tissues. PTPL1 expression was positively correlated with overall survival of NSCLC patients. Then we treated A549 cells in vitro with TGF-ß1 (10 ng/mL) and assessed EMT. We found that knockdown of PTPL1 enhanced the migration and invasion capabilities of A549 cells, through enhancing TGF-ß1-induced EMT. In nude mice bearing A549 cell xenografts, knockdown of PTPL1 significantly promoted homing of cells and formation of tumor loci in the lungs. We further revealed that PTPL1 suppressed TGF-ß-induced EMT by counteracting the activation of canonical Smad2/3 and non-canonical p38 MAPK signaling pathways. Using immunoprecipitation assay we demonstrated that PTPL1 could bind to p38 MAPK, suggesting that p38 MAPK might be a direct substrate of PTPL1. In conclusion, these results unravel novel mechanisms underlying the regulation of TGF-ß signaling pathway, and have implications for prognostic assessment and targeted therapy of metastatic lung cancer.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Movimiento Celular/fisiología , Transición Epitelial-Mesenquimal/fisiología , Neoplasias Pulmonares/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 13/metabolismo , Células A549 , Animales , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Pronóstico , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Endothelial-mesenchymal transition (EnMT) plays a pivotal role in various diseases, including pulmonary hypertension (PH), and transcription factors like Snail are key regulators of EnMT. In this study we investigated how these factors were regulated by PH risk factors (e.g. inflammation and hypoxia) in human umbilical vein endothelial cells (HUVECs). We showed that treatment with interleukin 1ß (IL-1ß) induced EnMT of HUVECs via activation of NF-κB/Snail pathway, which was further exacerbated by knockdown of protein tyrosine phosphatase L1 (PTPL1). We demonstrated that PTPL1 inhibited NF-κB/Snail through dephosphorylating and stabilizing IκBα. IL-1ß or hypoxia could downregulate PTPL1 expression in HUVECs. The deregulation of PTPL1/NF-κB signaling was validated in a monocrotaline-induced rat PH (MCT-PH) model and clinical PH specimens. Our findings provide novel insights into the regulatory mechanisms of EnMT, and have implications for identifying new therapeutic targets for clinical PH.
Asunto(s)
Transdiferenciación Celular/efectos de los fármacos , Interleucina-1beta/farmacología , Subunidad p50 de NF-kappa B/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 13/fisiología , Transducción de Señal/fisiología , Factores de Transcripción de la Familia Snail/metabolismo , Animales , Transdiferenciación Celular/fisiología , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/fisiopatología , Interleucina-1beta/metabolismo , Masculino , Monocrotalina , Inhibidor NF-kappaB alfa/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 13/genética , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Many studies have proven the beneficial effects of regular exercise on psychiatric conditions. This study was set to explore the therapeutic effects and the mechanisms of treadmill exercise on a time-dependent sensitization (TDS) model which is a classical animal model for mimicking posttraumatic stress disorder (PTSD). METHODS: Forty-seven rats were randomly assigned to one of four groups: CON (control), TDS (model), EX (treadmill), or SER (sertraline). TDS model was developed to evaluate the anti-PTSD-like effects of moderate treadmill exercise with 4-week running program. High-performance liquid chromatography technology was used to determine the levels of monoamine neurotransmitters in TDS rats. The expression of key proteins in BDNF/PI3K/Akt/CREB signaling pathway were assayed by the Western blot method. RESULTS: The TDS procedures induced behavioral deficiencies. These deficiencies were reversed by treadmill exercise. Subsequent monoamine assays revealed that the treadmill exercise significantly increased serotonin levels in the hippocampus and decreased dopamine levels in the prefrontal cortex. Data from Western blot experiment demonstrated that exercise could normalize the decreased BDNF/TrkB/pAkt/pCREB levels in the hippocampus. CONCLUSIONS: This study deduced that treadmill exercise ameliorated contextual fear conditioning and anxiety-like behavior in TDS model. According to the study, the mechanism involved in alleviating PTSD symptoms by treadmill exercise was due to increased 5-HT levels in the hippocampus and decreased DA levels in the prefrontal cortex. It also involved the upregulation of BDNF and the related PI3K/AKT/CREB signaling pathway.
Asunto(s)
Terapia por Ejercicio , Trastornos por Estrés Postraumático/psicología , Trastornos por Estrés Postraumático/terapia , Animales , Ansiedad , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Miedo , Hipocampo/metabolismo , Masculino , Neurotransmisores/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Condicionamiento Físico Animal , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Transducción de Señal , Trastornos por Estrés Postraumático/metabolismoRESUMEN
BACKGROUND: Fast-acting and cognitive-enhancing antidepressants are desperately needed. Activation of translocator protein (18 kDa, TSPO) is a novel strategy for developing potential antidepressants, but there are no data available on the onset time of TSPO ligands. This study aimed to investigate the fast-onset antidepressant actions of AC-5216, a selective TSPO ligand, in TSPO knock-out (KO) mice. METHODS: TSPO wild-type (WT) and KO mice were subjected to a six-week chronic unpredicted stress (CUS) paradigm. Then, the mice were treated with AC-5216 and tested with depressive and cognitive behaviours. RESULTS: A single dose of AC-5216 (0.3 mg/kg) exerted anxiolytic- and antidepressant-like actions in TSPO WT mice. Moreover, in chronically stressed WT mice, two to four days of AC-5216 treatment (0.3 mg/kg, once per day) produced fast-onset antidepressant-like effects in the novelty-suppressed feeding and sucrose preference tests, as well as memory-enhancing effects in the novel object recognition test. In addition, a rapid (with five days of treatment) restoration of serum corticosterone levels and prefrontal cortex (PFC) allopregnanolone levels was found. Further studies showed that in these stress-exposed WT mice, AC-5216 significantly increased the levels of mTOR signalling-related proteins (mBDNF, p-mTOR, PSD-95, synapsin-1, GluR1), as well as the total dendritic length and branching points of pyramidal neurons in the PFC. CONCLUSIONS: These results suggest that TSPO mediates the fast-onset antidepressant-like and memory-enhancing effects of AC-5216, possibly through the rapid activation of mTOR signalling and restoration of dendritic complexity in the PFC.
Asunto(s)
Antidepresivos , Memoria/efectos de los fármacos , Receptores de GABA/fisiología , Estrés Psicológico/psicología , Animales , Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Enfermedad Crónica , Corticosterona/sangre , Dendritas/efectos de los fármacos , Dendritas/ultraestructura , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Pregnanolona/metabolismo , Purinas/farmacología , Células Piramidales/efectos de los fármacos , Células Piramidales/ultraestructura , Receptores de GABA/efectos de los fármacos , Receptores de GABA/genética , Reconocimiento en Psicología , Serina-Treonina Quinasas TOR/efectos de los fármacosRESUMEN
BACKGROUND: Postoperative cognitive dysfunction (POCD) is one of the common postoperative complications, which is more common in aged patients. POCD mainly manifests as cognitive function changes after surgery, such as memory decline and inattention. In some severe cases, patients may suffer from personality changes and (or) social behavior decline. The aim of the current study is to confirm the effect and elucidate the mechanism of bone marrow mesenchymal stem cells (BMSCs) in postoperative central inflammatory mice. METHODS: Mice were randomly assigned to four groups: sham, sham+BMSCs, model, and BMSCs group. In the model group, mice were intraperitoneally injected 8 mg/kg per day lipopolysaccharide for 5 days. In sham+BMSCs and BMSCs group, BMSCs (1 × 10 7 ) in 100 µL saline were injected into sham mice and model mice, respectively. RESULTS: In the model group, transforming growth factor ß (TGF-ß) protein expression was significantly increased, compared with that in the sham group. BMSCs were treated into postoperative central inflammatory mice, which resulted in a decreased of TGF-ß protein expression. TGF-ß and smad2 protein expression were suppressed, and apoptosis rate and inflammation were inhibited in coculture with BMSCs. The suppression of TGF-ß inhibited the effects of BMSCs on apoptosis rate and inflammation in postoperative central inflammatory through a smad2 signaling pathway. The promotion of TGF-ß reduced the effects of BMSCs on apoptosis rate and inflammation in postoperative central inflammatory through a smad2 signaling pathway. CONCLUSION: The present study demonstrates that BMSCs regulates TGF-ß to adjust neuroinflammation in postoperative central inflammatory mice.
Asunto(s)
Inflamación/metabolismo , Células Madre Mesenquimatosas/citología , Neuronas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Apoptosis , Conducta Animal , Células de la Médula Ósea/metabolismo , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Lipopolisacáridos/metabolismo , Masculino , Trasplante de Células Madre Mesenquimatosas , Ratones , Ratones Endogámicos C57BL , Periodo Posoperatorio , Transducción de Señal , Proteína Smad2/metabolismoRESUMEN
BACKGROUND: Hypoadiponectinemia is a high risk factor for type 2 diabetes and cardiovascular disease. Although adiponectin is a protective molecule in cardiovascular diseases, it is hampered due to short plasma half-life and high cost of production. This study aimed to investigate whether AdipoRon, a small-molecule adiponectin receptor agonist, alleviated saturated free fatty acids such as palmitic acid (PA)-induced cardiomyocyte injury by suppressing Nlrp3 inflammasome activation. METHODS: Cell viability was used with MTT assay. Cell apoptosis and mitochondria membrane potential were detected by flow cytometry. We also detected the ROS production and colocolization of inflammasome protein with fluorescence and immunofluorescence microscopic analysis, respectively. Then, IL-1ß was detected by Elisa assay and other protein expression was analyzed by Western blot. RESULTS: Our observations demonstrated PA dose-dependently promoted the cell injury, and such high lipotoxicity induced impairment of cardiomyocytes was significantly attenuated by AdipoRon treatment. Moreover, PA markedly activated the first phase of Nlrp3 inflammasome (NF-Æb) signaling. Notably, the stimulation of PA enhanced ROS production as regulators of Nlrp3 inflammasome activation. In addition, treatment with PA increased the Nlrp3 inflammasome protein expression and complex formation, while AdipoRon abolished it. Lastly, the suppressive effect of AdipoRon to PA-induced cell injury and Nlrp3 inflammasome activation was significantly reversed by Nlrp3 siRNA and pan-caspase inhibitor (z-vad-fmk). CONCLUSION: Taken together, these data suggested that AdipoRon suppressed PA-induced myocardial cell injury by suppressing Nlrp3 inflammasome activation. Thus, AdipoRon might possess potent protective effect in lipotoxicity injury such as obesity leading to cardiac disease.
RESUMEN
Abnormal wound healing by pulmonary artery smooth muscle cells (PASMCs) promotes vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Increasing evidence shows that both the mammalian target of rapamycin complex 1 (mTORC1) and nuclear factor-kappa B (NF-κB) are involved in the development of HPH. In this study, we explored the crosstalk between mTORC1 and NF-κB in PASMCs cultured under hypoxic condition and in a rat model of hypoxia-induced pulmonary hypertension (HPH). We showed that hypoxia promoted wound healing of PASMCs, which was dose-dependently blocked by the mTORC1 inhibitor rapamycin (5-20 nM). In PASMCs, hypoxia activated mTORC1, which in turn promoted the phosphorylation of NF-κB. Molecular docking revealed that mTOR interacted with IκB kinases (IKKs) and that was validated by immunoprecipitation. In vitro kinase assays and mass spectrometry demonstrated that mTOR phosphorylated IKKα and IKKß separately. Inhibition of mTORC1 decreased the level of phosphorylated IKKα/ß, thus reducing the phosphorylation and transcriptional activity of NF-κB. Bioinformatics study revealed that dipeptidyl peptidase-4 (DPP4) was a target gene of NF-κB; DPP4 inhibitor, sitagliptin (10-500 µM) effectively inhibited the abnormal wound healing of PASMCs under hypoxic condition. In the rat model of HPH, we showed that NF-κB activation (at 3 weeks) was preceded by mTOR signaling activation (after 1 or 2 weeks) in lungs, and administration of sitagliptin (1-5 mg/kg every day, ig) produced preventive effects against the development of HPH. In conclusion, hypoxia activates the crosstalk between mTORC1 and NF-κB, and increased DPP4 expression in PASMCs that leads to vascular remodeling. Sitagliptin, a DPP4 inhibitor, exerts preventive effect against HPH.
Asunto(s)
Miocitos del Músculo Liso/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Arteria Pulmonar/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Administración Oral , Animales , Hipoxia de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Biología Computacional , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Masculino , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , FN-kappa B/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Hypidone hydrochloride (YL-0919), is a novel structural antidepressant candidate as a triple selective serotonin re-uptake inhibitor (SSRI), 5-HT1A partial agonist and 5-HT6 agonist. Here, we investigated the rapid onset antidepressant-like effects of YL-0919 and the possible mechanism in rats exposed to a chronic unpredictable stress (CUS) paradigm. In the CUS rats, it was found that fluoxetine (FLX, 10 mg/kg) treatment exerted antidepressant actions on 20-22d, while YL-0919 or vilazodone (VLZ, a dual 5-HT1A partial agonist and SSRI) administrated once daily exerted faster antidepressant-like behaviors [4 days in the sucrose preference test (SPT) and 6 days in the novelty suppressed feeding test (NSF)]. Thereafter, the serum corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels were reversed by treatment with YL-0919 for 7 days. Furthermore, YL-0919 treatment for 5 days reversed the brain derived neurotrophic factor (BDNF)-mammalian target of rapamycin (mTOR) signaling and the key synaptic proteins, such as post-synaptic density (PSD95), GluR1 and presynaptic protein synapsin1. Meanwhile, the dendritic complexity of pyramidal neurons in prefrontal cortex (PFC) were also increased in the CUS rats. These data suggest that YL-0919 exerts a faster antidepressant-like effect on behaviors and this effect maybe at least partially mediated by the BDNF-mTOR signaling related dendritic complexity increase in the PFC.
Asunto(s)
Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Ingestión de Alimentos/efectos de los fármacos , Piperidinas/uso terapéutico , Piridonas/uso terapéutico , Animales , Antidepresivos/farmacología , Depresión/metabolismo , Modelos Animales de Enfermedad , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Masculino , Piperidinas/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Piridonas/farmacología , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Estrés Psicológico/metabolismo , Factores de TiempoRESUMEN
The translocator protein (18 kDa) (TSPO) recently attracted increasing attention in the pathogenesis of post-traumatic stress disorder (PTSD). This study is testing the hypothesis that the overexpression of TSPO in hippocampus dentate gyrus (DG) could alleviate the anxiogenic-like response in the mice model of PTSD induced by foot-shock. In this study, hippocampal DG overexpression of TSPO significantly reversed the increase of the contextual freezing response, the decrease of the percentage of both entries into and time spent in the open arms in elevated plus maze test and the decrease of the account of crossings from the dark to light compartments in light-dark transition test induced by electric foot-shocks procedure. It was further showed that the behavioral effects of TSPO overexpression were blocked by PK11195, a selective TSPO antagonist. In addition, the expression of TSPO and level of allopregnanolone (Allo) decreased in the mouse model of PTSD, which was blocked by overexpression of TSPO in hippocampal dentate gyrus. The difference of neurogenesis among groups was consistent with the changes of TSPO and Allo, as evidenced by bromodeoxyuridine (BrdU)- positive cells in the hippocampal dentate gyrus. These results firstly suggested that TSPO in hippocampal dentate gyrus could exert a great effect on the occurrence and recovery of PTSD in this animal model, and the anti-PTSD-like effect of hippocampal TSPO over-expression could be at least partially mediated by up-regulation of Allo and subsequent stimulation of the adult hippocampal neurogenesis.