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Cerebral ischemia-induced systemic inflammation and inflammasome-dependent pyroptotic cell death in ileum, causing serious intestinal injury. Glucocorticoid receptor (GR) mediates the effects of glucocorticoids and participates in inflammation. Escin has corticosteroid-like, neuroprotective, and anti-intestinal dysfunction effects. This study aimed to investigate the effect of Escin on the intestinal barrier injury in rats subjected to middle cerebral artery occlusion (MCAO) and on Caco-2 cells exposed to lipopolysaccharides. The MCAO-caused brain injury was evaluated by assessing neurological function, cerebral infarct volume, and plasma corticosterone (Cort) levels. Intestinal injury was evaluated by observing the histopathological changes, assessing the intestinal barrier function, and determining blood FD4, endotoxin and IL-1ß levels. The levels of the tight-junction proteins such as claudin-1, occludin, and ZO-1, and proteins involved in the GR/p38 MAPK/NF-κB pathway and NLRP3-inflammasome activation were evaluated using western blotting or immunofluorescence. Administration of Escin suppressed the cerebral ischemia-induced increases in Garcia-test scores and infarct volume, alleviated the injury to the intestinal barrier, and decreased the levels of Cort, endotoxin, and IL-1ß. Additionally, Escin upregulated GR and downregulated phospho(p)-p65, p-p38MAPK, NLRP3, GSDMD-N, and cleaved-caspase-1 in the intestine. The effects of Escin could be suppressed by the GR antagonist RU486 or enhanced by the p38 MAPK antagonist SB203580. We revealed details how Escin improves cerebral ischemia-induced intestinal barrier injury by upregulating GR and thereby inhibiting the pyroptosis induced by NF-κB-mediated NLRP3 activation. This study will provide a experimental foundation for the features of glucocorticoid-like activity and the discovery of new clinical application for Escin.
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Isquemia Encefálica , Escina , Inflamasomas , Piroptosis , Receptores de Glucocorticoides , Transducción de Señal , Animales , Humanos , Masculino , Ratas , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Células CACO-2 , Modelos Animales de Enfermedad , Escina/farmacología , Escina/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/inmunología , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Intestinos/patología , Intestinos/efectos de los fármacos , Intestinos/inmunología , Lipopolisacáridos , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Piroptosis/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Hemorrhagic transformation (HT) seriously affects the clinical application of recombinant tissue plasminogen activator (rt-PA). The main strategy for combating HT is to keep the blood-brain barrier (BBB) stable. Escin is the active ingredient of Aesculus hippocastanum and a natural mixture of triterpene saponins, and may play a part in mitigation of HT. PURPOSE: This study sought to investigate the effect of Escin in improving rt-PA-induced HT, explore possible mechanisms, and provide new ideas for the treatment of clinical HT. STUDY DESIGN AND METHODS: In in vivo experiments, transient middle cerebral artery occlusion (tMCAO) was undertaken in 6-week-old and 12-month-old mice, and rt-PA was administered to induce HT injury. The inhibitory effect of Escin on HT and its protective effect on neurobehavior, the BBB, and cerebrovascular endothelial cells was determined. In in vitro experiments, bEnd.3 cells were injured by oxygen-glucose deprivation/reperfusion (OGD/R) and rt-PA. The protective effect of Escin was measured by the CCK8 assay, release of lactate dehydrogenase (LDH), and expression of tight junction (TJ) proteins. In mechanistic studies, the effect of Escin on the adenosine monophosphate-activated kinase / caveolin-1 / matrix metalloprotease-9 (AMPK/Cav-1/MMP-9) pathway was investigated by employing AMPK inhibitor and Cav-1 siRNA. RESULTS: In mice suffering from ischemia, rt-PA caused HT as well as damage to the BBB and cerebrovascular endothelial cells. Escin reduced the infarct volume, cerebral hemorrhage, improved neurobehavioral deficits, and maintained BBB integrity in rt-PA-treated tMCAO mice while attenuating bEnd.3 cells damage caused by rt-PA and OGD/R injury. Under physiological and pathological conditions, Escin increased the expression of p-AMPK and Cav-1, leading to decreased expression of MMP-9, which further attenuated damage to cerebrovascular endothelial cells, and these effects were verified with AMPK inhibitor and Cav-1 siRNA. CONCLUSION: We revealed important details of how Escin protects cerebrovascular endothelial cells from HT, these effects were associated with the AMPK/Cav-1/MMP-9 pathway. This study provides experimental foundation for the development of new drugs to mitigate rt-PA-induced HT and the discovery of new clinical application for Escin.
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Accidente Cerebrovascular Isquémico , Animales , Ratones , Escina , Proteínas Quinasas Activadas por AMP , Células Endoteliales , Metaloproteinasa 9 de la Matriz , Activador de Tejido Plasminógeno , Barrera HematoencefálicaRESUMEN
AIMS: (-)-2,5-dimethoxy-4-methylamphetamine (DOM) induces the head-twitch response (HTR) primarily by activating the serotonin 5-hydroxytryptamine 2A receptor (5-HT2A receptor) in mice. However, the mechanisms underlying 5-HT2A receptor activation and the HTR remain elusive. Gßγ subunits are a potential treatment target in numerous diseases. The present study investigated the mechanism whereby Gßγ subunits influence DOM-induced HTR. MAIN METHODS: The effects of the Gßγ inhibitor 3',4',5',6'-tetrahydroxyspiro[2-benzofuran-3,9'-xanthene]-1-one (gallein) and antagonistic peptide ßARKct (ß-adrenergic receptor kinase C-terminal fragment) on DOM-induced HTR were studied via an HTR test. The activation of the phospholipase C ß (PLCß)/inositol triphosphate (IP3)/calcium (Ca2+) signaling pathway and extracellular signal-regulated kinase (ERK) following Gßγ subunit inhibition was detected by western blotting, Homogeneous Time-Resolved Fluorescence (HTRF) inositol phosphate (IP1) assay and Fluorometric Imaging Plate Reader (FLIPR) calcium 6 assay. The Gßγ subunit-mediated regulation of cyclic adenosine monophosphate (cAMP) was assessed via a GloSensor™ cAMP assay. KEY FINDINGS: The Gßγ subunit inhibitors gallein and ßARKct reduced DOM-induced HTR in C57BL/6J mice. Like the 5-HT2A receptor-selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907), gallein inhibited PLCß phosphorylation (pPLCß), IP1 production, Ca2+ transients, ERK1/2 phosphorylation (pERK1/2) and cAMP accumulation induced by DOM in human embryonic kidney (HEK) 293T cells stably or transiently transfected with the human 5-HT2A receptor. Moreover, PLCß protein inhibitor 1-[6-[[(8R,9S,13S,14S,17S)-3-methoxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl]amino]hexyl]pyrrole-2,5-dione (U73122) (10 nmol/mouse), intracellular Ca2+ blocker 6-[6-[6-[5-acetamido-4,6-dihydroxy-2-(sulfooxymethyl)oxan-3-yl]oxy-2-carboxy-4-hydroxy-5-sulfooxyoxan-3-yl]oxy-2-(hydroxymethyl)-5-(sulfoamino)-4-sulfooxyoxan-3-yl]oxy-3,4-dihydroxy-5-sulfooxyoxane-2-carboxylic acid (heparin) (5 nmol/mouse), L-type Ca2+ channel blocker 3-O-(2-methoxyethyl) 5-O-propan-2-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (nimodipine) (4 mg/kg), mitogen extracellular regulating kinase 1/2 (MEK1/2) inhibitor (Z)-3-amino-3-(4-aminophenyl)sulfanyl-2-[2-(trifluoromethyl)phenyl]prop-2-enenitrile (SL327) (30 mg/kg), and Gαs protein selective antagonist 4,4',4â³,4â´-(Carbonylbis-(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakisbenzene-1,3-disulfonic acid (NF449) (10 nmol/mouse) reduced DOM-induced HTR in C57BL/6J mice. SIGNIFICANCE: The Gßγ subunits potentially mediate the HTR after 5-HT2A receptor activation via the PLCß/IP3/Ca2+/ERK1/2 and cAMP signaling pathways. Inhibitors targeting the Gßγ subunits potentially inhibit the hallucinogenic effects of 5-HT2A receptor agonists.
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Quinasas MAP Reguladas por Señal Extracelular , Receptor de Serotonina 5-HT2A , Humanos , Animales , Ratones , Ratones Endogámicos C57BL , Fosfolipasa C beta , Calcio , Transducción de SeñalRESUMEN
The cortex of adrenal gland produces glucocorticoid, mineralocorticoid, and androgen. The medulla of adrenal gland secrets catecholamines. These hormones play an important role in regulating blood pressure, metabolism, and homeostasis of glucose or electrolytes. Hypersecretion or hyposecretion by the adrenal gland will cause a complex cascade of hormone effects and lead to diseases, including Addison's disease, Cushing's syndrome, and congenital adrenal cortical hyperplasia. Skin is the largest organ of body. It provides protection and acts as a barrier against external damage factors like infectious organisms, chemicals, and allergens. Endocrinologic disorders often induce cutaneous abnormalities. According to the previous evidences, natural products have the potential properties for attenuating skin disorders and improving dermatologic symptoms by inhibiting inflammation through MAPK or PI3K/AKT-dependent NF-κB pathways. The natural products may also promote skin wound healing by inhibiting the production of matrix metalloproteinase-9. We systematically searched the relevant articles from databases, including PubMed, Embase, and Cochrane library databases, to review the effects of natural products on skin disorders. This article summarized the effects of natural products on skin inflammation caused by abnormal hormone secreted by adrenal gland. And the published papers indicated that natural products might be a potential source for treating skin diseases.
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Purpose: The aim is to investigate the effect of toludesvenlafaxine (Tdv), a reuptake inhibitor of serotonin, norepinephrine, and dopamine, on the neurological function in cerebral ischemic rats and the underlying mechanisms. Material and Methods: Middle cerebral artery occlusion/reperfusion (MCAO/R) model was induced in rats and the neuroprotective effects of Tdv were evaluated by infarct size, Garcia test, and beam walking test. Neuronal apoptosis in the peri-infarct area was observed by TUNEL staining. And the apoptosis-related proteins were evaluated with Western blotting. The role of CREB pathway in effect of Tdv was also investigated using Western blotting and immunofluorescence. Results: In the MCAO/R model, administration of Tdv reduced the infarct size, promoted neural functional recovery, decreased the expression of Bax and Caspase-3, and increased the expression of Bcl-2 and BDNF. In addition, Tdv reduced neuronal apoptosis in the peri-infarct area. Tdv increased the expression of phosphorylated CREB. The application of the specific CREB inhibitor, compound 666-15, could reverse the anti-ischemic cerebral injury of Tdv in MCAO/R rats. Conclusion: Tdv ameliorated cerebral ischemic injury through reducing neuronal apoptosis and increasing the expression of BDNF via the activation of CREB pathway.
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Gastric carcinoma is a highly malignant tumor that still lacks effective molecular targets. Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an essential oncogenic driver overexpressed in various cancers. The potential role of hnRNPA2B1 in oncotherapy has not been revealed because of the absence of active chemical molecules. In this study, we identified the pseudourea derivative XI-011 as a novel hnRNPA2B1 ligand using chemical proteomics. An interaction study indicated that XI-011 could bind the nucleotide-binding domain to disrupt the recruitment of hnRNPA2B1 to the promoter and untranslated region of the murine double minute X (MDMX) gene, thereby inhibiting its transcription. In addition, chemical targeting of hnRNPA2B1 recovered inactivated p53 and enhanced the therapeutic efficacy of apatinib in vivo. This work presented a novel strategy to restore p53 activity for the treatment of gastric cancers via chemically targeting hnRNPA2B1.
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Neoplasias Gástricas , Proteína p53 Supresora de Tumor , Humanos , Animales , Ratones , Ligandos , Ribonucleoproteínas Nucleares Heterogéneas , Proteínas Proto-Oncogénicas c-mdm2/metabolismoRESUMEN
Hyperactivity of HPA axis results in intestinal dysfunction, which may play a role in brain injury caused by ischemic stroke (IS). Escin shows a neuroprotective effect but it may not penetrate blood brain barrier (BBB). Previous work in our laboratory showed that escin ameliorated intestinal injury in animals. The aim of this study is to investigate whether escin attenuates brain injury by improving intestinal dysfunction in middle cerebral artery occlusion (MCAO) rats, to mimic IS. MCAO rats and lipopolysaccharides (LPS)-induced Caco-2 cells were used to evaluate the effects of escin in vivo and in vitro. The results showed that escin could not penetrate BBB but reduced brain infarct volume, improved neurological function, inhibited neuroinflammation, ameliorated intestinal dysfunction and tissue integrity by increasing the expression of the tight junction protein in vivo and in vitro. Escin reduced the increased corticosterone and endotoxin level in blood of MCAO rats, regulated GR/p38 MAPK/NF-κB signaling pathway in ileal tissue and LPS/TLR4/NF-κB signaling pathway in ischemic brain tissue. These findings suggest that escin could attenuate ischemic brain injury by improving intestinal dysfunction, and it may be a promising way to protect brain injury by protecting intestine, instead of targeting the brain directly after IS.
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Lesiones Encefálicas , Isquemia Encefálica , Enfermedades Gastrointestinales , Enfermedades Intestinales , Accidente Cerebrovascular Isquémico , Daño por Reperfusión , Accidente Cerebrovascular , Humanos , Ratas , Animales , FN-kappa B/metabolismo , Escina , Lipopolisacáridos/farmacología , Eje Cerebro-Intestino , Células CACO-2 , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológicoRESUMEN
Acetylcholinesterase (AChE) inhibitor (AChEI) is well established as ï¬rst-line agents for relieving the symptoms of Alzheimer's disease (AD). Injectable sustained-release formulation of AChEI may be suitable for treating AD patients. However, it needs to know whether continuous inhibition of AChE could deteriorate or attenuate myocardial damage if myocardial ischemia (MI) occurs. Huperzine A microspheres (HAM) are a sustained-release formulation releasing sustainably huperzine A (an AChEI) for more than 7 days after a single dose of HAM. This study aimed to investigate the myocardial damage in an isoprenaline (ISO)-induced MI mice model during HAM treatment. The heart injury was evaluated by assaying serum CK-MB, Tn-I and observing histopathological changes. The levels of proinflammatory cytokines in serum were detected. The level of p-P65 and the expression of proteins in the JAK2/STAT3 signaling pathway were assayed with Western blot. Administration with a single dose of HAM resulted in inhibiting the MI-induced increases of CK-MB and Tn-I, alleviating the damage of heart tissue, and decreasing the levels of TNF-α and IL-6. In addition, HAM decreased the levels of p-P65, p-JAK2, and p-STAT3 in heart tissue. The effects of HAM could be weakened or abolished by the specific α7nAChR antagonist. These findings suggest that continuous AChE inhibition could protect the heart from ischemic damage during administration of sustained-release formulation of AChEI, which is associated with the anti-inflammatory effect of HAM by regulating α7nAChR-dependent JAK2/STAT3 signaling pathway.
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Lesiones Cardíacas , Isquemia Miocárdica , Ratones , Animales , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Microesferas , Acetilcolinesterasa/metabolismo , Preparaciones de Acción Retardada/farmacología , Isquemia Miocárdica/tratamiento farmacológico , Transducción de Señal , Factor de Transcripción STAT3/metabolismo , Janus Quinasa 2/metabolismoRESUMEN
BACKGROUND AND ETHNOPHARMACOLOGICAL RELEVANCE: Semen aesculi (SA), a traditional Chinese herb, has been used in the treatment of gastrointestinal disease for thousands of years. The escin was the main components of SA. A growing number of research showed that escin has a wide range of pharmacological activities in intestinal barrier dysfunction. AIM OF THE STUDY: Inflammatory bowel diseases (IBD) are an idiopathic disease of the intestinal tract with the hallmark features of mucosal inflammation and loss of barrier function. The theory of traditional Chinese medicine (TCM) suggests that SA plays a potential role in protecting the gastrointestinal diseases. The present study aimed to explore the effects of SA on the intestinal barrier under existing inflammatory conditions and elucidate underlying mechanisms. MATERIALS AND METHODS: The bioactive components of SA and their predicted biological targets were combined to develop a compound target pathway network. It is used to predict the bioactive components, molecular targets, and molecular pathways of SA in improving IBD. The ingredients of SA were extracted by decoction either in water and ethanol and separated into four fractions (AE, EE, PEE and PCE). The effects of extractions were evaluated in the lipopolysaccharide (LPS)-induced RAW264.7 macrophages cell model, LPS-induced intestinal barrier injury model and imodium-induced constipation model. The high-performance liquid chromatography (HPLC) analysis was performed to identify the bioactive components. RESULTS: The compound-target pathway network was identified with 10 bioactive compounds, 166 IBD-related targets, and 52 IBD-related pathways. In LPS-induced RAW264.7 cells, PEE and PCE significantly decreased nitric oxide (NO) production and TNF-α level. In mice, PEE and PCE administration improved intestinal barrier damage, increased intestinal motility, reduced levels of TNF-α and diamine oxidase (DAO). Furthermore, PEE and PCE administration not only decreased expression of p-Akt, p-IκBα, nuclear p-p65, and TNF-α level, but also increased expression of the zonula occludin-1 (ZO-1) in LPS-induced intestinal barrier injury model. The escin content of AE, EE, PEE and PCE gradually increased with an increase of the bioactivity. CONCLUSIONS: Escin was the main bioactive components of SA. The effects of SA on IBD were mediated by repairing the intestinal barrier and promoting intestinal motility. The mechanism of action of SA is related to inhibiting the Akt/NF-κB signaling pathway in intestinal tissue, at least, in part. Our results provide a scientific basis for further exploring the mechanisms involved in the beneficial effects of SA in IBD.
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Enfermedades Inflamatorias del Intestino , Lipopolisacáridos , Animales , Escina , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Lipopolisacáridos/farmacología , Ratones , FN-kappa B/metabolismo , Farmacología en Red , Proteínas Proto-Oncogénicas c-akt , Semen , Factor de Necrosis Tumoral alfaRESUMEN
Approximately, one in three ischemic stroke survivors suffered from depression, namely, post-stroke depression (PSD). PSD affects functional rehabilitation and may lead to poor quality of life of patients. There are numerous explanations about the etiologies of PSD. Here, we speculated that PSD are likely to be the result of specific changes in brain pathology. We hypothesized that the stroke-induced hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis plays an important role in PSD. Stroke initiates a complex sequence of events in neuroendocrine system including HPA axis. The HPA axis is involved in the pathophysiology of depression, especially, the overactivity of the HPA axis occurs in major depressive disorder. This review summarizes the possible etiologies of PSD, focusing on the stroke-induced activation of HPA axis, mainly including the stress followed by severe brain damage and the proinflammatory cytokines release. The role of hyperactive of HPA axis in PSD was discussed in detail, which includes the role of high level corticotropin-releasing hormone in PSD, the effects of glucocorticoids on the alterations in specific brain structures, the expression of enzymes, excitotoxicity, the change in intestinal permeability, and the activation of microglia. The relationship between neuroendocrine regulation and inflammation was also described. Finally, the therapy of PSD by regulating HPA axis, neuroendocrine, and immunity was discussed briefly. Nevertheless, the change of HPA axis and the occurring of PSD maybe interact and promote on each other, and future investigations should explore this hypothesis in more depth.
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Trastorno Depresivo Mayor , Accidente Cerebrovascular , Depresión/metabolismo , Trastorno Depresivo Mayor/metabolismo , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Calidad de Vida , Accidente Cerebrovascular/metabolismoRESUMEN
Many studies showed that dopamine receptors (DRs) agonists have anti-inflammatory effects. Rotigotine, a non-ergot dopamine receptor agonist, mainly actives DRD2/DRD3/DRD1. Rotigotine extended-release microspheres (RoMS) are a sustained-release formulation that can release sustainably rotigotine for more than 7 days after a single dose of RoMS. This study aimed to investigate whether RoMS can attenuate the lipopolysaccharide (LPS)-induced liver injury of mice. The liver injury was evaluated by assaying serum transaminase and observing histopathological changes. The levels of pro-inflammatory cytokines in serum were also detected. Western blot was employed to assay the expression of proteins in the Akt/NF-κB pathway. The results showed that pre-administration with a single dose of RoMS could inhibit the increase of serum transaminase induced by LPS, alleviate the pathological damage of liver tissue, and decrease the levels of tumor necrosis factor-α and interleukin-6. In addition, RoMS decreased Toll-like receptor 4 protein expression in liver tissue. RoMS mitigated liver injury by activating DRs and negatively regulating the ß-arrestin2-dependent Akt/NF-κB signaling pathway. The effects of RoMS could be weakened or abolished by the specific DRD2 antagonist, R121. In conclusion, activation of DRs inhibited the releases of pro-inflammatory cytokines and alleviated the immune-mediated liver injury induced by LPS in mice. The anti-inflammatory mechanism of RoMS may be related to the regulation of the ß-arrestin2-dependent Akt/NF-κB signaling pathway.
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Dysfunction of p53 is observed in many malignant tumors, which is related to cancer susceptibility. In cervical cancer, p53 is primarily degradated through the complex of high-risk human papillomaviruses (HPV) oncoprotein E6 and E6-associated protein (E6AP) ubiquitin ligase. What is less clear is the mechanism and role of murine double minute X (MDMX) in cervical carcinogenesis due to the inactive status of murine double minute 2 (MDM2). In the current study, XI-011 (NSC146109), a small-molecule inhibitor of MDMX, showed robust anti-proliferation activity against several cervical cancer cell lines. XI-011 promoted apoptosis of cervical cancer cells via stabilizing p53 and activating its transcription activity. Moreover, XI-011 inhibited the growth of xenograft tumor in HeLa tumor-bearing mice, as well as enhanced the cytotoxic activity of cisplatin both in vitro and in vivo. Interestingly, MDMX co-localized with E6AP and seems to be a novel binding partner of E6AP to promote p53 ubiquitination. In conclusion, this work revealed a novel mechanism of ubiquitin-dependent p53 degredation via MDMX-E6AP axis in cervical carcinogenesis, and offered the first evidence that MDMX could be a viable drug target for the treatment of cervical cancer.
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Proteínas Oncogénicas Virales , Neoplasias del Cuello Uterino , Animales , Carcinogénesis , Femenino , Humanos , Ratones , Proteínas Oncogénicas Virales/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patologíaRESUMEN
Dopamine (DA) is a crucial neurotransmitter that plays an important role in maintaining physiological function in human body. In the past, most studies focused on the relationship between the dopaminergic system and neurological-related diseases. However, it has been found recently that DA is an immunomodulatory mediator and many immune cells express dopamine receptors (DRs). Some immune cells can synthesize and secrete DA and then participate in regulating immune function. DRs agonists or antagonists can improve the dysfunction of immune system through classical G protein signaling pathways or other non-receptor-dependent pathways. This article will discuss the relationship between the dopaminergic system and the immune system. It will also review the use of DRs agonists or antagonists to treat chronic and acute inflammatory diseases and corresponding immunomodulatory mechanisms.
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Sistema Nervioso Central/metabolismo , Dopamina/fisiología , Sistema Inmunológico/metabolismo , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Humanos , Factores Inmunológicos/fisiología , Neurotransmisores/fisiología , Transducción de SeñalRESUMEN
Hormonal drugs are essential treatment options for some hormone-dependent or hormone- sensitive tumors. The common dosage forms of hormonal drugs have a short half-life. Hence, frequent administration is needed, which results in poor patient compliance. Nevertheless, using drug delivery technology, somatostatin analogues (SSAs) and gonadotropin-releasing hormone (GnRH) analogues are prepared into long-acting formulations that can significantly prolong the action time of these drugs, reducing medication frequency and increasing patient compliance. Such drugs are advantageous when treating acromegaly, gastroenteropancreatic neuroendocrine tumors (GEP-NETs), breast cancer, prostate cancer, and other diseases having a relatively long course. SSAs and GnRH analogues are two typical hormonal drugs, the long-acting formulations of which are essential in clinical practice. This review summarized the preparation methods and clinical application of long-acting formulations in cancer. Further, the action mechanism and new research of SSAs and GnRH analogues were discussed, and suggestions related to the development of long-acting SSAs and GnRH analogues were provided.
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Neoplasias Intestinales , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Hormona Liberadora de Gonadotropina , Humanos , Neoplasias Intestinales/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Somatostatina/uso terapéuticoRESUMEN
Glucocorticoids are drugs that are widely used to suppress inflammation and the activation of the immune system. However, the prolonged use or at high doses of glucocorticoid can result in adverse side effects including osteoporosis, bone loss, and an increased risk of fracture. A number of compounds derived from natural plant sources have been reported to exert anti-inflammatory activity by interacting with the glucocorticoid receptor (GR), likely owing to their chemical similarity to glucocorticoids, or by regulating GR, without a concomitant risk of treatment-related side effects such as osteoporosis. Other herbal compounds can counteract the pathogenic processes underlying glucocorticoid-induced osteoporosis (GIOP) by regulating homeostatic bone metabolic processes. Herein, we systematically searched the PubMed, Embase, and Cochrane library databases to identify articles discussing such compounds published as of May 01, 2021. Compounds reported to exert anti-inflammatory glucocorticoid-like activity without inducing GIOP include escin, ginsenosides, and glycyrrhizic acid, while compounds reported to alleviate GIOP by improving osteoblast function or modulating steroid hormone synthesis include tanshinol and icariin.
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Glucocorticoides/efectos adversos , Medicina de Hierbas/métodos , Osteoporosis/inducido químicamente , Osteoporosis/prevención & control , Preparaciones de Plantas/uso terapéutico , Animales , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea , Femenino , Humanos , MasculinoRESUMEN
Low dopamine levels may cause depressive symptoms. Dopamine is also involved in sexual behavior. Rotigotine is a nonergolinic dopamine agonist. Fluoxetine, an antidepressant that acts as a selective serotonin (5-HT) reuptake inhibitor, may cause moderate or severe sexual dysfunction. This study aims to investigate the effects of rotigotine-loaded microspheres (RoMS) and rotigotine on fluoxetine-induced impairment of sexual function and their efficacy in depression-model rats. Rats with depressive-like behavior, induced by bilateral olfactory bulbectomy, were treated intragastrically with fluoxetine and co-administered RoMS or rotigotine subcutaneously. Then, copulatory behavior and open field tests were conducted. Serum luteinizing hormone and testosterone levels were assayed with enzyme-linked immunosorbent assay kits. The concentrations of 5-HT, dopamine, and norepinephrine were measured in the raphe nucleus and amygdala. The results showed that sexual function was decreased in olfactory bulbectomy rats and significantly deteriorated by fluoxetine. Co-administration of RoMS partly reversed the fluoxetine-induced impairment of sexual function, but rotigotine administration did not produce any improvement. Hyperactivity in olfactory bulbectomy rats was significantly attenuated by fluoxetine but was not influenced by co-administration of RoMS. Compared with the fluoxetine group, RoMS increased the testosterone, luteinizing hormone, dopamine, and norepinephrine levels. These findings indicated that RoMS improved the fluoxetine-induced impairment of sexual function and did not affect its antidepressant efficacy in depressive rats, which provides a potential treatment for patients with depression that can reduce the possibility of sexual dysfunction. Additionally, co-administration of fluoxetine with RoMS may be beneficial for Parkinson's disease patients with depression.
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Agonistas de Dopamina , Fluoxetina , Animales , Depresión , Humanos , Microesferas , Ratas , Tetrahidronaftalenos , TiofenosRESUMEN
Homologous recombination repair (HRR) is crucial for genomic stability of cancer cells and is an attractive target in cancer therapy. Holliday junction (HJ) is a four-way DNA intermediate that performs an essential role in homology-directed repair. However, few studies about regulatory mechanisms of HJs have been reported. In this study, to better understand the biological effects of HJs, VE-822 was identified as an effective DNA HJ stabilizer to promote the assembly of HJs both in vitro and in cells. This compound could inhibit the HRR level, activate DNA-PKCS to trigger DNA damage response (DDR) and induce telomeric DNA damage via stabilizing DNA HJs. Furthermore, VE-822 was demonstrated to sensitize the osteosarcoma cells to doxorubicin (Dox) by enhancing DNA damage and cellular apoptosis. This work thus reports one novel HJ stabilizer, and provide a potential anticancer strategy through the modulation of DNA HJs.
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Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , ADN/genética , Isoxazoles/farmacología , Osteosarcoma/tratamiento farmacológico , Pirazinas/farmacología , Recombinación Genética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , ADN/química , Doxorrubicina/uso terapéutico , Humanos , Osteosarcoma/metabolismoRESUMEN
Rotigotine-loaded microspheres (RoMS), a sustained-release formulation with a continuous release of rotigotine for more than 7 days in vivo, have been conducted a clinical trial for the treatment of Parkinson's disease (PD). Previous work from our laboratory showed that RoMS exerted an antinociceptive effect in rat models of inflammatory pain. The purpose of this study was to investigate the mechanisms of action underlying the antinociceptive effect of RoMS. A rat model of inflammatory pain was prepared by an intraplantar injection of carrageenan. The hot plate test and the Randall-Selitto test were used to evaluate the effect of domperidone (selective D2 receptor antagonist), D2D3 shRNA, and naloxone (nonselective opioid receptor antagonist) on RoMS-mediated antinociceptive efficacy. The expressions of D2 and D3 receptors in the striatum and periaqueductal gray were measured by Western blotting. Intracerebroventricular injection of domperidone abated the antinociceptive effect of RoMS. However, intraperitoneal injection of domperidone had no significant effect on the antinociceptive action of RoMS. Intracerebroventricular injection with D2D3 shRNA significantly attenuated the expressions of D2 and D3 receptors in the striatum and the periaqueductal gray. D2 and D3 receptors silence significantly weakened RoMS-mediated antinociceptive effect. Intracerebroventricular injection of naloxone also alleviated the antinociceptive effect of RoMS. The results suggest that RoMS-mediated antinociceptive efficacy is associated with activating central dopamine D2 and D3 receptors. Opioid receptors play a role in the antinociceptive effect of RoMS.
Asunto(s)
Analgésicos/farmacología , Dopaminérgicos/farmacología , Dopamina/metabolismo , Microesferas , Dolor/tratamiento farmacológico , Tetrahidronaftalenos/farmacología , Tiofenos/farmacología , Analgésicos/administración & dosificación , Animales , Carragenina/toxicidad , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Domperidona/administración & dosificación , Domperidona/farmacología , Dopaminérgicos/administración & dosificación , Antagonistas de los Receptores de Dopamina D2/administración & dosificación , Antagonistas de los Receptores de Dopamina D2/farmacología , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inyecciones , Masculino , Naloxona/administración & dosificación , Naloxona/farmacología , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/farmacología , Dolor/etiología , Sustancia Gris Periacueductal/metabolismo , Ratas Sprague-Dawley , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Estrés Mecánico , Temperatura , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificaciónRESUMEN
The pathological of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute liver injury is similar to what is seen clinically, and be mediated by the release of pro-inflammatory mediators. A growing body of studies have shown that dopamine (DA) and DA receptor agonist are associated with inflammation and immune response. Rotigotine, a non-ergoline dopamine receptor agonist, is a drug for the treatment of Parkinson's disease. Rotigotine-loaded microspheres (RoMS) is an intramuscular extended-release agent, which can steadily release rotigotine for more than 7 days after a single administration. The present study aimed to investigate the effects of rotigotine and RoMS on inflammation and acute liver injury induced by LPS/D-Gal in mice. The LPS/D-Gal-induced liver injury was evidenced by increases of serum aminotransferases activities and liver histological lesions. Pretreatment with rotigotine or RoMS not only ameliorated the liver histologic lesions, but also reduced the activities of serum aminotransferases and the production of TNF-α. It also showed that rotigotine and RoMS increased DA receptor 2 (DRD2) expression in LPS/D-Gal-exposed mice. Rotigotine and RoMS activated ß-arrestin 2, inhibited the phosphorylation of Akt, IκB and the transposition of NF-κB. In line with the above findings, the protective effects of rotigotine and RoMS were abrogated by haloperidol, a DA receptor antagonist. In conclusion, dopamine receptor agonist can regulate NF-κB inflammatory signaling pathway and exert protective effects in LPS/D-Gal-induced liver injury.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Agonistas de Dopamina/administración & dosificación , Tetrahidronaftalenos/administración & dosificación , Tiofenos/administración & dosificación , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Galactosamina , Lipopolisacáridos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos BALB C , Microesferas , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Stroke is a common cause of death and disability. Allisartan isoproxil (ALL) is a new angiotensin II receptor blocker and a new antihypertensive drug discovered and developed in China. In the present study we investigated the therapeutic effects of ALL in stroke-prone renovascular hypertensive rats (RHR-SP) and the underlying mechanisms. The model rats were generated via two-kidney two-clip (2K2C) surgery, which led to 100% of hypertension, 100% of cerebrovascular damage as well as 100% of mortality 1 year after the surgery. Administration of ALL (30 mg · kg-1 · d-1 in diet, for 55 weeks) significantly decreased stroke-related death and prolonged lifespan in RHR-SP, but the survival ALL-treated RHR-SP remained of hypertension and cardiovascular hypertrophy compared with sham-operated normal controls. In addition to cardiac, and aortic protection, ALL treatment for 10 or 12 weeks significantly reduced cerebrovascular damage incidence and scoring, along with a steady reduction of blood pressure (BP) in RHR-SP. Meanwhile, it significantly decreased serum aldosterone and malondialdehyde levels and cerebral NAD(P)H oxidase expressions in RHR-SP. We conducted 24 h continuous BP recording in conscious freely moving RHR-SP, and found that a single intragastric administration of ALL produced a long hypotensive effect lasting for at least 12 h on systolic BP. Taken together, our results in RHR-SP demonstrate that ALL can be used for stroke prevention via BP reduction and organ protection, with the molecular mechanisms related to inhibition of angiotensin-aldosterone system and oxidative stress. This study also provides a valuable scoring for evaluation of cerebrovascular damage and drug efficacy.