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Drugs produce their therapeutic effects by modulating specific targets, and there are 89 innovative targets of first-in-class drugs approved in 2004-17, each with information about drug clinical trial dated back to 1984. Analysis of the clinical trial timelines of these targets may reveal the trial-speed differentiating features for facilitating target assessment. Here we present a comprehensive analysis of all these 89 targets, following the earlier studies for prospective prediction of clinical success of the targets of clinical trial drugs. Our analysis confirmed the literature-reported common druggability characteristics for clinical success of these innovative targets, exposed trial-speed differentiating features associated to the on-target and off-target collateral effects in humans and further revealed a simple rule for identifying the speedy human targets through clinical trials (from the earliest phase I to the 1st drug approval within 8 years). This simple rule correctly identified 75.0% of the 28 speedy human targets and only unexpectedly misclassified 13.2% of 53 non-speedy human targets. Certain extraordinary circumstances were also discovered to likely contribute to the misclassification of some human targets by this simple rule. Investigation and knowledge of trial-speed differentiating features enable prioritized drug discovery and development.
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Ensayos Clínicos como Asunto , Aprobación de Drogas , Descubrimiento de Drogas , Humanos , Estudios de Tiempo y MovimientoRESUMEN
Androgen receptor (AR), a ligand-activated transcription factor, is a master regulator in the development and progress of prostate cancer (PCa). A major challenge for the clinically used AR antagonists is the rapid emergence of resistance induced by the mutations at AR ligand binding domain (LBD), and therefore the discovery of novel anti-AR therapeutics that can combat mutation-induced resistance is quite demanding. Therein, blocking the interaction between AR and DNA represents an innovative strategy. However, the hits confirmed targeting on it so far are all structurally based on a sole chemical scaffold. In this study, an integrated docking-based virtual screening (VS) strategy based on the crystal structure of the DNA binding domain (DBD) of AR was conducted to search for novel AR antagonists with new scaffolds and 2-(2-butyl-1,3-dioxoisoindoline-5-carboxamido)-4,5-dimethoxybenzoicacid (Cpd39) was identified as a potential hit, which was competent to block the binding of AR DBD to DNA and showed decent potency against AR transcriptional activity. Furthermore, Cpd39 was safe and capable of effectively inhibiting the proliferation of PCa cell lines (i.e., LNCaP, PC3, DU145, and 22RV1) and reducing the expression of the genes regulated by not only the full-length AR but also the splice variant AR-V7. The novel AR DBD-ARE blocker Cpd39 could serve as a starting point for the development of new therapeutics for castration-resistant PCa.
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Antagonistas de Receptores Androgénicos/farmacología , ADN/antagonistas & inhibidores , Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/química , Sitios de Unión/efectos de los fármacos , ADN/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Receptores Androgénicos/química , Relación Estructura-ActividadRESUMEN
Synthetic glucocorticoids (GCs) have been widely used in the treatment of a broad range of inflammatory diseases, but their clinic use is limited by undesired side effects such as metabolic disorders, osteoporosis, skin and muscle atrophies, mood disorders and hypothalamic-pituitary-adrenal (HPA) axis suppression. Selective glucocorticoid receptor modulators (SGRMs) are expected to have promising anti-inflammatory efficacy but with fewer side effects caused by GCs. Here, we reported HT-15, a prospective SGRM discovered by structure-based virtual screening (VS) and bioassays. HT-15 can selectively act on the NF-κB/AP1-mediated transrepression function of glucocorticoid receptor (GR) and repress the expression of pro-inflammation cytokines (i.e., IL-1ß, IL-6, COX-2, and CCL-2) as effectively as dexamethasone (Dex). Compared with Dex, HT-15 shows less transactivation potency that is associated with the main adverse effects of synthetic GCs, and no cross activities with other nuclear receptors. Furthermore, HT-15 exhibits very weak inhibition on the ratio of OPG/RANKL. Therefore, it may reduce the side effects induced by normal GCs. The bioactive compound HT-15 can serve as a starting point for the development of novel therapeutics for high dose or long-term anti-inflammatory treatment.
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Glucocorticoides , Receptores de Glucocorticoides , Antiinflamatorios/farmacología , Bioensayo , Glucocorticoides/farmacología , Estudios Prospectivos , Receptores de Glucocorticoides/metabolismoRESUMEN
Long non-coding RNAs have important roles in the occurrence and progression of various cancers. However, the molecular mechanism of lncRNAs in colorectal cancer (CRC) is not well illustrated. Thus, we used bioinformatics methods to find potential lncRNAs associated with CRC progression, and chose SH3PXD2A-AS1 as a candidate for further analysis. The roles of SH3PXD2A-AS1 in CRC cells were determined by CCK-8, transwell invasion, wound healing and flow cytometry assays. Besides, we established the CRC tumor models in nude mice to study the effect of SH3PXD2A-AS1 on the tumor growth. Based on the ceRNA hypothesis, we used miRDB and miRTarBase websites to identify the SH3PXD2A-AS1-related ceRNA regulatory network, and measured the roles of this network in CRC cells. The results revealed that the expression profiles of SH3PXD2A-AS1 from GEO and TCGA databases showed an aberrant high level in CRC tissues compared with colorectal normal tissues. SH3PXD2A-AS1 over-expression was also found in CRC cells. SH3PXD2A-AS1 knockdown inhibited the CRC cellular proliferation, invasion and migration but induced apoptosis. Besides, SH3PXD2A-AS1 knockdown also suppressed the growth of CRC tumors. Furthermore, SH3PXD2A-AS1 could function as a ceRNA of miR-330-5p. Additionally, UBA2 was proved to be a target gene of miR-330-5p. Moreover, SH3PXD2A-AS1 knockdown downregulated UBA2 expression through sponging miR-330-5p to inactivate the Wnt/ß-catenin signaling pathway, thereby inhibiting the cell growth and promoting apoptosis. Therefore, the SH3PXD2A-AS1/miR-330-5p/UBA2 network could regulate the progression of CRC through the Wnt/ß-catenin pathway. These findings offer new sights for understanding the pathogenesis of CRC and provide potential biomarkers for CRC treatment.
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Neoplasias Colorrectales , MicroARNs , ARN Largo no Codificante , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Ratones , Ratones Desnudos , MicroARNs/genética , ARN Largo no Codificante/genética , Vía de Señalización WntRESUMEN
BACKGROUND: Our previous study reports the causal role of high mobility group box 1 (HMGB1) in the development of depression; and we find glycyrrhizic acid (GZA) can be a potential treatment for major depressive disorder (MDD) considering its inhibition of HMGB1 activity. This study aims to further explore the exact cell types that release HMGB1 in the hippocampus. METHODS: We detected the effects of microglia conditioned medium on primary astrocytes and neurons. The effects of minocycline on depressive-like behaviors were tested in BABLB/c mice after four weeks of chronic unpredictable mild stress (CUMS) exposure. Furthermore, the immunofluorescence (IF) assays, hematoxylin-eosin (HE) and TUNEL staining were used to observe hippocampal slices to evaluate the release of HMGB1. The cytoplasmic translocations of HMGB1 protein were assayed by western-blot. RESULTS: Exposure to CUMS caused an active release of HMGB1 from microglia and neurons in the hippocampus. After minocycline administration for inhibiting the activation of microglia, both microglia and neurons reduced the release of HMGB1 and the protein level of central and peripheral HMGB1 recovered accordingly. Along with blocking the release of HMGB1, behavioral and cognitive deficits induced by CUMS were improved significantly by minocycline. In addition, the supernatant of primary microglia stimulated the secretion of HMGB1 in primary neurons, not in astrocytes, at 24 h after 4 h-LPS treatment. CONCLUSION: All the evidence supported our hypotheses that microglia and neurons are the main cell sources of HMGB1 release under CUMS condition, and that the release of HMGB1 by microglia may play an important role in the development of depressive-like behavior.
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Trastorno Depresivo Mayor , Proteína HMGB1 , Animales , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Proteína HMGB1/metabolismo , Hipocampo/metabolismo , Ratones , Microglía/metabolismo , Minociclina/farmacología , Neuronas/metabolismo , Estrés PsicológicoRESUMEN
This study aimed to investigate the effect of butyl alcohol extract of Baitouweng Decoction( BAEB) on Candida albicans biofilms based on pH signal pathway. The morphology of biofilms of the pH mutants was observed by scanning electron microscope. The biofilm thickness of the pH mutants was measured by CLSM. The biofilm activity of the pH mutants was analyzed by microplate reader.The biofilm damage of the pH mutants was detected by flow cytometry. The expression of pH mutant biofilm-related genes was detected by qRT-PCR. The results showed that the deletion of PHR1 gene resulted in the defect of biofilm,but there were more substrates for PHR1 complementation. BAEB had no significant effect on the two strains. RIM101 gene deletion or complementation did not cause significant structural damage,but after BAEB treatment,the biofilms of both strains were significantly inhibited. For the biofilm thickness,PHR1 deletion or complementation caused the thickness to decrease,after BAEB treatment,the thickness of the two strains did not change significantly. However,RIM101 gene deletion or complementation had little effect on the thickness,and the thickness of the two strains became thinner after adding BAEB. For biofilm activity,PHR1 deletion or complementation and RIM101 deletion resulted in decreased activity,RIM101 complementation did not change significantly; BAEB significantly inhibited biofilm activity of PHR1 deletion,PHR1 complemetation,RIM101 deletion and RIM101 complemetation strains. For the biofilm damage,PHR1 gene deletion or complementation,RIM101 gene deletion or complementation all showed different degrees of damage; after adding BAEB,the damage rate of PHR1 deletion or complementation was not significantly different,but the damage rate of RIM101 deletion or complementation was significantly increased. Except to the up-regulation of HSP90 gene expression,ALS3,SUN41,HWP1,UME6 and PGA10 genes of PHR1 deletion,PHR1 complementation,RIM101 deletion,and RIM101 complementation strains showed a downward expression trend. In a word,this study showed that mutations in PHR1 and RIM101 genes in the pH signaling pathway could enhance the sensitivity of the strains to the antifungal drug BAEB,thus inhibiting the biofilm formation and related genes expression in C. albicans.
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Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Extractos Vegetales/farmacología , Transducción de Señal , 1-Butanol , Proteínas Fúngicas , Regulación Fúngica de la Expresión Génica , Concentración de Iones de HidrógenoRESUMEN
Emerging rechargeable sodium-ion storage systems-sodium-ion and room-temperature sodium-sulfur (RT-NaS) batteries-are gaining extensive research interest as low-cost options for large-scale energy-storage applications. Owing to their abundance, easy accessibility, and unique physical and chemical properties, sulfur-based materials, in particular metal sulfides (MSx ) and elemental sulfur (S), are currently regarded as promising electrode candidates for Na-storage technologies with high capacity and excellent redox reversibility based on multielectron conversion reactions. Here, we present current understanding of Na-storage mechanisms of the S-based electrode materials. Recent progress and strategies for improving electronic conductivity and tolerating volume variations of the MSx anodes in Na-ion batteries are reviewed. In addition, current advances on S cathodes in RT-NaS batteries are presented. We outline a novel emerging concept of integrating MSx electrocatalysts into conventional carbonaceous matrices as effective polarized S hosts in RT-NaS batteries as well. This comprehensive progress report could provide guidance for research toward the development of S-based materials for the future Na-storage techniques.
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BACKGROUND: Depression is one of the most common mental disorders characterized mainly by low mood and loss of interest or pleasure. About a third of patients with depression do not respond to classic antidepressant treatments. Recent evidence suggests that Mrp8/14 (myeloid-related protein 8/14) plays a crucial role in cognitive dysfunction and neuroinflammatory diseases, yet its role in mood regulation remains largely uninvestigated. In the present work, we explored the potential role of Mrp8/14 in the progression of depression. METHODS: After 4 weeks of chronic unpredictable mild stress (CUMS), depressive-like symptoms and Mrp8/14 were determined. To verify the effects of Mrp8/14 on depressive-like behaviors, the inhibitor TAK-242 and recombinant Mrp8/14 were used. Furthermore, the molecular mechanisms in Mrp8/14-induced behavioral and biological changes were examined in vivo and ex vivo. RESULTS: Four-week CUMS contributed to the development of depressive symptoms. Mrp8 and Mrp14 were upregulated in the hippocampus and serum after exposure to CUMS. Pharmacological inhibition of Mrp14 attenuated CUMS-induced TLR4/NF-κB signaling activation and depressive-like behaviors. Furthermore, central administration of recombinant Mrp8, Mrp14, and Mrp8/14 resulted in neuroinflammation and depressive-like behaviors. Mrp8/14-provoked proinflammatory effects and depressive-like behaviors were improved by pretreatment with a TLR4 inhibitor. Moreover, pharmacological inhibition of TLR4 reduced the release of nitric oxide and reactive oxygen species in Mrp8/14-activated BV2 microglia. CONCLUSIONS: These data suggest that the hippocampal Mrp8/14-TLR4-mediated neuroinflammation contributes to the development of depressive-like behaviors. Targeting the Mrp8/14 may be a novel promising antidepressant approach.
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Calgranulina A/metabolismo , Calgranulina B/metabolismo , Depresión/patología , Regulación de la Expresión Génica/fisiología , Hipocampo/metabolismo , Animales , Calgranulina A/antagonistas & inhibidores , Línea Celular Transformada , Citocinas/metabolismo , Depresión/tratamiento farmacológico , Depresión/etiología , Modelos Animales de Enfermedad , Preferencias Alimentarias/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inmunosupresores/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Microglía/efectos de los fármacos , Microglía/metabolismo , Quinolinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estrés Psicológico/complicaciones , Sacarosa/administración & dosificación , Sulfonamidas/farmacologíaRESUMEN
Our previous study has reported that the proactive secretion and role of central high mobility group box 1 (HMGB1) in lipopolysaccharide-induced depressive behavior. Here, the potential mechanism of HMGB1 mediating chronic-stress-induced depression through the kynurenine pathway (KP) was further explored both in vivo and in vitro. Depression model was established with the 4-week chronic unpredictable mild stress (CUMS). Sucrose preference and Barnes maze test were performed to reflect depressive behaviors. The ratio of kynurenine (KYN)/tryptophan (Trp) represented the enzyme activity of indoleamine-2,3-dioxygenase (IDO). Gene transcription and protein expression were assayed by real-time RT-PCR and western-blot or ELISA kit respectively. Along with depressive behaviors, HMGB1 concentrations in the hippocampus and serum substantially increased post 4-week CUMS exposure. Concurrent with the upregulated HMGB1 protein, the regulator of translocation of HMGB1, sirtuin 1 (SIRT1) concentration in the hippocampus remarkably increased. In addition to HMGB1 and SIRT1, IDO, the rate limiting enzyme of KP, was upregulated at the level of mRNA expression and enzyme activity in stressed hippocampi and LPS/HMGB1-treated hippocampal slices. The gene transcription of kynurenine monooxygenase (KMO) and kynureninase (KYNU) in the downstream of KP also increased both in vivo and in vitro. Mice treated with ethyl pyruvate (EP), the inhibitor of HMGB1 releasing, were observed with lower tendency of developing depressive behaviors and reduced activation of enzymes in KP. All of these experiments demonstrate that the role of HMGB1 on the induction of depressive behavior is mediated by KP activation.
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Depresión/metabolismo , Proteína HMGB1/metabolismo , Animales , Depresión/fisiopatología , Trastorno Depresivo/metabolismo , Proteína HMGB1/fisiología , Hipocampo/metabolismo , Hidrolasas/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/genética , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Actividad Motora , Piruvatos/farmacología , Sirtuina 1/metabolismo , Estrés Psicológico/metabolismo , Triptófano/metabolismoRESUMEN
BACKGROUND: Abundant reports indicated that depression was often comorbid with type 2 diabetes and even metabolic syndrome. Considering they might share common biological origins, it was tentatively attributed to the chronic cytokine-mediated inflammatory response which was induced by dysregulation of HPA axis and overactivation of innate immunity. However, the exact mechanisms remain obscure. Herein, we mainly focused on the function of the NLRP3 inflammasome to investigate this issue. METHODS: Male C57BL/6 mice were subjected to 12 weeks of chronic unpredictable mild stress (CUMS), some of which were injected with glyburide or fluoxetine. After CUMS procedure, behavioral and metabolic tests were carried out. In order to evaluate the systemic inflammation associated with inflammasome activation, IL-1ß and inflammasome components in hippocampi and pancreases, as well as corticosterone and IL-1ß in serum were detected separately. Moreover, immunostaining was performed to assess morphologic characteristics of pancreases. RESULTS: In the present study, we found that 12 weeks' chronic stress resulted in depressive-like behavior comorbid with insulin resistance. Furthermore, antidiabetic drug glyburide, an inhibitor of the NLRP3 inflammasome, was discovered to be effective in preventing the experimental comorbidity. In brief, it improved behavioral performance, ameliorated insulin intolerance as well as insulin signaling in the hippocampus possibly through inhibiting NLRP3 inflammasome activation by suppressing the expression of TXNIP. CONCLUSIONS: All these evidence supported our hypothesis that chronic stress led to comorbidity of depressive-like behavior and insulin resistance via long-term mild inflammation. More importantly, based on the beneficial effects of blocking the activation of the NLRP3 inflammasome, we provided a potential therapeutic target for clinical comorbidity and a new strategy for management of both diabetes and depression.
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Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/metabolismo , Gliburida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina/fisiología , Animales , Comorbilidad , Trastorno Depresivo/psicología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
High mobility group box 1 (HMGB1) has been implicated as a key factor in several neuroinflammatory conditions. Our previous study suggested that the release of central HMGB1 acts as a late-phase mediator in lipopolysaccharide (LPS)-induced depression. Recent findings indicate that the redox state of HMGB1 is a critical determinant of its immunomodulatory properties. Here, we aimed to investigate the potential mechanisms that link the redox states of HMGB1 to depression in mice. Distinct redox forms of recombinant HMGB1 (rHMGB1) were used that included fully reduced HMGB (fr-HMGB1), which acted as a chemokine, and disulfide-HMGB1 (ds-HMGB1), which possessed cytokine activity. Fr-HMGB1 in vivo was partially oxidized into ds-HMGB1; thus, the mutant protein non-oxidizable chemokine-HMGB (nonoxid-HMGB1) was applied. Concurrent with depressive behavior induced by four-week stress exposure, the HMGB1 concentrations in the serum and cerebral cortex substantially increased. Therefore, a single dose of rHMGB1 (200ng/5µl/mice) or vehicle was administered to mice via intracerebroventricular (i.c.v.) injection. The receptor inhibitors of TLR4/RAGE/CXCR4 (TAK-242/FPS-ZM1/AMD3100) (3mg/kg) were intraperitoneally injected 30min prior to rHMGB1 treatment. Depressive-like behavior was measured 20h post i.c.v. injection. Administration of fr-HMGB1 prolonged the immobility duration in the tail suspension test (TST) and decreased sucrose preference. In addition to depressive behavior, the hippocampal TNF-α protein slightly increased. These depressive behaviors and upregulation of hippocampal TNF-α were alleviated or abrogated by pretreatment with the inhibitors AMD3100, FPS-ZM1, and TAK-242. Alternatively, nonoxid-HMGB1 failed to induce TNF-α protein or prolong the immobility duration. As expected, ds-HMGB1 administration substantially upregulated hippocampal TNF-α protein, increased the immobility time in the TST and decreased sucrose preference. Moreover, both glycyrrhizin and TAK-242 improved ds-HMGB1-induced depressive behavior. Furthermore, TAK-242 significantly blocked the upregulation of hippocampal TNF-α protein and protected hippocampal myelin basic protein from ds-HMGB1-induced reduction. These drugs had no effect on the total or central distance in the open field test. Collectively, this initial experiment demonstrates the role and receptor mechanisms of HMGB1 under different redox states on the induction of depressive-like behavior. Both ds-HMGB1 and fr-HMGB1 may induce depressive-like behavior in vivo mainly via neuroinflammatory response activation.
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Depresión/inducido químicamente , Depresión/psicología , Proteína HMGB1/genética , Proteína HMGB1/farmacología , Inflamación/inducido químicamente , Inflamación/psicología , Anhedonia , Animales , Proteína HMGB1/química , Suspensión Trasera , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos BALB C , Actividad Motora , Oxidación-Reducción , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Estrés Psicológico/psicología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
To explore the activity of essential oil extracted from Artemisia argyi (AAEO) in inducing the apoptosis of Candida albicans SC5314. The effect of AAEO on reactive oxygen species(ROS) and mitochondria membrane potential(MMP) of C. albicans SC5314 was detected by flow cytometry. Phosphatidylserine externalization was observed under fluorescence microscopic with Annexin-V/PI staining at the early stage of apoptosis in C. albicans. Metacaspase activity was observed under fluorescence microscopic with FITC-VAD-FMK staining at the early stage of apoptosis in C. albicans. C. albicans morphology was observed by DAPI nuclear staining and fluorescence microscopy. After intervention with 0.5 mLâ¢L⻹ AAEO, apoptosis of C. albicans significantly increased, metacaspase activity increased, nuclear pyknosis and fragmentation, and intracellular ROS were significantly increased, and mitochondrial membrane potential decreased significantly. The certain concentrations of AAEO could induce the apoptosis of C. albicans.
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Apoptosis , Artemisia/química , Candida albicans/efectos de los fármacos , Aceites Volátiles/farmacología , Aceites de Plantas/farmacología , Antifúngicos/farmacología , Potencial de la Membrana Mitocondrial , Fosfatidilserinas/análisis , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Evidence from both clinical and experimental research indicates that the immune-brain interaction plays a pivotal role in the pathophysiology of depression. A multi-protein complex of the innate immune system, the NLRP3 inflammasome regulates cleavage and secretion of proinflammatory cytokine interleukin-1ß. The inflammasome detects various pathogen-associated molecule patterns and damage-associated molecule patterns, which then leads to a series of immune-inflammatory reactions. METHODS: To explore the role of inflammasome activation in the underlying biological mechanisms of depression, we established a mouse model of depression with unpredictable chronic mild stress. RESULTS: Mice subjected to chronic mild stress for 4 weeks had significantly higher serum corticosterone levels, serum interleukin-1ß levels, and hippocampal active interleukin-1ß protein levels. They also displayed depressive-like symptoms, including decreased sucrose preference and increased immobility time. Moreover, the hippocampi of chronic mild stress-exposed mice had significantly higher activity of caspase-1, which accompanied by higher protein levels of NLRP3 and the apoptotic speck-containing protein with a card. Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreased serum and hippocampal levels of interleukin-1ß protein and significantly moderated the depressive-like behaviors induced by chronic mild stress. CONCLUSIONS: These data suggest the NLRP3 inflammasome mediates stress-induced depression via immune activation. Future procedures targeting the NLRP3 inflammasome may have promising effects in the prevention and treatment of depression.
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Proteínas Portadoras/metabolismo , Trastorno Depresivo/fisiopatología , Inflamación/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Antiinflamatorios no Esteroideos/farmacología , Antidepresivos/farmacología , Caspasa 1/metabolismo , Enfermedad Crónica , Corticosterona/sangre , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/etiología , Sacarosa en la Dieta , Dipéptidos/farmacología , Modelos Animales de Enfermedad , Preferencias Alimentarias/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Inflamación/tratamiento farmacológico , Inflamación/etiología , Interleucina-1beta/metabolismo , Masculino , Ratones Endogámicos BALB C , Actividad Motora/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , Distribución Aleatoria , Estrés Psicológico/complicaciones , Estrés Psicológico/tratamiento farmacológico , Incertidumbre , para-Aminobenzoatos/farmacologíaRESUMEN
Quantitative characterization of skin collagen on photo-thermal response and its regeneration process is an important but difficult task. In this study, morphology and spectrum characteristics of collagen during photo-thermal response and its light-induced remodeling process were obtained by second-harmonic generation microscope in vivo. The texture feature of collagen orientation index and fractal dimension was extracted by image processing. The aim of this study is to detect the information hidden in skin texture during the process of photo-thermal response and its regeneration. The quantitative relations between injured collagen and texture feature were established for further analysis of the injured characteristics. Our results show that it is feasible to determine the main impacts of phototherapy on the skin. It is important to understand the process of collagen remodeling after photo-thermal injuries from texture feature.
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Microscopía/métodos , Fototerapia/métodos , Regeneración , Piel/lesiones , Animales , Colágeno/química , Colágeno/metabolismo , Colágeno/ultraestructura , Análisis de Fourier , Fractales , Interpretación de Imagen Asistida por Computador , Ratones , Microscopía/estadística & datos numéricos , Regeneración/fisiología , Piel/patología , Piel/fisiopatologíaRESUMEN
Oviductal smooth muscle exhibits spontaneous rhythmic contraction (SRC) and controls the passage of the ova at the exact time, but its mechanistic regulation remains to be determined. In this study, female mice with Ano1SMKO (smooth muscle-specific deletion of Ano1) had reduced fertility. Deficiency of Ano1 in mice resulted in impaired oviductal SRC function and reduced calcium signaling in individual smooth muscle cells in the oviduct. The Ano1 antagonist T16Ainh-A01 dose-dependently inhibited SRCs and [Ca2+]i in the oviducts of humans and mice. A similar inhibitory effect of SRCs and [Ca2+]i was observed after treatment with nifedipine. In our study, ANO1 acted primarily as an activator or amplifier in [Ca2+]i and contraction of tubal smooth muscle cells. We found that tubal SRC was markedly attenuated in patients with ectopic pregnancy. Then, our study was designed to determine whether chloride channel Ano1-mediated smooth muscle motility is associated with tubal SRC. Our findings reveal a new mechanism for the regulation of tubal motility that may be associated with abnormal pregnancies such as ectopic pregnancies.
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Calcio , Músculo Liso , Animales , Femenino , Humanos , Ratones , Embarazo , Calcio/metabolismo , Canales de Cloruro/genética , Canales de Cloruro/metabolismo , Músculo Liso/metabolismo , Miocitos del Músculo Liso/metabolismo , Oviductos/metabolismoRESUMEN
Samples of ambient volatile organic compounds ï¼VOCsï¼ were collected using SUMMA canisters at three Country Control Sites in Shijiazhuang during the spring of 2019, 2021, and 2022, which were detected using gas chromatography/mass spectrometry ï¼GC/MSï¼. To investigate the characteristics and temporal variations of VOCs mass concentration levels, the online monitoring data of ozone ï¼O3ï¼ and PM2.5 at the same site were also collected. Subsequently, the ozone formation potential ï¼OFPï¼ and secondary organic aerosol formation potential ï¼SOAFPï¼ were utilized to assess the chemical activity of VOCs. Additionally, the potential source areas of VOCs in spring in Shijiazhuang were further identified using the potential source contribution factor ï¼PSCFï¼ method and concentration weight trajectory analysis ï¼CWTï¼. Hence, the major VOCs sources were evaluated with the VOCs initial mixing ratio. The results demonstrated that the averaged concentration of VOCs during the polluted period and clean period of spring in Shijiazhuang were 191.17 µg·m-3 and 122.18 µg·m-3, respectively. Meanwhile, the OFP was 361.23 µg·m-3 during the polluted period and 266.96 µg·m-3 during the clean period, whereas the SOAFP was 1.98 µg·m-3 and 1.61 µg·m-3, respectively. Therefore, effective control of benzene, toluene, ethylbenzene, and xylene ï¼BTEXï¼ is crucial for reducing PM2.5 and O3 pollution. Based on the results obtained from weight PSCF and CWT, the potential source areas of VOCs were further identified to be primarily located in the eastern Yuhua District, the high-tech district, and the northern Luancheng District of Shijiazhuang. These areas were influenced not only by local emissions but also by transport from neighboring regions, in which consistency between the CWT and PSCF results further supported these findings. Furthermore, the results obtained from the benzene/toluene/ethylbenzene ï¼B/T/Eï¼ and xylene/benzene ï¼X/Bï¼ ratios indicated that the main sources of VOCs in Shijiazhuang in spring were vehicle exhaust sources and burning sources, leading to a more serious air mass aging phenomenon. Hence, controlling vehicle emissions and implementing regional cooperative measures are the effective strategies for optimizing the air quality of Shijiazhuang.
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BACKGROUND: Currently, there is no consensus on the recommendation of peginterferon alfa (pegIFNα) to chronic hepatitis B (CHB) patients with poor viral response (EVR). This study aimed to assess the sustained curative efficacy of adefovir (ADV) add-on therapy in optimizing pegIFNα monotherapy. METHODS: A total of 85 hepatitis B e antigen (HBeAg)-positive CHB patients with poor virological response at month 6 after starting pegIFNα-2a were enrolled, and received either pegIFNα-2a continuing monotherapy (group A, n = 51) or add-on therapy with ADV (group B, n = 34). The treatment duration for all patients was 6 months, and the sustained responses after the end of treatment were evaluated between two groups. RESULTS: The baseline characteristics were comparable between two groups. At months 6 after treatment completion, the sustained virological response (SVR) rates were 31.4% and 73.5%, the sustained biochemical response (SBR) rates were 39.2% and 85.3% in group A and group B respectively, and the difference in either SVR or SBR was statistically significant (both p < 0.001). As compared to patients in group A, significantly more patients in group B obtained HBeAg loss (19.6% vs. 55.9%, p = 0.001) and seroconversion (13.7% vs. 41.2%, p = 0.004). CONCLUSION: ADV add-on therapy could significantly improve and sustain the curative efficacy of CHB patient with poor virological response to pegIFNα-2a monotherapy, but further large well-designed randomized controlled trials are needed to confirm our findings.
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Adenina/análogos & derivados , Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Organofosfonatos/uso terapéutico , Polietilenglicoles/uso terapéutico , Adenina/uso terapéutico , Adulto , Biomarcadores/sangre , Esquema de Medicación , Quimioterapia Combinada , Femenino , Antígenos e de la Hepatitis B/sangre , Hepatitis B Crónica/sangre , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Carga ViralRESUMEN
Depression is a very common mental health problem in our modern society. Stress is involved in the provocation of depression. The pathogenesis of depressive disorder is still not well known. The development of neuroendocrine immunology opens a new sight for clarification of mechanism underlying stress-induced depression. Chronic stress activates peripheral and central immune systems accompanied with the release of inflammatory mediators, including cytokines. Activated immune system mediates the process of depression through the interaction with neuron system and neuroendocrine system, including regulating the monoamine neurotransmitter system in synthesis, metabolism and reuptake, inducing the overactivation of hypothalamus-pituitary-adrenal (HPA) axis and its negative feedback regulation, and reducing neurogenesis. This present paper reviews the cytokines mechanisms underlying stress-induced depression.
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Citocinas/inmunología , Depresión/inmunología , Sistema Inmunológico , Estrés Psicológico/inmunología , Humanos , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-SuprarrenalRESUMEN
Depression is a prevalent psychiatric disorder with elusive pathogenesis. Studies have proposed that enhancement and persistence of aseptic inflammation in the central nervous system (CNS) may be closely associated with the development of depressive disorder. High mobility group box 1 (HMGB1) has obtained significant attention as an evoking and regulating factor in various inflammation-related diseases. It is a non-histone DNA-binding protein that can be released as a pro-inflammatory cytokine by glial cells and neurons in the CNS. Microglia, as the immune cell of the brain, interacts with HMGB1 and induces neuroinflammation and neurodegeneration in the CNS. Therefore, in the current review, we aim to investigate the role of microglial HMGB1 in the pathogenetic process of depression.
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Drought intensity and frequency have been increased as a result of global warming. Exploring the drought resistance mechanism of Robinia pseudoacacia plantations of different stand ages on the Loess Plateau is crucial for understanding the stability of forest productivity in the region. We investigated anatomical traits, hydraulic function, and non-structural carbohydrate content of the xylem, as well as their association, in R. pseudoacacia plantations of different stand ages in a semi-arid region. The results showed that the vessel diameter, total pit membrane area, pit membrane area, vesture area, and vestured overlap of young and middle-aged stands were larger than those of mature stands, and the pit density was significantly lower in mature stands. Hydraulic conductivity was significantly related to vessel diameter, pit membrane area, and vesture area. Hydraulic conductivities of branches in young, middle-aged, and mature stands were 2.30, 2.12, and 0.76 kg·m-1·s-1·MPa-1, respectively, with embolism values of 54.5%, 53.8%, and 45.1%. Hydraulic conductivity was significantly related to soluble sugar and starch contents. The soluble sugar contents of branches in young, middle-aged and mature stands were 4.9%, 4.2%, and 3.8%, respectively. Xylem growth capacity of R. pseudoacacia in mature stand declined, resulting in the formation of small vessels with many small pits, which reduced hydraulic conductivity while maintaining hydraulic safety, resulting in a decrease of non-structural carbohydrates content. This study revealed the drought response mechanism of R. pseudoacacia plantations with different ages, providing a scientific foundation for the management and nurturing of R. pseudoacacia plantations on the Loess Plateau.