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Sleep loss robustly disrupts mood and emotion regulation in healthy individuals but can have a transient antidepressant effect in a subset of patients with depression. The neural mechanisms underlying this paradoxical effect remain unclear. Previous studies suggest that the amygdala and dorsal nexus (DN) play key roles in depressive mood regulation. Here, we used functional MRI to examine associations between amygdala- and DN-related resting-state connectivity alterations and mood changes after one night of total sleep deprivation (TSD) in both healthy adults and patients with major depressive disorder using strictly controlled in-laboratory studies. Behavioral data showed that TSD increased negative mood in healthy participants but reduced depressive symptoms in 43% of patients. Imaging data showed that TSD enhanced both amygdala- and DN-related connectivity in healthy participants. Moreover, enhanced amygdala connectivity to the anterior cingulate cortex (ACC) after TSD associated with better mood in healthy participants and antidepressant effects in depressed patients. These findings support the key role of the amygdala-cingulate circuit in mood regulation in both healthy and depressed populations and suggest that rapid antidepressant treatment may target the enhancement of amygdala-ACC connectivity.
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Transtorno Depressivo Maior , Adulto , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Privação do Sono/diagnóstico por imagem , Tonsila do Cerebelo/diagnóstico por imagem , Giro do Cíngulo/diagnóstico por imagem , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Imageamento por Ressonância Magnética/métodosRESUMO
In the face of rising global temperatures, the mechanisms behind an organism's ability to acclimate to heat stress remain enigmatic. The rice leaf folder, Cnaphalocrocis medinalis, traditionally viewed as temperature-sensitive, paradoxically exhibits robust larval acclimation to heat stress. This study used the heat-acclimated strain HA39, developed through multigenerational exposure to 39°C during the larval stage, and the unacclimated strain HA27 reared at 27°C to unravel the transgenerational effects of heat acclimation and its regulatory mechanisms. Heat acclimation for larvae incurred a fitness cost in pupae when exposed to high temperature, yet a significant transgenerational effect surfaced, revealing heightened fitness benefit in pupae from HA39, even without additional heat exposure during larval recovery at 27°C. This transgenerational effect exhibited a short-term memory, diminishing after two recovery generations. Moreover, the effect correlated with increased superoxide dismutase (SOD) enzyme activity and expression levels of oxidoreductase genes, representing physiological and molecular foundations of heat acclimation. Heat-acclimated larvae displayed elevated DNA methylation levels, while pupae from HA39, in recovery generations, exhibited decreased methylation indicated by the upregulation of a demethylase gene and downregulation of two methyltransferase genes at high temperatures. In summary, heat acclimation induces DNA methylation, orchestrating heat-stress memory and influencing the expression levels of oxidoreductase genes and SOD activity. Heat-stress memory enhances the acclimation of the migratory insect pest to global warming.
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Sleep loss impacts a broad range of brain and cognitive functions. However, how sleep deprivation affects risky decision-making remains inconclusive. This study used functional MRI to examine the impact of one night of total sleep deprivation (TSD) on risky decision-making behavior and the underlying brain responses in healthy adults. In this study, we analyzed data from N = 56 participants in a strictly controlled 5-day and 4-night in-laboratory study using a modified Balloon Analogue Risk Task. Participants completed two scan sessions in counter-balanced order, including one scan during rested wakefulness (RW) and another scan after one night of TSD. Results showed no differences in participants' risk-taking propensity and risk-induced activation between RW and TSD. However, participants showed significantly reduced neural activity in the anterior cingulate cortex and bilateral insula for loss outcomes, and in bilateral putamen for win outcomes during TSD compared with RW. Moreover, risk-induced activation in the insula negatively correlated with participants' risk-taking propensity during RW, while no such correlations were observed after TSD. These findings suggest that sleep loss may impact risky decision-making by attenuating neural responses to decision outcomes and impairing brain-behavior associations.
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Tomada de Decisões , Privação do Sono , Adulto , Humanos , Tomada de Decisões/fisiologia , Encéfalo , Cognição , Giro do Cíngulo , Imageamento por Ressonância Magnética , Assunção de RiscosRESUMO
Global warming is posing a threat to animals. As a large group of widely distributed poikilothermal animals, insects are liable to heat stress. How insects deal with heat stress is worth highlighting. Acclimation may improve the heat tolerance of insects, but the underlying mechanism remains vague. In this study, the high temperature of 39 °C was used to select the third instar larvae of the rice leaf folder Cnaphalocrocis medinalis, an important insect pest of rice, for successive generations to establish the heat-acclimated strain (HA39). The molecular mechanism of heat acclimation was explored using this strain. The HA39 larvae showed stronger tolerance to 43 °C than the unacclimated strain (HA27) persistently reared at 27 °C. The HA39 larvae upregulated a glucose dehydrogenase gene, CmGMC10, to decrease the reactive oxygen species (ROS) level and increase the survival rate under heat stress. The HA39 larvae maintained a higher activity of antioxidases than the HA27 when confronted with an exogenous oxidant. Heat acclimation decreased the H2O2 level in larvae under heat stress which was associated with the upregulation of CmGMC10. The rice leaf folder larvae may acclimate to global warming via upregulating CmGMC10 to increase the activity of antioxidases and alleviate the oxidative damage of heat stress.
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Aquecimento Global , Mariposas , Animais , Glucose Desidrogenase , Peróxido de Hidrogênio , Larva/fisiologia , Mariposas/fisiologia , Aclimatação , InsetosRESUMO
An imatinib controlled release film-forming system (FFS) was developed based on the drug ion-pair and newly designed oligomeric ionic liquids (OILs) for the topical therapy of cutaneous melanoma, which avoided the systemic side-effect of oral administration and maintained a long local therapy effect. The OILs significantly improved the drug release capacity about 1.5-fold, and the formability and stability of FFSs (verified by AFM/PLM). The in vivo anti-tumor efficacy studies in melanoma tumor bearing mice showed that compared with the oral capsules, the topical application of the optimized imatinib FFS significantly (p < 0.01) increased tumor inhibition rate (67.54 ± 2.72%) and the amount of apoptotic cells. As confirmed by FT-IR and NMR, the partial protonation of OILs were demonstrated to have high hydrogen bond forming capacity, thus showing low polarity and good biocompatibility. More importantly, based on 13C-NMR study, OILs demonstrated higher hydrogen bond forming capacity, and formed bridge between drug ion-pair (O-H of counter-ion) and PVA (O-H), increased the molecular mobility of PVA, thus maintaining a long drug release capacity. Therefore, an imatinib FFS was developed with good therapeutic effect and the effect of drug ion-pair and OILs on increasing the drug skin retention and controlled release of imatinib FFS for topical therapy was clarified at the molecular level, which provided a safe and effective way for the treatment of cutaneous melanoma.
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Líquidos Iônicos , Melanoma , Neoplasias Cutâneas , Camundongos , Animais , Mesilato de Imatinib , Neoplasias Cutâneas/tratamento farmacológico , Melanoma/tratamento farmacológico , Administração Cutânea , Preparações de Ação Retardada , Espectroscopia de Infravermelho com Transformada de Fourier , Pele , Óleos , Melanoma Maligno CutâneoRESUMO
This study aimed to prepare colchicine (CO), 4-hydroxyacetophenone (HA), and protocatechuic acid (CA) contained in transdermal rubber plasters into a more releasable and acrylate pressure-sensitive adhesive (PSA) to optimize traditional Touguling rubber plasters (TOU) with enhanced transdermal permeability by using deep eutectic solvents (DES) technology. We compared the difference in the release behavior of CO between rubber plaster and PSA, determined the composition of the patch through pharmacodynamic experiments, explored the transdermal behavior of the three components, optimized the patch formula factors, and improved the penetration of CO through the skin. We also focused on elucidating the interactions among the three components of DES and the intricate relationship between DES and the skin. The melting point of DES was determined using DSC, while FTIR, 13C NMR, and ATR-FTIR were used to explore the intricate molecular mechanisms underlying the formation of DES, as well as its enhancement of skin permeability. The results of this investigation confirmed the successful formation of DES, marked by a discernible melting point at 27.33°C. The optimized patch, formulated with a molar ratio of 1:1:1 for CO, HA, and CA, significantly enhanced skin permeability, with the measured skin permeation quantities being 32.26 ± 2.98 µg/cm2, 117.67 ± 7.73 µg/cm2, and 56.79 ± 1.30 µg/cm2 respectively. Remarkably, the optimized patch also demonstrated similar analgesic and anti-inflammatory effects compared to commercial diclofenac diethylamide patches in different pharmacodynamics studies. The formation of DES altered drug compatibility with skin lipids and increased retention, driven by the interaction among the three component molecules through hydrogen bonding, effectively shielding the skin-binding sites and enhancing component permeation. In summary, the study demonstrated that optimized DES patches can concurrently enhance the penetration of CO, HA, and CA, thereby providing a promising approach for the development of DES in transdermal drug delivery systems. The findings also shed light on the molecular mechanisms underlying the transdermal behavior of DES and offer insights for developing more effective traditional Chinese medicine transdermal drug delivery systems.
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Solventes Eutéticos Profundos , Absorção Cutânea , Colchicina/metabolismo , Colchicina/farmacologia , Borracha/metabolismo , Borracha/farmacologia , Administração Cutânea , Pele/metabolismo , Adesivo TransdérmicoRESUMO
Human risk tolerance is highly idiosyncratic and individuals often show distinctive preferences when faced with similar risky situations. However, the neural underpinnings of individual differences in risk-taking remain unclear. Here we combined structural and perfusion MRI and examined the associations between brain anatomy and individual risk-taking behavior/risk tolerance in a sample of 115 healthy participants during the Balloon Analogue Risk Task, a well-established sequential risky decision paradigm. Both whole brain and region-of-interest analyses showed that the left cerebellum gray matter volume (GMV) has a strong association with individual risk-taking behavior and risk tolerance, outperforming the previously reported associations with the amygdala and right posterior parietal cortex (PPC) GMV. Left cerebellum GMV also accounted for risk tolerance and risk-taking behavior changes with aging. However, regional cerebral blood flow (CBF) provided no additional predictive power. These findings suggest a novel cerebellar anatomical contribution to individual differences in risk tolerance. Further studies are necessary to elucidate the underestimated important role of cerebellum in risk-taking.
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Substância Cinzenta , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Substância Cinzenta/fisiologia , Humanos , Assunção de RiscosRESUMO
BACKGROUND AND AIM: Quality of life (QOL) for patients with chronic gastritis (CG) is of interest worldwide and disease-specific instruments are needed for clinical research and practice. This paper focused on the development and validation of the CG scale under the system of Quality of Life Instruments for Chronic Diseases (QLICD-CG) by the modular approach and both classical test theory and generalizability theory. METHODS: The QLICD-CG was developed based on programmed decision procedures including multiple nominal and focus group discussions, in-depth interviews and quantitative statistical procedures. Based on the data measuring QOL 3 times before and after treatments from 142 inpatients with CG, the psychometric properties of the scale were evaluated with respect to validity, reliability and responsiveness employing correlation analysis, multi-trait scaling analysis, factor analyses, t tests and also G studies and D studies of generalizability theory analysis. RESULTS: Correlation, multi-trait scaling and factor analyses confirmed good construct validity and criterion-related validity when using SF-36 as a criterion. The internal consistency α for all domains were higher than 0.70 except for the social domain (0.62). Test-retest reliability coefficients (Pearson r and intraclass correlations) for the overall score and all domains were higher than 0.80 except for the social domain (0.77), while they were ranging between 0.72 to 0.94 at facets level; The overall score and scores for all domains/facets had statistically significant changes (P<0.01) after treatments except for facets of social effects and sexual function with standardized response mean ranging from 0.04 to 1.03, but from 0.34 to 1.03 for the domain level scores. G-coefficients and index of dependability (Ф coefficients) confirmed the reliability of the scale further with more exact variance components, and decision information on number of items changing. CONCLUSIONS: The QLICD-CG could be used as a useful instrument in assessing QoL for patients with CG, with good psychometric properties including validity, reliability and responsiveness and also several advantages.
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Gastrite , Qualidade de Vida , Doença Crônica , Humanos , Psicometria/métodos , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Engineering a system with a high mass fraction of active ingredients, especially water-soluble proteins, is still an ongoing challenge. In this work, we developed a versatile surface camouflage strategy that can engineer systems with an ultrahigh mass fraction of proteins. By formulating protein molecules into nanoparticles, the demand of molecular modification was transformed into a surface camouflage of protein nanoparticles. Thanks to electrostatic attractions and van der Waals interactions, we camouflaged the surface of protein nanoparticles through the adsorption of carrier materials. The adsorption of carrier materials successfully inhibited the phase transfer of insulin, albumin, ß-lactoglobulin, and ovalbumin nanoparticles. As a result, the obtained microcomposites featured with a record of protein encapsulation efficiencies near 100% and a record of protein mass fraction of 77%. After the encapsulation in microcomposites, the insulin revealed a hypoglycemic effect for at least 14 d with one single injection, while that of insulin solution was only â¼4 h.
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Nanopartículas , Adsorção , Insulina , ProteínasRESUMO
Quality of life (QOL) in patients with Chronic obstructive pulmonary disease (COPD) is a major global concern in respiratory care with the specific instruments used rarely being developed using a modular approach. This paper is aimed to develop the COPD scale of the system of QOL Instruments for Chronic Diseases (QLICD-COPD) by the modular approach based on Classical Test Theory and Generalizability Theory (GT). 114 inpatients with COPD were used to provide the data measuring QOL three times before and after treatments. The psychometric properties of the scale were evaluated with respect to validity, reliability and responsiveness employing correlation analysis, factor analyses, multi-trait scaling analysis, and also GT analysis. The Results showed that Multi-trait scaling analysis, correlation and factor analyses confirmed good construct validity and criterion-related validity with almost all correlation coefficients or factor loadings being above 0.40. The internal consistency α and test-retest reliability coefficients (Pearson r and Intra-class correlations ICC) for all domains except for the social domain were larger than 0.70, ranging between 0.70-0.86 with r = 0.85 for the overall. The overall score and scores for physical and the specific domains had statistically significant changes after treatments with moderate effect size SRM (standardized response mean) ranging from 0.32 to 0.44. All G-coefficients and index of dependability were all greater than 0.80 exception of social domain (0.546 and 0.500 respectively), confirming the reliability of the scale further. It concluded that the QLICD-COPD has good validity, reliability, and moderate responsiveness, and can be used as the QOL instrument for patients with COPD.
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Doença Pulmonar Obstrutiva Crônica , Qualidade de Vida , Doença Crônica , Humanos , Psicometria/métodos , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
The present work was to construct a roflumilast (ROF) cream for the treatment of psoriasis and clarify the dual roles of propylene glycol monocaprylate (PGM) in both molecular mobility of the cream, and drug-skin miscibility via drug-PGM-ceramide and drug-PGM-collagen intermolecular interaction. The cream formulation was screened through the stability study and in vitro skin administration study, optimized by Plackett-Burman and Box-Behnken design, and finally verified by the in vivo tissue distribution study. PGM demonstrated a significant drug skin retention enhancement effect (Rmax in vivo = 19.5 µg/g). It increased the molecular mobility of the oil phase of the cream by decreasing the molecular interaction of oil molecules proven by the rheology study (Ec = 3.73 × 10-4 mJ·m-3). More importantly, because of the good stratum corneum (SC) compatibility (∆H = - 403.88 J/g), PGM promoted an orderly flow of SC lipids (X-ray scattering, ΔLPP = 1.18 nm) and entered the viable epidermis/dermis (VE/DE) in large quantities (RPGM = 1186 µg/g), acting as a bridge to connect the drug to collagen through two H-bonds (LengthH-bond = 2.846 Å and 3.313 Å), thus increasing the miscibility of drug and VE/DE significantly (∆H = - 310.10 J/g, Emix = 21.66 kcal/mol). In this study, a ROF cream was developed successfully and the effect of PGM on the skin retention was clarified at molecular level.
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Aminopiridinas , Pele , Aminopiridinas/farmacologia , Benzamidas , Colágeno/farmacologia , Ciclopropanos , Preparações Farmacêuticas , Propilenoglicol/química , Propilenoglicóis , Creme para a PeleRESUMO
The control of cargo phase-transfer is of interest for many applications in science and technology. Herein, we report a simple, versatile and robust method to block the phase-transfer of cargo colloids by interfacial self-assembled amphiphilic polymer molecules. After simply increasing the concentration of amphiphilic polymers, the orientation of interfacial polymer molecules changed from flat to upright, forming a thick three-dimensional polymer layer at the oil-water interface. Even under fierce external force, this thick interfacial layer robustly prevented the phase-transfer of cargo colloids, resulting in an ultrahigh encapsulation efficiency (up to 97.1 %) for proteins and peptides. One single injection of high insulin-loaded microcomposites (58.3â wt%) kept the blood glucose level within the normoglycemic state for 10â days in typeâ 1 diabetic rats. The mass of administrated amphiphilic polymers was 1889â times smaller than that of microcomposites prepared with non-amphiphilic ones.
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Diabetes Mellitus Experimental , Insulinas , Ratos , Animais , Polímeros/química , Glicemia , Diabetes Mellitus Experimental/tratamento farmacológico , Coloides/química , Água/químicaRESUMO
Though pharmaceutical polymers were widely used in inhibiting drug recrystallization via strong intermolecular hydrogen and ionic bonds, the improved drug stability was achieved at the cost of the drug release rate or amount in the drug-in-adhesive transdermal patch. To overcame the difficulty, this study aimed to increase drug loading utilizing a novel drug-ionic liquid (drug-IL) strategy and illustrate the underlying molecular mechanism. Here, naproxen (NPX) and triamylamine (TAA) were chosen as the model drug and corresponding counterion, respectively. In addiiton, carboxylic pressure-sensitive adhesive (PSA) was chosen as the model polymer. The drug-IL (NPX-TAA) was synthesized and characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and proton nuclear magnetic resonance. The miscibility between NPX-TAA and PSA was assessed using microscopy study, X-ray diffraction, fluorescence spectroscopy, and solubility parameter calculation. In addition, molecular mechanisms of crystallization inhibition were revealed by FT-IR, Raman spectroscopy, DSC, X-ray photoelectron spectroscopy (XPS), and molecular docking. Finally, the release pattern of the high load patch of NPX-TAA was evaluated using in vitro drug release and verified by a skin permeation experiment. The results showed that drug loading in PSA was increased by 5.0 times, which was caused by the synergistic effect of strong ionic hydrogen bonding (the decreased intensity and blue shift of the O-H peak of COOH in PSA) formed between NPX-TAA and PSA-COO- and normal hydrogen bonding (red shift of the CâO peak in PSA) formed between NPX-TAA and the carbonyl group of PSA. In addition, -NH+ of TAA was confirmed as the molecular basis of ionic hydrogen bonding through new peak appearance (binding energy: 400.0 eV) in XPS spectra. Moreover, high drug release percent (80.8 ± 1.8%) was achieved even at high drug loading compared with the control group (72.4 ± 2.2%). Thus, this study introduced an effective drug-IL method to enhance drug loading capacity and illustrated the brand-new action mechanism, which provided a powerful instrument for the development of a high drug loading-high release patch.
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Adesivos/química , Hidrogênio/química , Líquidos Iônicos/química , Compostos Macrocíclicos/química , Adesivos/administração & dosagem , Animais , Varredura Diferencial de Calorimetria/métodos , Cristalização/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Ligação de Hidrogênio/efeitos dos fármacos , Compostos Macrocíclicos/administração & dosagem , Simulação de Acoplamento Molecular/métodos , Naproxeno/administração & dosagem , Naproxeno/química , Espectroscopia Fotoeletrônica/métodos , Polímeros/química , Coelhos , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Solubilidade/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Análise Espectral Raman/métodos , Adesivo Transdérmico , Difração de Raios X/métodosRESUMO
Chemical penetration enhancers (CPEs) are commonly added into transdermal patches to impart improved skin permeation of drug. However, significant unexplained variability in drug release kinetics in transdermal patches is possible as a result of the addition of CPEs; investigations into the underlying mechanisms are still limited. In the present study, a diverse set of CPEs was employed to draw broad conclusions. Solubility parameters of CPEs and acrylate pressure-sensitive adhesive were calculated by molecular dynamics simulation and Fedors group contribution method to evaluate drug-adhesive miscibility. CPE-adhesive interaction was characterized by FT-IR study, 13C NMR spectroscopy, and molecular docking simulation. Results showed that release enhancement ratio (ERR) of CPEs for zolmitriptan was rank ordered as isopropyl myristate > azone > Plurol Oleique® CC497 > Span® 80 > N-methylpyrrolidone > Transcutol® P. It was found that solubility parameter difference (Δδ) between CPE and adhesive was negatively related with ERR. It was proved that hydrogen bonding between CPE and adhesive would increase drug release rate, but only if the CPE showed good miscibility with adhesive. CPE like isopropyl myristate, which had good miscibility with adhesive, could decrease drug-adhesive interaction leading to the release of drug from adhesive.
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Adesivos/química , Simulação de Acoplamento Molecular , Miristatos/química , Oxazolidinonas/metabolismo , Adesivo Transdérmico , Triptaminas/metabolismo , Administração Cutânea , Animais , Liberação Controlada de Fármacos , Meia-Vida , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Masculino , Oxazolidinonas/química , Ratos , Ratos Wistar , Absorção Cutânea , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica , Triptaminas/químicaRESUMO
BACKGROUND: The rice leaf folder Cnaphalocrocis medinalis Güenée is a serious insect pest of rice in Asia. This pest occurs in summer, and it is sensitive to high temperature. However, the larvae exhibit heat acclimation/adaptation. To understand the underlying mechanisms, we established a heat-acclimated strain via multigenerational selection at 39 °C. After heat shock at 41 °C for 1 h, the transcriptomes of the heat-acclimated (S-39) and unacclimated (S-27) larvae were sequenced, using the unacclimated larvae without exposure to 41 °C as the control. RESULTS: Five generations of selection at 39 °C led larvae to acclimate to this heat stress. Exposure to 41 °C induced 1160 differentially expressed genes (DEGs) between the heat-acclimated and unacclimated larvae. Both the heat-acclimated and unacclimated larvae responded to heat stress via upregulating genes related to sensory organ development and structural constituent of eye lens, whereas the unacclimated larvae also upregulated genes related to structural constituent of cuticle. Compared to unacclimated larvae, heat-acclimated larvae downregulated oxidoreductase activity-related genes when encountering heat shock. Both the acclimated and unacclimated larvae adjusted the longevity regulating, protein processing in endoplasmic reticulum, antigen processing and presentation, MAPK and estrogen signaling pathway to responsed to heat stress. Additionally, the unacclimated larvae also adjusted the spliceosome pathway, whereas the heat-acclimated larvae adjusted the biosynthesis of unsaturated fatty acids pathway when encountering heat stress. Although the heat-acclimated and unacclimated larvae upregulated expression of heat shock protein genes under heat stress including HSP70, HSP27 and CRYAB, their biosynthesis, metabolism and detoxification-related genes expressed differentially. CONCLUSIONS: The rice leaf folder larvae could acclimate to a high temperature via multigenerational heat selection. The heat-acclimated larvae induced more DEGs to response to heat shock than the unacclimated larvae. The changes in transcript level of genes were related to heat acclimation of larvae, especially these genes in sensory organ development, structural constituent of eye lens, and oxidoreductase activity. The DEGs between heat-acclimated and unacclimated larvae after heat shock were enriched in the biosynthesis and metabolism pathways. These results are helpful to understand the molecular mechanism underlying heat acclimation of insects.
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Mariposas/crescimento & desenvolvimento , Termotolerância/genética , Transcriptoma , Animais , Perfilação da Expressão Gênica , Larva/metabolismo , Mariposas/enzimologia , Mariposas/genética , Mariposas/metabolismo , Oxirredutases/metabolismoRESUMO
Increased expression of the small nucleolar RNA host gene 6 (SNHG6) has been reported in different cancers, such as hepatocellular carcinoma, colorectal cancer, and lung cancer. The high expression level of SNHG6 is associated with tumor progression and poor prognosis. This paper provides an overview of recent studies on the oncogenic role and potential clinical utilities of SNHG6. Upregulated SNHG6 arrests tumor cell cycle and reduces apoptosis but promotes migration, invasion, metastasis, epithelial-mesenchymal transition (EMT), and chemoresistance in tumors. Mechanically, SNHG6 primarily sponges tumor suppressor microRNA (miRNA), functioning as a competing endogenous RNA. Once sponged, miRNA is unable to degrade, silence, or hamper the translation of its downstream, mostly oncogenic genes, ultimately driving cancer-related processes. Thus, SNHG6 might serve as a biomarker for cancer diagnosis and prognosis.
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BACKGROUND: Quality of life (QOL) for patients with Peptic ulcer disease (PUD) is of interest worldwide and disease-specific instruments are needed for clinical research and practice. This paper focus on the development and validation of the PUD scale under the system of quality of life instruments for chronic diseases (QLICD-PU) by the modular approach and both classical test theory and Generalizability Theory. METHODS: The QLICD-PU is developed based on programmatic decision-making procedures, including multiple nominal and focus group discussions, in-depth interviews, and quantitative statistical procedures. Based on the data of 153 PUD inpatients, correlation analysis, factor analysis, t-test, and Generalizability Theory analysis (including generalizability study and decision study, ie. G-study and D-study) were used to assess the validity, reliability, and responsiveness of the scale. RESULTS: When the popular scale health survey short form (SF-36) was used as the standard, correlation and factor analysis confirmed good construct validity and criterion-related validity of QLICD-PU. Except for the social domain (0.62), the internal consistency α of all domains is higher than 0.70. The overall score and the test-retest reliability coefficients (Pearson r and intra-class correlation ICC) in all domains are higher than 0.80 (0.77 in the social domain). After treatments, the overall score and scores of all domains have statistically significant changes (P < 0.01), except for social impact and sexual function scores. The SRM (Standardized response mean) of domain-level scores ranges from 0.34 to 1.03. The G coefficient and reliability index (Ф coefficient) further confirm the reliability of the scale through more accurate variance components and decision-making information about changes in the number of items. CONCLUSIONS: The QLICD-PU can be used as a useful measurement to assess the quality of life of PUD patients with good psychometric characteristics and multiple advantages.
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Úlcera Péptica , Qualidade de Vida , Doença Crônica , Humanos , Psicometria , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Aberrant substance P/neurokinin-1 receptor (SP/NK-1R) system activation plays a critical role in various disorders, however, little is known about the expression and the detailed molecular mechanism of the SP and NK-1R in gallbladder cancer (GBC). In this study, we firstly analyzed the expression and clinical significance of them in patients with GBC. Then, cellular assays were performed to clarify their biological role in GBC cells. Moreover, we investigated the molecular mechanisms regulated by SP/NK-1R. Meanwhile, mice xenografted with human GBC cells were analyzed regarding the effects of SP/NK1R complex in vivo. Finally, patient samples were utilized to investigate the effect of SP/NK-1R. The results showed that SP and NK-1R were highly expressed in GBC. We found that SP strongly induced GBC cell proliferation, clone formation, migration and invasion, whereas antagonizing NK-1R resulted in the opposite effects. Moreover, SP significantly enhanced the expression of NF-κB p65 and the tumor-associated cytokines, while, Akt inhibitor could reverse these effects. Further studies indicated that decreasing activation of NF-κB or Akt diminished GBC cell proliferation and migration. In consistent with results, immunohistochemical staining showed high levels of Akt, NF-κB and cytokines in tumor tissues. Most importantly, the similar conclusion was obtained in xenograft mouse model. Our findings demonstrate that NK-1R, after binding with the endogenous agonist SP, could induce GBC cell migration and spreading via modulation of Akt/NF-κB pathway.
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Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias da Vesícula Biliar/metabolismo , Receptores da Neurocinina-1/metabolismo , Substância P/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias da Vesícula Biliar/genética , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Receptores da Neurocinina-1/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Transcrição RelA/metabolismo , Transplante Heterólogo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A series of NH2-sulfonyl oseltamivir analogues were designed, synthesized, and their inhibitory activities against neuraminidase from H5N1 subtype evaluated. The results indicated that the IC50 value of compound 4a, an oseltamivir analogue via methyl sulfonylation of C5-NH2, was 3.50 µM. Molecular docking simulations suggested that 4a retained most of the interactions formed by oseltamivir carboxylate moieties and formed an additional hydrogen bond with the methylsulfonyl group. Meanwhile, 4a showed high stability towards human liver microsomes. More importantly, 4a without basic moieties is not a zwitterion as reported on the general structure of neuraminidase inhibitors. This research will provide valuable reference for the research of new types of neuraminidase inhibitors.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Oseltamivir/análogos & derivados , Oseltamivir/síntese química , Antivirais/química , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Neuraminidase/metabolismo , Oseltamivir/química , Oseltamivir/farmacologiaRESUMO
Chemical penetration enhancers are widely used in transdermal drug delivery system. However, few studies have focused on changes of concentration in chemical penetration enhancers. In this study, the effect of concentrations of enhancers on drug release and its mechanism were investigated. Zolmitriptan (ZOL) was used as a model drug and isopropyl palmitate (IPP) was used as a model enhancer to investigate drug release behaviors in pressure-sensitive adhesives (PSAs). The IPP concentrations were 2, 5, 10, 12, and 15%. Drug release percents increased by 4.8, 11.5, 16, 15.1, and 14.8%, respectively. Interestingly, the linear relationship between concentrations of IPP and release percents was improved in the 0-10% and remained unchanged in the 10-15%. Moreover, thermal and rheology studies were performed to investigate changes of the fluidity of PSAs. FT-IR and molecular dynamics simulation were conducted to confirm the interaction strength among ZOL, IPP, and PSAs. The results elucidated that IPP increased fluidity of PSAs and vied for drug from PSAs. As a result, the interaction among three components played a major role in changing release behaviors of ZOL, but the increased fluidity only worked in the concentration of less than 10%.