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Low-dose 5-aminolevulinic acid photodynamic therapy (ALA-PDT) has been used to cope with skin photoaging, and is thought to involve DNA damage repair responses. However, it is still unknown how low-dose ALA-PDT regulates DNA damage repair to curb skin photoaging. We established a photoaging model using human dermal fibroblasts (HDFs) and rat skin. RNA-sequencing (RNA-seq) analysis was conducted to identify differentially expressed genes (DEGs) in HDFs before and after low-dose ALA-PDT treatment, followed by bioinformatics analysis. Senescence-associated ß-galactosidase (SA-ß-gal) staining was employed to assess skin aging-related manifestations and Western blotting to evaluate the expression of associated proteins. A comet assay was used to detect cellular DNA damage, while immunofluorescence to examine the expression of 8-hydroxy-2'-deoxyguanosine (8-oxo-dG) in cells and skin tissues. In both in vivo and in vitro models, low-dose ALA-PDT alleviated the manifestations of ultraviolet B (UVB)-induced skin photoaging. Low-dose ALA-PDT significantly reduced DNA damage in photoaged HDFs. Furthermore, low-dose ALA-PDT accelerated the clearance of the photoproduct 8-oxo-dG in photoaged HDFs and superficial dermis of photoaged rat skin. RNA-seq analysis suggested that low-dose ALA-PDT upregulated the expression of key genes in the base excision repair (BER) pathway. Further functional validation showed that inhibition on BER expression by using UPF1069 significantly suppressed SA-ß-gal activity, G2/M phase ratio, expression of aging-associated proteins P16, P21, P53, and MUTYH proteins, as well as clearance of the photoproduct 8-oxo-dG in photoaged HDFs. Low-dose ALA-PDT exerts anti-photoaging effects by activating the BER signalling pathway.
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Ácido Aminolevulínico , Dano ao DNA , Reparo do DNA , Fibroblastos , Fotoquimioterapia , Transdução de Sinais , Envelhecimento da Pele , Raios Ultravioleta , Ácido Aminolevulínico/farmacologia , Reparo do DNA/efeitos dos fármacos , Animais , Raios Ultravioleta/efeitos adversos , Humanos , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Fotoquimioterapia/métodos , Ratos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Pele/patologia , Masculino , Fármacos Fotossensibilizantes/farmacologia , 8-Hidroxi-2'-Desoxiguanosina/metabolismoRESUMO
Keratinocytes, located in the outermost layer of human skin, are pivotal cells to resist environmental damage. Cellular autophagy plays a critical role in eliminating damaged organelles and maintaining skin cell homeostasis. Low-dose 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) has been demonstrated to enhance skin's antistress ability; however, the regulatory mechanisms of autophagy in keratinocytes remain unclear. In this study, we treated immortalized human keratinocytes (HaCaT cells) with low-dose ALA-PDT (0.5 mmol/L, 3 J/cm2). Through RNA-sequencing analysis, we identified that low-dose ALA-PDT modulated autophagy-related pathways in keratinocytes and pinpointed Unc-51-like kinase 1 (ULK1) as a key gene involved. Western blot results revealed that low-dose ALA-PDT treatment upregulated the expression of autophagy-related proteins Beclin-1 and LC3-II/LC3-I ratio. Notably, low-dose ALA-PDT regulated autophagy by inducing an appropriate level of reactive oxygen species (ROS), transiently reducing mitochondrial membrane potential, and decreasing adenosine triphosphate production; all these processes functioned on the AMP-activated protein kinase (AMPK)/ULK1 pathway to activate autophagy. Finally, we simulated external environmental damage using ultraviolet B (UVB) at a dose of 60 mJ/cm2 and observed that low-dose ALA-PDT mitigated UVB-induced cell apoptosis; however, this protective effect was reversed when using the autophagy inhibitor 3-methyladenine. Overall, these findings highlight how low-dose ALA-PDT enhances antistress ability in HaCaT cells through controlling ROS generation and activating the AMPK/ULK1 pathway to arouse cellular autophagy.
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Proteínas Quinases Ativadas por AMP , Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Autofagia , Queratinócitos , Transdução de Sinais , Humanos , Ácido Aminolevulínico/farmacologia , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/efeitos dos fármacos , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Células HaCaT , Queratinócitos/metabolismo , Queratinócitos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , FotoquimioterapiaRESUMO
Transient receptor potential melastatin 4 (TRPM4) is considered to be a potential target for cancer and other human diseases. Herein, a series of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives were designed and synthesized as new TRPM4 inhibitors, aiming to improve cellular potency. One of the most promising compounds, 7d (ZX08903), displayed promising antiproliferative activity against prostate cancer cell lines. 7d also suppressed colony formation and the expression of androgen receptor (AR) protein in prostate cancer cells. Furthermore, 7d can concentration-dependently induce cell apoptosis in prostate cancer cells. Collectively, these findings indicated that compound 7d may serve as a promising lead compound for further anticancer drug development.
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Antineoplásicos , Neoplasias da Próstata , Canais de Cátion TRPM , Masculino , Humanos , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Proliferação de Células , Relação Estrutura-Atividade , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura MolecularRESUMO
Ferroptosis is an iron-dependent form of oxidative cell death induced by lipid peroxidation accumulation. Glutathione peroxidase 4 (GPX4) plays a key role in the regulation of ferroptosis and is considered to be a promising therapeutic target for cancer and other human diseases. Herein, we describe our design, synthesis, and biological evaluation of a series of HyT-based degraders of the GPX4. One of the most promising compounds, 7b (ZX782), effectively induces dose- and time-dependent degradation of GPX4 protein and potently suppresses the growth of human fibrosarcoma HT1080 cells, which are highly sensitive to ferroptosis and widely used for evaluating compound specificity in ferroptosis. Mechanism investigation indicated that 7b depletes GPX4 through both the ubiquitin-proteasome and the autophagy-lysosome. Furthermore, the degradation of GPX4 induced by 7b could significantly increase the accumulation of lipid reactive oxygen species (ROS) in HT1080 cells, ultimately leading to ferroptosis. Overall, compound 7b exhibits robust potency in depleting endogenous GPX4, thereby modulating ferroptosis in cancer cells.
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Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/metabolismo , Morte Celular , Peroxidação de Lipídeos , OxirreduçãoRESUMO
Artificial light at night (ALAN) pollution has been regarded as a global environmental concern. More than 80% of the global population is exposed to light pollution. Exacerbating this issue, artificially lit outdoor areas are growing by 2.2% per year, while continuously lit areas have brightened by 2.2% each year due to rapid population growth and expanding urbanization. Furthermore, the increasing prevalence of night shift work and smart device usage contributes to the inescapable influence of ALAN. Studies have shown that ALAN can disrupt endogenous biological clocks, resulting in a disturbance of the circadian rhythm, which ultimately affects various physiological functions. Up until now, scholars have studied various disease mechanisms caused by ALAN that may be related to the response of the circadian system to light. This review outlines the molecular mechanisms by which ALAN causes circadian rhythm abnormalities in sleep disorders, endocrine diseases, cardiovascular disease, cancer, immune impairment, depression, anxiety and cognitive impairments.
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Poluição Luminosa , Jornada de Trabalho em Turnos , Iluminação/efeitos adversos , Ritmo Circadiano/fisiologia , Poluição AmbientalRESUMO
OBJECTIVE: To analyze the clinical efficacy and safety of fractional microneedle radiofrequency (FMR) for facial atrophic acne scars in a real-world setting. METHODS: The clinical data of patients with atrophic acne scars who had received FMR therapy from February 2018 to August 2022 were retrospectively analyzed. The improvement of atrophic acne scars was assessed using the ECCA Grading Scale (échelle d'évaluation clinique des cicatrices d'acné), Global Aesthetic Improvement Scale (GAIS), and modified Manchester Scar Scale (mMSS). Adverse reactions during FMR treatment were also recorded. Univariate and multivariate logistic regression analyses were performed to evaluate the efficacy and safety of FMR for atrophic acne scars. RESULTS: A total of 126 patients with facial atrophic acne scars were included. A total of 590 FMR treatment sessions were accomplished, with each of 82 patients receiving 4 or more treatment sessions, and 1 receiving a maximum of 14 sessions. All patients showed improvement in symptoms after FMR treatment, with moderate to significant improvement (ECCA score reduction of 26%-100%) in 92 (73.0%) patients. As the number of treatment sessions increased, the ECCA score gradually decreased from an average of 85.6 before to 35.0 after FMR. The average scores for distortion, color, and visual analogue scale (VAS) of mMSS all showed certain reductions. The change in GAIS score indicated improvement after treatment, with minimal improvement in 16 patients (12.7%), good improvement in 57 patients (45.2%), significant improvement in 45 patients (35.7%), and optimal improvement in 8 patients (6.4%). The univariate and multivariate logistic regression analyses revealed that the long pulse width and the number of FMR treatment sessions were positively associated with clinical efficacy. Compared to the short pulse-width group (200 ms), the longer pulse-width group (300 ms) (odds ratio [OR] = 8.3, p = 0.003) and the even longer pulse-width group (400-500 ms) (OR = 52.6, p < 0.001) demonstrated stronger efficacies. Patients who received more than three treatment sessions had better outcomes compared to those who received three or fewer treatment sessions (OR = 4.0, p = 0.036). All patients experienced posttreatment transient erythema, but no crusting, infection, or blister. Six cases developed grid-like erythema around 1 month posttreatment and one case experienced hyperpigmentation, both of which resolved within 1-3 months after appropriate management. CONCLUSION: FMR is a safe and effective treatment modality for improving facial atrophic acne scars, and the number of FMR treatment sessions and pulse width are associated with clinical efficacy.
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Acne Vulgar , Cicatriz , Humanos , Cicatriz/etiologia , Cicatriz/terapia , Estudos Retrospectivos , Resultado do Tratamento , Acne Vulgar/complicações , Atrofia/complicações , EritemaRESUMO
Two new aporphine alkaloids, 6aR-2'-(3-oxobutenyl)-thaliadin (1) and N-methylthalisopynine (2), along with ten known analogs (3-12), were isolated from the roots of Thalictrum omeiense W. T. Wang et S. H. Wang. Their structures were determined by extensive spectroscopic and X-ray crystallographic analyses. Compounds 1-7 and 9-12 were tested for their antiproliferative effects in vitro against two human cancer cell lines (A549 and MCF-7). Among them, compounds 1, 3, and 7 exhibited moderate inhibitory activity against the tested cell lines with IC50 values ranging from 23.73 to 34.97 µM.
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In recent years, with sinomenine hydrochloride as the main ingredient, Qingfengteng had been formulated as various dosage forms for clinical treatment. Subsequent findings confirmed a variety of biological roles for sinomenine. Here, 15 H2S-donating sinomenine derivatives were synthesized. Target hybrids a11 displayed substantial cytotoxic effects on cancer cell lines, particularly against K562 cells, with an IC50 value of 1.36 µM. In-depth studies demonstrated that a11 arrested cell cycle at G1 phase, induced apoptosis via both morphological changes in nucleus and membrane potential collapse in mitochondria. These results indicated a11 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.
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Coal is the primary energy source in China, and its life cycle inventory (LCI) is widely used as background data for life cycle assessment studies. Previous research indicates that the inventory of coal production varies regionally. However, the development of complete regionalized LCIs for coal production is quite limited. Here, we establish the first provincial-level LCIs of local coal production and market for coal in China, based on a database of 6,122 coal mines and developed models. In the inventory results of local coal production, the coefficients of variation (CVs) of nine indicators exceed 0.5, especially SO2 and particulate matter emission factors (CVs > 1). Compared with that, the interprovincial coal trade homogenizes the provincial production inventory of market for coal relatively, despite four indicators with CVs exceeding 0.5. Therefore, the regionalized inventory with remarkable spatial differentiation can provide more accurate fundamental data for future research such as electricity production. Furthermore, CH4 emissions from coal production account for 24% of China's total methane emissions, highlighting its significance in mitigating global warming. Moreover, through the increasing coal trade, the significant and implicit plunder of water resources from the three coal net-exporting provinces, located in water-scarce areas, should be noted.
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Carvão Mineral , Material Particulado , Animais , Material Particulado/análise , China , Eletricidade , Estágios do Ciclo de VidaRESUMO
In the monitoring the discharge of ballast water, the count of living algal cells is of utmost significant. Variable fluorescence, denoted as Fv, stands as an optimal parameter for photosynthetic fluorescence, efficiently charactering the living algal cells count, unaffected by the ballast waters' complex background fluorescence environment. This study deeply investigates the quantitative relationship between Fv and the count of living algal cells. Observations indicate that single cell fluorescence yield (abbreviated as SCF) varies significantly across different algae species, leading to considerable errors in quantifying living algal cell count in ballast water with unknown components using the calibration relationship between Fv and the cell count. Thus, correcting SCF prior to calibration becomes necessary. The paper proposes an innovative SCF correction method based on cell cross-sectional area and an eµ factor (where µ is the expected value of the functional absorption cross-section of PSII) This method mitigates the influence of cell size and species differences on quantifying the living algal cell count. Correction operation trials revealed that dividing the SCF measurement by cell cross-sectional area and multiplying by eµ enhanced the correction effect. Comparative experiments demonstrated marked improvement: Relative errors (REs) for Chlorella pyrenoidosa and Chlorella marine, both belonging to the Chlorophyta group, fell from 92.1% and 90.6% to 37.2% and 9.5% respectively post-correction. Similarly, REs for Thalassiosira weissflogii and Nitzschia closterium minutissima, from the Bacillariophyta group, decreased from 74.7% and 68.1% to 14.3% and 19.1% respectively. The RE of Peridinium from the Pyrrophyta group dropped from 28.4% to 12.1%. The results underscore the effectiveness of cell cross-sectional area and eµ in correcting SCF, thus offering a novel correction method for swift and precise measurement of living algal cell count in ballast water, based on variable fluorescence.
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BACKGROUND: Few studies have reported postoperative relapse of condyloma acuminatum (CA) after 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in human immunodeficiency virus (HIV) positive patients. METHODS: The clinical data of HIV-positive CA patients treated with ALA-PDT from October 2018 to December 2019 were analyzed retrospectively. Univariate and multivariate Cox regression was used to analyze the variables related to postoperative recurrence. Pearson correlation test was employed to analyze the correlation between CD4+ T cell count and postoperative recurrence rate. Kaplan-Meier method was used to compare the CA recurrence after ALA-PDT in low CD4 group and high CD4 group. RESULTS: A total of 38 HIV-positive patients with CA were included in the study. Among them, 26 patients experienced CA recurrence within 6 months, and the recurrence rate was 68.4%. CD4+ T cell count was 187.0 (79.0-596.0) cells/µl in relapsed patients and 406.0 (89.0-612.0) cells/µl in non-relapsed patients, showing a statistically significant difference (p = .005). Pearson correlation coefficient analysis revealed a negative correlation between CD4+ T cell count and postoperative recurrence rate (p = .005, r = -.443). Univariate regression analysis showed that CD4+ T cell count was correlated with postoperative recurrence, hazard ratio (HR) was 0.99 [95% Confidence interval (CI) = 0.99-1.0, p = .012]. Multivariate Cox regression analysis showed that with the low CD4+ T cell count as the reference, the high CD4+ T cell count was negatively correlated with postoperative recurrence (HR = 0.09, 95% CI 0.01-0.87, p = .038). CONCLUSIONS: Peripheral blood CD4+ T cell count can predict the CA recurrence rate after ALA-PDT in HIV-positive patients.
Assuntos
Condiloma Acuminado , Soropositividade para HIV , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/uso terapêutico , Estudos Retrospectivos , Fotoquimioterapia/métodos , Ácido Aminolevulínico/uso terapêutico , Condiloma Acuminado/tratamento farmacológico , Condiloma Acuminado/etiologia , Linfócitos T CD4-Positivos , Contagem de CélulasRESUMO
BACKGROUND: This study explored the impact of MTM service on MMD patients with hypertension. METHODS: A total of 120 MMD inpatients from September to November 2019 were received and randomly divided into intervention group and control group. General services for noninfectious chronic diseases were given to the control group, while a standard MTM service was given to the intervention group. Patients' blood pressure, EQ-5D utility value, readmission rate, drug-related problems, and average daily medication therapy cost were compared between the two groups and within the groups. This was done at the initial admission phase and in the first, third, sixth, and twelfth months after discharge. RESULTS: The intervention group had significantly lower blood pressure and average daily medication therapy cost 12 months after discharge compared to the control group (systolic blood pressure: P = 0.023, diastolic blood pressure: P < 0.001, average daily medication therapy cost: P = 0.049); the number of DRPs decreased in both groups 12 months after discharge; the number of DRPs solved in the intervention group in the third, sixth and twelfth months after discharge were statistically higher compared with that in the control group (P = 0.013, P = 0.012, P = 0.001); there was no significant difference in the EQ-5D utility value and readmission rate between the two groups (P > 0.05). CONCLUSIONS: MTM implementation in MMD patients can improve health outcomes and reduce healthcare-related costs among MMD patients. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR2200065111, date of registration: October 28, 2022.
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Hipertensão , Conduta do Tratamento Medicamentoso , Humanos , Multimorbidade , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Pressão Sanguínea , Custos de Cuidados de SaúdeRESUMO
Prenatal single and combined exposure to lead (Pb) and stress (Ps) impairs neurodevelopment. Prenatal single exposure to Pb or Ps affects the composition of intestinal microbiota, and bidirectional communication between gut microbiota and central nervous system has been well recognized. However, whether gut microbiota mediated the effects of prenatal Pb+Ps co-exposure on neurodevelopmental deficits remains unclear. This study established rat models with prenatal single and combined exposure to Ps and Pb. We investigated the effects of such prenatal single and combined exposure on hippocampal structures using morphological analyses, on learning/memory using the Morris-water-maze test, and on fecal microbiota using 16S rRNA sequencing. The mediating roles of gut microbiota were analyzed using the bootstrap method. The study found both single and combined exposure affected hippocampal ultra-structures and spatial learning/memory, and the most significant impairments were observed in the Pb+Ps group. Prenatal Pb+Ps co-exposure decreased fecal microbial alpha/beta-diversity. Significantly lower levels of B/F-ratio, class-Bacteroidia, order-Bacteroidales, and family-S24-7, and significantly higher levels of class-Bacilli, order-Lactobacillales, family-Lactobacillaceae, and genus-Lactobacillus were observed in the co-exposure group, compared with the controls. Increased relative abundances of genus-Helicobacter mediated the detrimental effect of prenatal Ps+Pb co-exposure on learning/memory [ß (95%CI) for the total and indirect effects: - 10.70 (-19.19, -2.21) and - 4.65(-11.07, -1.85)], accounting for 43.47% of the total effect. As a result, increased relative abundances of genus-Lactobacillus alleviated the adverse effects of the co-exposure on learning/memory, and the alleviation effect accounted for 44.55% of the direct effect [ß (95%CI) for the direct and indirect effects: - 0.28(-0.48, -0.08) and 0.13(0.01, 0.41)]. This study suggested that prenatal combined exposure to Pb and Ps induced more impairments in offspring gut microbiota and neurodevelopment than single exposure, and alterations in fecal microbiome may mediate the developmental neurotoxicity induced by such prenatal co-exposure.
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Microbioma Gastrointestinal , Humanos , Gravidez , Feminino , Ratos , Animais , Chumbo/toxicidade , RNA Ribossômico 16S/genética , Exposição Materna/efeitos adversos , Bacteroidetes , Memória EspacialRESUMO
Acute kidney injury (AKI) is one of the most challenging clinical problems in kidney disease due to serious complications and high mortality rate, which can lead to acute lung injury (ALI) through inflammatory reactions and oxidative stress. Adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway has been reported to be involved in the development of renal ischemia-reperfusion through autophagy and it remains unclear whether AMPK/mTOR pathway has an effect on the AKI-induced ALI. In this study, we aimed to investigate the effects of autophagy-related AMPK/mTOR signaling pathway on inflammatory factors and oxidative stress in an AKI-induced ALI model. The 48 male Sprague-Dawley rats were divided into four groups randomly: (i) sham, (ii) ischemia/reperfusion injury (IRI), (iii) IRI + rapamycin (RA), and (iv) IRI + 3-methyladenine (3-MA). Unilateral flank incisions were made and right kidneys were excised. The left kidney was subjected to 60 min of ischemia followed by 12, 24, 48, and 72 h of reperfusion. The levels of Scr, blood urea nitrogen (BUN), Wet/Dry ratio, indexes of inflammation, and oxidative stress were assayed. Histological examinations were performed. The protein expression of AMPK, mTOR, LC3-II/LC3-I ratio, and Beclin-1, ULK1 was evaluated by western blotting and immunohistochemistry. Compared to the rats from the sham group, IRI rats showed significantly pulmonary damage after AKI with increased Scr, BUN, Wet/Dry ratio, indexes of inflammation, and oxidative stress. The expression of AMPK, LC3-II/LC3-I ratio, Beclin-1, and ULK1 and were increased, while p62 and mTOR were decreased. In addition, RA treatment significantly attenuated lung injury by promoting autophagy through the activation of the AMPK/mTOR pathway, and 3-MA treatment exhibited adverse effects inversely. Therefore, the activation of the AMPK/mTOR pathway after renal IRI induction could significantly attenuate kidney injury and following AKI-induced ALI by inducing autophagy, which alienates inflammation, oxidative stress, and apoptosis.
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Injúria Renal Aguda , Lesão Pulmonar Aguda , Traumatismo por Reperfusão , Ratos , Masculino , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Ratos Sprague-Dawley , Sirolimo/farmacologia , Proteína Beclina-1/metabolismo , Proteína Beclina-1/farmacologia , Rim/metabolismo , Rim/patologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/farmacologia , Autofagia/fisiologia , Traumatismo por Reperfusão/complicações , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Inflamação , Mamíferos/metabolismoRESUMO
Two new iridoid glycosides, named 3'-O-benzoyl-dolichocymboside D (1) and dolichocymboside E (2), along with ten known glycosides (3-12), were isolated from the ethanol extract of the whole plants of Odontites vulgaris Moench. The structures of the isolated compounds were elucidated by 1D and 2D NMR and HR-ESI-MS spectra and by comparison with those reported in the literature. This is the first report on compounds 11 and 12 isolated from the family Scrophulariaceae, and compounds 8-10 were isolated from the genus Odontites.
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Glicosídeos Iridoides , Extratos Vegetais , Glicosídeos Iridoides/química , Extratos Vegetais/química , Glicosídeos/química , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
In response to injury, vascular smooth muscle cells (VSMCs) of the arterial wall dedifferentiate into a proliferative and migratory phenotype, leading to intimal hyperplasia. The ERK1/2 pathway participates in cellular proliferation and migration, while dual-specificity phosphatase 6 (DUSP6, also named MKP3) can dephosphorylate activated ERK1/2. We showed that DUSP6 was expressed in low baseline levels in normal arteries; however, arterial injury significantly increased DUSP6 levels in the vessel wall. Compared with wild-type mice, Dusp6-deficient mice had smaller neointima. In vitro, IL-1ß induced DUSP6 expression and increased VSMC proliferation and migration. Lack of DUSP6 reduced IL-1ß-induced VSMC proliferation and migration. DUSP6 deficiency did not affect IL-1ß-stimulated ERK1/2 activation. Instead, ERK1/2 inhibitor U0126 prevented DUSP6 induction by IL-1ß, indicating that ERK1/2 functions upstream of DUSP6 to regulate DUSP6 expression in VSMCs rather than downstream as a DUSP6 substrate. IL-1ß decreased the levels of cell cycle inhibitor p27 and cell-cell adhesion molecule N-cadherin in VSMCs, whereas lack of DUSP6 maintained their high levels, revealing novel functions of DUSP6 in regulating these two molecules. Taken together, our results indicate that lack of DUSP6 attenuated neointima formation following arterial injury by reducing VSMC proliferation and migration, which were likely mediated via maintaining p27 and N-cadherin levels.
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Fosfatases de Especificidade Dupla , Neointima , Lesões do Sistema Vascular , Animais , Camundongos , Caderinas , Movimento Celular , Proliferação de Células , Células Cultivadas , Fosfatases de Especificidade Dupla/genética , Hiperplasia , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso , Neointima/genética , Neointima/prevenção & controle , Lesões do Sistema Vascular/genéticaRESUMO
The present study aimed to explore the chemical constituents from the stems and leaves of Cephalotaxus fortunei. Seven lignans were isolated from the 75% ethanol extract of C. fortunei by various chromatographic methods, including silica gel, ODS column chromatography, and HPLC. The structures of the isolated compounds were elucidated according to physicochemical properties and spectral data. Compound 1 is a new lignan named cephalignan A. The known compounds were identified as 8-hydroxy-conidendrine(2), isolariciresinol(3), leptolepisol D(4), diarctigenin(5), dihydrodehydrodiconiferyl alcohol 9'-O-ß-D-glucopyranoside(6), and dihydrodehydrodiconiferyl alcohol 4-O-ß-D-glucopyranoside(7). Compounds 2 and 5 were isolated from the Cephalotaxus plant for the first time.
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Cephalotaxus , Lignanas , Lignanas/análise , Folhas de Planta/química , Etanol , Cromatografia Líquida de Alta PressãoRESUMO
Tripterygium glycosides liposome(TPGL) were prepared by thin film-dispersion method, which were optimized accor-ding to their morphological structures, average particle size and encapsulation rate. The measured particle size was(137.39±2.28) nm, and the encapsulation rate was 88.33%±1.82%. The mouse model of central nervous system inflammation was established by stereotaxic injection of lipopolysaccharide(LPS). TPGL and tripterygium glycosides(TPG) were administered intranasally for 21 days. The effects of intranasal administration of TPG and TPGL on behavioral cognitive impairment of mice due to LPS-induced central ner-vous system inflammation were estimated by animal behavioral tests, hematoxylin-eosin(HE) staining of hippocampus, real-time quantitative polymerase chain reaction(RT-qPCR) and immunofluorescence. Compared with TPG, TPGL caused less damage to the nasal mucosa, olfactory bulb, liver and kidney of mice administered intranasally. The behavioral performance of treated mice was significantly improved in water maze, Y maze and nesting experiment. Neuronal cell damage was reduced, and the expression levels of inflammation and apoptosis related genes [tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), BCL2-associated X(Bax), etc.] and glial activation markers [ionized calcium binding adaptor molecule 1(IBA1) and glial fibrillary acidic protein(GFAP)] were decreased. These results indicated that liposome technique combined with nasal delivery alleviated the toxic side effects of TPG, and also significantly ameliorated the cognitive impairment of mice induced by central nervous system inflammation.
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Glicosídeos Cardíacos , Disfunção Cognitiva , Camundongos , Animais , Tripterygium , Lipossomos , Glicosídeos/uso terapêutico , Administração Intranasal , Lipopolissacarídeos , Sistema Nervoso Central , Disfunção Cognitiva/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Collagens are the main components of extracellular matrix in the tumor microenvironment. Both fibrillar and nonfibrillar collagens are involved in tumor progression. The nonfibrillar network-forming collagens such as type IV and type VIII collagens are frequently overexpressed in various types of human cancers, which promotes tumor cell proliferation, adhesion, invasion, metastasis and angiogenesis. Studies on the roles of these collagens have shed light on the mechanisms underpinning the effects of this protein family. Future research has to explicit the role of network-forming collagens with respect to cancer progression and treatment. Herein, we review the regulation of network-forming collagens expression in cancer; the roles of network-forming collagens in tumor invasion, metastasis and angiogenesis; and the clinical significance of network-forming collagens expression in cancer patients.
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Colágeno , Neoplasias , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Humanos , Colágenos não Fibrilares , Microambiente TumoralRESUMO
Marimastat is one of the potent inhibitors of MMP (MMPIs) with few side effects. The impact of marimastat on cellular senescence remains unexplored. Our study evaluated the marimastate effect on oxidative stress-induced cell senescence using NIH3T3 cells. Marimastate administration was found to suppress senescence-ß-galactosidase (SA-ß-gal) activity and development linked with aging. Furthermore, we observed that this effect of marimastat was closely linked with the recovery of autophagy dysfunction and mTOR suppression in H2O2-treated cells. Notably, this study demonstrated the marimastat effect on senescence inhibition for the first time.