RESUMEN
Three unusual ajmaline-macroline type bisindole alkaloids, alsmaphylines A-C, together with their postulated biogenetic precursors, were isolated from the stem barks and leaves of Alstonia macrophylla via the building blocks-based molecular network (BBMN) strategy. Alsmaphyline A represents a rare ajmaline-macroline type bisindole alkaloid with an S-shape polycyclic ring system. Alsmaphylines B and C are two novel ajmaline-macroline type bisindole alkaloids with N-1-C-21' linkages, and the former possesses an unconventional stacked conformation due to the presence of intramolecular noncovalent interactions. The chemical structures including absolute configurations of alsmaphylines A-C were established by comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray crystallography. In addition, a plausible biosynthetic pathway of these bisindole alkaloids as well as their ability to promote the protein synthesis on HT22 cells were discussed.
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Alcaloides , Alstonia , Oxindoles , Alstonia/química , Ajmalina , Alcaloides Indólicos/química , Estructura Molecular , Alcaloides/químicaRESUMEN
Four new alkaloids, arecatines A-D (1-4), were isolated from the peels of Areca catechu. Compound 1 is an unusual piperidine-pyridine hybrid alkaloid, whereas compounds 2-4 feature bis-piperidine alkaloids. Their structures were elucidated by UV, IR, HRESIMS, and NMR spectra analysis. The molecular docking analysis indicated that compound 3 exhibited the best binding affinity with the GABAA receptor, indicating its potential anti-epilepsy activity.
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Dysregulation of NLRP3 inflammasome results in uncontrolled inflammation, which participates in various chronic diseases. TWIK2 potassium channel mediates potassium efflux that has been reported to be an essential upstream mechanism for ATP-induced NLRP3 inflammasome activation. Thus, TWIK2 potassium channel could be a potential drug target for NLRP3-related inflammatory diseases. In the present study we investigated the effects of known K2P channel modulators on TWIK2 channel expressed in a heterologous system. In order to increase plasma membrane expression and thus TWIK2 currents, a mutant channel with three mutations (TWIK2I289A/L290A/Y308A) in the C-terminus was expressed in COS-7 cells. TWIK2 currents were assessed using whole-cell voltage-clamp recording. Among 6 known K2P channel modulators tested (DCPIB, quinine, fluoxetine, ML365, ML335, and TKDC), ML365 was the most potent TWIK2 channel blocker with an IC50 value of 4.07 ± 1.5 µM. Furthermore, ML365 selectively inhibited TWIK2 without affecting TWIK1 or THIK1 channels. We showed that ML365 (1, 5 µM) concentration-dependently inhibited ATP-induced NLRP3 inflammasome activation in LPS-primed murine BMDMs, whereas it did not affect nigericin-induced NLRP3, or non-canonical, AIM2 and NLRC4 inflammasomes activation. Knockdown of TWIK2 significantly impaired the inhibitory effect of ML365 on ATP-induced NLRP3 inflammasome activation. Moreover, we demonstrated that pre-administration of ML365 (1, 10, 25 mg/kg, ip) dose-dependently ameliorated LPS-induced endotoxic shock in mice. In a preliminary pharmacokinetic study conducted in rats, ML365 showed good absolute oral bioavailability with F value of 22.49%. In conclusion, ML365 provides a structural reference for future design of selective TWIK2 channel inhibitors in treating related inflammatory diseases.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Adenosina Trifosfato/metabolismo , Animales , Proteínas de Unión al ADN , Inflamasomas/metabolismo , Inflamación , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , RatasRESUMEN
AIM: To investigate the clinical factors and factors that affect the decisions regarding storage of cryopreserved embryos obtained using assisted reproductive technology. METHODS: Clinical characteristics affecting the decisions regarding cryopreserved embryos were analyzed in 5724 Japanese couples who underwent in vitro fertilization (IVF) or intra-cytoplasmic sperm insemination (ICSI) and embryo transfer over 4 years since April 2015 at our clinic. Statistical analysis was carried out using JMP software. RESULTS: The number of oocytes retrievals and embryos stored, outcomes and number of children, and age of the female patients and male partners were related to the decision-making regarding cryopreserved embryos. Childbearing and no wish for another child were the major reasons for discontinuing embryo storage. The number of oocytes retrievals and embryos in storage, age of the female patients, and sex of the child were independently associated with this decision-making in 2682 patients with a single child. Women with male children were more likely to choose discontinuation of embryo storage than those with female children. CONCLUSION: Already having a child and not wishing for further treatment due to age along with the presence of a male child affect the decision to continue or discontinue embryo storage in Japanese patients with infertility.
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Infertilidad , Niño , Criopreservación , Transferencia de Embrión , Femenino , Fertilización In Vitro , Humanos , Japón , MasculinoRESUMEN
Diosgenin is widely distributed in many plants, such as Polygonatum sibiricum, Paris polyphylla, Dioscorea oppositifolia, Trigonella foenum-graecum, Costus speciosus, Tacca chantrieri, which has good anti-tumor activity and preferable effects on preventing atherosclerosis, protecting the heart, treating diabetes, etc. This review combed through the anti-tumor mechanisms of diosgenin encompassing lung, breast, gallbladder, liver, oral cavity, stomach, bladder, bone marrow, etc. Besides, it was discovered that diosgenin mainly exerts its effect by inhibiting tumor cell migration, suppressing tumor cell proliferation and growth, and inducing cell apoptosis. However, problems like low yield and bioavailability frequently exist in natural diosgenin. This review introduced methods such as structural modification, dosage form optimization and combination medication to improve the yield and anti-tumor activity of diosgenin. Via the summary of this paper, it is expected to provide theoretical basis for the rational exploitation and utilization of diosgenin.
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Productos Biológicos , Diosgenina , Trigonella , Apoptosis , Proliferación Celular , Diosgenina/farmacologíaRESUMEN
2-Deoxyglucose (2DG) is a non-metabolizable glucose analog currently in clinical trials to determine its efficacy in enhancing the therapeutic effects of radiotherapy and chemotherapy of several types of cancers. It is thought to preferentially kill cancer cells by inhibiting glycolysis because cancer cells are more dependent on glycolysis for their energy needs than normal cells. However, we found that the toxicity of 2DG in cancer cells is mediated by the enzymatic activities of AKR1B1 and/or AKR1B10 (AKR1Bs), which are often overexpressed in cancer cells. Our results show that 2DG kills cancer cells because, in the process of being reduced by AKR1Bs, depletion of their cofactor NADPH leads to the depletion of glutathione (GSH) and cell death. Furthermore, we showed that compounds that are better substrates for AKR1Bs than 2DG are more effective than 2DG in killing cancer cells that overexpressed these 2 enzymes. As cancer cells can be induced to overexpress AKR1Bs, the anticancer mechanism we identified can be applied to treat a large variety of cancers. This should greatly facilitate the development of novel anticancer drugs.
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Aldehído Reductasa/metabolismo , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/metabolismo , Desoxiglucosa/farmacología , Neoplasias/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Aldehído Reductasa/genética , Miembro B10 de la Familia 1 de las Aldo-Ceto Reductasas/genética , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Células CACO-2 , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Desoxiglucosa/metabolismo , Glucólisis/efectos de los fármacos , Células HCT116 , Células HT29 , Células Hep G2 , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
A fungus strain, Neopestalotiopsis clavispora AL01, was isolated from the leaf spot of the plant Phoenix dactylifera. Further chemical investigation of the fermentation extract of this strain afforded six new secondary metabolites (1-6), along with 11 known compounds (7-17) which included a new natural compound (7). Their structures were determined by extensive spectroscopic analysis including one-and two-dimensional (1D and 2D) NMR spectroscopy, high-resolution electrospray ionization mass spectrometry (HRESIMS), and ECD and NMR calculations. All compounds were evaluated for their phytotoxic activities. Among them, compounds 10, 12 and 13 exhibited phytotoxic activities against Nicotiana tabacum. Compound 3 exhibited weak antibacterial activity against methicillin-resistant Staphylococcus aureus, Micrococcus luteus and Vibrio harveyi. Taken collectively, these findings establish a solid research foundation for future investigations on bioactive natural products derived from phytopathogenic fungi.
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Antibacterianos , Policétidos , Terpenos , Estructura Molecular , Antibacterianos/farmacología , Antibacterianos/aislamiento & purificación , Antibacterianos/química , Policétidos/farmacología , Policétidos/aislamiento & purificación , Policétidos/química , Terpenos/farmacología , Terpenos/aislamiento & purificación , Hojas de la Planta/química , Nicotiana , Pruebas de Sensibilidad Microbiana , China , Productos Biológicos/farmacología , Productos Biológicos/aislamiento & purificación , Productos Biológicos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacosRESUMEN
BACKGROUND: Oncomelania hupensis is the exclusive intermediate host of Schistosoma japonicum in China. Snail control is an essential component of schistosomiasis elimination programme. With 70 years of continuous efforts, the range of O. hupensis had reduced significantly, but slowed down in last decades. A large number of levees against flooding were constructed along Yangtze River and its affiliated lakes in the middle and lower reaches, which influenced the hydrology and ecology in the alluvial plains. The purpose of this study was to assess the impact of levees on the distribution of O. hupensis in the middle and lower reaches of the Yangtze River. METHODS: The snail habitats were digitalised by hand-held GPS system. The years for discovery and elimination of snail habitats were extracted from historical records. The accumulated snail-infested range for each habitat was calculated on the basis of annual reports. The current distribution of O. hupensis was determined by systematic and environmental sampling. The geographical distribution of levees was obtained from satellite imagery. To assess the impact of levees, the data pertaining to O. hupensis were divided into two parts: inside and outside the Yangtze River. Joinpoint regression was utilised to divide the study time span and further characterise the regression in each period. The 5-year-period moving averages of eliminated area infested by snails were calculated for the habitats inside and outside Yangtze River. The moving routes of corresponding geographical median centres were simulated in ArcGIS. Hotspot analysis was used to determine the areas with statistical significance clustering of O. hupensis density. RESULTS: Three periods were identified according to Joinpoint regression both inside and outside Yangtze River. The area infested by O. hupensis increased in the first two periods. It decreased rapidly outside Yangtze River year over year after 1970, while that inside the Yangtze River did not change significantly. Furthermore, the latter was significantly higher than the former. It was observed that the present density of O. hupensis inside Yangtze River was lower than outside the Yangtze River. The median centre for eliminated ranges inside Yangtze River wavered between the east (lower reach) and the west (middle reach). In contrast, the median centre for eliminated ranges continuously moved from the east to the west. CONCLUSIONS: Our findings indicated that the levees had a considerable negative impact on the distribution of O. hupensis outside Yangtze River. Some hotspots observed in the irrigation areas need a sluice system at the inlet of branch for snail control. The major distribution of O. hupensis located in Hubei might be caused by severe waterlogging. The intensive surveillance should be implemented there. The biggest two freshwater lakes, the major endemic regions historically, were identified as cold spots. The long-term impact of Three Gorges Dam on the distribution of O. hupensis in the lakes should be monitored and evaluated.
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Ecosistema , Ríos , Schistosoma japonicum , Caracoles , Animales , Caracoles/parasitología , Ríos/parasitología , China , Schistosoma japonicum/fisiología , Esquistosomiasis Japónica/transmisión , Esquistosomiasis Japónica/epidemiología , Esquistosomiasis Japónica/parasitologíaRESUMEN
Chemical investigation of Streptomyces sp. NA07423 led to the discovery of two unreported macrolactams, nagimycins A (1) and B (2). Their structures were elucidated by NMR, HRESIMS, X-ray crystallography, and comparison of experimental and theoretical ECD spectra. The nagimycins have a unique butenolide moiety rarely found in ansamycin antibiotics. Genome analysis revealed the putative biosynthetic gene cluster for nagimycins, and a likely biosynthetic pathway was proposed. Notably, compounds 1 and 2 exhibited potent antibacterial activity against two pathogenic Xanthomonas bacteria.
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Rifabutina , Streptomyces , Lactamas Macrocíclicas/química , Rifabutina/química , Streptomyces/química , Antibacterianos/química , Espectroscopía de Resonancia MagnéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) poses a growing challenge to global health efforts. The 5-year survival rate of HCC patients is still dismal. A traditional prescription Qi-Wei-Wan (QWW) comprising Astragali Radix and Schisandra chinensis Fructus has traditionally been used for HCC treatment according to traditional Chinese medicine theory, but the pharmacological basis is not clear. AIM OF THE STUDY: This study aims to investigate the anti-HCC effects of an ethanolic extract of QWW (hereafter, QWWE) and the mechanism of action. MATERIALS AND METHODS: An UPLC-Q-TOF-MS/MS method was developed to control the quality of QWWE. Two human HCC cell lines (HCCLM3 and HepG2) and a HCCLM3 xenograft mouse model were employed to investigate the anti-HCC effects of QWWE. The anti-proliferative effect of QWWE in vitro was determined by MTT, colony formation and EdU staining assays. Apoptosis and protein levels were examined by flow cytometry and Western blotting, respectively. Nuclear presence of signal transducer and activator of transcription 3 (STAT3) was examined by immunostaining. Transient transfection of pEGFP-LC3 and STAT3C plasmids was performed to assess autophagy and determine the involvement of STAT3 signaling in QWWE's anti-HCC effects, respectively. RESULTS: We found that QWWE inhibited the proliferation of and triggered apoptosis in HCC cells. Mechanistically, QWWE inhibited the activation of SRC and STAT3 at Tyr416 and Tyr705, respectively; inhibited the nuclear translocation of STAT3; lowered Bcl-2 protein levels, while increased Bax protein levels in HCC cells. Over-activating STAT3 attenuated the cytotoxic and apoptotic effects of QWWE in HCC cells. Moreover, QWWE induced autophagy in HCC cells by inhibiting mTOR signaling. Blocking autophagy with autophagy inhibitors (3-methyladenine and chloroquine) enhanced the cytotoxicity, apoptotic effect and the inhibitory effect on STAT3 activation of QWWE. Intragastric administration of QWWE at 10 mg/kg and 20 mg/kg potently repressed tumor growth and inhibited STAT3 and mTOR signaling in tumor tissues, but did not significantly affect mouse body weight. CONCLUSION: QWWE exhibited potent anti-HCC effects. Inhibiting the STAT3 signaling pathway is involved in QWWE-mediated apoptosis, while blocking mTOR signaling contributes to QWWE-mediated autophagy induction. Blockade of autophagy enhanced the anti-HCC effects of QWWE, indicating that the combination of an autophagy inhibitor and QWWE might be a promising therapeutic strategy for HCC management. Our findings provide pharmacological justifications for the traditional use of QWW in treating HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Schisandra , Humanos , Animales , Ratones , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Línea Celular Tumoral , Espectrometría de Masas en Tándem , Apoptosis , Serina-Treonina Quinasas TOR/metabolismo , Autofagia , Proliferación CelularRESUMEN
OBJECTIVE: To evaluate the effect of comprehensive control strategy of schistosomiasis with emphasis on infection source control in Anhui province. METHODS: Forty endemic villages in Guichi district, Chizhou city, Anhui province were selected as national pilot villages in the years from 2006 to 2008, and another 10 provincial pilot villages were respectively selected from 10 highly endemic villages in 7 cities in 2007. The comprehensive infection source control measures, including "replace cattle with machines", "raise livestock in pens", "improve the sanitary toilets", "supply safe water " and so on were carried out among the above pilot villages. At the end of 2008, 13 national pilot villages and 6 provincial pilot villages were selected to investigate the popularity of schistosomiasis, and the effect of the comprehensive control strategy in those villages were compared. RESULTS: After implementing the comprehensive control strategy, the infectious rate of schistosomiasis in national pilot villages decreased from 4.57% (487/10 659) to 1.76% (147/8370), with the reduction rate at 61.49%, whose difference showed statistical significance (χ(2) = 115.16, P < 0.01); and the density of infected snails decreased from 0.0067/0.1 m(2) to 0.0008/0.1 m(2), the infectious rate of snails decreased from 0.28% to 0.04%, whose reduction rates were 88.06% and 85.71% respectively. While as to the provincial pilot villages, the infectious rate of schistosomiasis decreased from 1.27% (54/4254) to 0.21% (14/6592), with the reduction rate at 83.46%, whose difference showed statistical significance (χ(2) = 94.57, P < 0.01); and the density of infected snails decreased from 0.0025/0.1 m(2) to 0.0003/0.1 m(2), the infection rate of snails decreased from 0.13% to 0.05%, whose reduction rates were 88.00% and 61.54% respectively. CONCLUSION: The comprehensive control strategy with emphasis on infection source control implemented in marshland and lake regions can effectively control the transmission of schistosomiasis.
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Control de Infecciones/métodos , Esquistosomiasis/epidemiología , Esquistosomiasis/prevención & control , Caracoles/parasitología , Animales , China/epidemiología , Reservorios de Enfermedades/parasitología , Humanos , Ganado , Proyectos Piloto , Salud Rural , Esquistosomiasis/parasitologíaRESUMEN
Black carbon (BC) is an important component of airborne fine particulate matter, with significant impacts on global climate change and human health. Taking Minhang District of Shanghai as the study area, a microaethalometer (MA200) and GPS were installed on the electric taxi to form a mobile observation platform to identify the spatial distribution and hot spots of atmospheric BC in urban environment. We analyzed the sources and influencing factors of BC. The results showed that the overall characteristics of the spatial distribution pattern of near surface atmospheric BC in Minhang District of Shanghai were high in the north and low in the south. The average BC concentration was (4.11±4.87) µg·m-3. The average concentrations of BC in working days and non-working days were (4.22±1.49) and (3.52±2.26) µg·m-3. The variability of BC concentration in the high value area was large, indicating that the increases of BC concentration in mobile observation were related to traffic accidents in the road section. In addition to human activities, large-scale dense vegetation might inhibit BC diffusion. The Absorption î ngström Exponent (AAE) was (0.82±0.54), which was closer to that of fossil fuel combustion. The contributions of fossil fuel emissions, biomass combustion, and mixed sources to BC sources were 67.5%, 4.9% and 27.6%, respectively.
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Contaminantes Atmosféricos , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , Carbono/análisis , China , Monitoreo del Ambiente/métodos , Combustibles Fósiles/análisis , Humanos , Material Particulado/análisis , Hollín/análisisRESUMEN
BACKGROUND: Pancreatic cancer has been characterized by poor prognosis, early metastasis and dissatisfactory treatment outcome. The high basal level of autophagy in tumor cells leads to chemoresistance and tumor progression. Thus, it is imminent to explore novel effective chemotherapeutic adjuvants to increase patients' survival rate. Isoliquiritigenin (ISL) is a bioactive flavonoid obtained from the Traditional Chinese herbal medicine Glycyrrhiza glabra, and it possesses a broad range of pharmacological effects. In this study, the anti-cancer effect of ISL in pancreatic cancer treatment and the underlying mechanism are investigated. METHODS: MTT assay, colony formation and EdU analysis were performed to explore the growth inhibition of ISL on pancreatic cancer cells. Apoptosis were analyzed using TUNEL and flow cytometry. The formations of autophagosomes were analyzed by immunofluorescence microscopy and transmission electron microscopy. RFP-GFP-LC3B probe was applied to detect the autophagy flux. To assess the structural interaction of ISL with p38 protein, molecular docking assays were performed. The molecular mechanism was elucidated by using western immunoblotting. Subsequently, the inhibition of ISL on tumor growth was determined in vivo using pancreatic tumor mice model. RESULTS: ISL inhibited pancreatic cancer cell growth and induced apoptosis, both in vitro and in vivo. ISL caused accumulation of autophagosome through blockade of late stage autophagic flux. Moreover, autophagy inducer rapamycin enhanced ISL-evoked cell growth inhibition and promoted apoptosis, while inhibition of autophagosome formation by siAtg5 attenuated ISL-induced apoptosis. It is remarkable that ISL synergistically sensitized the cytotoxic effect of gemcitabine and 5-fluorouracil on pancreatic cancer cells as both drugs induced autophagy. Molecular docking analysis has indicated that ISL acted by direct targeting of p38 MAPK, which was confirmed by ISL-induced phosphorylation of p38. The autophagy flux induced by p38 inhibitor SB203580 was blocked by ISL, with further increasing toxicity of ISL in pancreatic cancer cells. CONCLUSION: The results have revealed that ISL inhibited pancreatic cancer progression by blockade of autophagy through p38 MAPK signaling.
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Chalconas , Medicamentos Herbarios Chinos , Neoplasias Pancreáticas , Animales , Apoptosis , Autofagia , Línea Celular Tumoral , Chalconas/farmacología , Medicamentos Herbarios Chinos/farmacología , Fluorouracilo/farmacología , Ratones , Simulación del Acoplamiento Molecular , Neoplasias Pancreáticas/tratamiento farmacológico , Sirolimus/farmacología , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
BACKGROUND: Liver cancer is one of the leading causes of cancer-related death worldwide. Dihydrotanshinone I (DHI) was shown to inhibit the growth of several types of cancer. However, research related to hepatoma treatment using DHI is limited. PURPOSE: Here, we explored the inhibitory effect of DHI on the growth of hepatoma cells, and investigated the underlying molecular mechanisms. METHODS: The proliferation of Hep3B, SMCC-7721 and SK-Hep1 hepatoma cells was evaluated using the MTS and Edu staining assay. Hepatoma cell death was analyzed with a LIVE/DEAD Cell Imaging Kit. The relative expression and phosphorylation of proto-oncogene tyrosine-protein kinase Src (Src) and signal transducer and activator of transcription-3 (STAT3) proteins in hepatoma cells, as well as the expression of other protein components, were measured by western blotting. The structural interaction of DHI with Src proteins was evaluated by molecular docking, molecular dynamics simulation, surface plasmon resonance imaging and Src kinase inhibition assay. Src overexpression was achieved by infection with an adenovirus vector encoding human Src. Subsequently, the effects of DHI on tumor growth inhibition were further validated using mouse xenograft models of hepatoma. RESULTS: In vitro studies showed that treatment with DHI inhibited the proliferation and promoted cell death of Hep3B, SMCC-7721 and SK-Hep1 hepatoma cells. We further identified and verified Src as a direct target of DHI by using molecular stimulation, surface plasmon resonance image and Src kinase inhibition assay. Treatment with DHI reduced the in vitro phosphorylation levels of Src and STAT3, a transcription factor regulated by Src. In the xenograft mouse models, DHI dose-dependently suppressed tumor growth and Src and STAT3 phosphorylation. Moreover, Src overexpression partly abrogated the inhibitory effects of DHI on the proliferation and cell death in hepatoma cells. CONCLUSION: Our results suggest that DHI inhibits the growth of hepatoma cells by direct inhibition of Src.
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Carcinoma Hepatocelular , Furanos/farmacología , Fenantrenos , Quinonas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Ratones , Simulación del Acoplamiento Molecular , Fenantrenos/farmacología , Fosforilación , Factor de Transcripción STAT3/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
Pancreatic cancer is amongst the most lethal malignancies, while its poor prognosis could be associated with promotion of autophagy and the tumor immune microenvironment. Studies have confirmed the pro-tumorigenic nature of the cathelicidin family of peptide LL-37 in several types of cancer. However, at higher doses, LL-37 exerts significant cytotoxicity against gastrointestinal cancer cells. In our study, we investigated the anti-tumorigenic potential of LL-37 in pancreatic cancer and the underlying mechanisms. Our results have shown that LL-37 inhibited the growth of pancreatic cancer both in vitro and in vivo. Mechanistic studies have demonstrated that LL-37 induced DNA damage and cell cycle arrest through induction of reactive oxygen species (ROS). Further study indicates that LL-37 suppressed autophagy in pancreatic cancer cells through activation of mTOR signaling, leading to more accumulation of ROS production and induction of mitochondrial dysfunctions. With combined treatment of LL-37 with the mTOR inhibitor rapamycin, LL-37-induced ROS production and cancer cell growth inhibition were attenuated. Subsequent in vivo study has shown that LL-37 downregulated the immunosuppressive myeloid-derived suppressor cells and M2 macrophages while upregulated the anti-cancer effectors CD8+ and CD4+ T cells in the tumor microenvironment. By using an in vitro co-culture system, it was shown that promotion of M2 macrophage polarization would be suppressed by LL-37 with inhibition of autophagy, which possessed significant negative impact on cancer growth. Taken together, our findings implicate that LL-37 could attenuate the development of pancreatic cancer by suppressing autophagy and reprogramming of the tumor immune microenvironment.
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OBJECTIVE: To study the effects of total ginsenosides (TG) extract from Panax ginseng on neural stem cell (NSC) proliferation and differentiation and their underlying mechanisms. METHODS: The migration of NSCs after treatment with various concentrations of TG extract (50, 100, or 200 µ g/mL) were monitored. The proliferation of NSCs was examined by a combination of cell counting kit-8 and neurosphere assays. NSC differentiation mediated by TG extract was evaluated by Western blotting and immunofluorescence staining to monitor the expression of nestin and microtubule associated protein 2 (MAP2). The GSK-3ß/ß-catenin pathway in TG-treated NSCs was examined by Western blot assay. The NSCs with constitutively active GSK-3ß mutant were made by adenovirus-mediated gene transfection, then the proliferation and differentiation of NSCs mediated by TG were further verified. RESULTS: TG treatment significantly enhanced NSC migration (P<0.01 or P<0.05) and increased the proliferation of NSCs (P<0.01 or P<0.05). TG mediation also significantly upregulated MAP2 expression but downregulated nestin expression (P<0.01 or P<0.05). TG extract also significantly induced GSK-3ß phosphorylation at Ser9, leading to GSK-3ß inactivation and, consequently, the activation of the GSK-3ß/ß-catenin pathway (P<0.01 or P<0.05). In addition, constitutive activation of GSK-3ß in NSCs by the transfection of GSK-3ß S9A mutant was found to significantly suppress TG-mediated NSC proliferation and differentiation (P<0.01 or P<0.05). CONCLUSION: TG promoted NSC proliferation and neuronal differentiation by inactivating GSK-3ß.
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Ginsenósidos , Células-Madre Neurales , Panax , Animales , Diferenciación Celular , Proliferación Celular , Ginsenósidos/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células-Madre Neurales/metabolismo , Extractos Vegetales/farmacología , Ratas , beta Catenina/metabolismoRESUMEN
Based on the ground-based observations from seven atmospheric background stations during 2009 to 2018 in monsoon Asia (including BKT station in Indonesia, LLN and WLG stations in China, RYO and YON stations in Japan, TAP station in Republic of Korea, and UUM station in Mongolia), we analyzed the temporal and spatial variation of atmospheric CH4 concentration and its driving factors using harmonic model and maximal information-based nonparametric exploration. The results showed that the CH4 concentration in monsoon Asia varied from 1853.04 to 1935.61 nmol·mol-1, higher than that in Mauna Loa (MLO) station (1838.33 nmol·mol-1) in Hawaii, USA. The CH4 concentration decreased from north to south, with the highest value in TAP station (1935.61 nmol·mol-1) in Republic of Korea and RYO station (1907.19 nmol·mol-1) in Japan. The average seasonal amplitude at YON station in Japan was the largest (108.20 nmol·mol-1); while that at WLG station in China was the smallest (29.48 nmol·mol-1). The seasonal amplitude of TAP station in Republic of Korea changed faster at the rate of 4.49 nmol·mol-1·a-1. Except for WLG and TAP stations, CH4 concentrations were low in summer and high in winter. From the long-term perspective, the CH4 concentration at LLN (7.68 nmol·mol-1·a-1) and WLG (7.56 nmol·mol-1·a-1) stations in China exhibited the most obvious growth trend. Compared with wind speed, temperature and precipitation had greater impact on CH4 concentration, which were negatively associated with CH4 concentration. Local CH4 emission at some stations had a significant positive effect on CH4 concentration.
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Contaminantes Atmosféricos , Monitoreo del Ambiente , Contaminantes Atmosféricos/análisis , Asia , China , Mongolia , República de Corea , Estaciones del AñoRESUMEN
The angucylines are a family of aromatic polyketides featuring a tetracyclic benz[a]anthraquinone skeleton. This class of polycyclic aromatic polyketides are exclusively associated with actinomycetes and can undergo many modifications such as oxidation, ring cleavage, glycosylation and dimerization. Here we report the discovery of a new ether-linked benz[a]anthraquinone heterodimer, named mycolatone (1), from a grasshopper-derived actinomycete, Amycolatopsis sp. HCa1. The structure of mycolatone (1) was determined by comprehensive two-dimensional NMR analysis, high-resolution electrospray ionization mass spectrometry and biogenetic consideration. This new heterodimeric molecule is structurally derived from the dimerization of two tetracyclic angucylines, 2-hydroxy-5-O-methyltetragomycin and PD116779, through an ether bond between C-8 and C-8'. This new structural feature enrich the structural diversity of angucylines. Additionally, the surface tension activity and cytotoxic activities of 1 against human cervical cancer cell line (Hela), human gastric adenocarcinoma cell line (SGC-7901) and human lung adenocarcinoma cell line (SPC-A-1) were evaluated.
Asunto(s)
Amycolatopsis/química , Antraquinonas/farmacología , Antineoplásicos/farmacología , Saltamontes/microbiología , Animales , Antraquinonas/aislamiento & purificación , Antineoplásicos/aislamiento & purificación , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Línea Celular Tumoral , China , Dimerización , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Policétidos/aislamiento & purificación , Policétidos/farmacologíaRESUMEN
BACKGROUND: A steady progress on schistosomiasis control in the Peoples' Republic of China (P.R. China) was achieved and broadened into the twelve-year medium and long term national plan (MLNP) which marled the implementation of an integrated control strategy across all endemic areas in P.R. China in 2004. To understand the endemic trends of schistosomiasis to assess the effectiveness of an integrated strategy, we conducted an analysis of schistosomiasis surveillance data spanned from 2005 to 2015. METHODS: The schistosomiasis sentinel surveillance data from sentinel sites were collected and analyzed from 2005 to 2015. In these sentinel sites, residents aged 6 years or above were screened annually by indirect hemagglutination assay (IHA), while only antibody positives were followed by stool examination either Kato-katz method (KK) and/or hatching technique (HT). Domestic animals raised in sentinel sites were examined by HT for confirming the infection of schistosomes. Snail investigation was conducted each year through systematic sampling method combined with environmental sampling method. The snails collected from field were tested by microscopic dissection method. The infection rates of schistosomes in residents, domestic animals and snails, as well as the indicators reflecting the snails' distribution were calculated and analyzed. ANOVA analysis was used to examine the changes of the number of eggs per gram feces in population and Chi-square test was used to examine any change in proportions among groups. RESULTS: A total of 148 902 residents from sentinel sites attended this study and 631 676 blood samples were examined by IHA test during the 11 covered years. The annual average antibody positive rates presented a significant decrease trends, from 17.48% (95% CI: 17.20-17.75%) in 2005 to 5.93% (95% CI: 5.71-6.15%) (χ2 = 8890.47, P < 0.001) in 2015. During 2005-2015, the average infection rate of schistosomes in residents declined from 2.07% (95% CI: 1.96-2.17%) to 0.13% (95% CI: 0.09-0.16%), accompanied by significant decrease of infection intensity in population. In 2015, the stool positives were only found in farmers, fishermen and boatmen with infection rate of 0.16% (95% CI: 0.11-0.20%), 0.17% (95% CI: 0-0.50%) respectively. The infection rate of schistosomes in domestic animals dropped from 9.42% (538/5711, 95% CI: 8.66-10.18%) to 0.08% (2/2360, 95% CI: 0-0.20%) from 2005 to 2015. Infections were found in eight species of domestic animals at the beginning of surveillance while only two cattle were infected in 2015. Totally 98 ha of new snail habitats were found, while 94.90% (93/98) distributed in lake and marshland regions. The percentage of frames with snails decreased from 16.96% (56 884/33 5391, 95% CI: 16.83-17.09%) in 2005 to 4.28% (18 121/423 755, 95% CI: 4.22-4.34%) in 2014, with a slightly increase in 2015. Meanwhile, the infection rate of schistosomes in snails was decreased from 0.26% (663/256 531, 95% CI: 0.24-0.28%) to zero during 2005-2015. CONCLUSIONS: The infection rate of schistosomes declined significantly, providing evidence that the goal of the MLNP was achieved. Elimination of schistosomiasis as a public health problem defined as WHO was also reached in P.R. China nationwide. Surveillance-response system should be improved and strengthened to realize the final goal of schistosomiasis elimination.
Asunto(s)
Animales Domésticos , Esquistosomiasis , Vigilancia de Guardia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Niño , China/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Salud Pública , Esquistosomiasis/epidemiología , Esquistosomiasis/prevención & control , Esquistosomiasis/transmisión , Esquistosomiasis/veterinaria , Caracoles/parasitología , Adulto JovenRESUMEN
Apoptosis in intestinal epithelial cells (IECs) promotes the development of ulcerative colitis (UC), a type of inï¬ammatory bowel disease (IBD). Efficient clearance of apoptotic cells is essential for tissue homeostasis in metazoans. Actin related protein 3 (ARP3) promotes endothelial dysfunction. The expression and function of ARP3 in UC remains unclear. In this study, the expression of apoptotic markers as p53, Bax, Cleaved-Caspease9 and Cleaved-Caspease3 were proved to be increased in the intestinal epithelial cells (IECs) of UC patients and in a mouse disuccinimidyl suberate(DSS)-induced colitis model; meanwhile, ARP3 expression was elevated. ARP3 expression levels and the severity of symptoms in patients with UC were positively correlated. By knocking down ARP3 in a TNF-α-treated NCM-460 cell colitis model, the apoptotic markers described above were all decreased. In conclusion, our data indicates that ARP3 might promote the apoptosis of IECs in UC, revealing a potential molecular target for treating UC.