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This article introduces a simple, cost-saving and high efficient for the extraction and separation of microplastics (MPs) from soil with a high organic matter (SOM) content. In this study, MP with particle sizes of 154-600 µm of polyethylene (PE), polypropylene (PP), polystyrene (PS), polyvinyl chloride (PVC) and polyethylene terephthalate (PET) were artificially added into the five Mollisols with the high SOM. Three flotation solutions were used to extract these MPs from soils, and four digestion solutions were used to digest the SOM. As well, their destruction effects on MPs were also examined. The results showed that the flotation recovery rates of PE, PP, PS, PVC and PET were 96.1%-99.0% by ZnCl2 solution, while were 102.0%-107.2% by rapeseed oil, were 100.0%-104.7% by soybean oil. The digestion rate of SOM was 89.3% by H2SO4:H2O2 (1:40, v:v) at 70 °C for 48 h, and this was higher than by H2O2 (30%), NaOH and Fenton's reagent. However, the digestion rate of PE, PP, PS, PVC and PET were 0.0%-0.54% by H2SO4:H2O2 (1:40, v:v), and this was lower than by H2O2 (30%), NaOH and Fenton's reagent. As well, the factors influencing on MP extraction was also discussed. Generally, the best flotation solution was ZnCl2 (ρ > 1.6 g cm-3) and the best digestion method was H2SO4:H2O2 (1:40, v:v) at 70 °C for 48 h. The optimal extraction and digestion method were verified by the known concentrations of MPs (recovery rate of MPs was 95.7-101.7%), and this method was also used to extract MPs from long-term mulching vegetable fields in Mollisols of Northeast China.
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Microplásticos , Contaminantes Químicos del Agua , Peróxido de Hidrógeno , Plásticos , Suelo , Descontaminación , Hidróxido de Sodio , Polipropilenos , Poliestirenos , Polietileno , Tereftalatos Polietilenos , Contaminantes Químicos del Agua/análisisRESUMEN
Plastics production has been increasing over years, while their recycling rate is lower, resulting in huge amounts of microplastics (MP) accumulating in the environment. Although the environmental behaviors of MPs have been focused on in recent years, the migration, distribution and adverse effects of MPs in terrestrial and aquatic environments are still not systematically understood. In this review, based on the newest publications from the core database of the Web of Science, both the migration and distribution of MPs were summarized, as well as MPs transfer in biota and their biological effects were also focused on. Generally, the complicated and numerous pathways of MPs migration lead to their distribution throughout or nearly all environments on a global scale. However, the migration mechanisms of MPs with various sizes, shapes, and colors by physicochemical and biological processes, and the prediction models of MP migration and distribution, are deficient, despite these properties being highly related to MPs migration and bio-safety. Although MPs have already invaded microorganisms, plants, animals, and even human beings, the biological effects still need more study, so far as their sizes and shapes and also their composition and adsorption are concerned. Moreover, based on the highlights and deficiencies of current studies, further studies have also been proposed. This review aims to help people re-evaluate the uncertain behaviors of MPs in various environments, and could be helpful to fully understand their biological effects in different environmental conditions.
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Microplásticos , Contaminantes Químicos del Agua , Animales , Humanos , Plásticos/química , Monitoreo del Ambiente , Contaminantes Químicos del Agua/análisis , BiotaRESUMEN
Cardiac troponin I (cTnI) is a specific biomarker of acute myocardial infarction (AMI). However, cTnI detection kits prepared with antibodies have many defects. Nucleic acid aptamers are sequences of single-strand DNA or RNA that can overcome the deficiency of antibodies. Herein, sandwich ELONA methods were established based on aptamers. Two selected ssDNA aptamers (Apt3 and Apt6) showed high binding affinity and sensibility (Apt3: Kd = 1.01 ± 0.07 nM, Apt6: k = 0.68 ± 0.05) and did not bind to the same domain of cTnI. Therefore, these two aptamers can be applied to the ELONA methods. The detection range of cTnI using the dual-aptamer sandwich ELONA method was 0.05-200 ng/mL, and the bioanalytical method verification results can meet the national standard of Chinese Pharmacopoeia (2020 Edition). There was no difference between results of the dual-aptamer sandwich ELONA method and the diagnostic results of serum obtained from 243 people (P = 0.39, P Ë 0.05). The sensitivity and specificity of the ELONA with cTnI in serum were 96.46% and 93.85%, respectively. Compared with the FICA kit, which is clinically used, the consequences of ELONA method are closer to the diagnostic results. This study suggests that the aptamers Apt3 and Apt6 have high affinity and strong specificity and that the dual-aptamer sandwich ELONA method has a wide detection range and can be used to determine cTnI in serum, with potential applications in the diagnosis of AMIs.
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Aptámeros de Nucleótidos/metabolismo , ADN de Cadena Simple/metabolismo , Infarto del Miocardio/diagnóstico , Miocardio/metabolismo , Troponina I/metabolismo , Humanos , Límite de Detección , Reproducibilidad de los ResultadosRESUMEN
Tyrosinase plays a key role in the melanin biosynthesis since it catalyzes the transformation of tyrosine into L-dopaquinone. A large number of studies have also shown that molecules to efficiently inhibit the activity of tyrosinase would be potentially used in treating many depigmentation-related disorders. In this study, we targeted a series of structure-based 3-aryl substituted xanthone derivatives in which diverse functional groups were respectively attached on 3-aromatic ring moiety as new tyrosinase inhibitors. The results demonstrated that all obtained compounds had potent tyrosinase inhibitory activities with IC50 values at micromolar range. Especially, compound 4t was found to be the most active tyrosinase inhibitor with the IC50 value of 11.3 µM, uncovering that the introduction of the proper hydroxyl group in the 3-aromatic ring was beneficial for enhancing the inhibitory potency against tyrosinase. Moreover, the inhibition mechanism and inhibition kinetics studies revealed that compound 4t presented such inhibitory effect by acting as the reversible and competitive-uncompetitive mixed-II type inhibitor. Further molecular docking simulation showed that 3-aromatic ring of compound 4t was inserted into the narrow regions of binuclear copper-binding site at the bottom of the enzyme binding pocket, while the xanthone skeleton was positioned at the surface of tyrosinase. Taken together, these data suggested that such type of molecules might be utilized for the development of new and promising candidate for the treatment of depigmentation-related disorders.
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Inhibidores Enzimáticos/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Xantonas/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Monofenol Monooxigenasa/metabolismo , Relación Estructura-Actividad , Xantonas/síntesis química , Xantonas/químicaRESUMEN
Deposition of amyloid ß (Aß) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aß is generated from sequential cleavages of the ß-amyloid precursor protein (APP) by the ß- and γ-secretases, and ß-site APP-cleaving enzyme 1 (BACE1) is the essential ß-secretase for Aß generation. Vulnerable regions in AD brains show increased BACE1 protein levels. However, the underlying mechanism how BACE1 is regulated remains to be further illustrated. Nuclear Factor of Activated T-cells (NFAT) has been implicated in AD pathogenesis. Despite the increasing appreciation for the importance of NFAT-dependent transcription in the nervous system, the regulation and function of specific NFAT isoforms in neurons is poorly understood. In this report we found that both BACE1 and NFAT3 levels were significantly increased in the brains of APP/PS1 transgenic mice. We found that overexpression of NFAT3 resulted in increase of BACE1 promoter activity and BACE1 transcription, while disruption of NFAT3 expression decreased BACE1 gene transcription and protein expression in SAS1 cells. In a addition, overexpression of NFAT3 leads to increase levels of Aß production. Chromatin immunoprecipitation analysis revealed direct binding of NFAT3 to specific DNA sequences within BACE1 promoter region. Taken together, our results indicate that NFAT is a BACE1 transcription factor. Our study suggests that inhibition of NFAT-mediated BACE1 expression may be a valuable drug target for AD therapy.
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Secretasas de la Proteína Precursora del Amiloide/genética , Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/genética , Regulación de la Expresión Génica , Factores de Transcripción NFATC/fisiología , Transcripción Genética , Animales , Técnicas de Silenciamiento del Gen , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Regiones Promotoras GenéticasRESUMEN
Gullies with lower altitudes compared to the surrounding environment are widely distributed in farmland of the watershed and their numbers are still expanding. However, it is still unclear how these gullies regulate the functional insects in farmland. In this study, land use types combined with the herbaceous plant, herbicide application, soil moisture, topography and climatic factors during crop growth were considered to understand how gullies influence the dynamics of functional insects in farmland from a watershed (240 ha) of Northeast China. The primary findings demonstrate that the richness and abundance of functional insects are generally greatest in gullies, particularly in stable gullies, and decrease in the following order: forest belts, grasslands, and farmlands within the watershed. Notably, the ratios of beneficial insects to pests (BI/Pest) in terms of richness and abundance were lower in gullies before July but reversed after July, in comparison to farmland. Stable gullies exhibited higher BI/Pest abundance and diversity ratios than developing gullies. The richness and abundance of functional insects were higher in the middle sections of gullies compared to their heads and tails. Furthermore, the ratios of BI/Pest were generally lower in farmlands than in any gully position. Functional insect dynamics were mainly determined by season, followed by plant abundance and biomass in the gullies, and rarely by soil moisture in the both watershed and single gullies scales. Generally, the richness and abundance of functional insects in farmland were mainly influenced by gullies, especially influenced by the gully middle position. Insect composition in farmland influenced by stable gullies was stronger than by developing gullies, and stable gullies were more beneficial in reducing the threat of pests to crops in the farmland of the watershed.
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Objective To explore a simple and feasible method for whole-mount immunofluorescence staining of lymphatic vessels in the ApoE-/- mouse model of atherosclerosis. Methods Aortic specimens were carefully excised from the ApoE-/- mouse model. Following immunostaining with specific antibodies against smooth muscle actin (SMA) and lymphatic vessel endothelial receptor 1 (LYVE1), the aortas, including the aortic root, were subjected to a 30-minute treatment with 5 g/L Sudan Black B solution. This step was instrumental in minimizing the autofluorescent background of the tissue. Thereafter, the aortas were processed through a clearing protocol and imaged within a purpose-built chamber under a fluorescence microscope. Results The pretreatment with 5 g/L Sudan Black B effectively suppressed the autofluorescent signals emanating from the vascular structures, thereby enhancing the contrast and clarity of the specific fluorescence signals associated with the lymphatic vessels. This enhancement in signal quality did not compromise the integrity or specificity of the immunofluorescent markers. Conclusion A facile, highly specific, and effective approach for the visualization of lymphatic vessels in whole-mount aortic preparations from ApoE-/- mice is established.
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Aorta , Apolipoproteínas E , Técnica del Anticuerpo Fluorescente , Vasos Linfáticos , Animales , Vasos Linfáticos/metabolismo , Vasos Linfáticos/diagnóstico por imagen , Ratones , Aorta/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/deficiencia , Apolipoproteínas E/metabolismo , Técnica del Anticuerpo Fluorescente/métodos , Adventicia/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Coloración y Etiquetado/métodos , Microscopía Fluorescente/métodosRESUMEN
Colorectal cancer (CRC) is the third most common cancer and has ranked the third leading cause in cancerassociated death globally. Metastasis is the leading cause of death in colorectal cancer patients. The role of tumor microenvironment (TME) in colorectal cancer metastasis has received increasing attention. As the most abundant cell type in the TME of solid tumors, cancer-associated fibroblasts (CAFs) have been demonstrated to have multiple functions in advancing tumor growth and metastasis. They can remodel the extracellular matrix (ECM) architecture, promote epithelial-mesenchymal transition (EMT), and interact with cancer cells or other stromal cells by secreting growth factors, cytokines, chemokines, and exosomes, facilitating tumor cell invasion into TME and contributing to distant metastasis. This article aims to analyze the sources and heterogeneity of CAFs in CRC, as well as their role in invasion and metastasis, in order to provide new insights into the metastasis mechanism of CRC and its clinical applications.
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The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8â¯nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC.
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Proliferación Celular , Neoplasias Colorrectales , Liposomas , Ratones Endogámicos BALB C , Oxaliplatino , Sirolimus , Oxaliplatino/farmacología , Oxaliplatino/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Animales , Sirolimus/farmacología , Sirolimus/administración & dosificación , Humanos , Proliferación Celular/efectos de los fármacos , Ratones , Línea Celular Tumoral , Ratones Desnudos , Apoptosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ácido Fólico/química , Ácido Fólico/administración & dosificación , MasculinoRESUMEN
OBJECTIVES: Monotherapy is often ineffective for treating colorectal cancer. In this study, we developed PEG-modified liposomes loaded with rapamycin (Rapa) and resveratrol (Res) (Rapa/Res liposomes, or RRL) to investigate their therapeutic potential in colorectal cancer. METHODS: RRL were constructed using the reversed-phase evaporation method. We assessed the cytotoxicity, apoptosis, and ferroptotic effects of RRL on colorectal cancer HCT116 cells. The anti-tumor efficacy of RRL was evaluated in HCT116 xenograft mice. RESULTS: RRL had a particle size of 86.67 ± 1.10 nm and a zeta potential of -33.13 ± 0.49 mV. The coloaded formulation demonstrated satisfactory performance both in vitro and in vivo, resulting in increased cytotoxicity to HCT116 cells and significant suppression of HCT116 xenografts tumor growth. Mechanically, RRL significantly increased the apoptosis rate of HCT116 cells, induced ROS accumulation in tumor cells, and effectively downregulated the expression of the ferroptosis-associated proteins GPX4 and SLC7A11, demonstrating its superior efficacy compared to that of Rapa liposomes (Rapa/Lps) or Res liposomes (Res/Lps) alone. CONCLUSION: Coloading Rapa and Res into liposomes to promote apoptosis and ferroptosis in tumor cells represents a promising strategy for the treatment of colorectal cancer.
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Apoptosis , Neoplasias Colorrectales , Ferroptosis , Liposomas , Ratones Desnudos , Resveratrol , Sirolimus , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Apoptosis/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Células HCT116 , Resveratrol/administración & dosificación , Resveratrol/farmacología , Resveratrol/química , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Sirolimus/administración & dosificación , Sirolimus/farmacología , Ratones , Nanopartículas/química , Ratones Endogámicos BALB C , Especies Reactivas de Oxígeno/metabolismo , Polietilenglicoles/química , Tamaño de la PartículaRESUMEN
The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5â¯% of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA+ cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8+ T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8+ T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.
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Antígeno B7-H1 , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Ratones Endogámicos BALB C , Sirolimus , Microambiente Tumoral , Animales , Microambiente Tumoral/efectos de los fármacos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Sirolimus/farmacología , Antígeno B7-H1/metabolismo , Ratones , Línea Celular Tumoral , Inhibidores de Puntos de Control Inmunológico/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Masculino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologíaRESUMEN
Microplastics (MPs) have been widely found in soils, however, the mechanism of MPs influencing plant growth is still debated and possibly attributed to the soil environment changed by MPs. In this study, 0.0 %, 0.1 %, 0.5 %, 1.0 %, 2.0 %, and 5.0 % (w/w) content of low-density polyethylene MPs (LDPE-MPs) with the particle sizes of 75-2000 µm was used to test how MPs alter the germination and the early growth of lettuce (Lactuca sativa var. ramosa Hort.) in Mollisols under both natural condition and regular incubation condition. Soil temperature (ST), soil moisture (SM) and the ratio of cracks area to surface soil area (CA) and cracks length to surface soil area (CL) were monitored. As well, the dynamics of water and nutrient infiltration reported by our previous publication were combined to analyze the relationship between soil properties and crop growth influenced by MP concentration. The main results showed that: (1) compared with CK (0.0 %), the germination and plant height of lettuce were lowest in treatments with the middle concentration of MPs (0.5 % and 1 %, w/w), but was highest in treatments of high concentration of MPs (5.0 %, w/w) during the whole 14 days of incubation; (2) increasing MP concentration weakened the influence of SM on ST in Mollisols; (3) the average of SM and ST were highest at 5 % of MP concentration, while was lowest at 0.5 % and 1 % of MP concentration from the 2nd to the 9th day; (3) compared with CK and other treatments, the CA and CL were lowest in 1.0 % MP concentration, but were highest in 0.1 % and 5.0 % of MP concentration. This study provides insight that middle, rather than high and low levels of MP concentration, significantly decrease the SM and ST and increase nitrogen leaching which further leads to negative impacts on emergent and early growth of crops in soils with heavy texture (Mollisols).
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Germinación , Lactuca , Microplásticos , Plásticos , Temperatura , Polietileno , SueloRESUMEN
Background: The activation of lymphatic vessel function is the crux to resolving atherosclerosis (AS), a chronic inflammatory disease. Rapamycin (RAPA) recently has attracted considerable attention as a potent drug to induce atherosclerotic plaque attenuation. The objective of this work was to develop a ligand-decorated, RAPA-loaded liposome for lymphatic-targeted delivery of drugs to improve abnormal lymphatic structure and function, resulting in highly effective regression of atherosclerotic plaques. Methods: Hyaluronic acid-decorated, RAPA-loaded liposomes (HA-RL) were fabricated by emulsion-solvent evaporation. The average size, zeta potential, entrapment efficiency were characterized, and the stability and drug release in vitro were investigated. Furthermore, the in vitro and in vivo lymphatic targeting ability were evaluated on lymphatic endothelial cells and LDLR-/- mice, and the efficiency of this nano-system in inducing the attenuation of atherosclerotic plaques was confirmed. Results: HA-RL had a size of 100 nm, over 90% drug encapsulation efficiency, the storage stability was distinguished, demonstrating a slow release from the lipid nano-carriers. The mean retention time (MRT) and elimination half-life (t1/2ß) achieved from HA-RL were 100.27±73.08 h and 70.74±50.80 h, respectively. HA-RL acquired the most prominent efficacy of lymphatic-targeted delivery and atherosclerotic plaques attenuation, implying the successful implementation of this novel drug delivery system in vivo. Conclusion: HA-RL exhibited the most appreciable lymphatic targeting ability and best atherosclerotic plaques attenuation efficiency, opening a new paradigm and promising perspective for the treatment of arteriosclerosis.
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Aterosclerosis , Placa Aterosclerótica , Ratones , Animales , Liposomas/química , Ácido Hialurónico/química , Sirolimus/farmacología , Placa Aterosclerótica/tratamiento farmacológico , Células Endoteliales , Sistemas de Liberación de Medicamentos/métodos , Aterosclerosis/tratamiento farmacológicoRESUMEN
Nowadays, the dynamics of nutrients leaching from the soils and their driving mechanism have been focused on, however, it is still unclear how microplastics (MPs) influence the nutrients' leaching in soils. In this study, five concentrations (w/w, 0.0 %, 0.5 %, 1 %, 2 %, 3 %) and three sizes of MPs of polyethylene (PE) (0.15-0.36 mm, 0.36-0.60 mm and 0.60-1.00 mm) influencing the leaching of NO3--N and water-soluble potassium (WSK) was simulated by a column method in Mollisols, and both the pre-fertilization and post-fertilization were considered. The results showed that, before KNO3 addition, there was a negative power function relationship between the NO3--N concentration and the leaching solution volume/leaching time. The amount and concentration of NO3--N leaching was higher in the early leaching stage. Compared with the CK, PE0.5% significantly reduced the leaching amount of WSK, while increased the leaching amount of NO3--N but not significantly. The leaching amount of WSK decreased with the increasing size of PEMP when the PEMP concentration was the same, while NO3--N was opposite. PE0.60-1.00 increased the leaching amount of NO3--N, while reduced the leaching amount of WSK. After KNO3 addition, compared with CK, PE1% significantly reduced the leaching amount of NO3--N, and PE1% had the lowest leaching amount of WSK. However, when the PEMP concentration in the soil reached a certain threshold (w/w, >1 %), the leaching amount of NO3--N and WSK increased gradually with PEMP increasing. PE0.60-1.00 reduced the leaching amount of NO3--N and WSK most obviously. In general, low concentrations (w/w, <1 %) and large sizes (0.60-1.00 mm) of PEMP promoted NO3--N leaching and inhibited the WSK leaching from the soil before the addition of KNO3, however, they both inhibited the leaching of NO3--N and WSK from the soil after addition of KNO3.
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The dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of chemotherapeutics and therapeutic antibodies, causing poor chemoimmunotherapy responses. We designed a multi-targeted pH-sensitive liposome which encapsulates cisplatin (Pt) in its water core (denoted as ATF@Pt Lps) and shows high affinity for uPAR receptors in pancreatic cancer cells, tumor-associated macrophages, and cancer-associated fibroblasts. Systemic administration of ATF@Pt Lps enabled overcoming the central stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in a Panc02 cell derived transplanted tumor mouse model. More importantly, ATF@Pt Lps degradation of collagen contributes to the infiltration of CD8+ T cells into tumors as well as an enhanced accumulation of anti PD-1 monoclonal antibodies. Furthermore, the killing of tumor cells by Pt also leads to the release of tumor antigens, which promote the proliferation of immune cells, especially CD83+ cells, Th1 CD4+ cells, and CD8+ cytotoxic T cells, that converted an immunoscore "cold" pancreatic cancer into a pro-immune "hot" tumor. A further combination with an immune checkpoint agent, anti PD-1 antibodies that inhibit PD-1, can enhance tumor specific cytotoxic T cell response. Accordingly, ATF@Pt Lps displays multi-targeting, controlled drug release, stromal disruption, enhanced penetration, killing of cancer cells, modification of the immunosuppressive microenvironment, and enhancement of immunity. This study provides important mechanistic information for the further development of a combination of ATF@Pt Lps and anti PD-1 antibodies for the effective treatment of pancreatic cancer.
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Antineoplásicos , Neoplasias Pancreáticas , Ratones , Animales , Cisplatino/farmacología , Liposomas/farmacología , Linfocitos T CD8-positivos , Lipopolisacáridos/farmacología , Neoplasias Pancreáticas/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Pancreatic cancer treatment faces challenges due to drug resistance as well as liver metastasis. As a new strategy for treating pancreatic cancer, combination therapy is now available, but the dense mesenchymal barrier in the tumor tissue blocks drug delivery and impairs its therapeutic efficacy. To address this issue, we prepared an ATF peptide-decorated liposomal co-loaded with cisplatin and rapamycin (ATF@Pt/Rapa Lps), which targets both tumor cells and cancer-associated fibroblasts that express uPAR receptors. In tumor sphere penetration experiments, ATF peptide modified liposomes significantly enhanced deep penetration. More importantly, the ATF@Pt/Rapa Lps disrupted the stroma, as demonstrated by the downregulation of É-SMA, I collagen, and fibronectin protein in vivo and in vitro. In this way, highly effective drug delivery to tumor cells can be achieved. As expected, there was a stronger inhibition of cell proliferation and migration by ATF@Pt/Rapa Lps in vitro compared to free Pt/Rapa and Pt/Rapa Lps. Furthermore, ATF@Pt/Rapa Lps showed greater therapeutic effects in PANC02 transplanted tumor mice and liver metastasis mice models. Ultimately, multi-targeting nanomedicines co-loaded with Rapa and cisplatin may provide a new approach to treating metastatic pancreatic cancer.
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Neoplasias Hepáticas , Neoplasias Pancreáticas , Animales , Ratones , Cisplatino/farmacología , Liposomas , Sirolimus/farmacología , Lipopolisacáridos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Péptidos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Línea Celular Tumoral , Neoplasias PancreáticasRESUMEN
Cisplatin, or DDP, is a highly successful and well-known chemotherapy drug used to treat cancer. Acquired resistance to chemotherapy is a major clinical concern, yet the mechanisms of this resistance are still unknown. Ferroptosis is a type of cell death distinct from other forms, fueled by a buildup of iron-associated lipid reactive oxygen species (ROS). Gaining insight into the process of ferroptosis could lead to novel treatments for overcoming cancer resistance. In this study, the combination of isoorientin (IO) and DDP treatment resulted in a significant decrease in the viability of drug-resistant cells, a substantial increase in intracellular iron, malondialdehyde (MDA) and ROS concentrations, a notable decrease in glutathione concentration, and the occurrence of ferroptosis in cells, as revealed by in vitro and in vivo experiments. Additionally, there was a decrease in the expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and sirtuin 6 (SIRT6) proteins, and an increase in cellular ferroptosis. Isoorientin acts as a mediator to regulate cellular ferroptosis and reverse drug resistance in lung cancer cells by controlling the SIRT6/Nrf2/GPX4 signaling pathway. The findings of this study suggest that IO can promote ferroptosis and reverse drug resistance in lung cancer through the SIRT6/Nrf2/GPX4 signaling pathway, thus offering a theoretical basis for its potential clinical application.
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Ferroptosis , Neoplasias Pulmonares , Sirtuinas , Humanos , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , Transducción de Señal , Resistencia a Antineoplásicos , Glicosiltransferasas , Neoplasias Pulmonares/tratamiento farmacológico , HierroRESUMEN
The deposition of amyloid ß-protein (Aß) fibrils into plaques within the brain parenchyma and along cerebral blood vessels is a hallmark of Alzheimer's disease (AD). Aß42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. Drugs that inhibit Aß42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of AD. However, the effects of CTS on the Aß aggregation and toxicity are unclear. The current work shows the effectiveness of CTS on the inhibition of Aß42 aggregation and toxicity to human neuroblastoma cells. In this study, we demonstrated that CTS can inhibit Aß42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron microscopy. Furthermore, we investigated the effects of CTS on Aß-induced oxidative cell death in cultured SH-SY5Y cells. MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Aß42. CTS also dramatically reduced Aß42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS may be useful in the inhibition or prevention of AD development and progression.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Fenantrenos/farmacología , Péptidos beta-Amiloides/metabolismo , Línea Celular Tumoral , Citometría de Flujo , Humanos , L-Lactato Deshidrogenasa/metabolismo , Microscopía Electrónica de TransmisiónRESUMEN
This study aimed to identify the characteristics of recombinant-adenovirus-modified PBMC-derived dendritic cells and their resistance to HIV-1 infection by integrating the CCR5∆32, CCR5siRNA, HIV-1 pol and HIV-1 int genes into a recombinant adenovirus vector using the AdEasy system. Dendritic cells (DCs) were isolated from human PBMCs from blood of healthy donors. The expression of CCR5∆32, CCR5, CXCR4 and HIV-1 p24 in PBMCs or modified cells was measured by western blot, p24 expression in cell lysates was measured by ELISA, and HIV-1 entry was measured by ß-galactosidase assay. Furthermore, T-cell immunity induced by the recombinant adenovirus was measured by ELISPOT assay. After the cells were modified by Ad-R5∆32siRNA, the expression of CCR5∆32 increased, while the expression of CCR5 and CXCR4 decreased. There was no adverse effect of adenoviral gene transfer on DC development. CD83 expression on the surface of mature DCs did not change after gene transfer. The expression of p24 remained at low levels in modified cells when challenged by HIV-1. The modified cells showed resistance to HIV-1 infection. Results indicated that recombinant-adenovirus-modified cells demonstrated good resistance to HIV-1 infection. Modification of HSC-derived immune cells, such as DCs, may be a potent strategy to resist HIV-1 infection.
Asunto(s)
Adenoviridae/genética , Células Dendríticas/virología , Vectores Genéticos , VIH-1/patogenicidad , Acoplamiento Viral , Replicación Viral , Silenciador del Gen , Integrasa de VIH/biosíntesis , Integrasa de VIH/genética , Humanos , Receptores CCR5/biosíntesis , Receptores CCR5/genética , Receptores del VIH/biosíntesis , Receptores del VIH/genética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/biosíntesis , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
Plastic pollution in farmland ecosystems has been widely concerned. However, the heterogeneity and driving mechanisms of plastic residue (PR) remain unclear in the farmland surrounded by complex pollution points. In this study, the abundance, mass, and accumulation areas of PR of mulch film (MF) and non-MF (NMF) were investigated in a large area of the vegetable field covered by plastic mulching in a long-term in Northeast China. Geostatistics combined with classical statistics were used to clarify how pollution source and migration factors change the PR heterogeneity in the farmlands. Results indicated that the MF type was only polyethylene (PE) (79.1 % of total PR), while NMF accounted for 20.9 % of total PR. As well, NMF-polypropylene (PP) and NMF-PE accounted for 45.3 % and 39.7 % of total NMF respectively, followed by polystyrene accounting for 7.5 %. In the 0-20 cm soil layer, the spatial autocorrelation of mass and accumulation areas of MF were significantly (p < 0.05) positive, and their spatial pattern tended to cluster. The accumulation areas of MF was predoniment in northwest and southeast near the roadside in all soil layers, while the accumulation areas of NMF was higher near the landfill in the 0-20 cm soil layer. Landfill and residential areas were critical sources of PR for the farmland. Southwest wind and southeast wind were the main driving force of PR migration and their annual migration rates were 23.7 and 19.8 m·year-1. The functional groups on the surface of plastics were different after degradation (including different types and different utilization methods), and PR was oxidized could release or adsorb toxic substances from the soils. Generally, in order to reduce PR pollution, in addition to source control and recycling, farmland tillage should be avoided in the weather when the wind speed is strong, especially near the PR pollution source.