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Background: Using a toxin-induced lethal acute liver failure (ALF) monkey model, we have recently shown that early peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) can alleviate liver damage and improve animal survival by suppressing the activation of circulating monocytes and the subsequent cytokine storm. Here, we explored whether the administration of hUC-MSCs could still improve ALF when the cytokine storm is fully developed. Method: We treated ALF monkeys with peripheral delivery of hUC-MSCs at 48 hr after toxin challenge. Liver indices, histology, imaging, and animal survival were recorded and analyzed. Results: In our cohort study, we conducted and demonstrated that the infusion of hUC-MSCs significantly improved liver histology, effectively controlled inflammatory cytokine storms, and increased survival rates. Additionally, the administration of a higher dose of hUC-MSCs (2 × 107/monkey) yielded superior outcomes compared to a lower dose (1 × 107/monkey). Conclusion: Treatment of hUC-MSCs can significantly improve the pathological and survival outcomes of ALF even when the cytokine storm has been fully developed, indicating a promising clinical solution for ALF.
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STK39 is reportedly a critical negative regulator of intestinal barrier. Pharmacological targeting of STK39 is expected to protect the intestinal barrier and thereby weaken metabolic dysfunction-associated steatohepatitis (MASH); Proximal colon biopsy tissues from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and those without MASLD were analyzed for STK39 expression. Wildtype (WT) mice and systemic STK39 gene knockout (STK39-/-) male mice were fed a normal diet or a high-fat methionine-choline deficient diet (HFMCD) for 8 weeks. The MASH mice were grouped and treated with ZT-1a (a STK39 inhibitor) or vehicle intraperitoneal injection during the procedure of HFMCD induction. Liver and intestinal tissues were collected for further examination; Colon tissues from patients with MASLD exhibited higher levels of STK39 than those from subjects without MASLD. Knockout of STK39 diminished CD68+ Kupffer cells and α-SMA+ hepatic stellate cells infiltration in mouse MASH model. Treatment with ZT-1a also prevented severe steatohepatitis in a mouse MASH model, including milder histological and pathological manifestations (lobular inflammation and fibrosis) in the liver. Interestingly, Inhibition of STK39 had minimal effects on hepatic lipid metabolism. The reduced liver injury observed in mice with STK39 inhibition was linked to significant decreases in mucosal inflammation, tight junction disruption and intestinal epithelial permeability to bacterial endotoxins; Collectively, we have revealed that inhibiting STK39 prevents the progression of MASH by protecting the intestinal epithelial barrier.
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Mucosa Intestinal , Ratones Noqueados , Proteínas Serina-Treonina Quinasas , Animales , Humanos , Masculino , Ratones , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Hígado Graso/patología , Hígado Graso/metabolismo , Hígado Graso/genética , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Hígado/efectos de los fármacos , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
Type 1 diabetes mellitus (T1DM) is a chronic disease affecting millions worldwide. Insulin therapy is currently the golden standard for treating T1DM; however, it does not restore the normal glycaemic balance entirely, which increases the risk of secondary complications. Beta-cell therapy may be a possible way of curing T1DM and has already shown promising results in the clinic. However, low retention rates, poor cell survival, and limited therapeutic potential are ongoing challenges, thus increasing the need for better cell encapsulation devices. This study aimed to develop a mechanically reinforced vascular endothelial growth factor (VEGF)-delivering encapsulation device suitable for beta cell encapsulation and transplantation. Poly(l-lactide-co-ε-caprolactone) (PLCL)/gelatin methacryloyl (GelMA)/alginate coaxial nanofibres were produced using electrospinning and embedded in an alginate hydrogel. The encapsulation device was physically and biologically characterised and was found to be suitable for INS-1E beta cell encapsulation, vascularization, and transplantation in terms of its biocompatibility, porosity, swelling ratio and mechanical properties. Lastly, VEGF was incorporated into the hydrogel and the release kinetics and functional studies revealed a sustained release of bioactive VEGF for at least 14 days, making the modified alginate system a promising candidate for improving the beta cell survival after transplantation.
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Alginatos , Gelatina , Hidrogeles , Células Secretoras de Insulina , Factor A de Crecimiento Endotelial Vascular , Hidrogeles/química , Alginatos/química , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/citología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/administración & dosificación , Gelatina/química , Animales , Poliésteres/química , Ratas , Supervivencia Celular/efectos de los fármacos , Humanos , Diabetes Mellitus Tipo 1/terapia , Metacrilatos/química , Inductores de la Angiogénesis/química , Inductores de la Angiogénesis/farmacología , Inductores de la Angiogénesis/administración & dosificación , Propiedades de SuperficieRESUMEN
OBJECTIVES: This study aimed to develop a model to predict World Health Organization/International Society of Urological Pathology (WHO/ISUP) low-grade or high-grade clear cell renal cell carcinoma (ccRCC) using 3D multiphase enhanced CT radiomics features (RFs). METHODS: CT data of 138 low-grade and 60 high-grade ccRCC cases were included. RFs were extracted from four CT phases: non-contrast phase (NCP), corticomedullary phase, nephrographic phase, and excretory phase (EP). Models were developed using various combinations of RFs and subjected to cross-validation. RESULTS: There were 107 RFs extracted from each phase of the CT images. The NCP-EP model had the best overall predictive value (AUC = 0.78), but did not significantly differ from that of the NCP model (AUC = 0.76). By considering the predictive ability of the model, the level of radiation exposure, and model simplicity, the overall best model was the Conventional image and clinical features (CICFs)-NCP model (AUC = 0.77; sensitivity 0.75, specificity 0.69, positive predictive value 0.85, negative predictive value 0.54, accuracy 0.73). The second-best model was the NCP model (AUC = 0.76). CONCLUSIONS: Combining clinical features with unenhanced CT images of the kidneys seems to be optimal for prediction of WHO/ISUP grade of ccRCC. This noninvasive method may assist in guiding more accurate treatment decisions for ccRCC. ADVANCES IN KNOWLEDGE: This study innovatively employed stability selection for RFs, enhancing model reliability. The CICFs-NCP model's simplicity and efficacy mark a significant advancement, offering a practical tool for clinical decision-making in ccRCC management.
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Carcinoma de Células Renales , Neoplasias Renales , Clasificación del Tumor , Tomografía Computarizada por Rayos X , Humanos , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/patología , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/patología , Tomografía Computarizada por Rayos X/métodos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Organización Mundial de la Salud , Estudios Retrospectivos , Valor Predictivo de las Pruebas , Adulto , Imagenología Tridimensional/métodos , Sensibilidad y Especificidad , Anciano de 80 o más Años , RadiómicaRESUMEN
AIM OF THE STUDY: To evaluate the in vitro and in vivo anti-metastasis efficacy of Jianpi Yangzheng (JPYZ) decoction against gastric cancer (GC) and its potential mechanisms. MATERIALS AND METHODS: The distant metastasis of GC cells administered via tail vein injection was assessed using the pre-metastatic niche (PMN) model. 16S rRNA sequencing and GC-MS/MS were applied to determine the component of the gut microbiota and content of short-chain fatty acids (SCFAs) in feces of mice, respectively. The proportion of myeloid-derived suppressor cells (MDSCs) in the lung was evaluated by flow cytometry and immunofluorescence. Serum or tissue levels of inflammation factors including IL-6, IL-10 and TGF-ß were determined by ELISA or Western blot respectively. RESULTS: Injecting GC cells into the tail vein of mice led to the development of lung metastases and also resulted in alterations in the composition of gut microbiota and the levels of SCFAs produced. Nevertheless, JPYZ treatment robustly impeded the effect of GC cells administration. Mechanically, JPYZ treatment not only prevented the alteration in gut microbiota structure, but also restored the SCFAs content induced by GC cells administration. Specifically, JPYZ treatment recovered the relative abundance of genera Moryella, Helicobacter, Lachnoclostridium, Streptococcus, Tuzzerella, GCA-900066575, uncultured_Lachnospiraceae, Rikenellaceae_RC9_gut_group and uncultured_bacterium_Muribaculaceae to near the normal control levels. In addition, JPYZ abrogated MDSCs accumulation in the lung tissue and blocked inflammation factors overproduction in the serum and lung tissues, which subsequently impede the formation of the immunosuppressive microenvironment. Correlation analysis revealed that the prevalence of Rikenellaceae in the model group exhibited a positive correlation with MDSCs proportion and inflammation factor levels. Conversely, the scarcity of Muribaculaceae in the model group showed a negative correlation with these parameters. This suggests that JPYZ might exert an influence on the gut microbiota and their metabolites, such as SCFAs, potentially regulating the formation of the PMN and consequently impacting the outcome of GC metastasis. CONCLUSION: These findings suggest that GC cells facilitate metastasis by altering the gut microbiota composition, affecting the production of SCFAs, and recruiting MDSCs to create a pro-inflammatory pre-metastatic niche. JPYZ decoction counteracts this process by reshaping the gut microbiota structure, enhancing SCFA production, and inhibiting the formation of the pre-metastatic microenvironment, thereby exerting an anti-metastatic effect.
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Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Neoplasias Pulmonares , Células Supresoras de Origen Mieloide , Neoplasias Gástricas , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Medicamentos Herbarios Chinos/farmacología , Ratones , Células Supresoras de Origen Mieloide/efectos de los fármacos , Línea Celular Tumoral , Ácidos Grasos Volátiles/metabolismo , Ratones Endogámicos BALB C , Humanos , ARN Ribosómico 16S , Masculino , Heces/microbiología , FemeninoRESUMEN
BACKGROUND: Autophagy could sense metabolic conditions and safeguard cells against nutrient deprivation, ultimately supporting the survival of cancer cells. Nobiletin (NOB) is a kind of bioactive component of the traditional Chinese medicine Citri Reticulatae Pericarpium and has been proven to induce GC cell death by reducing de novo fatty acid synthesis in our previous study. Nevertheless, the precise mechanisms by which NOB induces cell death in GC cells still need further elucidation. OBJECTIVES: To examine the mechanism by which NOB inhibits gastric cancer progression through the regulation of autophagy under the condition of lipid metabolism inhibition. METHODS/ STUDY DESIGN: Proliferation was detected by the CCK-8 assay. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Electron microscopy and mRFP-GFP-LC3 lentiviral transfection were performed to observe autophagy in vitro. Western blot, plasmid transfection, immunofluorescence staining, and CUT & Tag-qPCR techniques were utilized to explore the mechanisms by which NOB affects GC cells. Molecular docking and molecular dynamics simulations were conducted to predict the binding mode of NOB and SREBP1. CETSA was adopted to verify the predicted of binding model. A patient-derived xenograft (PDX) model was employed to verify the therapeutic efficacy of NOB in vivo. RESULTS: We conducted functional studies and discovered that NOB inhibited the protective effect of autophagy via the PI3K/Akt/mTOR axis in GC cells. Based on previous research, we found that the overexpression of ACLY abrogated the NOB-induced autophagy-dependent cell death. In silico analysis predicted the formation of a stable complex between NOB and SREBP1. In vitro assays confirmed that NOB treatment increased the thermal stability of SREBP1 at the same temperature conditions. Moreover, CUT&TAG-qPCR analysis revealed that NOB could inhibit SREBP1 binding to the ACLY promoter. In the PDX model, NOB suppressed tumor growth, causing SREBP1 nuclear translocation inhibition, PI3K/Akt/mTOR inactivation, and autophagy-dependent cell death. CONCLUSION: NOB demonstrated the ability to directly bind to SREBP1, inhibiting its nuclear translocation and binding to the ACLY promoter, thereby inducing autophagy-dependent cell death via PI3K/Akt/mTOR pathway.
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Autofagia , Flavonas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Neoplasias Gástricas , Serina-Treonina Quinasas TOR , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Flavonas/farmacología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Animales , Autofagia/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Ratones , Ratones Desnudos , Ratones Endogámicos BALB CRESUMEN
Diabetes is a prevalent chronic disease affecting millions of people globally. To address this health challenge, advanced beta cell therapy using biomaterials-based macroscale, microscale, and nanoscale encapsulation devices must tackle various obstacles. First, overcoming foreign body responses is a major focus of research. Strategies such as immunomodulatory materials and physical immunoshielding are investigated to reduce the immune response and improve the longevity of the encapsulated cells. Furthermore, oxygenating strategies, such as the use of oxygen-releasing biomaterials, are developed to improve oxygen diffusion and promote cell survival. Finally, yet importantly, promoting vascularization through the use of angiogenic growth factors and the incorporation of pre-vascularized materials are also explored to enhance nutrient and oxygen supply to the encapsulated cells. This review seeks to specifically highlight the emerging research strategies developed to overcome these challenges using micro and nanoscale biomaterial encapsulation devices. Continuously improving and refining these strategies make an advance toward realizing the improved therapeutic potential of the encapsulated beta cells.
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Materiales Biocompatibles , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Humanos , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Diabetes Mellitus Tipo 1/terapia , Animales , Materiales Biocompatibles/química , Encapsulación Celular/métodos , Oxígeno/químicaRESUMEN
BACKGROUND: Bioactive lipids involved in the progression of various diseases. Nevertheless, there is still a lack of biomarkers and relative regulatory targets. The lipidomic analysis of the samples from platinum-resistant in gastric cancer patients is expected to help us further improve our understanding of it. METHODS: We employed LC-MS based untargeted lipidomic analysis to search for potential candidate biomarkers for platinum resistance in GC patients. Partial least squares discriminant analysis (PLS-DA) and variable importance in projection (VIP) analysis were used to identify differential lipids. The possible molecular mechanisms and targets were obtained by metabolite set enrichment analysis and potential gene network screened. Finally, verified them by immunohistochemical of a tissue microarray. RESULTS: There were 71 differential lipid metabolites identified in GC samples between the chemotherapy-sensitivity group and the chemotherapy resistance group. According to Foldchange (FC) value, VIP value, P values (FC > 2, VIP > 1.5, p < 0.05), a total of 15 potential biomarkers were obtained, including MGDG(43:11)-H, Cer(d18:1/24:0) + HCOO, PI(18:0/18:1)-H, PE(16:1/18:1)-H, PE(36:2) + H, PE(34:2p)-H, Cer(d18:1 + hO/24:0) + HCOO, Cer(d18:1/23:0) + HCOO, PC(34:2e) + H, SM(d34:0) + H, LPC(18:2) + HCOO, PI(18:1/22:5)-H, PG(18:1/18:1)-H, Cer(d18:1/24:0) + H and PC(35:2) + H. Furthermore, we obtained five potential key targets (PLA2G4A, PLA2G3, DGKA, ACHE, and CHKA), and a metabolite-reaction-enzyme-gene interaction network was built to reveal the biological process of how they could disorder the endogenous lipid profile of platinum resistance in GC patients through the glycerophospholipid metabolism pathway. Finally, we further identified PLA2G4A and ACHE as core targets of the process by correlation analysis and tissue microarray immunohistochemical verification. CONCLUSION: PLA2G4A and ACHE regulated endogenous lipid profile in the platinum resistance in GC patients through the glycerophospholipid metabolism pathway. The screening of lipid biomarkers will facilitate earlier precision medicine interventions for chemotherapy-resistant gastric cancer. The development of therapies targeting PLA2G4A and ACHE could enhance platinum chemotherapy effectiveness.
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Neoplasias Gástricas , Humanos , Biomarcadores , Análisis Discriminante , Glicerofosfolípidos , Fosfolipasas A2 Grupo III , Fosfolipasas A2 Grupo IV , Metabolismo de los Lípidos/genética , Lípidos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genéticaRESUMEN
Carbon dots (CDs) are new carbon nanomaterials, among which those prepared from biomass are popular due to their excellent optical properties and environmental friendliness. As representative natural phenolic compounds, tea polyphenols are ideal precursors with fluorescent aromatic rings and phenolic hydroxyl structures. Usually, polyphenolic precursors can only be used to produce blue or green fluorescent CDs, and fluorescence in long wavelength domains, such as orange or red, cannot be achieved. Herein, the high reactivity of the phenolic hydroxyl groups in tea polyphenols with o-phthalaldehyde was exploited to modulate the pH during the carbonation process, which led to redshifts of the fluorescence wavelengths. Different pH values during the reaction caused the precursors to take different reaction paths and form fluorescent groups exhibiting different conjugated structures, resulting in carbon dots providing different fluorescent colors. Finally, by utilizing the in situ hydrolysis of ethyl orthosilicate, the tea polyphenol-based carbon dots were embedded into a silica matrix, inducing phosphorescence of the carbon dots. This study provides a new approach for green preparation and application of natural polyphenolic CDs.
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Objective: To identify phytochemical constituents present in the extract of flowers of Xanthoceras sorbifolia and evaluate their anti-oxidant and anti-hyperglycemic capacities. Methods: The AlCl3 colorimetric method and Prussian Blue assay were used to determine the contents of total flavonoids and total phenolic acids in extraction layers, and the bioactive layers was screened through anti - oxidative activity in vitro. The Waters ACQUITY UPLC system and a Waters ACQUITY UPLC BEH C18 column (2.0 mm × 150 mm, 5 µm) were used to identify the ingredients. And anti-oxidative ingredients were screened by off-line UPLC-QTOF-MS/MS-free radical scavenging. The ameliorative role of it was further evaluated in a high-fat, streptozotocin-induced type 2 diabetic rat model and the study was carried out on NADPH oxidase (PDB ID: 2CDU) by molecular docking. Results: Combined with the results of activity screening in vitro, the anti - oxidative part was identified as the ethyl acetate layer. A total of 24 chemical constituents were identified by liquid chromatography-mass spectrometry in the ethyl acetate layer and 13 main anti-oxidative active constituents were preliminarily screened out through off-line UPLC-QTOF-MS/MS-free radical scavenging. In vivo experiments showed that flowers of X. sorbifolia could significantly reduce the blood glucose level of diabetic mice and alleviate liver cell damage. Based on the results of docking analysis related to the identified phytocompounds and oxidase which involved in type 2 diabetes, quercetin 3-O-rutinoside, kaempferol-3-O-rhamnoside, isorhamnetin-3-O-glucoside, and isoquercitrin showed a better inhibitory profile. Conclusion: The ethyl acetate layer was rich in flavonoids and phenolic acids and had significant anti-oxidant activity, which could prevent hyperglycemia. This observed activity profile suggested X. sorbifolia flowers as a promising new source of tea to develop alternative natural anti-diabetic products with a high safety margin.
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CdS nanoparticles have wide applications as photocatalysts for degradation of organic pollutants, but due to their limited turnover number and off-pathway charge recombination processes, their degradation efficiency is low. Herein, aminated graphene quantum dots/CdS (GQDs/CdS) nanobelts were successfully fabricated by solvothermal and hydrothermal processes. The prepared GQDs/CdS were characterized by physical methods to investigate their structure, morphology, optical properties, specific surface area, element composition, and chemical state. GQDs/CdS materials promoted efficient charge separation, and showed high efficiency in the photocatalytic degradation of the organic dye Rhodamine B (RhB) under visible light. The degradation efficiency of RhB samples over 0.05 g of catalysts reached 97.40% after 150 min, a much higher efficiency in comparison to pure CdS. Electron paramagnetic resonance (EPR) spectroscopy provided direct evidence for ËOH and ËO2- as the reactive oxidative species using DMPO as a spin trap. Consistent with the experimental results, a possible mechanism of RhB photocatalytic degradation by GQDs/CdS under visible light was proposed. This work may provide environmentally friendly photocatalysts for degrading organic dyes and purifying water.
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Gastric cancer (GC) is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Similar to other types of tumors, GC cells undergo metabolic reprogramming and switch to a "predominantly glycolytic" metabolic pattern to promote its survival and metastasis, also known as "the Warburg effect", which is characterized by enhanced glucose uptake and lactate production. A large number of studies have shown that targeting cancer cells to enhanced glycolysis is a promising strategy, that can make cancer cells more susceptible to other conventional treatment methods of treatment, including chemotherapy, radiotherapy and immunotherapy, and so on. Therefore, this review summarizes the metabolic characteristics of glycolysis in GC cells and focuses on how abnormal lactate concentration can lead to immunosuppression through its effects on the differentiation, metabolism, and function of infiltrating immune cells, and how targeting this phenomenon may be a potential strategy to improve the therapeutic efficacy of GC.
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BACKGROUND: Hepatocellular carcinoma (HCC), the most common primary liver cancer, prevails mainly in males and has long been attributed to androgens and higher circumstantial levels of interleukin-6 (IL-6) produced by resident hepatic macrophages. METHODS: Constitutively hepatocyte-specific histone deacetylase 3 (HDAC3)-deficient (HDAC3LCKO) mice and constitutively hepatocyte-specific HDAC3 knockout and systemic IL-6 simultaneously ablated (HDAC3LCKO& IL-6-/-) mice were used in our study to explore the causes of sex differences in HCC. Additionally, we performed human HCC tissues with an IHC score. Correlation analysis and linear regression plots were constructed to reveal the association between HDAC3 and its candidate genes. To further elucidate that HDAC3 controls the expression of Foxa1/2, we knocked down HDAC3 in HUH7 liver cancer cells. RESULTS: We observed a contrary sex disparity, with an earlier onset and higher incidence of HCC in female mice when HDAC3 was selectively ablated in the liver. Loss of HDAC3 led to constant liver injury and the spontaneous development of HCC. Unlike the significant elevation of IL-6 in male mice at a very early age, female mice exhibit stable IL-6 levels, and IL-6 ablation did not eliminate the sex disparity in hepatocarcinogenesis in HDAC3-deficient mice. Oestrogen often protects the liver when combined with oestrogen receptor alpha (ERα); however, ovariectomy in HDAC3-ablated female mice significantly delayed tumourigenesis. The oestrogen-ERα axis can also play a role in tumour promotion in the absence of Foxa1 and Foxa2 in the receptor complex. Loss of HDAC3 profoundly reduced the expression of both Foxa1 and Foxa2 and impaired the binding between Foxa1/2 and ERα. Furthermore, a more frequent HDAC3 decrease accompanied by the simultaneous Foxa1/2 decline was found in female HCC compared to that in male HCC. CONCLUSION: In summary, we reported that loss of HDAC3 reduces Foxa1/2 and thus promotes HCC development in females in an oestrogen-dependent manner.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Femenino , Masculino , Ratones , Humanos , Animales , Carcinoma Hepatocelular/genética , Receptor alfa de Estrógeno/genética , Interleucina-6/genética , Neoplasias Hepáticas/genética , Hepatocitos , Receptores de Estrógenos , Carcinogénesis , Transformación Celular Neoplásica , EstrógenosRESUMEN
The rapid development of topological photonics has significantly revolutionized our comprehension of electromagnetic wave manipulation in recent decades. Recent research exploiting large-area topological states inserts an additional gapless PC structure between topologically trivial and nontrivial PCs, effectively introducing the mode width degree of freedom. Nevertheless, these heterostructures mainly support only single-type waveguide states operating within a single frequency band. To address these limitations, we propose a novel, to the best of our knowledge, tri-band three-layer heterostructure system, supporting both large-area pseudospin- and valley-locked states. The system showcases tunable mode widths with different operational bandwidths. Moreover, the heterostructures exhibit inherent topological characteristics and reflection-free interfacing, which are verified in the well-designed Z-shaped channels. The proposed heterostructure system can be used to design multi-band multi-functional high-flexibility topological devices, providing great advantages for enlarging the on-chip integrated communication systems.
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Coke used as a filler to treat imidacloprid (IMI) wastewater by both adsorption biological coupling and microbial electrolysis cells (MEC)-adsorption biological coupling technologies, the removal efficiencies on pollutions in wastewater containing IMI were investigated, and the key functional genes related to IMI degradation pathways were also revealed. Results showed that the removal rates of COD, ammonia nitrogen, TP, and IMI under the adsorption biological coupling treatment and MEC-adsorption biological coupling treatment were 94.61-95.54%, 93.37-95.79%, 73.69-83.80%, and 100%, respectively. MEC increased the relative abundance of Proteobacteria by 9.01% and transformed the dominant bacteria from Lysobacter and Reyranella to Brevundimonas and Aquincola. Moreover, MEC up-regulated the abundance of the coding genes PK (9.30%), narG (2.26%), pstS (3.63%), and phnD (1.32%), and converted the IMI degradation products to smaller molecular weight C6H8N2 and C6H6ClNO. This study provided an important reference information for efficient treatment of IMI wastewater using the MEC-adsorption biological coupling technology.
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Eliminación de Residuos Líquidos , Aguas Residuales , Eliminación de Residuos Líquidos/métodos , Adsorción , ElectrólisisRESUMEN
BACKGROUND: Gastric cancer (GC) is a common malignant tumor with limited treatment options. The natural flavonoid nobiletin (NOB) is a beneficial antioxidant that possesses anticancer activity. However, the mechanisms by which NOB inhibits GC progression remain unclear. METHODS: A CCK-8 assay was performed to determine cytotoxicity. Cell cycle and apoptosis analyses were performed by flow cytometry. RNA-seq was performed to detect differential gene expression after NOB treatment. RTâqPCR, Western blot and immunofluorescence staining were used to examine the underlying mechanisms of NOB in GC. Xenograft tumor models were constructed to verify the effect of NOB and its specific biological mechanism in GC. RESULTS: NOB inhibited cell proliferation, caused cell cycle arrest and induced apoptosis in GC cells. KEGG classification identified that the inhibitory effect of NOB on GC cells mainly involved the lipid metabolism pathway. We further showed that NOB reduced de novo fatty acid (FA) synthesis, as evidenced by the decreased levels of neutral lipids and the expression levels of ACLY, ACACA and FASN, and ACLY abrogated the effect of NOB on lipid deposits in GC cells. In addition, we also found that NOB triggered endoplasmic reticulum (ER) stress by activating the IRE-1α/GRP78/CHOP axis, but overexpression of ACLY reversed ER stress. Mechanistically, inhibiting ACLY expression with NOB significantly reduced neutral lipid accumulation, thereby inducing apoptosis by activating IRE-1α-mediated ER stress and inhibiting GC cell progression. Finally, in vivo results also demonstrated that NOB inhibited tumor growth by decreasing de novo FA synthesis. CONCLUSION: NOB could inhibit the expression of ACLY to activate IRE-1α-induced ER stress, which ultimately led to GC cell apoptosis. Our results provide novel insight into the use of de novo FA synthesis for GC treatment and are the first to reveal that NOB inhibits GC progression by ACLY-dependent ER stress.
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Neoplasias Gástricas , Animales , Humanos , Neoplasias Gástricas/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico , Lípidos , ApoptosisRESUMEN
BACKGROUND: Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear. METHODS: We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted. RESULTS: Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways. CONCLUSIONS: GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/metabolismo , Sorafenib/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/metabolismo , Glutamato-Amoníaco Ligasa/genética , Glutamato-Amoníaco Ligasa/metabolismo , Hepatectomía , Estudios Retrospectivos , Pronóstico , Recurrencia Local de Neoplasia/cirugíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Developing complementary and effective drugs with less toxicity is urgent for gastric cancer (GC) therapy. Jianpi Yangzheng Decoction (JPYZ) is a curative medical plants formula against GC in clinic while its molecular mechanism remains to be further elucidated. AIM OF THE STUDY: To evaluate the in vitro and in vivo anticancer efficacy of JPYZ against GC and its potential mechanisms. MATERIALS AND METHODS: The effect of JPYZ on regulating the candidate targets were screened and examined by RNA-Seq, qRT-PCR, luciferase reporter assay, and immunoblotting. Rescue experiment was conducted to authenticate the regulation of JPYZ on the target gene. Molecular interaction, intracellular localization and function of target genes were elucidated via Co-IP and cytoplasmic-nuclear fractionation. The impact of JPYZ on the abundance of target gene in clinical specimens of GC patients was evaluated by IHC. RESULTS: JPYZ treatment suppressed the proliferation and metastasis of GC cells. RNA seq revealed JPYZ significantly downregulated miR-448. A reporter plasmid containing CLDN18 3'-UTR WT exhibited significant decrease in luciferase activity when co-transfected with miR-448 mimic in GC cells. CLDN18.2 deficiency promoted the proliferation and metastasis of GC cells in vitro, as well as intensified the growth of GC xenograft in mice. JPYZ reduced the proliferation and metastasis of GC cells with CLDN18.2 abrogation. Mechanically, suppressed activities of transcriptional coactivator YAP/TAZ and its downstream targets were observed in GC cells with CLDN18.2 overexpression and those under JPYZ treatment, leading to cytoplasmic retention of phosphorylated YAP at site Ser-127. High abundance of CLDN18.2 was detected in more GC patients who received chemotherapy combined with JPYZ. CONCLUSION: JPYZ has an inhibitory effect on GC growth and metastasis partly by elevating CLDN18.2 abundance in GC cells, indicating more patients may benefit from combination therapy of JPYZ and the upcoming CLDN18.2 target agents.
Asunto(s)
MicroARNs , Neoplasias Gástricas , Humanos , Animales , Ratones , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Transducción de Señal , Factores de Transcripción/genética , Línea Celular Tumoral , MicroARNs/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Claudinas/genética , Claudinas/metabolismoRESUMEN
Influences of perfluoroalkyl substances on the performance and microbial metabolic pathways of constructed rapid infiltration systems are not fully understood. In this study, wastewater containing different concentrations of perfluorooctanoic acid (PFOA)/perfluorobutyric acid (PFBA) was treated in constructed rapid infiltration systems with coke as filler. The addition of 5 and 10 mg/L PFOA inhibited the removal of chemical oxygen demand (COD) (80.42%, 89.27%), ammonia nitrogen (31.32%, 41.14%), and total phosphorus (TP) (43.30%, 39.34%). Meanwhile, 10 mg/L PFBA inhibited TP removal of the systems. Based on X-ray photoelectron spectroscopy, the percentages of F- within the PFOA and PFBA groups were 12.91% and 48.46%, respectively. PFOA transformed Proteobacteria (71.79%) into the dominant phyla of the systems, whereas PFBA enriched Actinobacteria (72.51%). The PFBA up-regulated the coding gene of 6-phosphofructokinase by 14.44%, whereas PFOA down-regulated it by 4.76%. These findings provide insights into the toxicity of perfluoroalkyl substances on constructed rapid infiltration systems.
Asunto(s)
Coque , Fluorocarburos , Microbiota , Contaminantes Químicos del Agua , Aguas Residuales , Fluorocarburos/análisis , Fluorocarburos/química , FósforoRESUMEN
Reported in 2004, carbon dots (CDs) have been widely used in various fields due to their excellent optical properties. However, the mechanism of their fluorescence modulation is still a controversial issue, which also seriously affects the further development of carbon dots. In this paper, m-hydroxybenzaldehyde is used as a raw material to obtain multicolor luminescent CDs by pyrolysis under different reaction conditions, thereby revealing the forbidden band tuning and formation mechanism of CDs. Different acid-base conditions lead to different reaction paths of the precursors, forming molecular fluorophores with different conjugated structures, which aggregate to eventually form CDs and further enhance the photoluminescence of the system by inhibiting the movement of the fluorescent centers.