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A 1.57-µm coherent differential absorption lidar is demonstrated for measuring three-dimensional CO2 and wind fields simultaneously. The maximum detection range of CO2 is up to 6â km with a range resolution of 120 m and a time resolution of 1 min. A preliminary assessment of instrument performance is made with a 1-week continuous observation. The CO2 concentration over a column from 1920 to 2040â m is compared with the one measured by an optical cavity ring-down spectrometer placed on a 2â km-away meteorological tower. The concentration is strongly correlated with the in-situ spectrometer with a correlation coefficient and RMSE of 0.91 and 5.24â ppm. The measurement accuracy of CO2 is specified with a mean and standard deviation of 2.05â ppm and 7.18â ppm, respectively. The regional CO2 concentration and the three-dimensional wind fields are obtained through different scanning modes. Further analysis is conducted on vertical mixing and horizontal transport of CO2 by combining with the measured wind fields.
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Single-cell sequencing (scRNA-seq) technology provides higher resolution of cellular differences than bulk RNA sequencing and reveals the heterogeneity in biological research. The analysis of scRNA-seq datasets is premised on the subpopulation assignment. When an appropriate reference is not available, such as specific marker genes and single-cell reference atlas, unsupervised clustering approaches become the predominant option. However, the inherent sparsity and high-dimensionality of scRNA-seq datasets pose specific analytical challenges to traditional clustering methods. Therefore, a various deep learning-based methods have been proposed to address these challenges. As each method improves partially, a comprehensive method needs to be proposed. In this article, we propose a novel scRNA-seq data clustering method named AttentionAE-sc (Attention fusion AutoEncoder for single-cell). Two different scRNA-seq clustering strategies are combined through an attention mechanism, that include zero-inflated negative binomial (ZINB)-based methods dealing with the impact of dropout events and graph autoencoder (GAE)-based methods relying on information from neighbors to guide the dimension reduction. Based on an iterative fusion between denoising and topological embeddings, AttentionAE-sc can easily acquire clustering-friendly cell representations that similar cells are closer in the hidden embedding. Compared with several state-of-art baseline methods, AttentionAE-sc demonstrated excellent clustering performance on 16 real scRNA-seq datasets without the need to specify the number of groups. Additionally, AttentionAE-sc learned improved cell representations and exhibited enhanced stability and robustness. Furthermore, AttentionAE-sc achieved remarkable identification in a breast cancer single-cell atlas dataset and provided valuable insights into the heterogeneity among different cell subtypes.
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Perfilação da Expressão Gênica , Análise da Expressão Gênica de Célula Única , Perfilação da Expressão Gênica/métodos , Análise de Célula Única/métodos , Análise de Sequência de RNA/métodos , Análise por Conglomerados , AlgoritmosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is experiencing a concerning rise in both incidence and mortality rates. Current therapeutic strategies are limited in their effectiveness, largely due to the complex causes of the disease and significant levels of drug resistance. Given the latest developments in human umbilical cord mesenchymal stem cells (hUC-MSCs) research, there is a debate over the continued use of stem cell transplantation for treating tumors. Consequently, this study seeks to explore the role of hUC-MSCs in the management of HCC. METHODS AND RESULTS: HUC-MSCs increased the number (10.75 ± 1.50) in the DEN/TCPOBOP-induced mice hepatoma model, compared with DMSO group (7.25 ± 1.71). Moreover, the liver index in hUC-MSCs group (0.21 ± 0.06) was greater than that in DMSO group (0.09 ± 0.01). Immunohistochemical (IHC) analysis revealed that while hUC-MSCs did not alter Foxp3 expression, they significantly stimulated Ki67 expression, indicative of increased tumor cellular proliferation. Additionally, immunofluorescence (IF) studies showed that hUC-MSCs increased CD8+ T cell counts without affecting macrophage numbers. Notably, granzyme B expression remained nearly undetectable. We observed that serum IL-18 levels were higher in the hUC-MSCs group (109.66 ± 0.38 pg/ml) compared to the DMSO group (91.14 ± 4.37 pg/ml). Conversely, IL-1ß levels decreased in the hUC-MSCs group (63.00 ± 0.53 pg/ml) relative to the DMSO group (97.38 ± 9.08 pg/ml). CONCLUSIONS: According to this study, hUC-MSCs promoted the growth of liver tumors. Therefore, we proposed that hUC-MSCs are not suitable for treating HCC, as they exhibit clinically prohibited abnormalities.
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Carcinoma Hepatocelular , Proliferação de Células , Interleucina-18 , Neoplasias Hepáticas , Células-Tronco Mesenquimais , Cordão Umbilical , Células-Tronco Mesenquimais/metabolismo , Humanos , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , Cordão Umbilical/citologia , Interleucina-18/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Camundongos , Transplante de Células-Tronco Mesenquimais/métodos , Masculino , Linhagem Celular Tumoral , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologiaRESUMO
Anti-PD-1 immunotherapy is a promising treatment for hepatocellular carcinoma (HCC), but some patients with HCC do not experience clinical benefits. Autophagy promotes tumor progression and participates in drug resistance. Previous studies have revealed that suppressing the expression level of Yes-associated protein 1 (YAP1) improves anti-PD-1 therapy efficacy. Therefore, the relationship between YAP1 expression and autophagy activity during anti-PD-1 treatment was investigated in this study. A positive correlation was found between the expression level of YAP1 and LC3B by analyzing The Cancer Genome Atlas (TCGA), UALCAN databases, and HCC tissue microarray. Meanwhile, YAP1 expression and autophagy constituted positive feedback, in which YAP1 inhibition decreased the autophagy activity in liver tumor cells by hepatocyte-specific Yap1 knockout mice. Further, anti-PD-1 treatment increased autophagy and YAP1 expression levels in the cancer tissues from DEN/TCPOBOP-induced liver cancer mice. Finally, Yap1 knockout suppressed autophagy and improved anti-PD-1 therapy efficacy in hepatocyte-specific Yap1 knockout mice with liver tumors. These results suggested that YAP1 suppression was sensitized to anti-PD-1 treatment and inhibited autophagy activity in liver tumor cells. YAP1 is a promising target for improving the efficacy of anti-PD-1 immunotherapy in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Imunoterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos Knockout , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , HumanosRESUMO
Mercury (Hg) exposure is increasing in terrestrial birds; however, studies on its sources are scarce. In the present study, we elucidated the food composition of green-backed tit nestlings from three urban forest parks (CPL, AHL, and LCG) using live videography observation (LVO). Furthermore, the daily dietary intakes of inorganic Hg (IHg) (MDIIHg) and methylmercury (MeHg) (MDIMeHg) were determined using the Bayesian isotope mixing model (BIMM) to uncover the nestlings' specific dietary Hg contribution. Both LVO and BIMM indicated that Lepidoptera (primarily caterpillar) constituted the primary food source for the nestlings in the three forests, accounting for approximately 60% of their diet in all three forest parks. The estimated MDI of Hg revealed that lepidopterans and spiders primarily contributed to IHg exposure, with a co-contribution ratio of 71.8%-97.7%. Unexpectedly, dietary MeHg was mostly derived from spiders; the highest contribution ratio of 93.6% was recorded at CPL, followed by another peak ratio of 92.9% at LCG. However, the dietary exposure was primarily IHg, accounting for 69.8% (AHL), 62.0% (LCG), and 61.3% (CPL) of the nestlings. Our study findings highlight the importance of dietary IHg transfer in evaluating the effects of Hg in nestlings. LVO, coupled with BIMM, is an effective tool for determining the food compositions of songbird nestlings and estimating the contribution of specific diets.
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Mercúrio , Compostos de Metilmercúrio , Aves Canoras , Animais , Mercúrio/análise , Teorema de Bayes , Monitoramento Ambiental , Dieta , IsótoposRESUMO
The efficacy of anti-PD-1 therapy is not as expected in hepatocellular carcinoma (HCC). YAP1 was overexpressed and activated in HCC. The mechanism of YAP1 in HCC immune escape is unclear. Anti-PD-1 treatment increased YAP1 expression in liver tumor cells, and exhausted CD4+ and CD8+ T cells in the blood and spleen of liver tumor mice. YAP1 knockdown suppressed PD-L1 expression, which was involved in JAK1/STAT1, 3 pathways. Moreover, Yap1 knockout elevated CD4+ and CD8+ T cells in liver tumor niche. Consistently, verteporfin, YAP1 inhibitor, decreased TGF-ß and IFN-γ in liver tumor niche and exhausted CD8+ T cell in the spleen. DHA suppressed YAP1 expression and break immune evasion in liver tumor niche, characterized by decreased PD-L1 in liver tumor cells and increased CD8+ T cell infiltration. Furthermore, DHA combined with anti-PD-1 treatment promoted CD4+ T cell infiltration in the spleen and CD8+ T cell in tumor tissues of mice. In summary, YAP1 knockdown in liver tumor cells suppressed PD-L1 expression and recruited cytotoxic T lymphocytes (CTLs), leading to break immune evasion in tumor niche. Mechanistically, YAP1 knockdown suppressed PD-L1 expression, which was involved in JAK1/STAT1, 3 pathways. Finally, DHA inhibited YAP1 expression, which not only inhibited liver tumor proliferation but also break the immunosuppressive niche in liver tumor tissues and improve the effect of anti-PD-1 therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linfócitos T CD8-Positivos , Imunossupressores , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Microambiente Tumoral , Proteínas de Sinalização YAP/efeitos dos fármacos , Proteínas de Sinalização YAP/genéticaRESUMO
Superionic solid electrolytes (SEs) are essential for bulk-type solid-state battery (SSB) applications. Multicomponent SEs are recently attracting attention for their favorable charge-transport properties, however a thorough understanding of how configurational entropy (ΔSconf ) affects ionic conductivity is lacking. Here, we successfully synthesized a series of halogen-rich lithium argyrodites with the general formula Li5.5 PS4.5 Clx Br1.5-x (0≤x≤1.5). Using neutron powder diffraction and 31 P magic-angle spinning nuclear magnetic resonance spectroscopy, the S2- /Cl- /Br- occupancy on the anion sublattice was quantitatively analyzed. We show that disorder positively affects Li-ion dynamics, leading to a room-temperature ionic conductivity of 22.7â mS cm-1 (9.6â mS cm-1 in cold-pressed state) for Li5.5 PS4.5 Cl0.8 Br0.7 (ΔSconf =1.98R). To the best of our knowledge, this is the first experimental evidence that configurational entropy of the anion sublattice correlates with ion mobility. Our results indicate the possibility of improving ionic conductivity in ceramic ion conductors by tailoring the degree of compositional complexity. Moreover, the Li5.5 PS4.5 Cl0.8 Br0.7 SE allowed for stable cycling of single-crystal LiNi0.9 Co0.06 Mn0.04 O2 (s-NCM90) composite cathodes in SSB cells, emphasizing that dual-substituted lithium argyrodites hold great promise in enabling high-performance electrochemical energy storage.
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OBJECTIVE: To compare the positive rates of IGRA and TST in detection of LTBI. METHODS: We searched PubMed, Embase, and the Cochrane Library on March 12, 2022. A random-effects model was used to calculate pooled results. RESULTS: We included 458 head-to-head studies. Compared with immunocompetent controls, TST positive rate in immunosuppressed population decreased more than IGRA positive rate (OR 0.36 [95% CI: 0.31 to 0.41] versus 0.53 [0.46 to 0.61]). In immunocompetent BCG-vaccinated individuals, IGRA positive rate in low-TB burden areas was significantly lower than TST positive rate, but the difference was decreased in high-TB burden areas (OR 0.75 [0.60 to 0.94]). Additionally, IGRA positive rate was equal to that of TST in the elderly (OR 0.98 [0.66 to 1.46]). CONCLUSION: TST is more susceptible to immunosuppression than IGRA. The effect of BCG on TST might be weakened in high-TB burden areas, and TST response waned in the elderly. REVIEW REGISTRATION: PROSPERO CRD42020180163.
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Testes de Liberação de Interferon-gama , Tuberculose Latente , Humanos , Idoso , Testes de Liberação de Interferon-gama/métodos , Teste Tuberculínico/métodos , Tuberculose Latente/diagnóstico , Vacina BCG , Hospedeiro ImunocomprometidoRESUMO
Zymomonas mobilis (Z. mobilis) is a potential candidate strain for consolidated bioprocessing (CBP) in lignocellulosic biorefinery. However, the low-level secretion of cellulases limits this CBP process, and the mechanism of protein secretion that is affected by cell wall peptidoglycan is also not well understood. Here, we constructed several penicillin-binding protein (PBP)-deficient strains derived from Z. mobilis S192 to perturb the cell wall peptidoglycan network and then investigated the effects of peptidoglycan on the endoglucanase secretion. The results showed that extracellular recombinant endoglucanase production was significantly enhanced in PBP mutant strains, notably, Δ1089/0959 (4.09-fold) and Δ0959 (5.76-fold) in comparison to parent strains. For PBP-deficient strains, the growth performance was not significantly inhibited, but cell morphology was altered. In addition, enhanced antibiotic sensitivity and reduced inhibitor tolerance were also detected in our study. The concentration of intracellular soluble peptidoglycan was increased, especially for single-gene deletion. Outer membrane permeability of PBP-deficient strains was also improved, notably, Δ1089/0959 (1.14-fold) and Δ0959 (1.07-fold), which might explain the increased endoglucanase extracellular secretion. Our findings indicated that PBP-deficient Z. mobilis was capable of increasing endoglucanase extracellular secretion via cell wall peptidoglycan disturbance, and it will provide a foundation for the development of CBP technology in Z. mobilis in the future. IMPORTANCE Cell wall peptidoglycan has the function to maintain cell robustness and acts as the barrier to secret recombinant proteins from the cytoplasm to extracellular space in Z. mobilis and other bacteria. Herein, we perturbed the peptidoglycan synthesis network via knocking out PBPs (ZMO0197, ZMO0959, ZMO1089) to enhance recombinant endoglycanase extracellular secretion in Z. mobilis S912. This study could lay the foundation for understanding the regulatory network of cell wall synthesis and guide the construction of CBP strains in Z. mobilis.
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Celulase , Celulases , Zymomonas , Celulase/genética , Celulase/metabolismo , Celulases/metabolismo , Proteínas de Ligação às Penicilinas , Peptidoglicano/metabolismo , Zymomonas/genética , Zymomonas/metabolismoRESUMO
Zymomonas mobilis is a gram-negative facultative anaerobic spore, which is generally recognized as a safe. As a promising ethanologenic organism for large-scale bio-ethanol production, Z. mobilis has also shown a good application prospect in food processing and food additive synthesis for its unique physiological characteristics and excellent industrial characteristics. It not only has obvious advantages in food processing and becomes the biorefinery chassis cell for food additives, but also has a certain healthcare effect on human health. Until to now, most of the research is still in theory and laboratory scale, and further research is also needed to achieve industrial production. This review summarized the physiological characteristics and advantages of Z. mobilis in food industry for the first time and further expounds its research status in food industry from three aspects of food additive synthesis, fermentation applications, and prebiotic efficacy, it will provide a theoretical basis for its development and applications in food industry. This review also discussed the shortcomings of its practical applications in the current food industry, and explored other ways to broaden the applications of Z. mobilis in the food industry, to promote its applications in food processing.
Potential applications of Zymomonas mobilis in food industry summarized for the first time.Research status of Z. mobilis in food additive synthesis, fermentation applications, and probiotics are discussed in details.Future research perspectives of Z. mobilis in food industry further proposed.
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The sense of one's own body is a pillar of self-consciousness and could be investigated by inducing human illusions of artificial objects as part of the self. Here, we present a nonhuman primate version of a rubber-hand illusion that allowed us to determine its computational and neuronal mechanisms. We implemented a video-based system in a reaching task in monkeys and combined a casual inference model to establish an objective and quantitative signature for the monkey's body representation. Similar to humans, monkeys were more likely to perceive an external object as part of the self when the dynamics (spatial disparity) and the features (shape and structure) of visual (V) input was closer to proprioceptive (P) signals. Neural signals in the monkey's premotor cortex reflected the strength of illusion and the likelihood of misattributing the illusory hand to oneself, thus, revealing a cortical representation of body ownership.
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Imagem Corporal/psicologia , Encéfalo/fisiologia , Macaca , Modelos Biológicos , Modelos Estatísticos , Animais , Humanos , Ilusões , Córtex Motor/fisiologia , Neurônios/fisiologiaRESUMO
Paragonimus proliferus, a lung fluke of the genus Paragonimus, was first reported in Yunnan province, China. P. proliferus can infect Sprague-Dawley (SD) rats and cause lung damage, but there is still no direct evidence of human infection. Until now, there has been a lack of studies on P. proliferus parasitism and development in mammalian lung tissue. The aim of this study was to perform transcriptomic profiling of P. proliferus at different developmental stages. SD rats were infected with P. proliferus metacercariae obtained from crabs; worms isolated from the lungs at different time points as well as metacercariae were subjected to whole transcriptome sequencing. Overall, 34,403 transcripts with the total length of 33,223,828 bp, average length of 965 bp, and N50 of 1833 bp were assembled. Comparative analysis indicated that P. proliferus, similar to other Paragonimus spp., expressed genes related to catabolism, whereas P. proliferus-specific transcripts were related to the maintenance of cellular redox homeostasis, sensitivity to bacteria, and immune response. Transcriptional dynamics analysis revealed that genes involved in the regulation of catabolism and apoptosis had stable expression over the P. proliferus life cycle, whereas those involved in development and immune response showed time-dependent changes. High expression of genes associated with immune response corresponded to that of genes regulating the sensitivity to bacteria and immune protection. We constructed a P. proliferus developmental model, including the development of the body, suckers, blood cells, reproductive and tracheal systems, lymph, skin, cartilage, and other tissues and organs, and an immune response model, which mainly involved T cells and macrophages. Our study provides a foundation for further research into the molecular biology and infection mechanism of P. proliferus.
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Pulmão/parasitologia , Paragonimíase/patologia , Paragonimus/embriologia , Paragonimus/crescimento & desenvolvimento , Animais , Braquiúros/parasitologia , China , Perfilação da Expressão Gênica , Humanos , Estágios do Ciclo de Vida , Metacercárias/crescimento & desenvolvimento , Paragonimíase/parasitologia , Paragonimus/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Transcriptoma/genéticaRESUMO
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. However, the immune tolerance limits the effect of chemotherapeutic drugs. Therefore, the mechanism of cisplatin in promoting PD-L1 expression by YAP1 was investigated in the present study, and we found that cisplatin increased the expression level of YAP1 in the mouse liver with H22 cells. Meanwhile, cisplatin improved the expression level of PD-L1, IL-1ß and CCL2 in the tumor microenvironment. Further, cisplatin also enhanced the expression level of YAP1 in shYAP1 HepG2215 cells. The expression of PD-L1 was decreased by Verteporfin, YAP1 inhibitor, during the treatment of DEN/TCPOBOP-induced liver cancer in C57BL/6 mice. These results suggested that cisplatin could deteriorate the immunosuppressive microenvironment through increasing PD-L1, CCL2, IL-1ß by upregulated YAP1 expression. Therefore, the study suggested that YAP1 blockade destroyed the immunosuppressive microenvironment of cancer to improve the effect of chemotherapy in HCC.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antígeno B7-H1/biossíntese , Carcinoma Hepatocelular/metabolismo , Cisplatino/farmacologia , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/farmacologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Fotossensibilizantes/farmacologia , Transdução de Sinais , Fatores de Transcrição/genética , Microambiente Tumoral , Verteporfina/farmacologia , Proteínas de Sinalização YAPRESUMO
An a priori map is often unavailable for a mobile robot in a new environment. In a large-scale environment, relying on manual guidance to construct an environment map will result in a huge workload. Hence, an autonomous exploration algorithm is necessary for the mobile robot to complete the exploration actively. This study proposes an autonomous exploration and mapping method based on an incremental caching topology-grid hybrid map (TGHM). Such an algorithm can accomplish the exploration task with high efficiency and high coverage of the established map. The TGHM is a fusion of a topology map, containing the information gain and motion cost for exploration, and a grid map, representing the established map for navigation and localization. At the beginning of one exploration round, the method of candidate target point generation based on geometry rules are applied to extract the candidates quickly. Then, a TGHM is established, and the information gain is evaluated for each candidate topology node on it. Finally, the node with the best evaluation value is selected as the next target point and the topology map is updated after each motion towards it as the end of this round. Simulations and experiments were performed to benchmark the proposed algorithm in robot autonomous exploration and map construction.
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As an effective antimalarial drug, Dihydroartemisinin (DHA) is readily isolated from the traditional Chinese medicine of Artemisia annua. DHA is not only an autophagy promoter but also a substance with strong antitumor efficiency. The relationship between autophagy and inflammasomes has been suggested in hepatocellular carcinoma (HCC). However, there are few reports describing relationships between inflammasomes and autophagy in HCC therapy. The present study demonstrated that DHA suppressed cell proliferation in HepG2215 cells in a dose- and time-dependent manner. The inhibitory activity is mediated by autophagy, in which reactive oxygen species (ROS) production induced nuclear and mitochondrial DNA damage. Then, DHA were first shown to promote AIM2/caspase-1 inflammasome. Compared with the DHA group, the autophagy inhibitor 3-MA significantly inhibited the expressions of activated Caspase-1, a pyroptotic marker proteins. Meanwhile, repression of mTOR by rapamycin promoted autophagy and AIM2/caspase-1 activation. The caspase-1 inhibitor Z-YVAD-FMK also notably blocked autophagy cell death characterized by the downexpression of Beclin-1 and LC3-II. Additionally, the study demonstrated that DHA suppressed pseudopodium formation and cell mobility. Therefore, we first reveal a novel mechanism that DHA promotes AIM2/caspase-1 inflammasome, which contributes to autophagy in HepG2215 cells. Moreover, nuclear and mitochondrial DNA damage was also involved in this process via ROS production.
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Antimaláricos/farmacologia , Artemisininas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Clorometilcetonas de Aminoácidos/farmacologia , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Carcinoma Hepatocelular/metabolismo , Caspase 1/metabolismo , Caspases/metabolismo , Proteínas de Ligação a DNA , Células Hep G2 , Humanos , Inflamassomos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Eupatorin is the major bioactive component of Java tea (Orthosiphon stamineus), exhibiting strong anticancer and anti-inflammatory activities. However, no research on the metabolism of eupatorin has been reported to date. In the present study, ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) combined with an efficient online data acquisition and a multiple data processing method were developed for metabolite identification in vivo (rat plasma, bile, urine and feces) and in vitro (rat liver microsomes and intestinal flora). A total of 51 metabolites in vivo, 60 metabolites in vitro were structurally characterized. The loss of CH2, CH2O, O, CO, oxidation, methylation, glucuronidation, sulfate conjugation, N-acetylation, hydrogenation, ketone formation, glycine conjugation, glutamine conjugation and glucose conjugation were the main metabolic pathways of eupatorin. This was the first identification of metabolites of eupatorin in vivo and in vitro and it will provide reference and valuable evidence for further development of new pharmaceuticals and pharmacological mechanisms.
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Flavonoides/farmacocinética , Glicoconjugados/isolamento & purificação , Microssomos Hepáticos/metabolismo , Orthosiphon/química , Acetilação , Animais , Bile/química , Biotransformação , Fezes/química , Flavonoides/sangue , Flavonoides/urina , Microbioma Gastrointestinal/fisiologia , Glicoconjugados/metabolismo , Hidrogenação , Masculino , Metilação , Oxirredução , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy".
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Carcinoma Hepatocelular , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Microambiente Tumoral/imunologia , Terapia de Alvo Molecular , Animais , Imunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: To explore the anti-tumor and anti-virus key active ingredients of Sini Decoction Plus Ginseng Soup (SNRS) and their mechanisms. METHODS: The main ingredients of SNRS were analyzed by network pharmacology, and quercetin was identified as the key active ingredient. Then, we obtained the targets of quercetin by using Drugbank, PharmMapper, and SwissTargetPrediction databases. Then, the targets of HBV-related hepatocellular carcinoma (HBV-related HCC) were obtained by using Genecards database. In addition, using the gene expression profiles of HBV-related HCC patients in GEO database and the genes with the greatest survival difference in GEPIA 2 database identified the potential targets of quercetin. In addition, the mechanism of potential genes was studied through GO, KEGG analysis, and PPI network. Using AUC and survival analysis to evaluate the diagnostic and prognostic value of cyclin-dependent kinase 1 (CDK1) and CCNB1. Finally, the effects of quercetin on proliferation of Hep3B and HepG2215 cells and the level of CDK1 and CCNB1 were verified in vitro. ELISA was used to measure the expression levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) after the intervention by quercetin for 24 h and 48 h in HepG2215 cell. RESULTS: The first 10 key ingredients of SNRS were identified, and quercetin was the most key ingredient. The 101 potential quercetin targets were identified for the treatment of HBV-related HCC. GO and KEGG showed that 101 potential target enrichment in cancer and cell cycle regulation. By Venn analysis, CDK1 and CCNB1 were intersection targets, which could be used as potential targets for the action of quercetin on HBV-related HCC. Moreover, the expression of CDK1 and CCNB1 was highly expressed in the high-risk group, while the OS rate was low. The 1-year, 3-year and 5-year area under the curve (AUC) curves of CDK1 and CCNB1 were 0.724, 0.676, 0.622 and 0.745, 0.678, 0.634, respectively. Moreover, experimental results also showed that quercetin inhibited cell proliferation and reduced CDK1 expression in Hep3B and HepG2215 cells. The expressions of HBsAg and HBeAg in HepG2215 cell supernatant and cell gradually decreased with the increase of intervention time of quercetin and CDK1 inhibitor. CONCLUSIONS: Quercetin is a key ingredient of anti-HBV-related HCC activity and inhibits HBV replication in SNRS by inhibiting CDK1.
Assuntos
Proteína Quinase CDC2 , Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Panax , Quercetina , Replicação Viral , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/farmacologia , Antivirais/química , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Proteína Quinase CDC2/efeitos dos fármacos , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/efeitos dos fármacos , Ciclina B1/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virologia , Panax/química , Quercetina/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
The Hippo signaling pathway plays a pivotal role in regulating cell growth and organ size. Its regulatory effects on hepatocellular carcinoma (HCC) encompass diverse aspects, including cell proliferation, invasion and metastasis, tumor drug resistance, metabolic reprogramming, immunomodulatory effects and autophagy. Yesassociated protein 1 (YAP1), a potent transcriptional coactivator and a major downstream target tightly controlled by the Hippo pathway, is influenced by various molecules and pathways. The expression of YAP1 in different cell types within the liver tumor microenvironment exerts varying effects on tumor outcomes, warranting careful consideration. Therefore, research on YAP1targeted therapies merits attention. This review discusses the composition and regulation mechanism of the Hippo/YAP1 signaling pathway and its relationship with HCC, offering insights for future research and cancer prevention strategies.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Carcinoma Hepatocelular , Via de Sinalização Hippo , Neoplasias Hepáticas , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fatores de Transcrição/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Sinalização YAP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , AnimaisRESUMO
Sepsis is a severe and life-threatening disease caused by infection, characterized by a dysregulated immune response. Unfortunately, effective treatment strategies for sepsis are still lacking. The intricate interplay between metabolism and the immune system limits the treatment options for sepsis. During sepsis, there is a profound shift in cellular energy metabolism, which triggers a metabolic reprogramming of immune cells. This metabolic alteration impairs immune responses, giving rise to excessive inflammation and immune suppression. Recent research has demonstrated that UCP2 not only serves as a critical target in sepsis but also functions as a key metabolic switch involved in immune cell-mediated inflammatory responses. However, the regulatory mechanisms underlying this modulation are complex. This article focuses on UCP2 as a target and discusses metabolic reprogramming during sepsis and the complex regulatory mechanisms between different stages of inflammation. Our research indicates that overexpression of UCP2 reduces the Warburg effect, restores mitochondrial function, and improves the prognosis of sepsis. This discovery aims to provide a promising approach to address the significant challenges associated with metabolic dysfunction and immune paralysis.