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Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
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Imunoterapia , Lipídeos , RNA , Microambiente Tumoral , Animais , Cães , Feminino , Humanos , Camundongos , Antígenos de Neoplasias/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Glioblastoma/terapia , Glioblastoma/imunologia , Glioma/terapia , Glioma/imunologia , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Neoplasias/imunologia , RNA/química , RNA/uso terapêutico , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Lipídeos/químicaRESUMO
The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.
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Proteína 7 Semelhante a Angiopoietina , Proteína 1 Inibidora de Diferenciação , Leucemia Mieloide Aguda , Animais , Camundongos , Proteína 7 Semelhante a Angiopoietina/genética , Proteína 7 Semelhante a Angiopoietina/metabolismo , Medula Óssea/metabolismo , Modelos Animais de Doenças , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Microambiente Tumoral , Humanos , Proteína 1 Inibidora de Diferenciação/metabolismoRESUMO
Contamination by toxic substances is a major global food safety issue, which poses a serious threat to human health. Mycotoxins are major class of food contaminants, mainly including aflatoxins (AFs), zearalenone (ZON), deoxynivalenol (DON), ochratoxin A (OTA), fumonisins (FBs) and patulin (PAT). Ferroptosis is a newly identified iron-dependent form of programmed or regulated cell death, which has been found to be involved in diverse pathological conditions. Recently, a growing body of evidence has shown that ferroptosis is implicated in the toxicities induced by certain types of food-borne mycotoxins, which provides novel mechanistic insights into mycotoxin-induced toxicities and paves the way for developing ferroptosis-based strategy to combat against toxicities of mycotoxins. In this review article, we summarize the key findings on the involvement of ferroptosis in mycotoxin-induced toxicities and propose issues that need to be addressed in future studies for better utilization of ferroptosis-based approach to manage the toxic effects of mycotoxin contamination.
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Ferroptose , Micotoxinas , Tricotecenos , Zearalenona , Humanos , Micotoxinas/toxicidade , Micotoxinas/análise , Tricotecenos/toxicidade , Tricotecenos/análise , Contaminação de Alimentos/análise , Apoptose , Zearalenona/análise , Zearalenona/toxicidadeRESUMO
Chiral aliphatic amine compounds exhibit a range of physiological activities, making them highly sought-after in the pharmaceutical industry and biological research. One notable obstacle in studying these compounds stems from the pronounced steric hindrance surrounding the nitrogen atom. This characteristic often leads to a weak affinity of acyclic secondary amines for molecular probes, making their chiral discrimination intricate. In response to this challenge, our research has unveiled a novel 19F-labeled probe adept at recognizing and distinguishing between enantiomers of these acyclic secondary amines. By strategically incorporating a single fluorine atom as the 19F label, we have managed to diminish the steric hindrance at the binding site. This alteration bolsters the probe's affinity toward bulkier analytes. As a testament to its effectiveness, we have successfully employed our probe in the chiral analysis of relevant pharmaceuticals, accurately determining their enantiocomposition.
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Neurotoxicity is a common side effect of certain types of therapeutic drugs, posing a major hurdle for their clinical application. Accumulating evidence suggests that ferroptosis is involved in the neurotoxicity induced by these drugs. Therefore, targeting ferroptosis is considered to be a reasonable approach to prevent such side effect. Arctigenin (ATG) is a major bioactive ingredient of Arctium lappa L., a popular medicinal plant in Asia, and has been reported to have multiple bioactivities including neuroprotection. However, the mechanisms underlying the neuroprotection of ATG has not been well elucidated. The purpose of this study was to investigate whether the neuroprotection of ATG was associated with its ability to protect neuronal cells from ferroptosis. Using neuronal cell ferroptosis model induced by either classic ferroptosis induces or therapeutic drugs, we demonstrated for the first time that ATG in the nanomolar concentration range effectively prevented neuronal cell ferroptosis induced by classic ferroptosis inducer sulfasalazine (SAS) and erastin (Era), or therapeutic drug oxaliplatin (OXA) and 5-fluorouracil (5-FU). Mechanistically, we uncovered that the anti-ferroptotic effect of ATG was attributed to its ability to activate SLC7A11-cystine-cysteine axis. The findings of the present study implicate that ATG holds great potential to be developed as a novel agent for preventing SLC7A11 inhibition-mediated neurotoxicity.
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Antineoplásicos , Ferroptose , Furanos , Lignanas , Síndromes Neurotóxicas , Humanos , Cisteína , Cistina , Fluoruracila , Antineoplásicos/farmacologia , Sistema y+ de Transporte de AminoácidosRESUMO
BACKGROUND: Patients with inflammatory bowel disease (IBD), dysbiosis, and immunosuppression who receive fecal microbiota transplantation (FMT) from healthy donors are at an increased risk of developing bacteremia. This study investigates the efficacy of a mixture of seven short-chain fatty acid (SCFA)-producing bacterial strains (7-mix), the resulting culture supernatant mixture (mix-sup), and FMT for treating experimental ulcerative colitis (UC) and evaluates underlying mechanisms. METHODS: Utilizing culturomics, we isolated and cultured SCFA-producing bacteria from the stool of healthy donors. We used a mouse model of acute UC induced by dextran sulfate sodium (DSS) to assess the effects of 7-mix, mix-sup, and FMT on intestinal inflammation and barrier function, microbial abundance and diversity, and gut macrophage polarization by flow cytometry, immunohistochemistry, 16S rRNA gene sequencing, and transwell assays. RESULTS: The abundance of several SCFA-producing bacterial taxa decreased in patients with UC. Seven-mix and mix-sup suppressed the inflammatory response and enhanced intestinal mucosal barrier function in the mouse model of UC to an extent similar to or superior to that of FMT. Moreover, 7-mix and mix-sup increased the abundance of SCFA-producing bacteria and SCFA concentrations in colitic mice. The effects of these interventions on the inflammatory response and gut barrier function were mediated by JAK/STAT3/FOXO3 axis inactivation in macrophages by inducing M2 macrophage polarization in vivo and in vitro. CONCLUSIONS: Our approach provides new opportunities to rationally harness live gut probiotic strains and metabolites to reduce intestinal inflammation, restore gut microbial composition, and expedite the development of safe and effective treatments for IBD.
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Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Fator de Transcrição STAT3 , Humanos , Camundongos , Animais , Colite Ulcerativa/terapia , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Ácidos Graxos Voláteis/efeitos adversos , Ácidos Graxos Voláteis/metabolismo , Bactérias/metabolismo , Modelos Animais de Doenças , Inflamação , Sulfato de Dextrana/efeitos adversos , Camundongos Endogâmicos C57BL , Colo , Proteína Forkhead Box O3/metabolismoRESUMO
BACKGROUND: Probiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis. RESULTS: The inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells. CONCLUSIONS: Abx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.
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Colite , Doenças Inflamatórias Intestinais , Probióticos , Humanos , Animais , Camundongos , Antibacterianos/efeitos adversos , Células Th2 , Células Th17 , Colite/induzido quimicamente , Colite/prevenção & controle , Probióticos/farmacologia , Inflamação , Imunidade , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Integral imaging is a kind of true three-dimensional (3D) display technology that uses a lens array to reconstruct vivid 3D images with full parallax and true color. In order to present a high-quality 3D image, it's vital to correct the axial position error caused by the misalignment and deformation of the lens array which makes the reconstructed lights deviate from the correct directions, resulting in severe voxel drifting and image blurring. We proposed a sub-pixel marking method to measure the axial position error of the lenses with great accuracy by addressing the sub-pixels under each lens and forming a homologous sub-pixel pair. The proposed measurement method relies on the geometric center alignment of image points, which is specifically expressed as the overlap between the test 3D voxel and the reference 3D voxel. Hence, measurement accuracy could be higher. Additionally, a depth-based sub-pixel correction method was proposed to eliminate the voxel drifting. The proposed correction method takes the voxel depth into consideration in the correction coefficient, and achieves accurate error correction for 3D images with different depths. The experimental results well confirmed that the proposed measuring and correction methods can greatly suppress the voxel drifting caused by the axial position error of the lenses, and greatly improve the 3D image quality.
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Taxol is widely used in the treatment of nasopharyngeal carcinoma (NPC); nevertheless, the acquired resistance of NPC to Taxol remains one of the major obstacles in clinical treatment. In this study, we aimed to investigate the role and mechanism of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in Taxol resistance of NPC. Taxol-resistant NPC cell lines were established by exposing to gradually increased concentration of Taxol. Relative mRNA and protein levels were tested using qRT-PCR and western blot, respectively. NPC cell viability and apoptosis were assessed by cell counting kit-8 and flow cytometry analysis, respectively. Cell migration and invasion capacities were measured using transwell assay. Interaction between IGF2BP1 and AKT2 was examined by RNA immunoprecipitation assay. The N6-methyladenosine level of AKT2 was tested using methylated RNA immunoprecipitation-qPCR. IGF2BP1 expression was enhanced in Taxol-resistant NPC cell lines. Knockdown of IGF2BP1 strikingly enhanced the sensitivity of NPC cells to Taxol and repressed the migration and invasion of NPC cells. Mechanistically, IGF2BP1 elevated the expression of AKT2 by increasing its mRNA stability. Furthermore, overexpression of AKT2 reversed the inhibitory roles of IGF2BP1 silence on Taxol resistance and metastasis. Our results indicated that IGF2BP1 knockdown enhanced the sensitivity of NPC cells to Taxol by decreasing the expression of AKT2, implying that IGF2BP1 might be promising candidate target for NPC treatment.
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Apoptose , Movimento Celular , Resistencia a Medicamentos Antineoplásicos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Paclitaxel , Proteínas Proto-Oncogênicas c-akt , Proteínas de Ligação a RNA , Humanos , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/genética , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/farmacologia , Regulação para Cima , Proliferação de Células/efeitos dos fármacos , Adenosina/análogos & derivados , Adenosina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
This study delves into the ion recognition capabilities of a novel host molecule, emphasizing the role of conformational locking in dictating ion selectivity. By employing the Buchwald-Hartwig cross-coupling reaction, we have notably shifted the ion receptor's selectivity from K+ to Na+. The findings are supported by computational simulations that reveal differences in binding energies and molecular strain impacting ion recognition. This innovative structural modification broadens the scope for alterations at the calix[4]arene's lower rim, paving the way for new methods and strategies in modulating ion recognition selectivity.
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B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-ß signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-ß or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.
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Cirrose Hepática , Transdução de Sinais , Camundongos , Animais , Humanos , Celecoxib/farmacologia , Celecoxib/uso terapêutico , Celecoxib/metabolismo , Ciclo-Oxigenase 2 , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/farmacologia , Células Epiteliais/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Receptores CXCR4/genética , Proliferação de CélulasRESUMO
BACKGROUND: The molecular diversity exhibited by diffuse large B-cell lymphoma (DLBCL) is a significant obstacle facing current precision therapies. However, scoring using the International Prognostic Index (IPI) is inadequate when fully predicting the development of DLBCL. Reprogramming lipid metabolism is crucial for DLBCL carcinogenesis and expansion, while a predictive approach derived from lipid metabolism-associated genes (LMAGs) has not yet been recognized for DLBCL. METHODS: Gene expression profiles of DLBCL were generated using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The LASSO Cox regression was used to construct an effective predictive risk-scoring model for DLBCL patients. The Kaplan-Meier survival assessment was employed to compare a given risk score with the IPI score and its impact on the survival of DLBCL patients. Functional enrichment examination was performed utilizing the KEGG pathway. After identifying hub genes via single-sample GSEA (ssGSEA), immunohistochemical staining and immunofluorescence were performed on lymph node samples from control and DLBCL patients to confirm these identified genes. RESULTS: Sixteen lipid metabolism- and survival-associated genes were identified to construct a prognostic risk-scoring approach. This model demonstrated robust performance over various datasets and emerged as an autonomous risk factor for predicting the development of DLBCL patients. The risk score could significantly distinguish the development of DLBCL patients from the low-risk and elevated-risk IPI classes. Results from the inhibitory immune-related pathways and lower immune scores suggested an immunosuppressive phenotype within the elevated-risk group. Three hub genes, MECR, ARSK, and RAN, were identified to be negatively correlated with activated CD8 T cells and natural killer T cells in the elevated-risk score class. Ultimately, it was determined that these three genes were expressed by lymphoma cells but not by T cells in clinical samples from DLBCL patients. CONCLUSION: The risk level model derived from 16 lipid metabolism-associated genes represents a prognostic biomarker for DLBCL that is novel, robust, and may have an immunosuppressive role. It can compensate for the limitations of the IPI score in predicting overall survival and has potential clinical application value.
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Metabolismo dos Lipídeos , Linfoma Difuso de Grandes Células B , Humanos , Metabolismo dos Lipídeos/genética , Linfoma Difuso de Grandes Células B/genética , Fatores de Risco , Carcinogênese , Bases de Dados FactuaisRESUMO
Working- and long-term memory are often studied in isolation. To better understand the specific limitations of working memory, effort is made to reduce the potential influence of long-term memory on performance in working memory tasks (e.g., asking participants to remember artificial, abstract items rather than familiar real-world objects). However, in everyday life we use working- and long-term memory in tandem. Here, our goal was to characterize how long-term memory can be recruited to circumvent capacity limits in a typical visual working memory task (i.e., remembering colored squares). Prior work has shown that incidental repetitions of working memory arrays often do not improve visual working memory performance - even after dozens of incidental repetitions, working memory performance often shows no improvement for repeated arrays. Here, we used a whole-report working memory task with explicit rather than incidental repetitions of arrays. In contrast to prior work with incidental repetitions, in two behavioral experiments we found that explicit repetitions of arrays yielded robust improvement to working memory performance, even after a single repetition. Participants performed above chance at recognizing repeated arrays in a later long-term memory test, consistent with the idea that long-term memory was used to rapidly improve performance across array repetitions. Finally, we analyzed inter-item response times and we found a response time signature of chunk formation that only emerged after the array was repeated (inter-response time slowing after two to three items); thus, inter-item response times may be useful for examining the coordinated interaction of visual working and long-term memory in future work.
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BACKGROUND: Accurate differentiation of extremity soft-tissue tumors (ESTTs) is important for treatment planning. PURPOSE: To develop and validate an ultrasound (US) image-based radiomics signature to predict ESTTs malignancy. MATERIAL AND METHODS: A dataset of US images from 108 ESTTs were retrospectively enrolled and divided into the training cohort (78 ESTTs) and validation cohort (30 ESTTs). A total of 1037 radiomics features were extracted from each US image. The most useful predictive radiomics features were selected by the maximum relevance and minimum redundancy method, least absolute shrinkage, and selection operator algorithm in the training cohort. A US-based radiomics signature was built based on these selected radiomics features. In addition, a conventional radiologic model based on the US features from the interpretation of two experienced radiologists was developed by a multivariate logistic regression algorithm. The diagnostic performances of the selected radiomics features, the US-based radiomics signature, and the conventional radiologic model for differentiating ESTTs were evaluated and compared in the validation cohort. RESULTS: In the validation cohort, the area under the curve (AUC), sensitivity, and specificity of the US-based radiomics signature for predicting ESTTs malignancy were 0.866, 84.2%, and 81.8%, respectively. The US-based radiomics signature had better diagnostic predictability for predicting ESTT malignancy than the best single radiomics feature and the conventional radiologic model (AUC = 0.866 vs. 0.719 vs. 0.681 for the validation cohort, all P <0.05). CONCLUSION: The US-based radiomics signature could provide a potential imaging biomarker to accurately predict ESTT malignancy.
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Extremidades , Neoplasias de Tecidos Moles , Ultrassonografia , Humanos , Feminino , Masculino , Ultrassonografia/métodos , Neoplasias de Tecidos Moles/diagnóstico por imagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Extremidades/diagnóstico por imagem , Idoso , Sensibilidade e Especificidade , Adulto Jovem , Valor Preditivo dos Testes , Adolescente , Idoso de 80 Anos ou mais , RadiômicaRESUMO
Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti-FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography-ion mobility spectrometry (GC-IMS), such as 2-heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath-induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti-FS effect through regulating neurotransmitter disorder and gut microbiota.
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BACKGROUND: Splenomegaly can exacerbate liver cirrhosis and portal hypertension. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the mechanism of cirrhotic splenomegaly remains unclear, thus becoming the focus of the present study. MATERIALS AND METHODS: Thioacetamide (TAA) intraperitoneal injection was used to induce cirrhotic splenomegaly. Rats were randomized into the control, TAA and TAA + celecoxib groups. Histological analysis and high-throughput RNA sequencing of the spleen were conducted. Splenic collagen III, α-SMA, Ki-67, and VEGF were quantified. RESULTS: A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib presents to ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA + celecoxib vs. TAA. Gene ontology (GO) and KEGG analyses collectively indicated that celecoxib may attenuate cirrhotic splenomegaly through the suppression of splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts on these factors were subsequently validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA. CONCLUSIONS: Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study sheds light on the therapeutic strategy of liver cirrhosis by targeting splenic abnormalities and provides COX-2 inhibitors as a novel medical treatment for cirrhotic splenomegaly.
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Cirrose Hepática , Esplenomegalia , Ratos , Animais , Celecoxib/farmacologia , Esplenomegalia/tratamento farmacológico , Esplenomegalia/etiologia , Esplenomegalia/patologia , Antígeno Ki-67 , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Colágeno , Inflamação/tratamento farmacológico , Perfilação da Expressão GênicaRESUMO
Acute kidney injury (AKI) is a common clinical problem with high morbidity and mortality. The discovery of ferroptosis has provided novel insights into the mechanisms underlying AKI and paves the way for developing ferroptosis-based approaches to treat AKI. Glycyrol (GC) is a representative coumarin compound isolated from licorice that demonstrates various pharmacological activities. However, its potential for a protective effect against kidney injury remains unknown. We hypothesized that GC might be able to protect against AKI via suppression of ferroptosis. This hypothesis was tested in a cell-culture model of RSL3-induced nephrocyte ferroptosis and a mouse model of folic acid-induced AKI. The results showed that GC exerted a significant protective effect against nephrocyte ferroptosis in vitro and was effective against folic acid-induced AKI in vivo, where it was mechanistically associated with suppressing HO-1-mediated heme degradation. Collectively, the findings of the present study support the hypothesis that GC holds considerable potential to be developed as a novel agent for treating ferroptosis-related AKI.
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Injúria Renal Aguda , Animais , Camundongos , Flavonoides , Técnicas de Cultura de Células , Ácido FólicoRESUMO
Recently, nanomaterials have attracted extensive attention in cancer-targeting therapy and as drug delivery vehicles owing to their unique surface and size properties. Multifunctional combinations of nanomaterials have become a research hotspot as researchers aim to provide a full understanding of their nanomaterial characteristics. In this study, metal-organic framework-capped gold nanorod hybrids were synthesized. Our research explored their ability to kill tumor cells by locally increasing the temperature via photothermal conclusion. The specific peroxidase-like activity endows the hybrids with the ability to disrupt the oxidative balance in vitro. Simultaneously, chemotherapeutic drugs are administered and delivered by loading and transportation for effective combinatorial cancer treatment, thereby enhancing the curative effect and reducing the unpredictable toxicity and side effects of large doses of chemotherapeutic drugs. These studies can improve combinatorial cancer therapy and enhance cancer treatment.
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Antineoplásicos , Ouro , Estruturas Metalorgânicas , Nanotubos , Neoplasias , Ouro/química , Nanotubos/química , Estruturas Metalorgânicas/química , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Nanopartículas Metálicas/química , AnimaisRESUMO
Chitosan was used as the raw material. A quaternization reaction was carried out between 2,3-epoxypropyltrimethylammonium chloride and water-soluble chitosan to prepare quaternary ammonium salt water-soluble chitosan (QWSC), and its corrosion inhibition performance against the corrosion of carbon steel in stone processing wastewater was evaluated. The corrosion inhibition efficiencies of QWSC on carbon steel in stone processing wastewater were investigated through weight loss, as well as electrochemical and surface morphology characterization techniques. The results show that QWSC has superior corrosion inhibition performance for A3 carbon steel. When an amount of 60 mL·L-1 is added, the corrosion inhibition efficiency can reach 59.51%. Electrochemical research has shown that a QWSC inhibitor is a mixed-type corrosion inhibitor. The inhibition mechanisms of the QWSC inhibitor revealed that the positive charge on the surface of carbon steel in stone wastewater was conducive to the adsorption of Cl- in the medium, which produced an excessive negative charge on the metal's surface. At the same time, the quaternary ammonium cation and amino cation formed in QWSC in stone processing wastewater can be physically absorbed on the surface of A3 carbon steel, forming a thin-film inhibitor to prevent metal corrosion.
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BACKGROUND: Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma. METHODS: We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up. FINDINGS: From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths. INTERPRETATION: Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.