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Pancreatic ductal adenocarcinoma (PDAC) is a digestive system malignancy characterized by challenging early detection, limited treatment alternatives, and generally poor prognosis. Although there have been significant advancements in immunotherapy for hematological malignancies and various solid tumors in recent decades, with impressive outcomes in recent preclinical and clinical trials, the effectiveness of these therapies in treating PDAC continues to be modest. The unique immunological microenvironment of PDAC, especially the abnormal distribution, complex composition, and variable activation states of tumor-infiltrating immune cells, greatly restricts the effectiveness of immunotherapy. Undoubtedly, integrating data from both preclinical models and human studies helps accelerate the identification of reliable molecules and pathways responsive to targeted biological therapies and immunotherapies, thereby continuously optimizing therapeutic combinations. In this review, we delve deeply into how PDAC cells regulate the immune microenvironment through complex signaling networks, affecting the quantity and functional status of immune cells to promote immune escape and tumor progression. Furthermore, we explore the multi-modal immunotherapeutic strategies currently under development, emphasizing the transformation of the immunosuppressive environment into an anti-tumor milieu by targeting specific molecular and cellular pathways, providing insights for the development of novel treatment strategies.
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Gout as a common inflammatory arthritis seriously affects the quality of life of a large number of people. Targeting NLRP3 inflammasome has been certified as a promising therapeutic strategy for gout. This study, a series of new imidazolidinone derivatives were validated as NLRP3 inhibitors by scaffold hopping from the reported NLRP3 inhibitor CSC-6. In contrast to the poor physicochemical properties of the template molecule, the representative compound 23 showed good plasma stability, water solubility, and no significant inhibitory toxicity to CYP450 enzymes. Surface plasmon resonance and immunoblotting experiments showed that compound 23 binds NLRP3 and inhibits NLRP3 activation. Finally, compound 23 showed good anti-inflammatory and analgesic effects in acute peritonitis and arthritis. Overall, the present study provides NLRP3 inhibitors with favorable pharmacological properties, which may not only serve as a tool molecule for studying NLRP3-related functions, but also may further facilitate the gout treatment.
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Anthocyanins, a group of flavonoids, play diverse roles in plant growth and environmental adaptation. The biosynthesis and accumulation of anthocyanin are regulated by environmental cues, such as high light. However, the precise mechanism underlying anthocyanin biosynthesis under high light conditions remains largely unclear. Here, we report that the R3-MYB repressor MYB-LIKE 2 (MYBL2) negatively regulates high light-induced anthocyanin biosynthesis by repressing two R2R3-MYB activators, PRODUCTION OF ANTHOCYANIN PIGMENT 1 (PAP1) and PAP2, which are core components of the MYB-bHLH-WD40 (MBW) complex. We found that MYBL2 interacts with PAP1/2 and reduces their transcriptional activation activities, thus disrupting the expression of key genes involved in anthocyanin biosynthesis, such as DIHYDROFLAVONOL 4-REDUCTASE (DFR) and TRANSPARENT TESTA 19 (TT19). Additionally, MYBL2 attenuates the transcriptional activation of PAP1 on its own expression, but not PAP2. Conversely, PAP1 collaborates with TT8, a bHLH member of the MBW complex, to activate MYBL2 transcription when excessive anthocyanins are accumulated. Taken together, our findings reveal a negative feedback regulatory module composed of MYBL2 and PAP1 that fine-tunes high light-induced anthocyanin biosynthesis through modulating MBW complex assembly.
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Lysosomes have a central role in the disposal of extracellular and intracellular cargo and also function as metabolic sensors and signalling platforms in the immunometabolic reprogramming of macrophages and other immune cells in atherosclerosis. Lysosomes can rapidly sense the presence of nutrients within immune cells, thereby switching from catabolism of extracellular material to the recycling of intracellular cargo. Such a fine-tuned degradative response supports the generation of metabolic building blocks through effectors such as mTORC1 or TFEB. By coupling nutrients to downstream signalling and metabolism, lysosomes serve as a crucial hub for cellular function in innate and adaptive immune cells. Lysosomal dysfunction is now recognized to be a hallmark of atherogenesis. Perturbations in nutrient-sensing and signalling have profound effects on the capacity of immune cells to handle cholesterol, perform phagocytosis and efferocytosis, and limit the activation of the inflammasome and other inflammatory pathways. Strategies to improve lysosomal function hold promise as novel modulators of the immunoinflammatory response associated with atherosclerosis. In this Review, we describe the crosstalk between lysosomal biology and immune cell function and polarization, with a particular focus on cellular immunometabolic reprogramming in the context of atherosclerosis.
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Verticillium wilt (VW) caused by Verticillium dahliae (V. dahliae) is one of the most destructive diseases in cotton (Gossypium spp.). Histone acetylation plays critical roles in plant development and adaptive responses to biotic and abiotic stresses. However, the relevance of histone acetylation in cotton VW resistance remains largely unclear. Here, we identified Histone Deacetylase 5 (GhHDA5) from upland cotton (Gossypium hirsutum L.), as a negative regulator of VW resistance. GhHDA5 expression was responsive to V. dahliae infection. Silencing GhHDA5 in upland cotton led to improved resistance to V. dahliae, while heterologous expression of GhHDA5 in Arabidopsis (Arabidopsis thaliana) compromised V. dahliae tolerance. GhHDA5 repressed the expression of several lignin biosynthesis-related genes, such as 4-coumarate: CoA ligase gene Gh4CL3 and ferulate 5-hydroxylase gene GhF5H, through reducing the acetylation level of Histone H3 Lysine 9 and 14 (H3K9K14ac) at their promoter regions, thereby resulting in an increased deposition of lignin, especially S monomers, in the GhHDA5-silenced cotton plants. The silencing of GhF5H impaired cotton VW tolerance. Additionally, the silencing of GhHDA5 also promoted the production of reactive oxygen species (ROS), elevated the expression of several pathogenesis-related genes (PRs), and altered the content and signaling of the phytohormones salicylic acid (SA), jasmonic acid (JA) and strigolactones (SLs) after V. dahliae infection. Taken together, our findings suggest that GhHDA5 negatively regulates cotton VW resistance through modulating disease-induced lignification and the ROS- and phytohormone-mediated defense response.
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Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are advancing cardiovascular development and disease modeling, drug testing, and regenerative therapies. However, hPSC-CM production is hindered by significant variability in the differentiation process. Establishment of early quality markers to monitor lineage progression and predict terminal differentiation outcomes would address this robustness and reproducibility roadblock in hPSC-CM production. An integrated transcriptomic and epigenomic analysis assesses how attributes of the cardiac progenitor cell (CPC) affect CM differentiation outcome. Resulting analysis identifies predictive markers of CPCs that give rise to high purity CM batches, including TTN, TRIM55, DGKI, MEF2C, MAB21L2, MYL7, LDB3, SLC7A11, and CALD1. Predictive models developed from these genes provide high accuracy in determining terminal CM purities at the CPC stage. Further, insights into mechanisms of batch failure and dominant non-CM cell types generated in failed batches are elucidated. Namely EMT, MAPK, and WNT signaling emerge as significant drivers of batch divergence, giving rise to off-target populations of fibroblasts/mural cells, skeletal myocytes, epicardial cells, and a non-CPC SLC7A11+ subpopulation. This study demonstrates how integrated multi-omic analysis of progenitor cells can identify quality attributes of that progenitor and predict differentiation outcomes, thereby improving differentiation protocols and increasing process robustness.
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Starting from a generic model based on the thermodynamics of mixing and abstracted from the chemistry and microscopic details of solution components, three consistent and complementary computational approaches are deployed to investigate the general condition for polymer cononsolvency in binary mixed solvents at the zeroth order. The study reveals χPS - χPC + χSC as the underlying universal parameter that regulates cononsolvency, where χαß is the immiscibility parameter between the α- and ß-component. Two disparate cononsolvency regimes are identified for χPS - χPC + χSC < 0 and χPS - χPC + χSC > 2, respectively, based on the behavior of the second osmotic virial coefficient at varying solvent mixture composition x C. The predicted condition is verified using self-consistent field calculations by directly examining the polymer conformational transition as a function of x C. It is further shown that in the regime χPS - χPC + χSC < 0, the reentrant polymer conformation transition is driven by maximizing the solvent-cosolvent contact, but in the regime χPS - χPC + χSC > 2, it is driven by promoting polymer and cosolvent contact. In-between the two regimes when neither effect is dominant, a monotonic response of polymer conformation to x C is observed. Effects of the mean-field approximation on the predicted condition are evaluated by comparing the mean-field calculations with computer simulations. It shows that the fluctuation effects lead to a higher threshold value of χPS - χPC + χSC in the second regime, where local enrichment of cosolvent in polymer proximity plays a critical role.
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The NRF2 pathway is a metabolic- and redox-sensitive signaling axis in which the transcription factor controls the expression of a multitude of genes that enable cells to survive environmental stressors, such as oxidative stress, mainly by inducing the expression of cytoprotective genes. Basal NRF2 levels are maintained under normal physiological conditions, but when exposed to oxidative stress, cells activate the NRF2 pathway, which is crucial for supporting cell survival. Recently, the NRF2 pathway has been found to have novel functions in metabolic regulation and interplay with other signaling pathways, offering novel insights into the treatment of various diseases. Numerous studies have shown that targeting its pathway can effectively investigate the development and progression of age-related musculoskeletal diseases, such as sarcopenia, osteoporosis, osteoarthritis, and intervertebral disc degeneration. Appropriate regulation of the NRF2 pathway flux holds promise as a means to improve musculoskeletal function, thereby providing a new avenue for drug treatment of age-related musculoskeletal diseases in clinical settings. The review summarized an overview of the relationship between NRF2 and cellular processes such as oxidative stress, apoptosis, inflammation, mitochondrial dysfunction, ferroptosis, and autophagy, and explores the potential of targeted NRF2 regulation in the treatment of age-related musculoskeletal diseases.
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Ovarian steroid cell tumor, not otherwise specified (SCT-NOS), is a rare subtype of sex cord-stromal tumor, characterized by hirsutism and virilization. There are, however, few tumor markers reported in the tumor. The following is a case report. Six years ago, the patient underwent a left adnexectomy after being diagnosed with a yolk sac tumor. Her serum CA72-4 levels were significantly elevated when she was diagnosed with SCT-NOS. She suffered from hirsutism and oligomenorrhea with long menstrual cycles. SCT-NOS was confirmed by her histopathological examination. When the tumor was diagnosed, serum CA72-4 levels were elevated. Following tumor resection, serum CA72-4 levels returned to the average reference interval. Whole-exome sequencing (WES) was utilized to identify ten mutations in MKI67, TICAM1, CHD3, ARID5B, ERBB4, POLD1, FZR1, MTCP1, TBX3, and CLTC genes.
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Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Humanos , Feminino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/sangue , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/sangue , Tumores do Estroma Gonadal e dos Cordões Sexuais/cirurgia , Adulto , Antígenos Glicosídicos Associados a Tumores/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genéticaRESUMO
Large-scale biosafe T-cell cryopreservation is required to bring T-cell therapies to the market, but it remains challenging due to the cytotoxicity of common cryoprotectants [e.g., dimethyl sulfoxide (DMSO)] and unavoidable ice injuries to cells. Herein, inspired by natural globular antifreeze proteins, we establish a biocompatible zwitterionic magnetic nanoparticle (ZMNP)-based cryoprotection system, achieving large-scale cryopreservation of T cells for lymphoma immunotherapy. ZMNPs could form a globular hydration shell to inhibit water molecule aggregation as well as ice growth, and the surficial hydration strength-antifreeze performance relationship of ZMNPs was investigated. During the thawing process, ZMNPs possessed a magnetic field-mediated nanowarming property that enabled rapid heating and also facilitated easy magnetic separation for cell recovery. These combined effects resulted in a high post-thaw viability (>80%) of large-scale T-cell cryopreservation (20 mL). Notably, post-thaw T cells exhibited similar transcript profiles to fresh cells, while up- or downregulation of 1050 genes was found in the DMSO group. In a mouse E.G7-OVA lymphoma model, ZMNP-system-cryopreserved T cells achieved a tumor suppression rate of 77.5%, twice as high as the DMSO group. This work holds great promise for the application of advanced cryopreservation techniques in the development of therapeutic cellular products.
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AIMS: Silicosis is the most common and severe type of pneumoconiosis, imposing a substantial disease burden and economic loss on patients and society. The pathogenesis and key targets of silicosis are not yet clear, and there are currently no effective treatments available. Therefore, we conducted research on mefunidone (MFD), a novel antifibrotic drug, to explore its efficacy and mechanism of action in murine silicosis. METHODS: Acute 7-day and chronic 28-day silicosis models were constructed in C57BL/6J mice by the intratracheal instillation of silica and subsequently treated with MFD to assess its therapeutic potential. The effects of MFD on silica-induced inflammation, pyroptosis, and fibrosis were further investigated using immortalized mouse bone marrow-derived macrophages (iBMDMs). RESULTS: In the 7-day silica-exposed mouse models, MFD treatment significantly alleviated pulmonary inflammation and notably reduced macrophage infiltration into the lung tissue. RNA-sequencing analysis of silica-induced iBMDMs followed by gene set enrichment analysis revealed that MFD profoundly influenced cytokine-cytokine receptor interactions, chemokine signaling, and the toll-like receptor signaling pathways. MFD treatment also markedly reduced the secretion of inflammatory cytokines and chemokines from silica-exposed iBMDMs. Moreover, MFD effectively downregulated the activation of the TLR4-NF-κB/MAPK signaling pathway induced by silica and mitigated the upregulation of pyroptosis markers. Additionally, MFD treatment significantly suppressed the activation of fibroblasts and alveolar epithelial cells co-cultured with silica-exposed mouse macrophages. Ultimately, in the 28-day silica-exposed mouse models, MFD administration led to a substantial reduction in the severity of pulmonary fibrosis. CONCLUSION: MFD mitigates silica-induced pulmonary inflammation and fibrosis in mice by suppressing the TLR4-NF-κB/MAPK signaling pathway and reducing pyroptotic responses in macrophages. MFD could potentially emerge as a novel therapeutic agent for the treatment of silicosis.
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Sistema de Sinalização das MAP Quinases , Macrófagos , Piroptose , Dióxido de Silício , Silicose , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Fibrose Pulmonar/metabolismo , Piridonas/farmacologia , Piroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício/toxicidade , Silicose/tratamento farmacológico , Silicose/patologia , Silicose/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
The integrity of wheat (Triticum aestivum) production is increasingly jeopardized by the fungal pathogen Blumeria graminis f. sp. tritici (Bgt), particularly amid the vicissitudes of climate change. Here, we delineated the role of a wheat transcription factor, TaNAC1, which precipitates cellular apoptosis and fortifies resistance against Bgt. Utilizing BiFC, co-immunoprecipitation, protein quantification, luciferase report assays, we determined that cytoplasmic TaNAC1-7A undergoes phosphorylation at the S184/S258 sites by TaCDPK20, facilitating its nuclear translocation. This migration appears to prime further phosphorylation by TaMPK1, thereby enhancing transcriptional regulatory activity. Notably, the apoptotic activity of phosphorylated TaNAC1-7A is negatively modulated by the nuclear protein phosphatase PP2Ac. Furthermore, activation of TaNAC1 phosphorylation initiates transcription of downstream genes TaSec1a and TaCAMTA4, through binding to the C[T/G]T[N7]A[A/C]G nucleic acid motif. Suppression of TaNAC1, TaCDPK20, and TaMPK1 in wheat compromises its resistance to Bgt strain E09, whereas overexpression of TaNAC1 and silencing of PP2Ac markedly elevate resistance levels. Our results reveal the pivotal role of TaNAC1 in basal resistance which is mediated by its effects on homotypic fusion, vacuolar protein sorting, and the expression of defense-related genes. The findings highlight the potential through targeting TaNAC1 and its regulators as a strategy for improving wheat's resistance to fungal pathogens.
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BACKGROUND: Adriamycin (ADR) is a widely used chemotherapy drug in clinical practice and it causes toxicity in the myocardium affecting its clinical use. miR-432-5p is a miRNA primarily expressed in myocardial cells and has a protective effect in the myocardium. We aim to explore the protective effect of miR-432-5p on ADR-caused impaired mitochondrial ATP metabolism and endoplasmic reticulum stress (ERs). METHOD: The primary cardiomyocytes were obtained from neonatal mice and the ADR was added to cells, meanwhile, a mice model was constructed through intravenous ADR challenge, and expression levels of miR-432-5p were examined. Subsequently, the miR-432-5p was introduced in vitro and in vivo to explore its effect on the activity of mitochondrial ATP synthesis, autophagy, and ER stress. The bioinformatics analysis was performed to explore the target of miR-432-5p. RESULTS: ADR decreased the expression of miR-432-5p in cardiomyocytes. It also decreases mitochondrial ATP production and activates the ER stress pathway by increasing the expression of LC3B, Beclin 1, cleaved caspase 3, and induces cardiac toxicity. miR-432-5p exogenous supplementation can reduce the cardiotoxicity caused by ADR, and its protective effect on cardiomyocytes depends on the down-regulation of the RTN3 signaling pathway in ER. CONCLUSION: ADR can induce the low expression of miR-432-5p, and activate the RTN3 pathway in ER, increase the expression of LC3B, Beclin 1, cleaved caspase 3, CHOP, and RTN3, and induce cardiac toxicity.
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Cardiotoxicidade , Regulação para Baixo , Doxorrubicina , Estresse do Retículo Endoplasmático , MicroRNAs , Miócitos Cardíacos , Transdução de Sinais , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Doxorrubicina/toxicidade , Doxorrubicina/efeitos adversos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/genética , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , MasculinoRESUMO
Drought dramatically affects plant growth and yield. A previous study indicated that endophytic fungus Phomopsis liquidambaris can improve the drought resistance of peanuts, which is related with the root arbuscular mycorrhizal fungi (AMF) community; however, how root endophytes mediate AMF assembly to affect plant drought resistance remains unclear. Here, we explored the mechanism by which endophytic fungus recruits AMF symbiotic partners via rhizodeposits to improve host drought resistance. The results showed that Ph. liquidambaris enhanced peanut drought resistance by enriching the AMF genus Claroideoglomus of the rhizosphere. Furthermore, metabolomic analysis indicated that Ph. liquidambaris significantly promoted isoformononetin and salicylic acid (SA) synthesis in rhizodeposits, which were correlated with the increase in Claroideoglomus abundance following Ph. liquidambaris inoculation. Coinoculation experiments confirmed that isoformononetin and SA could enrich Claroideoglomus etunicatum in the rhizosphere, thereby improving the drought resistance. This study highlights the crucial role of fungal consortia in plant stress resistance.
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Arachis , Secas , Endófitos , Micorrizas , Raízes de Plantas , Rizosfera , Simbiose , Arachis/microbiologia , Arachis/crescimento & desenvolvimento , Arachis/metabolismo , Endófitos/fisiologia , Endófitos/metabolismo , Micorrizas/fisiologia , Raízes de Plantas/microbiologia , Raízes de Plantas/crescimento & desenvolvimento , Ascomicetos/fisiologia , Glomeromycota/fisiologia , Microbiologia do Solo , Resistência à SecaRESUMO
To improve the solubility of the fluoroquinolone drug fleroxacin (FL), based on the previous experience of our research group in synthesizing co-crystals/salts of quinolone drugs to improve the physicochemical properties of drugs, Fleroxacin-D-tartaric acid dihydrate salt (FL-D-TT, C17H19F3N3O3·C4H5O6·2(H2O)), was synthesized for the first time using fleroxacin and D/L-tartaric acid (D/L-TT). Structural characterization of FL-D-TT was carried out using single-crystal X-ray diffraction, infrared spectral analysis (FT-IR) and powder X-ray diffraction (PXRD). Molecular electrostatic potential analysis showed that D-tartaric acid interacted more readily with FL than L-tartaric acid. The solubility of FL-D-TT (9.71 mg/mL, 1.82 mg/mL) was significantly higher compared to FL (0.39 mg/mL, 0.71 mg/mL) in water and buffer solution at pH 7.4. This may be attributed to the formation of charge-assisted hydrogen bonds (CAHBs) between FL and D-TT that facilitates the dissociation of FL cations in the dissolution medium, leading to an increase in FL solubility. This also led to some improvement in the in vitro antimicrobial activity of FL-D-TT against E. coli, S. typhi, and S. aureus. In addition, the hygroscopic stability of FL has been improved. Surprisingly, FL-D-TT had better photostability than FL, which could be attributed to the introduction of D-TT to make the photosensitizing moiety of FL more stable, which led to the improvement of the photostability of FL.
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Estabilidade de Medicamentos , Fleroxacino , Solubilidade , Tartaratos , Tartaratos/química , Fleroxacino/química , Testes de Sensibilidade Microbiana/métodos , Molhabilidade , Difração de Raios X/métodos , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Staphylococcus aureus/efeitos dos fármacos , Sais/química , Química Farmacêutica/métodosRESUMO
To alleviate bone loss, most current drugs target osteoclasts. Saikosaponin A (Ssa), a triterpene saponin derived from Bupleurum falcatum (also known as Radix bupleuri), has immunoregulatory, neuromodulatory, antiviral, anticancer, anti-convulsant, anti-inflammatory, and anti-proliferative effects. Recently, modulation of bone homeostasis was shown to involve ferroptosis. Herein, we aimed to determine Ssa's inhibitory effects on osteoclastogenesis and differentiation, whether ferroptosis is involved, and the underlying mechanisms. Tartrate-resistant acid phosphatase (TRAP) staining, F-actin staining, and pit formation assays were conducted to confirm Ssa-mediated inhibition of RANKL-induced osteoclastogenesis in vitro. Ssa could promote osteoclast ferroptosis and increase mitochondrial damage by promoting lipid peroxidation, as measured by iron quantification, FerroOrange staining, Dichloro-dihydro-fluorescein diacetate, MitoSOX, malondialdehyde, glutathione, and boron-dipyrromethene 581/591 C11 assays. Pathway analysis showed that Ssa can promote osteoclasts ferroptosis by inhibiting the Nrf2/SCL7A11/GPX4 axis. Notably, we found that the ferroptosis inhibitor ferrostatin-1 and the Nrf2 activator tert-Butylhydroquinone reversed the inhibitory effects of Ssa on RANKL-induced osteoclastogenesis. In vivo, micro-computed tomography, hematoxylin and eosin staining, TRAP staining, enzyme-linked immunosorbent assays, and immunofluorescence confirmed that in rats with periodontitis induced by lipopolysaccharide, treatment with Ssa reduced alveolar bone resorption dose-dependently. The results suggested Ssa as a promising drug to treat osteolytic diseases.
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BACKGROUND: Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear. METHODS: Integration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed. RESULTS: We established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1+ metabolism subtype (Metab-subtype), TOP2A+ proliferation phenotype (Prol-phenotype), and S100A6+ pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-ß signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop between tumor cells and fibroblasts mediated by SPP1-CD44 and CCN2/TGF-ß-TGFBR1 interaction pairs. Inhibiting CCN2 disrupted the loop, mitigated the transformation to EMT-subtype, and suppressed metastasis. CONCLUSION: By establishing a heterogeneity landscape of malignant cells, we identified a three-subtype classification in HCC. Among them, S100A6+ tumor cells play a crucial role in metastasis. Targeting the feedback loop between tumor cells and fibroblasts is a promising anti-metastatic strategy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Análise de Célula Única , Microambiente Tumoral , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Regulação Neoplásica da Expressão Gênica , Transição Epitelial-Mesenquimal/genética , Animais , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Heterogeneidade Genética , Camundongos , Linhagem Celular Tumoral , Prognóstico , Perfilação da Expressão Gênica , Transcriptoma , Biologia Computacional/métodos , Metástase NeoplásicaRESUMO
Milk-derived extracellular vesicles (mEVs) are beneficial to the health of infants. However, the effect of mEVs on early intestinal inflammation is not well established. Herein, weaned colitic mice were used to explore the potential effects and underlying mechanisms of porcine mEVs (pmEVs) on intestinal inflammation during early life. We found that pmEVs administration attenuated early life intestinal inflammation and promoted colonic barrier integrity in mice. The anti-inflammatory effect of pmEVs was achieved by shifting a proinflammatory macrophage (M1) toward an anti-inflammatory macrophage (M2). Moreover, pmEVs can be absorbed by macrophages and reduce proinflammatory polarization (stimulated by LPS) in vitro. Noteworthily, ssc-let-7c was found to be highly expressed in pmEVs that can regulate the polarization of macrophages by targeting the tensin homologue deleted on chromosome ten (PTEN), thereby activating the PI3K/Akt pathway. Collectively, our findings revealed a crucial role of mEVs in early intestinal immunity and its underlying mechanism.
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The atomic precision of metal nanoclusters and variability of surface ligands pave the way for its rational design and functionalization, whereas the property strengthening in multiple ways has been long challenging. Herein, improved amphiphilicity, chirality, thermostability, and strong CPL (circularly polarized luminescence) properties have been accomplished by facile ligand exchange of [Au23(CHT)16]- with HCapt (HCHT and HCapt denote cyclohexanethiol and captopril). In addition, the obtained chiral [Au23(SR)16]- (short for [Au23(CHT)16-x(Capt)x]-) clusters show specific binding affinity to remote-diamines (such as arginine and single/double strand DNA), originating from the hydrogen bonding and Van der Walls interaction among the surface Capt ligands and the di-amine groups.
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Solar-driven interface desalination has emerged as a promising strategy to address the global freshwater shortage crisis. However, the separation and recovery of multicomponent oil-contaminated seawater remain a key challenge. This study reports a novel high-strength Janus photothermal membrane with a unique reverse wettability design. On one side, the membrane has hydrophilic and oleophobic properties, while on the other, it has hydrophobic and oleophilic characteristics. The Janus membrane demonstrates dual functionality: solar desalination and oil-water separation. This dual functionality enables efficient separation and recovery of four components from contaminated seawater: purified water, salt crystals, light oil, and heavy oil. As a result, the Janus membrane achieves an evaporation rate of 2.06 kg m-2 h-1 under 1.0 sun. The ion (Na+, K+, Ca2+, and Mg2+) removal rate approaches 100% with nearly complete recovery of salt crystals. Furthermore, various types of oils can be accurately separated, with separation efficiency approaching 100%. An integrated separation device successfully separates and recovers the four components. This research presents significant potential for efficient separation and recovery of complex components in oil-contaminated seawater.