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Cellulose molecules, as the basic unit of biomass cellulose, have demonstrated advancements in versatile engineering and modification of cellulose toward sustainable and promising materials in our low-carbon society. However, harvesting high-quality cellulose molecules from natural cellulosic fibers (CF) remains challenging due to strong hydrogen bonds and unique crystalline structure, which limit solvents (such as ionic liquid, IL) transport and diffusion within CF, making the process energy/time-intensively. Herein, we superfast and sustainably engineer biomass fibers into high-performance cellulose molecules via ethanol pre-swelling of CF followed by IL treatment in the microwave (MW) system. Ethanol-pre-swelled cellulosic fibers (SCF) feature modified morphological and structural distinctions, with improved fiber width, pore size, and specific surface area. The ethanol in the SCF structure is appropriately removed through MW heating and cooling, leaving transport and diffusion pathways of IL within the SCF. Such strategy enables the superfast (140 s) and large-scale (kilogram level) harvesting of cellulose molecules with high molecular weight, resulting in high-performance, versatile cellulose ionogel with a 300 % increase in strength and 1027 % in toughness, monitoring human movement, external pressure, and temperature. Our strategy paves the way for time/energy-effectively, sustainably harvesting high-quality polymer molecules from natural sources beyond cellulose toward versatile and advanced materials.
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Class I histone deacetylases (HDACs) are closely associated with the development of a diverse array of diseases, including cancer, neurodegenerative disorders, HIV, and inflammatory diseases. Considering the essential roles in tumorigenesis, class I HDACs have emerged as highly desirable targets for therapeutic strategies, particularly in the field of anticancer drug development. However, the conventional class I HDAC inhibitors faced several challenges such as acquired resistance, inherent toxicities, and limited efficacy in inhibiting non-enzymatic functions of HDAC. To address these problems, novel strategies have emerged, including the development of class I HDAC dual-acting inhibitors, targeted protein degradation (TPD) technologies such as PROTACs, molecular glues, and HyT degraders, as well as covalent inhibitors. This review provides a comprehensive overview of class I HDAC enzymes and inhibitors, by initially introducing their structure and biological roles. Subsequently, we focus on the recent advancements of class I HDAC modulators, including isoform-selective class I inhibitors, dual-target inhibitors, TPDs, and covalent inhibitors, from the perspectives of rational design principles, pharmacodynamics, pharmacokinetics, and clinical progress. Finally, we also provide the challenges and outlines future prospects in the realm of class I HDAC-targeted drug discovery for cancer therapeutics.
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Inibidores de Histona Desacetilases , Histona Desacetilases , Humanos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Estrutura Molecular , Animais , Relação Estrutura-AtividadeRESUMO
The Lesser Xing'an-Zhangguangcai Range of northeast China is located in the eastern segment of the Central Asian Orogenic Belt (CAOB), which records intense magmatism during the Mesozoic. The petrogenesis and geodynamic setting of the Early Jurassic intrusive rocks in this region are unclear. In this paper, we present new zircon U-Pb age and whole-rock geochemical data for these intrusive rocks to investigate their origins and tectonic setting. Zircon U-Pb dating suggests these intrusive rocks were emplaced during the Early Jurassic (197-187 Ma). The granites are enriched in silica and alkali, and depleted in MgO and CaO. They are metaluminous to weakly peraluminous, and have high A/CNK values and low zircon saturation temperatures (TZr ~ 779°C), suggesting they are highly fractionated I-type granites derived by partial melting of lower crustal materials. The granites exhibit negative Nb, Ta, P, Eu, and Ti anomalies due to fractional crystallization. The diorites and gabbros have low SiO2 contents and high Mg# values, and are enriched in light rare earth and large-ion lithophile (Ba, K, and Sr) elements, and depleted in heavy rare earth and high field strength (Nb, Ta, and Ti) elements. The geochemical characteristics show that the mafic magmas were derived by partial melting of mantle that had been metasomatized by subduction-related fluids. Based on the geochemical characteristics of coeval intrusive rocks and the regional geological setting, we suggest the Early Jurassic intrusive rocks in the Lesser Xing'an-Zhangguangcai Range were formed along an active continental margin, possibly as a result of bidirectional subduction of the Mudanjiang Oceanic plate between the Jiamusi and Songnen-Zhangguangcai Range massifs.
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Sedimentos Geológicos , China , Sedimentos Geológicos/análise , Sedimentos Geológicos/química , Geologia , Fenômenos Geológicos , Zircônio/química , Dióxido de Silício/química , Dióxido de Silício/análise , SilicatosRESUMO
Hypoxia-inducible factor 2α (HIF-2α) is a critical transcription factor that regulates cellular responses under hypoxic conditions. In situations of insufficient oxygen supply or patients with Von Hippel-Lindau (VHL) mutations, HIF-2α accumulates and forms a heterodimeric complex with aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF-ß). This complex further binds to coactivator p300 and interacts with hypoxia response elements (HREs) on the DNA of downstream target genes, regulating the transcription of a variety of genes (e.g. VEGFA, CCND1, CXCR4, SLC2A1, etc) involved in various processes like angiogenesis, mitochondrial metabolism, cell proliferation, and metastasis. Targeting HIF-2α holds great promise for effectively addressing solid tumors associated with aberrant oxygen-sensing pathways and hypoxia mechanisms, offering broad application prospects. In this review, we provide an overview of recent advancements (2009-2024) in HIF-2α modulators such as inhibitors, agonists, and degraders for cancer therapy. Additionally, we discuss in detail the challenges and future directions regarding HIF-2α modulators.
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Antineoplásicos , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Desenvolvimento de Medicamentos , Animais , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
Histone deacetylase 6 (HDAC6) plays a crucial role in the initiation and progression of various cancers, as its overexpression is linked to tumor growth, invasion, migration, survival, apoptosis, and angiogenesis. Therefore, HDAC6 has emerged as an attractive target for anticancer drug discovery in the past decade. However, the development of conventional HDAC6 inhibitors has been hampered by their limited clinical efficacy, acquired resistance, and inability to inhibit non-enzymatic functions of HDAC6. To overcome these challenges, new strategies, such as dual-acting inhibitors, targeted protein degradation (TPD) technologies (including PROTACs, HyT), are essential to enhance the anticancer activity of HDAC6 inhibitors. In this review, we focus on the recent advances in the design and development of HDAC6 modulators, including isoform-selective HDAC6 inhibitors, HDAC6-based dual-target inhibitors, and targeted protein degraders (PROTACs, HyT), from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and clinical status. Finally, we discuss the challenges and future directions for HDAC6-based drug discovery for cancer therapy.
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Antineoplásicos , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Neoplasias , Humanos , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêuticoRESUMO
In this work, a series of bifunctional PD-L1/CD73 (cluster of differentiation 73) small-molecule inhibitors were designed and synthesized. Among them, CC-5 showed the strongest PD-L1 inhibitory effects with an IC50 of 6 nM and potent anti-CD73 activity with an IC50 of 0.773 µM. The high PD-L1/CD73 inhibitory activity of CC-5 was further confirmed by SPR assays with KD of 182 nM for human PD-L1 and 101 nM for CD73, respectively. Importantly, CC-5 significantly suppressed tumor growth in a CT26 and B16-F10 tumor model with TGI of 64.3% and 39.6%, respectively. Immunohistochemical (IHC) and flow cytometry analysis of tumor-infiltrating lymphocytes (TILs) indicated that CC-5 exerted anticancer effects via activating the tumor immune microenvironment. Collectively, CC-5 represents the first dual PD-L1/CD73 inhibitor worthy of further research as a bifunctional immunotherapeutic agent.
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5'-Nucleotidase , Antígeno B7-H1 , Imunoterapia , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Humanos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Animais , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Descoberta de Drogas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Camundongos Endogâmicos C57BL , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB C , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/síntese químicaRESUMO
In this work, a novel series of heterotricyclic DNA-PK inhibitors were rationally designed, synthesized, and assessed for their biological activity. In the DNA-PK biochemical assay, most compounds displayed potent enzymatic activity, with IC50 values between 0.11 and 71.5 nM. Among them, SK10 exhibited the most potent DNA-PK-inhibitory activity (IC50 = 0.11 nM). Studies of the mechanism of action indicated that SK10 could lower γH2A.X expression levels and demonstrate optimal synergistic antiproliferative activity against Jurkat cells (IC50 = 25 nM) when combined with doxorubicin. Importantly, in CT26 and B16-F10 tumor-bearing mouse models, the combination therapies of SK10 with chemotherapeutic drug doxorubicin, a PD-L1 antibody, and SWS1 (a potent PD-L1 small-molecule inhibitor) demonstrated superior synergistic anticancer and potential immunomodulatory effects. Furthermore, SK10 possessed favorable in vivo pharmacokinetic properties [e.g., oral bioavailability (F) = 31.8%]. Taken together, SK10 represents a novel heterotricyclic DNA-PK inhibitor with antitumor immune effects and favorable pharmacokinetics.
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Antineoplásicos , Disponibilidade Biológica , Proteína Quinase Ativada por DNA , Inibidores de Proteínas Quinases , Humanos , Animais , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/metabolismo , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Administração Oral , Imunoterapia/métodos , Doxorrubicina/farmacologia , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Descoberta de Drogas , Camundongos Endogâmicos C57BL , Linhagem Celular Tumoral , Sinergismo Farmacológico , FemininoRESUMO
OBJECTIVE: The effects of arsenic trioxide (As2O3) on hepatocellular carcinoma have been documented widely. Autophagy plays dual roles in the survival and death of cancer cells. Therefore, we investigated the exact role of autophagy in As2O3-induced apoptosis in liver cancer cells. METHODS: The viability of hepatoma cells was determined using the MTT assay with or without fetal bovine serum. The rate of apoptosis in liver cancer cells treated with As2O3 was evaluated using flow cytometry, Hoechst 33258 staining, and TUNEL assays. The rate of autophagy among liver cancer cells treated with As2O3 was detected using immunofluorescence, Western blot assay and transmission electron microscopy. RESULTS: Upon treatment with As2O3, the viability of HepG2 and SMMC-7721 cells was decreased in a time- and dose-dependent manner. The apoptosis rates of both liver cancer cell lines increased with the concentration of As2O3, as shown by flow cytometry. Apoptosis in liver cancer cells treated with As2O3 was also shown by the activation of the caspase cascade and the regulation of Bcl-2/Bax expression. Furthermore, As2O3 treatment induced autophagy in liver cancer cells; this finding was supported by Western blot, immunofluorescence of LC3-II and beclin 1, and transmission electron microscopy. In liver cancer cells, As2O3 inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway that plays a vital role in both apoptosis and autophagy. The PI3K activator SC-79 partially reversed As2O3-induced autophagy and apoptosis. Furthermore, inhibiting autophagy with 3-methyladenine partially reversed the negative effects of As2O3 on cell viability. Serum starvation increased autophagy and amplified the effect of As2O3 on cell death. CONCLUSION: As2O3 induces apoptosis and autophagy in liver cancer cells. Autophagy induced by As2O3 may have a proapoptotic effect that helps to reduce the viability of liver cancer cells. This study provides novel insights into the effects of As2O3 against liver cancer. Please cite this article as: Deng ZT, Liang SF, Huang GK, Wang YQ, Tu XY, Zhang YN, Li S, Liu T, Cheng BB. Autophagy plays a pro-apoptotic role in arsenic trioxide-induced cell death of liver cancer. J Integr Med. 2024; 22(3): 295-302.
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Antineoplásicos , Apoptose , Trióxido de Arsênio , Arsenicais , Autofagia , Neoplasias Hepáticas , Óxidos , Trióxido de Arsênio/farmacologia , Humanos , Autofagia/efeitos dos fármacos , Arsenicais/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Apoptose/efeitos dos fármacos , Óxidos/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Células Hep G2 , Sobrevivência Celular/efeitos dos fármacosRESUMO
DNA damage response (DDR) defects in cells play a crucial role in tumor development by promoting DNA mutations. These mutations create vulnerabilities specific to cancer cells, which can be effectively targeted through synthetic lethality-based therapies. To date, numerous small molecule DDR inhibitors have been identified, and some of them have already been approved for clinical use. However, due to the complexity of the tumor microenvironment, mutations may occur in the amino acid residues of DDR targets. These mutations can affect the efficacy of small molecule inhibitors targeting DDR pathways. Therefore, researchers have turned their attention to next-generation DNA damage repair modulators, particularly those based on PROTAC technology. From this perspective, we overviewed the recent progress on DDR-targeting PROTAC degraders for cancer therapy. In addition, we also summarized the biological functions of different DDR targets. Finally, the challenges and future directions for DDR-target PROTAC degraders are also discussed in detail.
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Dano ao DNA , Reparo do DNA , Humanos , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Purpose: Transcatheter arterial chemoembolization (TACE) is commonly used in the treatment of hepatocellular carcinoma (HCC). However, not all patients respond to this treatment. TACE typically leads to hypoxia in the tumor microenvironment. Therefore, we aimed to construct a prognostic model based on hypoxia-related differentially expressed microRNA (miRNAs) in hepatocellular carcinoma (HCC) and to investigate the potential target mRNAs for predicting TACE response. Methods: The hypoxia-related miRNAs (HRMs) were identified in liver cancer cells, then global test was performed to further select the miRNAs which were associated with recurrence and vascular invasion. A prognostic model was constructed based on multivariate Cox regression analysis; qRT-PCR analysis was used to validate the differentially expressed miRNAs in HCC cell lines under hypoxic condition. We further identified the putative target genes of the miRNAs and investigate the relationship between the target genes and TACE response, immune cells infiltration. Results: We established a HRMs prognostic model for HCC patients, containing two miRNAs (miR-638, miR-501-5p), the patients with high-HRMs score showed worse survival in discovery and validation cohort; qRT-PCR analysis confirmed that these two miRNAs are up-regulated in hepatoma cells under hypoxic condition. Furthermore, four putative target genes of these two miRNAs were identified (ADH1B, CTH, FTCD, RCL1), which were significantly associated with TACE response, immune score, immunosuppressive immune cells infiltration, PDCD1 and CTLA4. Conclusion: The HCC-HRMs signature may be utilized as a promising prognostic factor and may have implications for guiding TACE and immune therapy.
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Alternative splicing (AS) of messenger RNAs occurs in â¼95% of multi-exon human genes and generates diverse RNA and protein isoforms. We investigated AS events associated with human epidermal differentiation, a process crucial for skin function. We identified 6,413 AS events, primarily involving cassette exons. We also predicted 34 RNA-binding proteins (RBPs) regulating epidermal AS, including 19 previously undescribed candidate regulators. From these results, we identified FUS as an RBP that regulates the balance between keratinocyte proliferation and differentiation. Additionally, we characterized the function of a cassette exon AS event in MAP3K7, which encodes a kinase involved in cell signaling. We found that a switch from the short to long isoform of MAP3K7, triggered during differentiation, enforces the demarcation between proliferating basal progenitors and overlying differentiated strata. Our findings indicate that AS occurs extensively in the human epidermis and has critical roles in skin homeostasis.
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Processamento Alternativo , Splicing de RNA , Humanos , Processamento Alternativo/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Isoformas de Proteínas/metabolismo , ÉxonsRESUMO
BACKGROUND: Pulmonary premetastatic niche (PMN) formation plays a key role in the lung metastasis of hepatocellular carcinoma (HCC). Hypoxia promotes the secretion of tumor-derived exosomes (TDEs) and facilitates the formation of PMN. However, the mechanisms remain unexplored. METHODS: TDEs from normoxic (N-TDEs) or hypoxic (H-TDEs) HCC cells were used to induce fibroblast activation in vitro and PMN formation in vivo. Oleanolic acid (OA) was intragastrically administered to TDEs-preconditioned mice. Bioinformatics analysis and drug affinity responsive target stability (DARTS) assays were performed to identify targets of OA in fibroblasts. RESULTS: H-TDEs induced activation of pulmonary fibroblasts, promoted formation of pulmonary PMN and subsequently facilitated lung metastasis of HCC. OA inhibited TDEs-induced PMN formation and lung metastasis and suppressed TDEs-mediated fibroblast activation. MAPK1 and MAPK3 (ERK1/2) were the potential targets of OA. Furthermore, H-TDEs enhanced ERK1/2 phosphorylation in fibroblasts in vitro and in vivo, which was suppressed by OA treatment. Blocking ERK1/2 signaling with its inhibitor abated H-TDEs-induced activation of fibroblasts and PMN formation. H-TDEs-induced phosphorylation of ERK1/2 in fibroblasts touched off the activation NF-κB p65, which was mitigated by OA. In addition, the ERK activator C16-PAF recovered the activation of ERK1/2 and NF-κB p65 in H-TDEs-stimulated MRC5 cells upon OA treatment. CONCLUSION: The present study offers insights into the prevention of TDEs-induced PMN, which has been insufficiently investigated. OA suppresses the activation of inflammatory fibroblasts and the development of pulmonary PMN by targeting ERK1/2 and thereby has therapeutic potential in the prevention of lung metastasis of HCC.
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Carcinoma Hepatocelular , Exossomos , Neoplasias Hepáticas , Neoplasias Pulmonares , Ácido Oleanólico , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Ácido Oleanólico/metabolismo , NF-kappa B/metabolismo , Sistema de Sinalização das MAP Quinases , Exossomos/metabolismo , Hipóxia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismoRESUMO
Among 14 patients with C. psittaci pneumonia, there were 9 critical and 5 non-critical cases. Ten patients improved clinically and were discharged to home; however, four patients died. Seven patients had a history of contact with birds or poultry. All 14 patients had a high fever as the presenting symptom, but most had a normal white blood cell count. Most of the patients had a significant increase in high-sensitivity C-reactive protein and procalcitonin levels. The lymphocyte count in the critical group was considerably lower than in the non-critical group. Patients in the critical group were more advanced in age than in the non-critical group. In addition, serum urea nitrogen, creatinine, procalcitonin, and lactate dehydrogenase levels were significantly higher in the critical group than in the non-critical group (P<0.05). The 4 patients who died had significantly increased procalcitonin levels compared to the 10 patients who survived (P<0.05). In summary, a high fever is usually the presenting complaint of patients with C. psittaci pneumonia. Such patients often progress to severe disease; however, early diagnostic confirmation by mNGS and appropriate treatment dramatically improve the prognosis. Age, lymphocyte count, procalcitonin, blood urea nitrogen, creatinine, and lactate dehydrogenase levels were shown to predict disease severity.
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Chlamydophila psittaci , Pneumonia , Humanos , Creatinina , Pró-Calcitonina , Lactato DesidrogenasesRESUMO
HDAC inhibitors, which can inhibit the activity of HDAC enzymes, have been extensively studied in tumor immunotherapy and have shown potential therapeutic effects in cancer immunotherapy. To date, numerous small molecule HDAC inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, HDAC inhibitor-based combination therapies, and other HDAC modulators (e.g. PROTAC degraders, dual-acting agents) have attracted great attention with significant advancements achieved in the past few years due to their superior efficacy compared to single-target HDAC inhibitors. In this review, we overviewed the recent progress on HDAC-based drug discovery with a focus on HDAC inhibitor-based drug combination therapy and other HDAC-targeting strategies (e.g. selective HDAC inhibitors, HDAC-based dual-target inhibitors, and PROTAC HDAC degraders) for cancer immunotherapy. In addition, we also summarized the reported co-crystal structures of HDAC inhibitors in complex with their target proteins and the binding interactions. Finally, the challenges and future directions for HDAC-based drug discovery in cancer immunotherapy are also discussed in detail.
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Inibidores de Histona Desacetilases , Neoplasias , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/química , Quimioterapia Combinada , Neoplasias/tratamento farmacológico , Epigênese Genética , ImunoterapiaRESUMO
Dysregulated protein synthesis is a hallmark of tumors. mRNA translation reprogramming contributes to tumorigenesis, which is fueled by abnormalities in ribosome formation, tRNA abundance and modification, and translation factors. Not only malignant cells but also stromal cells within tumor microenvironment can undergo transformation toward tumorigenic phenotypes during translational reprogramming. Ribosome-inactivating proteins (RIPs) have garnered interests for their ability to selectively inhibit protein synthesis and suppress tumor growth. This review summarizes the role of dysregulated translation machinery in tumor development and explores the potential of RIPs in cancer treatment.
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Neoplasias , Proteínas Inativadoras de Ribossomos , Humanos , Proteínas Inativadoras de Ribossomos/genética , Proteínas Inativadoras de Ribossomos/uso terapêutico , Proteínas Inativadoras de Ribossomos/metabolismo , Ribossomos/genética , Biossíntese de Proteínas , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Microambiente TumoralRESUMO
Background: Hypoxia plays an important role in the lung metastasis of hepatocellular carcinoma (HCC). However, the process by which hypoxia promotes the formation of a pre-metastatic niche (PMN) and its underlying mechanism remain unclear. Methods: Exosomes derived from normoxic and hypoxic HCC cells were collected to induce fibroblast activation in vitro and PMN formation in vivo. The micro RNA (miR) profiles of the exosomes were sequenced to identify differentially expressed miRNAs. Gain- and loss-of-function analyses were performed to investigate miR-4508 function. Dual-luciferase, western blotting, and real-time reverse transcription-PCR analyses were used to identify the direct targets of miR-4508 and its downstream signaling pathways. To demonstrate the roles of hypoxic tumor-derived exosomes (H-TDEs) and miR-4508 in the lung metastasis of liver cancer, H22 tumor cells were injected through the tail vein of mice. Blood plasma-derived exosomes from patients with HCC who underwent transarterial chemoembolization (TACE) were applied to determine clinical correlations. Results: We demonstrated that H-TDEs activated lung fibroblasts and facilitated PMN formation, thereby promoting lung metastasis in mice. Screening for upregulated exosomal miRNAs revealed that miR-4508 and its target, regulatory factor X1 (RFX1), were involved in H-TDE-induced lung PMN formation. Moreover, miR-4508 was significantly upregulated in plasma exosomes derived from patients with HCC after TACE. We confirmed that the p38 MAPK-NF-κB signaling pathway is involved in RFX1 knockdown-induced fibroblast activation and PMN formation. In addition, IL17A, a downstream target of RFX1, was identified as a link between RFX1 knockdown and p38 MAPK activation in fibroblasts. Conclusion: Hypoxia enhances the release of TDEs enriched with miR-4508, thereby promoting lung PMN formation by targeting the RFX1-IL17A-p38 MAPK-NF-κB pathway. These findings highlight a novel mechanism underlying hypoxia-induced pulmonary metastasis of HCC.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Exossomos , Neoplasias Hepáticas , Neoplasias Pulmonares , MicroRNAs , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , NF-kappa B/metabolismo , Fator Regulador X1/genética , Exossomos/genética , Exossomos/metabolismo , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Pulmonares/metabolismo , Hipóxia/metabolismo , Pulmão/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Interleucina-17/genéticaRESUMO
In this work, we rationally designed, synthesized, and evaluated a series of novel d-(+)-biotin-conjugated PD-L1 inhibitors for targeted cancer therapy. Among them, SWS1 exhibited the highest anti-PD-1/PD-L1 activity with an IC50 of 1.8 nM. In addition, SWS1 dose-dependently promoted tumor cell death in a HepG2/Jurkat cell co-culture model. Importantly, SWS1 displayed high antitumor efficacy in a B16-F10 mouse model with tumor growth inhibition of 66.1%, which was better than that of P18 (44.3%). Furthermore, SWS1 exerted antitumor effects by increasing the number of tumor-infiltrating lymphocytes and reducing the expression of PD-L1 in tumor tissues. Moreover, tissue distribution studies revealed a substantial accumulation of SWS1 in tumors (404.1 ng/mL). Lastly, the safety profiles of SWS1 were better (e.g., less immune-mediated colitis) than those of P18, indicating the advantages of biotin-enabled tumor targeting capability. Taken together, our results suggest that these novel tumor-targeted PD-L1 inhibitors are worthy of further investigation as potential anticancer agents for targeted cancer immunotherapy.
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Inibidores de Checkpoint Imunológico , Neoplasias , Camundongos , Animais , Antígeno B7-H1 , Biotina , Imunoterapia/métodos , Resorcinóis , Linhagem Celular TumoralRESUMO
OBJECTIVE: Jiedu Recipe (JR), a Chinese herbal remedy, has been shown to prolong overall survival time and decrease recurrence and metastasis rates in patients with hepatocellular carcinoma (HCC). This work investigated the mechanism of JR in HCC treatment. METHODS: The chemical constituents of JR were detected using liquid chromatography-mass spectrometry. The potential anti-HCC mechanism of JR was screened using network pharmacology and messenger ribonucleic acid (mRNA) microarray chip assay, followed by experimental validation in human HCC cells (SMMC-7721 and Huh7) in vitro and a nude mouse subcutaneous transplantation model of HCC in vivo. HCC cell characteristics of proliferation, migration and invasion under hypoxic setting were investigated using thiazolyl blue tetrazolium bromide, wound healing and Transwell assays, respectively. Image-iT™ Hypoxia Reagent was added to reveal hypoxic conditions. Stem cell sphere formation assay was used to detect the stemness. Epithelial-mesenchymal transition (EMT) markers like E-cadherin, vimentin and α-smooth muscle actin, and pluripotent transcription factors including nanog homeobox, octamer-binding transcription factor 4, and sex-determining region Y box protein 2 were analyzed using Western blotting and real-time polymerase chain reaction. Western blot was performed to ascertain the anti-HCC effect of JR under hypoxia involving the Wnt/ß-catenin pathway. RESULTS: According to network pharmacology and mRNA microarray chip analysis, JR may potentially act on hypoxia and inhibit the Wnt/ß-catenin pathway. In vitro and in vivo experiments showed that JR significantly decreased hypoxia, and suppressed HCC cell features of proliferation, migration and invasion; furthermore, the hypoxia-induced increases in EMT and stemness marker expression in HCC cells were inhibited by JR. Results based on the co-administration of JR and an agonist (LiCl) or inhibitor (IWR-1-endo) verified that JR suppressed HCC cancer stem-like properties under hypoxia by blocking the Wnt/ß-catenin pathway. CONCLUSION: JR exerts potent anti-HCC effects by inhibiting cancer stemness via abating the Wnt/ß-catenin pathway under hypoxic conditions. Please cite this article as: Guo BJ, Ruan Y, Wang YJ, Xiao CL, Zhong ZP, Cheng BB, Du J, Li B, Gu W, Yin ZF. Jiedu Recipe, a compound Chinese herbal medicine, inhibits cancer stemness in hepatocellular carcinoma via Wnt/ß-catenin pathway under hypoxia. J Integr Med. 2023; 21(5): 474-486.
Assuntos
Carcinoma Hepatocelular , Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , beta Catenina/genética , beta Catenina/metabolismo , beta Catenina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , RNA Mensageiro/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Movimento Celular , Regulação Neoplásica da Expressão GênicaRESUMO
Tumor-derived exosome (TDE)-mediated premetastatic niche (PMN) formation is a potential mechanism underlying the organotropic metastasis of primary tumors. Traditional Chinese medicine (TCM) has shown considerable success in preventing and treating tumor metastasis. However, the underlying mechanisms remain elusive. In this review, we discussed PMN formation from the perspectives of TDE biogenesis, cargo sorting, and TDE recipient cell alterations, which are critical for metastatic outgrowth. We also reviewed the metastasis-preventive effects of TCM, which act by targeting the physicochemical materials and functional mediators of TDE biogenesis, regulating the cargo sorting machinery and secretory molecules in TDEs, and targeting the TDE-recipient cells involved in PMN formation.