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Porcine circovirus type 3 (PCV3) is closely associated with various diseases, such as the porcine dermatitis, nephropathy syndrome, and multisystemic clinicopathological diseases. PCV3-associated diseases are increasingly recognized as severe diseases in the global swine industry. Ring finger protein 2 (RNF2), an E3 ubiquitin ligase exclusively located in the nucleus, contributes to various biological processes. This ligase interacts with the PCV3 Cap. However, its role in PCV3 replication remains unclear. This study confirmed that the nuclear localization signal domain of the Cap and the RNF2 N-terminal RING domain facilitate the interaction between the Cap and RNF2. Furthermore, RNF2 promoted the binding of K48-linked polyubiquitination chains to lysine at positions 139 and 140 (K139 and K140) of the PCV3 Cap, thereby degrading the Cap. RNF2 knockdown and overexpression increased or decreased PCV3 replication, respectively. Moreover, the RING domain-deleted RNF2 mutant eliminated the RNF2-induced degradation of the PCV3 Cap and RNF2-mediated inhibition of viral replication. This indicates that both processes were associated with its E3 ligase activity. Our findings demonstrate that RNF2 can interact with and degrade the PCV3 Cap via its N-terminal RING domain in a ubiquitination-dependent manner, thereby inhibiting PCV3 replication.IMPORTANCEPorcine circovirus type 3 is a recently described pathogen that is prevalent worldwide, causing substantial economic losses to the swine industry. However, the mechanisms through which host proteins regulate its replication remain unclear. Here, we demonstrate that ring finger protein 2 inhibits porcine circovirus type 3 replication by interacting with and degrading the Cap of this pathogen in a ubiquitination-dependent manner, requiring its N-terminal RING domain. Ring finger protein 2-mediated degradation of the Cap relies on its E3 ligase activity and the simultaneous existence of K139 and K140 within the Cap. These findings reveal the mechanism by which this protein interacts with and degrades the Cap to inhibit porcine circovirus type 3 replication. This consequently provides novel insights into porcine circovirus type 3 pathogenesis and facilitates the development of preventative measures against this pathogen.
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Proteínas do Capsídeo , Circovirus , Ubiquitina-Proteína Ligases , Ubiquitinação , Replicação Viral , Circovirus/genética , Circovirus/metabolismo , Circovirus/fisiologia , Animais , Suínos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Humanos , Células HEK293 , Proteólise , Linhagem Celular , Doenças dos Suínos/virologia , Doenças dos Suínos/metabolismo , Infecções por Circoviridae/virologia , Infecções por Circoviridae/metabolismo , Ligação ProteicaRESUMO
Avian metapneumovirus subgroup C (aMPV/C), an important pathogen causing acute respiratory infection in chickens and turkeys, contributes to substantial economic losses in the poultry industry worldwide. aMPV/C has been reported to induce autophagy, which is beneficial to virus replication. Sequestosome 1 (SQSTM1/P62), a selective autophagic receptor, plays a crucial role in viral replication by clearing ubiquitinated proteins. However, the relationship between SQSTM1-mediated selective autophagy and aMPV/C replication is unclear. In this study, we found that the expression of SQSTM1 negatively regulates aMPV/C replication by reducing viral protein expression and viral titers. Further studies revealed that the interaction between SQSTM1 and aMPV/C M2-2 protein is mediated via the Phox and Bem1 (PB1) domain of the former, which recognizes a ubiquitinated lysine at position 67 of the M2-2 protein, and finally degrades M2-2 via SQSTM1-mediated selective autophagy. Collectively, our results reveal that SQSTM1 degrades M2-2 via a process of selective autophagy to suppress aMPV/C replication, thereby providing novel insights for the prevention and control of aMPV/C infection.IMPORTANCEThe selective autophagy plays an important role in virus replication. As an emerging pathogen of avian respiratory virus, clarification of the effect of SQSTM1, a selective autophagic receptor, on aMPV/C replication in host cells enables us to better understand the viral pathogenesis. Previous study showed that aMPV/C infection reduced the SQSTM1 expression accompanied by virus proliferation, but the specific regulatory mechanism between them was still unclear. In this study, we demonstrated for the first time that SQSTM1 recognizes the 67th amino acid of M2-2 protein by the interaction between them, followed by M2-2 degradation via the SQSTM1-mediated selective autophagy, and finally inhibits aMPV/C replication. This information supplies the mechanism by which SQSTM1 negatively regulates viral replication, and provides new insights for preventing and controlling aMPV/C infection.
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Autofagia , Aves , Metapneumovirus , Proteólise , Proteína Sequestossoma-1 , Proteínas Virais , Replicação Viral , Animais , Humanos , Células HEK293 , Metapneumovirus/classificação , Metapneumovirus/crescimento & desenvolvimento , Infecções por Paramyxoviridae/metabolismo , Infecções por Paramyxoviridae/veterinária , Infecções por Paramyxoviridae/virologia , Ligação Proteica , Proteína Sequestossoma-1/química , Proteína Sequestossoma-1/metabolismo , Células Vero , Proteínas Virais/química , Proteínas Virais/metabolismo , Aves/virologiaRESUMO
As the feature size of integrated circuits continues to decrease, ruthenium (Ru) has been suggested as the successor to traditional Ta/TaN bilayers for barrier layer materials due to its unique properties. This research delves into the effects of ammonium nitrilotriacetate (NTA(NH4)3) on the chemical mechanical polishing (CMP) performance of Ru in H2O2-based slurry. The removal rate (RR) of Ru surged from 47 to 890 Å min-1, marking an increase of about 17 times. The essence of this mechanism lies in the triple synergistic effects of NTA(NH4)3 in promoting ruthenium (Ru) removal: 1) The interaction between NH 4 + ${\mathrm{NH}}_{\mathrm{4}}^{\mathrm{+}}$ from NTA(NH4)3 and SiO2 abrasives; 2) The chelating action of [(NH4)N(CH2COO)3]2-â from NTA(NH4)3 on Ru and its oxides; 3) The ammoniation and chelation of Ru and its oxides by NH 4 + ${\mathrm{NH}}_{\mathrm{4}}^{\mathrm{+}}$ from NTA(NH4)3, which enhance the dissolution and corrosion of oxidized Ru, making its removal during the barrier layer CMP process more efficient through mechanical means. This research introduces a synergistic approach for the effective removal of Ru, shedding light on potential applications of CMP in the field of the integrated circuits.
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IMPORTANCE: Porcine circovirus type 3 (PCV3) is an emerging pathogen that causes multisystem disease in pigs and poses a severe threat to the swine industry. However, the mechanisms of how PCV3 uses host proteins to regulate its own life cycle are not well understood. In this study, we found that PCV3 capsid protein interacts with nucleolin and degrades it. Degradation of nucleolin by the PCV3 capsid protein requires recruitment of the enzyme RNF34, which is transported to the nucleolus from the cytoplasm in the presence of the PCV3 capsid protein. Nucleolin also decreases PCV3 replication by promoting the release of interferon ß. These findings clarify the mechanism by which nucleolin modulates PCV3 replication in cells, thereby facilitating to provide an important strategy for preventing and controlling PCV3 infection.
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Proteínas do Capsídeo , Infecções por Circoviridae , Circovirus , Nucleolina , Doenças dos Suínos , Animais , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Infecções por Circoviridae/metabolismo , Infecções por Circoviridae/veterinária , Infecções por Circoviridae/virologia , Circovirus/metabolismo , Nucleolina/metabolismo , Filogenia , Suínos , Doenças dos Suínos/virologia , UbiquitinaçãoRESUMO
The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 system, a groundbreaking innovation in genetic engineering, has revolutionized our approach to surmounting complex diseases, culminating in CASGEVY™ approved for sickle cell anemia. Derived from a microbial immune defense mechanism, CRISPR/Cas9, characterized as precision, maneuverability and universality in gene editing, has been harnessed as a versatile tool for precisely manipulating DNA in mammals. In the process of applying it to practice, the consecutive exploitation of novel orthologs and variants never ceases. It's conducive to understanding the essentialities of diseases, particularly cancer, which is crucial for diagnosis, prevention, and treatment. CRISPR/Cas9 is used not only to investigate tumorous genes functioning but also to model disparate cancers, providing valuable insights into tumor biology, resistance, and immune evasion. Upon cancer therapy, CRISPR/Cas9 is instrumental in developing individual and precise cancer therapies that can selectively activate or deactivate genes within tumor cells, aiming to cripple tumor growth and invasion and sensitize cancer cells to treatments. Furthermore, it facilitates the development of innovative treatments, enhancing the targeting efficiency of reprogrammed immune cells, exemplified by advancements in CAR-T regimen. Beyond therapy, it is a potent tool for screening susceptible genes, offering the possibility of intervening before the tumor initiative or progresses. However, despite its vast potential, the application of CRISPR/Cas9 in cancer research and therapy is accompanied by significant efficacy, efficiency, technical, and safety considerations. Escalating technology innovations are warranted to address these issues. The CRISPR/Cas9 system is revolutionizing cancer research and treatment, opening up new avenues for advancements in our understanding and management of cancers. The integration of this evolving technology into clinical practice promises a new era of precision oncology, with targeted, personalized, and potentially curative therapies for cancer patients.
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Sistemas CRISPR-Cas , Neoplasias , Medicina de Precisão , Humanos , Sistemas CRISPR-Cas/genética , Medicina de Precisão/métodos , Neoplasias/genética , Neoplasias/terapia , Edição de Genes/métodos , Animais , Oncologia/métodos , Oncologia/tendênciasRESUMO
The Seneca Valley virus (SVV) is a recently discovered porcine pathogen that causes vesicular diseases and poses a significant threat to the pig industry worldwide. Erythropoietin-producing hepatoma receptor A2 (EphA2) is involved in the activation of the AKT/mTOR signaling pathway, which is involved in autophagy. However, the regulatory relationship between SVV and EphA2 remains unclear. In this study, we demonstrated that EphA2 is proteolysed in SVV-infected BHK-21 and PK-15 cells. Overexpression of EphA2 significantly inhibited SVV replication, as evidenced by decreased viral protein expression, viral titers, and viral load, suggesting an antiviral function of EphA2. Subsequently, viral proteins involved in the proteolysis of EphA2 were screened, and the SVV 3C protease (3Cpro) was found to be responsible for this cleavage, depending on its protease activity. However, the protease activity sites of 3Cpro did not affect the interactions between 3Cpro and EphA2. We further determined that EphA2 overexpression inhibited autophagy by activating the mTOR pathway and suppressing SVV replication. Taken together, these results indicate that SVV 3Cpro targets EphA2 for cleavage to impair its EphA2-mediated antiviral activity and emphasize the potential of the molecular interactions involved in developing antiviral strategies against SVV infection.
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Proteases Virais 3C , Autofagia , Picornaviridae , Receptor EphA2 , Transdução de Sinais , Serina-Treonina Quinases TOR , Proteínas Virais , Replicação Viral , Animais , Receptor EphA2/metabolismo , Receptor EphA2/genética , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular , Suínos , Picornaviridae/fisiologia , Picornaviridae/genética , Proteases Virais 3C/metabolismo , Proteínas Virais/metabolismo , Proteínas Virais/genética , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/genética , Proteólise , Cricetinae , Interações Hospedeiro-Patógeno , Carga ViralRESUMO
BACKGROUND: Epigenetic alterations contribute greatly to the development and progression of colorectal cancer, and effect of aberrant miR-622 expression is still controversial. This study aimed to discover miR-622 regulation in CRC proliferation. METHODS: miR-622 expression and prognosis were analyzed in clinical CRC samples from Nanfang Hospital. miR-622 regulation on cell cycle and tumor proliferation was discovered, and FOLR2 was screened as functional target of miR-622 using bioinformatics analysis, which was validated via dual luciferase assay and gain-of-function and loss-of-function experiments both in vitro and in vivo. RESULTS: miR-622 overexpression in CRC indicated unfavorable prognosis and it regulated cell cycle to promote tumor growth both in vitro and in vivo. FOLR2 is a specific, functional target of miR-622, which negatively correlates with signature genes in cell cycle process to promote CRC proliferation. CONCLUSIONS: miR-622 upregulates cell cycle process by targeting FOLR2 to promote CRC proliferation, proposing a novel mechanism and treatment target in CRC epigenetic regulation of miR-622.
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Proliferação de Células , Neoplasias Colorretais , Receptor 2 de Folato , MicroRNAs , Humanos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Epigênese Genética , Receptor 2 de Folato/genética , Receptor 2 de Folato/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismoRESUMO
The programmed cell death 1 (PD-1) signaling pathway, a key player in immune checkpoint regulation, has become a focal point in cancer immunotherapy. In the context of cancer, upregulated PD-L1 on tumor cells can result in T cell exhaustion and immune evasion, fostering tumor progression. The advent of PD-1/PD-L1 inhibitor has demonstrated clinical success by unleashing T cells from exhaustion. Nevertheless, challenges such as resistance and adverse effects have spurred the exploration of innovative strategies, with bispecific antibodies (BsAbs) emerging as a promising frontier. BsAbs offer a multifaceted approach to cancer immunotherapy by simultaneously targeting PD-L1 and other immune regulatory molecules. We focus on recent advancements in PD-1/PD-L1 therapy with a particular emphasis on the development and potential of BsAbs, especially in the context of solid tumors. Various BsAb products targeting PD-1 signaling are discussed, highlighting their unique mechanisms of action and therapeutic potential. Noteworthy examples include anti-TGFß × PD-L1, anti-CD47 × PD-L1, anti-VEGF × PD-L1, anti-4-1BB × PD-L1, anti-LAG-3 × PD-L1, and anti-PD-1 × CTLA-4 BsAbs. Besides, we summarize ongoing clinical studies evaluating the efficacy and safety of these innovative BsAb agents. By unraveling the intricacies of the tumor microenvironment and harnessing the synergistic effects of anti-PD-1/PD-L1 BsAbs, there exists the potential to elevate the precision and efficacy of cancer immunotherapy, ultimately enabling the development of personalized treatment strategies tailored to individual patient profiles.
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Anticorpos Biespecíficos , Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Anticorpos Biespecíficos/uso terapêutico , Antígeno B7-H1 , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais , Microambiente TumoralRESUMO
Antimony (Sb) isotopic fractionation is frequently used as a proxy for biogeochemical processes in nature. However, to date, little is known about Sb isotope fractionation in biologically driven reactions. In this study, Pseudomonas sp. J1 was selected for Sb isotope fractionation experiments with varying initial Sb concentration gradients (50-200 µM) at pH 7.2 and 30 °C. Compared to the initial Sb(III) reservoir (δ123Sb = 0.03 ± 0.01 â¼ 0.06 ± 0.01), lighter isotopes were preferentially oxidized to Sb(V). Relatively constant isotope enrichment factors (ε) of -0.62 ± 0.06 and -0.58 ± 0.02 were observed for the initial Sb concentrations ranging between 50 and 200 µM during the first 22 days. Therefore, the Sb concentration has a limited influence on Sb isotope fractionation during Sb(III) oxidation that can be described by a kinetically dominated Rayleigh fractionation model. Due to the decrease in the Sb-oxidation rate by Pseudomonas sp. J1, observed for the initial Sb concentration of 200 µM, Sb isotope fractionation shifted toward isotopic equilibrium after 22 days, with slightly heavy Sb(V) after 68 days. These findings provide the prospect of using Sb isotopes as an environmental tracer in the Sb biogeochemical cycle.
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Antimônio , Isótopos , Oxirredução , Pseudomonas , Antimônio/metabolismo , Pseudomonas/metabolismo , Cinética , Fracionamento QuímicoRESUMO
Metamaterial filters represent an essential method for researching the miniaturization of infrared spectral detectors. To realize an 8-2 µm long-wave infrared tunable transmission spectral structure, an extraordinary optical transmission metamaterial model was designed based on the grating diffraction effect and surface plasmon polariton resonance theory. The model consisted of an Al grating array in the upper layer and a Ge substrate in the lower layer. We numerically simulated the effects of different structural parameters on the transmission spectra, such as grating height (h), grating width (w), grating distance (d), grating constant (p), and grating length (S 1), by utilizing the finite-difference time-domain method. Finally, we obtained the maximum transmittance of 81.52% in the 8-12 µm band range, with the corresponding structural parameters set to h=50n m, w=300n m, d=300n m, and S 1=48µm, respectively. After Lorentz fitting, a full width at half maximum of 0.94±0.01µm was achieved. In addition, the Ge substrate influence was taken into account for analyzing the model's extraordinary optical transmission performance. In particular, we first realized the continuous tuning performance at the transmission center wavelength (8-12 µm) of long-wave infrared within the substrate tuning thickness (D) range of 1.9-2.9 µm. The structure designed in this paper features tunability, broad spectral bandwidth, and miniaturization, which will provide a reference for the development of miniaturized long-wave infrared spectral filter devices.
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OBJECTIVES: This study aimed to explore the long-term impacts of exposure to earthquake in adolescence on later-life cognitive function in China. METHODS: Data were from the 2015 China Health and Retirement Longitudinal Study (CHARLS). Our analytical sample comprised 4394 participants aged 49 to 78 from two birth cohorts born between 1937 and 1966: exposed cohort during adolescence (born between 1952 and 1966), and non-exposed cohort during adolescence (born between 1937 and 1951). We defined earthquake exposure as the exposure severity of the 1976 Great Tangshan Earthquake (GTE). We selected community environmental characteristics as our key moderators. A difference-in-differences (DID) method was employed to estimate the long-term impact of the GTE on later-life cognitive function. RESULTS: We found that exposure to the earthquake during adolescence resulted in higher scores of later-life cognitive function (for males: ß = 2.18; 95% CI: 0.70-3.66; for females: ß = 1.22; 95% CI: 0.11-2.33). For males, this impact was moderated by community environmental characteristics including the old-age allowance program (ß = 3.07; 95% CI: 1.94-4.19) and the condition of basic community infrastructures (ß = 1.52; 95% CI: 0.84-2.19). CONCLUSIONS: Our study supports the post-traumatic growth theory. This finding suggest that individuals with early-life traumatic exposure need to be focused on. Additionally, improving the conditions of community infrastructures and establishing a community environment with comfort and security may be pretty important for promoting cognitive function and post-traumatic growth.
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Avian metapneumovirus subgroup C (aMPV/C) causes respiratory diseases and egg dropping in chickens and turkeys, resulting in severe economic losses to the poultry industry worldwide. Integrin ß1 (ITGB1), a transmembrane cell adhesion molecule, is present in various cells and mediates numerous viral infections. Herein, we demonstrate that ITGB1 is essential for aMPV/C infection in cultured DF-1 cells, as evidenced by the inhibition of viral binding by EDTA blockade, Arg-Ser-Asp (RSD) peptide, monoclonal antibody against ITGB1, and ITGB1 short interfering (si) RNA knockdown in cultured DF-1 cells. Simulation of the binding process between the aMPV/C fusion (F) protein and avian-derived ITGB1 using molecular dynamics showed that ITGB1 may be a host factor benefiting aMPV/C attachment or internalization. The transient expression of avian ITGB1-rendered porcine and feline non-permissive cells (DQ cells and CRFK cells, respectively) is susceptible to aMPV/C infection. Kinetic replication of aMPV/C in siRNA-knockdown cells revealed that ITGB1 plays an important role in aMPV/C infection at the early stage (attachment and internalization). aMPV/C was also able to efficiently infect human non-small cell lung cancer (A549) cells. This may be a consequence of the similar structures of both metapneumovirus F protein-specific motifs (RSD for aMPV/C and RGD for human metapneumovirus) recognized by ITGB1. Overexpression of avian-derived ITGB1 and human-derived ITGB1 in A549 cells enhanced aMPV/C infectivity. Taken together, this study demonstrated that ITGB1 acts as an essential receptor for aMPV/C attachment and internalization into host cells, facilitating aMPV/C infection.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Metapneumovirus , Humanos , Animais , Gatos , Suínos , Metapneumovirus/genética , Integrina beta1/genética , Galinhas , Anticorpos AntiviraisRESUMO
Seneca Valley virus (SVV), a new pathogen resulting in porcine vesicular disease, is prevalent in pig herds worldwide. Although an understanding of SVV biology pathogenesis is crucial for preventing and controlling this disease, the molecular mechanisms for the entry and post-internalization of SVV, which represent crucial steps in viral infection, are not well characterized. In this study, specific inhibitors, Western blotting, and immunofluorescence detection revealed that SVV entry into PK-15 cells depends on low-pH conditions and dynamin. Furthermore, results showed that caveolae-mediated endocytosis (CavME) contributes crucially to the internalization of SVV, as evidenced by cholesterol depletion, downregulation of caveolin-1 expression by small interfering RNA knockdown, and overexpression of a caveolin-1 dominant negative (caveolin-1-DN) in SVV-infected PK-15 cells. However, SVV entry into PK-15 cells did not depend on clathrin-mediated endocytosis (CME). Furthermore, treatment with specific inhibitors demonstrated that SVV entry into PK-15 cells via macropinocytosis depended on the Na+/H+ exchanger (NHE), p21-activated kinase 1 (Pak1), and actin rearrangement, but not phosphatidylinositol 3-kinase (PI3K). Electron microscopy showed that SVV particles or proteins were localized in CavME and macropinocytosis. Finally, knockdown of GTPase Rab5 and Rab7 by siRNA significantly inhibited SVV replication, as determined by measuring viral genome copy numbers, viral protein expression, and viral titers. In this study, our results demonstrated that SVV utilizes caveolae-mediated endocytosis and macropinocytosis to enter PK-15 cells, dependent on low pH, dynamin, Rab5, and Rab7. IMPORTANCE Entry of virus into cells represents the initiation of a successful infection. As an emerging pathogen of porcine vesicular disease, clarification of the process of SVV entry into cells enables us to better understand the viral life cycle and pathogenesis. In this study, patterns of SVV internalization and key factors required were explored. We demonstrated for the first time that SVV entry into PK-15 cells via caveolae-mediated endocytosis and macropinocytosis requires Rab5 and Rab7 and is independent of clathrin-mediated endocytosis, and that low-pH conditions and dynamin are involved in the process of SVV internalization. This information increases our understanding of the patterns in which all members of the family Picornaviridae enter host cells, and provides new insights for preventing and controlling SVV infection.
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Caveolina 1 , Dinaminas , Picornaviridae , Internalização do Vírus , Proteínas rab5 de Ligação ao GTP , Animais , Cavéolas/metabolismo , Caveolina 1/metabolismo , Clatrina/metabolismo , Dinaminas/metabolismo , Endocitose , Picornaviridae/fisiologia , RNA Interferente Pequeno/genética , Suínos , Doença Vesicular Suína , Proteínas rab5 de Ligação ao GTP/metabolismo , Pinocitose , Linhagem CelularRESUMO
Metabolic syndrome (MetS) is suggested to participate in the pathogenesis and progress of some cancers via inducing low-grade systemic inflammation. However, the influence of MetS on patients with gastric cancer (GC) remains not fully determined. A systematic review and meta-analysis was therefore performed to evaluate the influence of MetS on clinical outcomes of patients with GC. A search of PubMed, Embase, Web of Science, Wanfang, and CNKI retrieved relevant cohort studies from the inception of the databases to October 11, 2022. We pooled the results using a random-effects model that incorporates heterogeneity. In the meta-analysis, 6649 patients with GC were included, and all of them received gastrectomy. A total of 1248 (18.8%) patients had MetS at baseline. Pooled results showed that MetS was associated with higher risks of postoperative complications [risk ratio (RR): 2.41, 95% confidence interval (CI): 1.85 to 3.14, p<0.001; I2=55%], overall mortality (RR: 1.73, 95% CI: 1.85 to 3.14, p<0.001; I2=77%), and recurrence of GC (RR: 2.00, 95% CI: 1.10 to 3.63, p=0.02; I2=39%). Subgroup analyses showed similar results in prospective and retrospective cohort studies and in studies with MetS diagnosed with the Chinese Diabetes Society criteria and the National Cholesterol Education Program Adult Treatment Panel III criteria (p for subgroup difference all>0.05). In patients with GC after gastrectomy, MetS may be a predictor of high incidence of postoperative complications, cancer recurrence, and overall mortality.
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Síndrome Metabólica , Neoplasias Gástricas , Adulto , Humanos , Síndrome Metabólica/epidemiologia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Estudos Retrospectivos , Estudos Prospectivos , Recidiva Local de NeoplasiaRESUMO
Obesity is a public-health challenge resulting from an imbalance between energy expenditure and calorie intake. This health problem exacerbates a variety of metabolic complications worldwide. Adipose tissue is an essential regulator of energy homeostasis, and the functions within it are regulated by purinergic receptors. A1R, P2X7R, and P2YR mainly mediate energy homeostasis primarily through regulating energy storage and adipokines secretion in white adipose tissue (WAT). P2X5R is a novel-specific cell surface marker in brown/beige adipocytes. A2R is a promising therapeutic target for stimulating energy expenditure in brown adipose tissue (BAT) and also mediating WAT browning. Based on these features, purinergic receptors may be an appropriate target in treating obesity. In this review, the role of purinergic receptors in different types of adipose tissue is summarized. An improved understanding of purinergic receptor functions in adipose tissue may lead to more effective treatment interventions for obesity and its related metabolic disorders.
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Tecido Adiposo Marrom , Tecido Adiposo Branco , Humanos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Obesidade/metabolismo , Metabolismo Energético , Receptores Purinérgicos/metabolismoRESUMO
A lack of knowledge about antimony (Sb) isotope fractionation mechanisms in key geochemical processes has limited its environmental applications as a tracer. Naturally widespread iron (Fe) (oxyhydr)oxides play a key role in Sb migration due to strong adsorption, but the behavior and mechanisms of Sb isotopic fractionation on Fe (oxyhydr)oxides are still unclear. Here, we investigate the adsorption mechanisms of Sb on ferrihydrite (Fh), goethite (Goe), and hematite (Hem) using extended X-ray absorption fine structure (EXAFS) and show that inner-sphere complexation of Sb species with Fe (oxyhydr)oxides occurs independent of pH and surface coverage. Lighter Sb isotopes are preferentially enriched on Fe (oxyhydr)oxides due to isotopic equilibrium fractionation, with neither surface coverage nor pH influencing the degree of fractionation (Δ123Sbaqueous-adsorbed). Limited Fe atoms are present in the second shell of Hem and Goe, resulting in weaker surface complexes and leading to greater Sb isotopic fractionation than with Fh (Δ123Sbaqueous-adsorbed of 0.49 ± 0.004, 1.12 ± 0.006, and 1.14 ± 0.05 for Fh, Hem, and Goe, respectively). These results improve the understanding of the mechanism of Sb adsorption by Fe (oxyhydr)oxides and further clarify the Sb isotope fractionation mechanism, providing an essential basis for future application of Sb isotopes in source and process tracing.
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Antimônio , Óxidos , Óxidos/química , Adsorção , Antimônio/química , Raios X , Compostos Férricos , Isótopos , ÁguaRESUMO
Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular eye diseases, but responses are incomplete in some patients. Recent evidence shows that integrins are involved in the pathogenesis of neovascular age-related macular degeneration and diabetic retinopathy. JP1, derived from an optimized seven-amino-acid fragment of JWA protein, is a polypeptide specifically targeting integrin αVß3. In this study we evaluated the efficacy of JP1 on laser-induced choroidal neovascularization (CNV) and retinal vascular leakage. CNV mice received a single intravitreal (IVT) injection of JP1 (10, 20, 40 µg) or ranibizumab (RBZ, 10 µg). We showed that JP1 injection dose-dependently inhibited laser-induced CNV; the effect of RBZ was comparable to that of 20 µg JP1; a combined IVT injection of JP1 (20 µg) and RBZ (5 µg) exerted a synergistic effect on CNV. In the 3rd month after streptozotocin injection, diabetic mice receiving IVT injection of JP1 (40 µg) or RBZ (10 µg) once a week for 4 weeks showed significantly suppressed retinal vascular leakage. In both in vivo and in vitro experiments, JP1 counteracted oxidative stress and inflammation via inhibiting ROS/NF-κB signaling in microglial cells, and angiogenesis via modulating MEK1/2-SP1-integrin αVß3 and TRIM25-SP1-MMP2 axes in vascular endothelial cells. In addition, intraperitoneal injection of JP1 (1, 5 or 10 mg) once every other day for 3 times also dose-dependently inhibited CNV. After intraperitoneal injection of FITC-labeled JP1 (FITC-JP1) or FITC in laser-induced CNV mice, the fluorescence intensity in the CNV lesion was markedly increased in FITC-JP1 group, compared with that in FITC group, confirming that JP1 could penetrate the blood-retinal barrier to target CNV lesion. We conclude that JP1 can be used to design novel CNV-targeting therapeutic agents that may replace current invasive intraocular injections.
Assuntos
Neovascularização de Coroide , Diabetes Mellitus Experimental , Retinopatia Diabética , Animais , Camundongos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Fluoresceína-5-Isotiocianato/uso terapêutico , Integrina alfaVbeta3/uso terapêutico , Peptídeos/uso terapêuticoRESUMO
Cigarette smoking is an independent risk factor for lung cancer. Nicotine, as an addictive substance in tobacco and e-cigarettes, is known to promote tumor progression and metastasis despite being a non-carcinogen. As a tumor suppressor gene, JWA is widely involved in the inhibition of tumor growth and metastasis and the maintenance of cellular homeostasis, including in non-small cell lung cancer (NSCLC). However, the role of JWA in nicotine-induced tumor progression remains unclear. Here, we reported for the first time that JWA was significantly downregulated in smoking-related lung cancer and associated with overall survival. Nicotine exposure reduced JWA expression in a dose-dependent manner. Gene Set Enrichment Analysis (GSEA) analysis showed the tumor stemness pathway was enriched in smoking-related lung cancer, and JWA was negatively associated with stemness molecules CD44, SOX2, and CD133. JWA also inhibited nicotine-enhanced colony formation, spheroid formation, and EDU incorporation in lung cancer cells. Mechanically, nicotine downregulated JWA expression via the CHRNA5-mediated AKT pathway. Lower JWA expression enhanced CD44 expression through inhibition of ubiquitination-mediated degradation of Specificity Protein 1 (SP1). The in vivo data indicated that JAC4 through the JWA/SP1/CD44 axis inhibited nicotine-triggered lung cancer progression and stemness. In conclusion, JWA via down-regulating CD44 inhibited nicotine-triggered lung cancer cell stemness and progression. Our study may provide new insights to develop JAC4 for the therapy of nicotine-related cancers.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Sistemas Eletrônicos de Liberação de Nicotina , Neoplasias Pulmonares , Receptores Nicotínicos , Humanos , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Nicotina/toxicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Receptores de Hialuronatos/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Nicotínicos/metabolismo , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismoRESUMO
BACKGROUND: Circular RNA (circRNA) has been shown to play an important regulatory role in the development of various cancers, including osteosarcoma (OS). However, the role of circRNA ABCC1 (circABCC1) in OS was still poorly understood. The aim of our study was to investigate the role of circABCC1 in OS progression and its potential molecular mechanisms. METHODS: The expression of circABCC1, microRNA-591 (miR-591) and histone deacetylase 4 (HDAC4) in OS tissues or cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) analyses. In vitro experiments, the viability, proliferation, apoptosis, migration, invasion and autophagy of U2OS and HOS cells were assessed in vitro using cell counting kit-8 (CCK-8) assay, 5-ethynyl-29-deoxyuridine (EdU) assay, flow cytometry (FCM) assay, transwell migration and invasion assays (transwell) and WB assay, respectively. Interactions between circABCC1 and miR-591, miR-591 and HDAC4 were confirmed using a dual luciferase reporter gene assay system. The oncogenic role of circABCC1 in OS in vivo was examined by establishing a tumor xenograft model. RESULTS: CircABCC1 was significantly elevated in OS tissues (about 3.1-folds) and cells (U2OS (about 2.1-folds) and HOS (about 2.8-folds)) compared with the control (p < .05). Silencing of circABCC1 significantly reduced the viability and proliferation, promoted apoptosis, impaired migration and invasion, and increased autophagy of U2OS and HOS cells (p < .05). In addition, miR-591 was confirmed to be a target of circABCC1, exerting an opposite effect to circABCC1 (p < .05). MiR-591 attenuation in U2OS and HOS cells was able to reply to the inhibition of cell proliferation, migration and invasion as well as promotion of cell apoptosis and autophagy mediated by silencing circABCC1 (p < .05). HDAC4 was verified to be the target gene of miR-591 in U2OS and HOS cells and was regulated by the circABCC1/miR-591 axis (p < .05), and restoration of HDAC4 levels in U2OS and HOS cells was able to restore the altered cellular function caused by silencing circABCC1 (p < .05). In addition, knockdown of circABCC1 attenuated tumor growth in vivo (p < .05). CONCLUSION: Silencing of circABCC1 inhibits osteosarcoma progression by attenuating HDAC4 expression through sponging miR-591.
Assuntos
Neoplasias Ósseas , MicroRNAs , Osteossarcoma , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Linhagem Celular Tumoral , Neoplasias Ósseas/patologia , Osteossarcoma/metabolismo , Proliferação de Células/genética , Histona Desacetilases/genética , Movimento Celular/genética , Proteínas RepressorasRESUMO
Lung adenocarcinoma (LUAD) is the most common lung cancer, with high mortality. As a tumor-suppressor gene, JWA plays an important role in blocking pan-tumor progression. JAC4, a small molecular-compound agonist, transcriptionally activates JWA expression both in vivo and in vitro. However, the direct target and the anticancer mechanism of JAC4 in LUAD have not been elucidated. Public transcriptome and proteome data sets were used to analyze the relationship between JWA expression and patient survival in LUAD. The anticancer activities of JAC4 were determined through in vitro and in vivo assays. The molecular mechanism of JAC4 was assessed by Western blot, quantitative real-time PCR (qRT-PCR), immunofluorescence (IF), ubiquitination assay, co-immunoprecipitation, and mass spectrometry (MS). Cellular thermal shift and molecule-docking assays were used for confirmation of the interactions between JAC4/CTBP1 and AMPK/NEDD4L. JWA was downregulated in LUAD tissues. Higher expression of JWA was associated with a better prognosis of LUAD. JAC4 inhibited LUAD cell proliferation and migration in both in-vitro and in-vivo models. Mechanistically, JAC4 increased the stability of NEDD4L through AMPK-mediated phosphorylation at Thr367. The WW domain of NEDD4L, an E3 ubiquitin ligase, interacted with EGFR, thus promoting ubiquitination at K716 and the subsequent degradation of EGFR. Importantly, the combination of JAC4 and AZD9191 synergistically inhibited the growth and metastasis of EGFR-mutant lung cancer in both subcutaneous and orthotopic NSCLC xenografts. Furthermore, direct binding of JAC4 to CTBP1 blocked nuclear translocation of CTBP1 and then removed its transcriptional suppression on the JWA gene. The small-molecule JWA agonist JAC4 plays a therapeutic role in EGFR-driven LUAD growth and metastasis through the CTBP1-mediated JWA/AMPK/NEDD4L/EGFR axis.