RESUMO
Changes in mechanosensitive ion channels following radiation have seldom been linked to therapeutic sensitivity or specific factors involved in antitumor immunity. Here, in this study, we found that the mechanical force sensor, Piezo2, was significantly upregulated in tumor cells after radiation, and Piezo2 knockout in tumor cells enhanced tumor growth suppression by radiotherapy. Specifically, loss of Piezo2 in tumor cells induced their IL-15 expression via unleashing JAK2/STAT1/IRF-1 axis after radiation. This increase in IL-15 activates IL-15Rα on tumor-infiltrating CD8+ T cells, thereby leading to their augmented effector and stem cell-like properties, along with reduced terminal exhausted feature. Importantly, Piezo2 expression was negatively correlated with CD8 infiltration, as well as with radiosensitivity of patients with rectum adenocarcinoma receiving radiotherapy treatment. Together, our findings reveal that tumor cell-intrinsic Piezo2 induces radioresistance by dampening the IRF-1/IL-15 axis, thus leading to impaired CD8+ T cell-dependent antitumor responses, providing insights into the further development of combination strategies to treat radioresistant cancers.
Assuntos
Linfócitos T CD8-Positivos , Interleucina-15 , Canais Iônicos , Tolerância a Radiação , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Humanos , Canais Iônicos/metabolismo , Canais Iônicos/genética , Tolerância a Radiação/genética , Camundongos , Interleucina-15/metabolismo , Interleucina-15/genética , Linhagem Celular Tumoral , Janus Quinase 2/metabolismo , Janus Quinase 2/genética , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Camundongos Endogâmicos C57BL , Feminino , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Masculino , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Transdução de SinaisRESUMO
Drugs specifically targeting YKL-40, an over-expressed gene (CHI3L1) in various diseases remain developed. The current study is to create a humanized anti-YKL-40 neutralizing antibody and characterize its potentially therapeutic signature. We utilized in silico CDR-grafting bioinformatics to replace the complementarity determining regions (CDRs) of human IgG1 with mouse CDRs of our previously established anti-YKL-40 antibody (mAY). In fifteen candidates (VL1-3/VH1-5) of heavy and light chain variable region combination, one antibody L3H4 named Rosazumab demonstrated strong binding affinity with YKL-40 (KD = 4.645 × 10-8 M) and high homology with human IgG (80 %). In addition, we established different overlapping amino acid peptides of YKL-40 and found that Rosazumab specifically bound to residues K337, K342, and R344, the KR-rich functional domain of YKL-40. Rosazumab inhibited migration and tube formation of YKL-40-expressing tumor cells and induced tumor cell apoptosis. Mechanistically, Rosazumab induced interaction of N-cadherin with ß-catenin and activation of downstream MST1/RASSF1/Histone H2B axis, leading to chromosomal DNA breakage and cell apoptosis. Treatment of xenografted tumor mice with Rosazumab twice a week for 4 weeks inhibited tumor growth and angiogenesis, but induced tumor apoptosis. Rosazumab injected in mice distributed to blood, tumor, and other multiple organs, but did not impact in function or structure of liver and kidney, indicating non-detectable toxicity in vivo. Collectively, the study is the first one to demonstrate that a humanized YKL-40 neutralizing antibody offers a valuable means to block tumor development.
Assuntos
Anticorpos Monoclonais Humanizados , Proteína 1 Semelhante à Quitinase-3 , Neoplasias , Animais , Feminino , Humanos , Camundongos , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Linhagem Celular Tumoral , Proteína 1 Semelhante à Quitinase-3/antagonistas & inibidores , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
In order to improve photocatalytic activity and maximize solar energy use, a new composite material Fe2O3/P2Mo18 was prepared by combining polyoxometalates (P2Mo18) with Fe2O3 nanosheets. FT-IR, XRD, XPS, SEM, TEM, UV-vis, EIS, and PL were used to characterize the composite material, and nano-Fe2O3 of different sizes and morphologies with a controllable absorption range was prepared by adjusting the reaction time, and, when combined with P2Mo18, a composite photocatalyst with efficient visible light response and photocatalytic activity was constructed. The EIS, Bode, and PL spectra analysis results show that the Fe2O3/P2Mo18 composite material has outstanding interfacial charge transfer efficiency and potential photocatalytic application possibilities. Model reactions of methylene blue (MB) and Cr (VI) photodegradation were used to evaluate the redox activity of Fe2O3/P2Mo18 composites under simulated visible light. The photocatalytic degradation rate was as high as 98.98% for MB and 96.86% for Cr (VI) when the composite ratio was Fe2O3/P2Mo18-5%. This research opens up a new avenue for the development of high-performance photocatalysts.
RESUMO
The mesenchymal subtype of glioblastoma (mGBM), which is characterized by rigorous vasculature, resists anti-tumor immune therapy. Here, we investigated the mechanistic link between tumor vascularization and the evasion of immune surveillance. Clinical datasets with GBM transcripts showed that the expression of the mesenchymal markers YKL-40 (CHI3L1) and Vimentin is correlated with elevated expression of PD-L1 and poor disease survival. Interestingly, the expression of PD-L1 was predominantly found in vascular endothelial cells. Orthotopic transplantation of glioma cells GL261 over-expressing YKL-40 in mice showed increased angiogenesis and decreased CD8+ T cell infiltration, resulting in a reduction in mouse survival. The exposure of recombinant YKL-40 protein induced PD-L1 and VE-cadherin (VE-cad) expression in endothelial cells and drove VE-cad-mediated nuclear translocation of ß-catenin/LEF, where LEF upregulated PD-L1 expression. YKL-40 stimulated the dissociation of VE-cad from PD-L1, rendering PD-L1 available to interact with PD-1 from CD8+-positive TALL-104 lymphocytes and inhibit TALL-104 cytotoxicity. YKL-40 promoted TALL-104 cell migration and adhesion to endothelial cells via CCR5-dependent chemotaxis but blocked its anti-vascular immunity. Knockdown of VE-cad or the PD-L1 gene ablated the effects of YKL-40 and reinvigorated TALL-104 cell immunity against vessels. In summary, our study demonstrates a novel vascular immune escape mechanism by which mGBM promotes tumor vascularization and malignant transformation.
RESUMO
CD8+ T cells are the key executioners of the adaptive immune arm, which mediates antitumor and antiviral immunity. Naïve CD8+ T cells develop in the thymus and are quickly activated in the periphery after encountering a cognate antigen, which induces these cells to proliferate and differentiate into effector cells that fight the initial infection. Simultaneously, a fraction of these cells become long-lived memory CD8+ T cells that combat future infections. Notably, the generation and maintenance of memory cells is profoundly affected by various in vivo conditions, such as the mode of primary activation (e.g., acute vs. chronic immunization) or fluctuations in host metabolic, inflammatory, or aging factors. Therefore, many T cells may be lost or become exhausted and no longer functional. Complicated intracellular signaling pathways, transcription factors, epigenetic modifications, and metabolic processes are involved in this process. Therefore, understanding the cellular and molecular basis for the generation and fate of memory and exhausted CD8+ cells is central for harnessing cellular immunity. In this review, we focus on mammalian target of rapamycin (mTOR), particularly signaling mediated by mTOR complex (mTORC) 2 in memory and exhausted CD8+ T cells at the molecular level.
Assuntos
Linfócitos T CD8-Positivos , Serina-Treonina Quinases TOR , Diferenciação Celular , Serina-Treonina Quinases TOR/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Memória ImunológicaRESUMO
OBJECTIVE: Dexmedetomidine (Dex) is a highly selective α2-adrenoceptor agonist with sedative, analgesic, sympatholytic, and hemodynamic-stabilizing properties, which plays a neuroprotective role in diabetic peripheral neuropathy (DPN) and diabetes-induced nerve damage. However, the related molecular mechanisms are not fully understood. Therefore, our study explored the mechanism of Dex in DPN using rat and RSC96 cell models. METHODS: Sciatic nerve sections were observed under an optical microscope and the ultrastructure of the sciatic nerves was observed under a transmission electron microscope. Oxidative stress was assessed by detecting MDA, SOD, GSH-Px, and ROS levels. The motor nerve conduction velocity (MNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) of rats were measured. Cell viability, apoptosis, and the changes in the expression of related genes and proteins were examined. Furthermore, the relationship between microRNA (miR)-34a and SIRT2 or SIRT2 and S1PR1 was analyzed. RESULTS: Dex reversed DPN-induced decreases in MNCV, MWT, and TWL. Dex alleviated oxidative stress, mitochondrial damage, and apoptosis in both the rat and RSC96 cell models of DPN. Mechanistically, miR-34a negatively targeted SIRT2, and SIRT2 inhibited S1PR1 transcription. The overexpression of miR-34a or S1PR1 or the inhibition of SIRT2 counteracted the neuroprotective effects of Dex in DPN in vivo and in vitro. CONCLUSION: Dex alleviates oxidative stress and mitochondrial dysfunction associated with DPN by downregulating miR-34a to regulate the SIRT2/S1PR1 axis.
Assuntos
Dexmedetomidina , Diabetes Mellitus , Neuropatias Diabéticas , MicroRNAs , Ratos , Animais , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Sirtuína 2/metabolismo , Estresse Oxidativo , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Apoptose , Receptores de Esfingosina-1-Fosfato/metabolismoRESUMO
The high-temperature solid-phase approach was used to synthesize Eu3+-doped SrMo0.5W0.5O4 phosphors, whose morphological structure and luminescence properties were then characterized by XRD, SEM, FT-IR, excitation spectra, emission spectra, and fluorescence decay curves. The results reveal that the best phosphor synthesis temperature was 900 °C and that the doping of Eu3+ and charge compensators (K+, Li+, Na+, NH4+) had no effect on the crystal phase change. SrMo0.5W0.5O4:Eu3+ has major excitation peaks at 273 nm, 397 nm, and 464 nm, and a main emission peak at 615 nm, making it a potential red fluorescent material to be used as a down converter in UV LEDs (273 nm and 397 nm) and blue light LEDs (464 nm) to achieve Red emission. The emission spectra of Sr1-yMo0.5W0.5O4:yEu3+(y = 0.005, 0.01, 0.02, 0.05, 0.07) excited at 273 were depicted, with the Eu3+ concentration increasing the luminescence intensity first increases and then decreases, the emission peak intensity of SrMo0.5W0.5O4:Eu3+ achieves its maximum when the doping concentration of Eu3+ is 1%, and the critical transfer distance is calculated as 25.57 Å. When various charge compensators such as K+, Li+, Na+, and NH4+ are added to SrMo0.5W0.5O4:Eu3+, the NH4+ shows the best effect with the optimal doping concentration of 3wt%. The SrMo0.5W0.5O4:Eu3+,NH4+ color coordinate is (0.656,0.343), which is close to that of the ideal red light (0.670,0.333).
RESUMO
Supported catalysts, consisting of PMo12 immobilized on silver nanomaterials at different recombination time and the silver nanomaterials with different template sodium citrate amount characterized by FT-IR, XRD, SEM, UV-vis and other test methods. The results show that the AgNPs are relatively uniformed with sizes between 100-300 nm when the sodium citrate addition amount is 9.0 mL. As the reaction time of PMo12/AgNPs increases, the adhesion of AgNPs on the surface of PMo12 becomes more complete. Using PMo12 and PMo12/AgNPs composite materials as catalysts, methylene blue (MB) is photocatalytically degraded under simulated visible light conditions. The results show that PMo12 can catalyze MB effectively, and the decolorization rate reached 98.6% when the catalyst content is 2 g/L, the solution pH is 3 and the MB concentration is 5 mg/L. Under the same experimental conditions, photocatalytic performance of the PMo12/AgNPs system is better than that of the PMo12 further improved the photocatalytic degradation effect of the MB solution with a decolorization rate of 100%. The composite still keeps good photocatalytic activity and stability after three cycles of use. Finally, the catalytic mechanism of the POMs composite material is preliminarily discussed.
Assuntos
Azul de Metileno , Prata , Catálise , Espectroscopia de Infravermelho com Transformada de Fourier , Compostos de TungstênioRESUMO
BACKGROUND: Ivacaftor (KALYDECO™, VX-770) is a CFTR potentiator that increased CFTR channel activity and improved lung function in patients age 6 years and older with CF who have the G551D-CFTR gating mutation. The aim of this in vitro study was to evaluate the effect of ivacaftor on mutant CFTR protein forms with defects in protein processing and/or channel function. METHODS: The effect of ivacaftor on CFTR function was tested in electrophysiological studies using a panel of Fischer rat thyroid (FRT) cells expressing 54 missense CFTR mutations that cause defects in the amount or function of CFTR at the cell surface. RESULTS: Ivacaftor potentiated multiple mutant CFTR protein forms that produce functional CFTR at the cell surface. These included mutant CFTR forms with mild defects in CFTR processing or mild defects in CFTR channel conductance. CONCLUSIONS: These in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.
Assuntos
Aminofenóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/agonistas , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Ativação do Canal Iônico/efeitos dos fármacos , Mutação de Sentido Incorreto , Quinolonas/farmacologia , Animais , Linhagem Celular , Cloretos/metabolismo , Fibrose Cística/genética , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Humanos , Técnicas In Vitro , Ativação do Canal Iônico/genética , Ratos , Ratos Endogâmicos F344 , Glândula Tireoide/citologiaRESUMO
Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of l0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , FenótipoRESUMO
BACKGROUND: The investigational CFTR potentiator ivacaftor (VX-770) increased CFTR channel activity and improved lung function in subjects with CF who have the G551D CFTR gating mutation. The aim of this in vitro study was to determine whether ivacaftor potentiates mutant CFTR with gating defects caused by other CFTR gating mutations. METHODS: The effects of ivacaftor on CFTR channel open probability and chloride transport were tested in electrophysiological studies using Fischer rat thyroid (FRT) cells expressing different CFTR gating mutations. RESULTS: Ivacaftor potentiated multiple mutant CFTR forms with defects in CFTR channel gating. These included the G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D CFTR gating mutations. CONCLUSION: These in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D.
Assuntos
Aminofenóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , DNA/genética , Mutação/efeitos dos fármacos , Quinolonas/uso terapêutico , Animais , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Análise Mutacional de DNA , Modelos Animais de Doenças , Ativação do Canal Iônico/genética , Transporte de Íons/genética , Prognóstico , Ratos , Ratos Endogâmicos F344 , Glândula Tireoide/metabolismo , Glândula Tireoide/patologiaRESUMO
In the title compound, [Zn(C(18)H(14)N(4))(2)(H(2)O)(4)](NO(3))(2)·1.49H(2)O, the Zn(II) atom, lying on an inversion center, is coordinated by two N atoms from two N,N'-bis-(pyridin-3-yl-methyl-idene)benzene-1,4-diamine ligands and four water mol-ecules in a distorted octa-hedral geometry. The nitrate anion is disordered over two sets of sites, with an occupancy ratio of 0.744â (4):0.256â (4). The uncoordinated water mol-ecule is also disordered with an occupancy factor of 0.744â (4). O-Hâ¯O and O-Hâ¯N hydrogen bonds link the complex cations, nitrate anions and uncoordinated water mol-ecules into a supra-molecular layer parallel to (102).
RESUMO
The title arsenatomolybdate, K(5)[Mo(8)O(24)(OH)(2)(AsO(4))]·2H(2)O, which was obtained hydro-thermally, features an [AsMo(8)O(28)(OH)(2)](5-) anion, which is formed by two Mo(4)O(14)(OH) units that are linked by As in a sandwich-like fashion. The overall symmetry of the anion is m2m. The {Mo(4)O(14)(OH)} core is composed of two pairs of confacial biocta-hedral {Mo(2)O(9)} units with two µ(4)-O atoms which have been characterized as hydroxyl groups. The anions are further inter-connected by potassium cations, forming a three-dimensional network structure with the uncoordinated water mol-ecules occupying the channels. The structure is further stabilized by O-Hâ¯O hydrogen bonding.
RESUMO
In the title organic-inorganic hybrid vanadate complex, [Cu(2)V(6)O(17)(C(10)H(8)N(2))(4)](n), the Cu(II) atom is six-coordinated by two chelating 2,2'-bipyridine (bipy) ligands and two vanadate O atoms in a distorted octa-hedral geometry. Two [Cu(bipy)(2)V(3)O(8)] units are linked by a bridging O atom, which lies on an inversion center, forming a dimeric unit. The dimeric units are further connected by bridging vanadate O atoms into a two-dimensional layer parallel to (100). The layers are connected by weak C-Hâ¯O hydrogen bonds.
RESUMO
The title compound, (C(4)H(12)N(2))(3)[PMo(12)O(40)] or (H(2)pip)(3)[PMo(12)O(40)] (pip is piperazine), was prepared under hydro-thermal conditions. The asymmetric unit contains one-sixth of a mixed-valent Mo(V,VI) pseudo-Keggin-type [PMo(12)O(40)](6-) anion and half a piperazinediium cation, (H(2)pip)(2+). The discrete Keggin-type [PMo(12)O(40)](6- )anion has site symmetry and the three (H(2)pip)(2+) cations each have site symmetry at the centres of the mol-ecules. The central P atom is on special position , which is a roto-inversion position and generates the disorder of the PO(4) tetra-hedron. Furthermore, six doubly bridging oxide groups are also disordered with an occupancy factor of 0.5 for each O atom. The anions and cations are linked by an extensive network of inter-molecular N-Hâ¯O and C-Hâ¯O hydrogen bonds.
RESUMO
In the title compound, C(21)H(18)N(2)O, the dihedral angle between the phenol ring and the carbazole system is 39.34â (2)°. Inter-molecular O-Hâ¯N hydrogen bonds and C-Hâ¯π and π-π inter-actions [centroid-centroid distances = 3.426â (2) and 3.768â (2)â Å] stabilize the crystal structure.
RESUMO
The title compound, tris-(4,4'-bipyridinium) diarsenoocta-deca-molybdate(VI), (C(10)H(10)N(2))(3)[As(2)Mo(18)O(62)], featuring protonated bipyridine mol-ecules and a classical Dawson-type polyoxo-anion, has been synthesized under hydro-thermal conditions. The polyoxoanions are linked together via the bipyridyl cations, acting as hydrogen-bond donors, generating a two-dimensional supra-molecular network. The asymmetric unit contains 1.5 4,4'-bipyridinium (H(2)bpy) units, with an inversion centre in the central bond of the second H(2)bpy unit. The site symmetry of the anion is .
RESUMO
In the title complex, [Cu(2)V(8)O(21)(2,2'-bpy)(2)](n) (bpy = bipyridine, C(10)H(8)N(2)), the asymmetric unit contains four independent V atoms briged by 11 O atoms, one of which lies on an inversion center, and a [Cu(2,2'-bpy)](2+) unit. Three V atoms in the polyoxoanion exhibit distorted tetra-hedral coordination geometries while the fourth V atom adopts a trigonal-bipyramidal geometry. The Cu atom adopts a square-pyramidal geometry being coordinated by two nitro-gen donors of a 2,2'-bpy ligand, and three bridging O atoms which are linked with V atoms. The V(8) polyoxoanion is connected to [Cu(2,2'-bpy)](2+) cations, resulting in a two-dimensional layer structure extending parallel to (010). C-Hâ¯O hydrogen bonding consolidates the structure.
RESUMO
The first polyoxometal complex possessing affirmatory mixed molybdenum-tungsten capped Keggin-type structure has been hydrothermally synthesized.