RESUMEN
Precise manipulation of chromatin folding is important for understanding the relationship between the three-dimensional genome and nuclear function. Existing tools can reversibly establish individual chromatin loops but fail to manipulate two or more chromatin loops. Here, we engineer a powerful CRISPR system which can manipulate multiple chromatin contacts using bioorthogonal reactions, termed the bioorthogonal reaction-mediated programmable chromatin loop (BPCL) system. The multiinput BPCL system employs engineered single-guide RNAs recognized by discrete bioorthogonal adaptors to independently and dynamically control different chromatin loops formation without cross-talk in the same cell or to establish hubs of multiway chromatin contacts. We use the BPCL system to successfully juxtapose the pluripotency gene promoters to enhancers and activate their endogenous expression. BPCL enables us to independently engineer multiway chromatin contacts without cross-talk, which provides a way to precisely dissect the high complexity and dynamic nature of chromatin folding.
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Ensamble y Desensamble de Cromatina , Cromatina , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Cromatina/genética , Cromosomas , Elementos de Facilitación Genéticos , Genoma , Regiones Promotoras Genéticas , ARN Guía de KinetoplastidaRESUMEN
Bioorthogonal chemistry represents a powerful tool in chemical biology, which shows great potential in epigenetic modulation. As a proof of concept, the epigenetic modulation model of mitochondrial DNA (mtDNA) is selected because mtDNA establishes a relative hypermethylation stage under oxidative stress, which impairs the mitochondrion-based therapeutic effect during cancer therapy. Herein, we design a new biocompatible hydrogen-bonded organic framework (HOF) for a HOF-based mitochondrion-targeting bioorthogonal platform TPP@P@PHOF-2. PHOF-2 can activate a prodrug (pro-procainamide) in situ, which can specifically inhibit DNA methyltransferase 1 (DNMT1) activity and remodel the epigenetic modification of mtDNA, making it more susceptible to ROS damage. In addition, PHOF-2 can also catalyze artemisinin to produce large amounts of ROS, effectively damaging mtDNA and achieving better chemodynamic therapy demonstrated by both in vitro and in vivo studies. This work provides new insights into developing advanced bioorthogonal therapy and expands the applications of HOF and bioorthogonal catalysis.
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ADN Mitocondrial , Epigénesis Genética , Mitocondrias , Especies Reactivas de Oxígeno , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Humanos , ADN Mitocondrial/genética , Epigénesis Genética/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Enlace de Hidrógeno , Animales , Ratones , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/antagonistas & inhibidores , ADN (Citosina-5-)-Metiltransferasa 1/genética , Profármacos/farmacología , Profármacos/química , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacologíaRESUMEN
Natural killer (NK) cell-based immunotherapy has received much attention in recent years. However, the practical application is still suffering from the decreased function, inadequate infiltration, and immunosuppressive microenvironment in solid tumor. Herein, we construct the light-responsive porphyrin Fe array-armed NK cells (denoted as NK@p-Fe) for cell behavior modulation via bioorthogonal catalysis. By installing cholesterol-modified porphyrin Fe molecules on NK cell surface, it forms a catalytic array with light-harvesting capabilities. This functionality transforms NK cells into cellular factories, capable of catalyzing the production of active agents in a light-controlled manner. The NK@p-Fe can generate active antineoplastic drug doxorubicin through bioorthogonal reactions to enhance the cytotoxic function of NK cells. Beyond drug synthesis, the NK@p-Fe can also bioorthogonally catalyze to produce FDA approved immune agonist, imiquimod (IMQ). The activated immune agonist plays a dual role by inducing DC maturation for NK cells activation and reshaping tumor immunosuppressive microenvironment for NK cells infiltration. This work represents a paradigm for modulation of adoptive cell behaviors to boost cancer immunotherapy by bioorthogonal catalysis.
RESUMEN
The creation of artificial high-performance photosynthetic assemblies with a tailorable antenna system to deliver absorbed solar energy to a photosynthetic reaction center, thereby mimicking biological photosynthesis, remains a major challenge. We report the construction of recyclable, high-performance photosynthetic nanofibers with a crystalline π-conjugated polyfluorene core as an antenna system that funnels absorbed solar energy to spatially defined sensitized Co(II) porphyrin photocatalysts for the hydrogen evolution reaction. Highly effective energy funneling was achieved by tuning the dimensions of the nanofibers to exploit the very long exciton diffusion lengths (>200 nm) associated with the highly crystalline polyfluorene core formed using the living crystallization-driven self-assembly seeded growth method. This enabled efficient solar light-driven hydrogen production from water with a turnover number of over 450 for 8 h of irradiation, an H2 production rate of ca. 65 mmol h-1 g-1, and an overall quantum yield of 0.4% in the wavelength region (<405 nm) beyond the absorption of the molecular photocatalyst. The strategy of using a tailored antenna system based on π-conjugated polymers and maximizing exciton transport to a reaction center reported in this work opens up future opportunities for potential applications in other fields such as solar overall water splitting, CO2 reduction, and photocatalytic small molecule synthesis.
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Combination therapies involving metabolic regulation and immune checkpoint blockade are considered an encouraging new strategy for cancer therapy. However, the effective utilization of combination therapies for activating tumor-associated macrophages (TAMs) remains challenging. Herein, a lactate-catalyzed chemodynamic approach to activate the therapeutic genome editing of signal-regulatory protein α (SIRPα) to reprogram TAMs and improve cancer immunotherapy is proposed. This system is constructed by encapsulating lactate oxidase (LOx) and clustered regularly interspaced short palindromic repeat-mediated SIRPα genome-editing plasmids in a metal-organic framework (MOF). The genome-editing system is released and activated by acidic pyruvate, which is produced by the LOx-catalyzed oxidation of lactate. The synergy between lactate exhaustion and SIRPα signal blockade can enhance the phagocytic ability of TAMs and promote the repolarization of TAMs to the antitumorigenic M1 phenotype. Lactate exhaustion-induced CD47-SIRPα blockade efficiently improves macrophage antitumor immune responses and effectively reverses the immunosuppressive tumor microenvironment to inhibit tumor growth, as demonstrated by in vitro and in vivo studies. This study provides a facile strategy for engineering TAMs in situ by combining CRISPR-mediated SIRPα knockout with lactate exhaustion for effective immunotherapy.
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Edición Génica , Neoplasias , Humanos , Ácido Láctico/metabolismo , Macrófagos/metabolismo , Neoplasias/tratamiento farmacológico , Inmunoterapia , Microambiente TumoralRESUMEN
Since polyoxometalates (POMs) can undergo reversible multi-electron redox transformations, they have been used to modulate the electronic environment of metal nanoparticles for catalysis. Besides, POMs possess unique electronic structures and acid-responsive self-assembly ability. These properties inspired us to tackle the drawbacks of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in biomedical applications, such as low catalytic efficiency and unsatisfactory disease selectivity. Herein, we construct molybdenum (Mo)-based POM nanoclusters doped with Cu (Cu-POM NCs) as a highly efficient bioorthogonal catalyst, which is responsive to pathologicallyacid and H2 S for selective antibiofilm therapy. Leveraging the merits of POMs, the Cu-POM NCs exhibit biofilm-responsive self-assembly behavior, efficient CuAAC-mediated in situ synthesis of antibacterial molecules, and a NIR-II photothermal effect selectively triggered by H2 S in pathogens. The consumption of bacterial H2 S at the pathological site by Cu-POM NCs extremely decreases the number of persisterbacteria, which is conducive to the inhibition of bacterial tolerance and elimination of biofilms. Unlocked at pathological sites and endowed with NIR-II photothermal property, the constructed POM-based bioorthogonal catalytic platform provides new insights into the design of efficient and selective bioorthogonal catalysts for disease therapy.
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Cobre , Molibdeno , Cobre/química , Molibdeno/química , Catálisis , Alquinos/químicaRESUMEN
A novel helix hydrogel with a G-quartet structure was synthesized from guanosine (Gua) and its derivative 5'-guanosine monophosphate (5'-GMP) under a molecular crowding environment. The chirality of the hydrogel is adjusted by controlling the gelling speed. The chiral hydrogel can induce an achiral dye Thioflavin T (ThT) to realize circularly polarized fluorescence (CPL). The CPL dissymmetry factor |glum| of the dye-hydrogels can reach 3 × 10-2 and can be switched easily.
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Hidrogeles , Luminiscencia , FluorescenciaRESUMEN
Telomeric DNA, whose length homeostasis is closely correlated with immortality of cancer cells, is regarded as a molecular clock for cellular lifespan. Regarding the capacity in forming G-quadruplex, G-rich 3'-overhang (G-overhang) has been considered as an attractive anticancer target. However, it is still challenging to precisely target telomeric G-overhang with current ligands because of the polymorphism of G-quadruplexes in cells. Herein, we construct a telomeric G-overhang-specific near-infrared-traceable DNA nano-hydrolase, which is composed of four parts: (i) dexamethasone for targeting cell nuclei; (ii) complementary DNA for hybridizing with G-overhang; (iii) multinuclear Ce(IV) complexes for hydrolyzing G-overhang; and (iv) upconversion nanoparticles for real-time tracking. The multivalent targeted DNA nano-hydrolase can be traced to precisely digest telomeric G-overhang, which contributes to telomeric DNA shortening and thereby causes cell aging and apoptosis. The anticancer treatment is further proved by in vivo studies. In this way, this design provides a telomeric G-overhang-specific eradication strategy based on a non-G-quadruplex targeting manner.
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Antineoplásicos/farmacología , Nanopartículas/química , Neoplasias Experimentales/tratamiento farmacológico , Compuestos Organometálicos/farmacología , Telómero/efectos de los fármacos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Cerio/química , Dexametasona/química , G-Cuádruplex , Humanos , Hidrólisis , Células MCF-7 , Ratones , Nanopartículas/metabolismo , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/uso terapéutico , Telómero/químicaRESUMEN
The intelligent nanomachine usually has a control center to carry out self-regulation. Unfortunately, most of the nanomaterials for chemodynamic therapy (CDT) do not have such a control center to sense and process the chemical or biological signals, which greatly weakens the selectivity and efficiency of CDT. To address this problem, here an intelligent nanomachine was constructed with a DNAzyme logic gate as the control center, and metal organic framework as the actuator. The well-designed nanomachine showed an enhanced killing effect on cancer cells but posed no harm to normal cells, acquiring better selectivity than clinical chemotherapy drugs (doxorubicin and cisplatin). To the best of our knowledge, this is the first reported cell-specific CDT by the guidance of DNAzyme logic gate. Our work highlights the great potential of DNAzymes in intelligent response networks, and extends the implementation of nanomachines in precision medicine.
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ADN Catalítico , LógicaRESUMEN
Chiral materials related to circularly polarized luminescence (CPL) make up a rapidly developing new field that has broad application prospects in optoelectronic devices, selective recognition, biomedicine, and other fields. Biofunctional chiral materials are also attracting increasing attention because of their unique biocompatibility, chiral recognition, and coding. However, there has been little discussion on biomolecule-based CPL till now. In this Review, the latest progress in CPL materials related with biomolecules are reviewed, including the chiral construction from molecular level to giant microstructure, as well as their emerging applications. In addition, we discuss the challenges and prospects of bio-based CPL materials, hoping this work will provide new perspectives and insights for more related research.
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Luminiscencia , Mediciones Luminiscentes , EstereoisomerismoRESUMEN
The formation of G-quadruplexes (G4) in human telomere and other important biological regions inhibits the replication and transcription of DNA, thereby influencing further cell proliferation. The investigation of G4 formation and unfolding is vital for understanding their modulation in biological processes and life science. Photo regulation is a facile and sensitive approach for monitoring the structures of biomacromolecules and material surface properties. The nanopore-based technique is also prevalent for label-free single-molecule characterization with high accuracy. This study provides a combination of solid-state nanopore technology with light-switch as a platform for the modulation of human telomere G4 formation and splitting under switchable light exposure. The introduction of molecular switch, namely azobenzene moiety at different positions of the DNA sequence influences the formation and stability of G4. Three azobenzenes immobilized on each of the G-quartet plane (hTelo-3azo-p) or four azobenzenes on the same plane (hTelo-4azo-4p) of the human telomere G4 sequence realized the reversible control of G4 folding/unfolding at the temporal scale upon photo regulation, and the formation and splitting of G4 with hTelo-4azo-4p is slower and not thorough compared to that with hTelo-3azo-p due to the coplanar steric hindrance. Moreover, the G4 formation recorded with the combined nanopore and photo-responsive approach was also characterized with fluorescence, and the variation in the fluorescence intensity of the NMM and G4 complex exhibited a different tendency under reverse light irradiation due to the distinct interactions of NMM with the azobenzene-modified G4. Our study demonstrated a controllable and sensitive way for the manipulation of G4 structures, which will be inspiring for the intervention of G4-related cell senescence, cancer diagnosis and drug exploration.
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G-Cuádruplex , Nanoporos , Nanotecnología/métodos , Telómero/química , Compuestos Azo/químicaRESUMEN
Although chemotherapy is one of the most widely used cancer treatments, there are serious side effects, drug resistance, and secondary metastasis. To address these problems, herein we designed a bimetallic metal-organic framework (MOF) encapsulated with DNAzyme for co-triggered in situ cancer drug synthesis and DNAzyme-based gene therapy. Once in cancer cells, MOFs would disassemble and liberate copper ions, zinc ions, and DNAzyme under the acidic environment of lysosomes. Copper ions can catalyze the synthesis of the chemotherapeutic drug through copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction after being reduced to CuI ; zinc ions act as the cofactor to activate the cleavage activity of DNAzyme. The anticancer drug is synthesized intracellularly and can kill cancer cells on site to minimize side effects to normal organisms. The activated DNAzyme starts gene therapy to inhibit tumor proliferation and metastasis by targeting and cleaving oncogene substrates.
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Antineoplásicos/síntesis química , Cobre/química , ADN Catalítico/química , Estructuras Metalorgánicas/química , Alquinos/química , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Azidas/química , Catálisis , Reacción de Cicloadición , ADN Catalítico/metabolismo , Portadores de Fármacos/química , Técnicas de Transferencia de Gen , Humanos , Concentración de Iones de Hidrógeno , Imidazoles/química , Células MCF-7 , Ratones , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Trasplante HeterólogoRESUMEN
The COVID-19 pandemic caused by SARS-CoV-2 has become a global threat. Understanding the underlying mechanisms and developing innovative treatments are extremely urgent. G-quadruplexes (G4s) are important noncanonical nucleic acid structures with distinct biofunctions. Four putative G4-forming sequences (PQSs) in the SARS-CoV-2 genome were studied. One of them (RG-1), which locates in the coding sequence region of SARS-CoV-2 nucleocapsid phosphoprotein (N), has been verified to form a stable RNA G4 structure in live cells. G4-specific compounds, such as PDP (pyridostatin derivative), can stabilize RG-1 G4 and significantly reduce the protein levels of SARS-CoV-2 N by inhibiting its translation both in vitro and in vivo. This result is the first evidence that PQSs in SARS-CoV-2 can form G4 structures in live cells, and that their biofunctions can be regulated by a G4-specific stabilizer. This finding will provide new insights into developing novel antiviral drugs against COVID-19.
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Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , G-Cuádruplex/efectos de los fármacos , ARN Viral/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Regulación Viral de la Expresión Génica/efectos de los fármacos , Genoma Viral , Humanos , Proteínas de la Nucleocápside/química , Proteínas de la Nucleocápside/efectos de los fármacos , Pliegue de Proteína , SARS-CoV-2/genética , Bibliotecas de Moléculas Pequeñas , TemperaturaRESUMEN
The design and synthesis of metal complexes that can specifically target DNA secondary structure has attracted considerable attention. Chiral metallosupramolecular complexes (e.g. helicates) in particular display unique DNA-binding behavior, however until recently few examples which are both water-compatible and enantiomerically pure have been reported. Herein we report that one metallohelix enantiomer Δ1a, available from a diastereoselective synthesis with no need for resolution, can enantioselectively stabilize human telomeric hybrid G-quadruplex and strongly inhibit telomerase activity with IC50 of 600 nM. In contrast, no such a preference is observed for the mirror image complex Λ1a. More intriguingly, neither of the two enantiomers binds specifically to human telomeric antiparallel G-quadruplex. To the best of our knowledge, this is the first example of one pair of enantiomers with contrasting selectivity for human telomeric hybrid G-quadruplex. Further studies show that Δ1a can discriminate human telomeric G-quadruplex from other telomeric G-quadruplexes.
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ADN/química , G-Cuádruplex , Metales/química , Complejos de Coordinación/química , Células HeLa , Humanos , Hierro/química , Isomerismo , Telomerasa/antagonistas & inhibidores , Telomerasa/metabolismoRESUMEN
BACKGROUND: Perineum necrotizing fasciitis, also known as Fournier gangrene (FG), is a rare but highly mortal infectious necrotizing fasciitis with or without involvement of the underlying muscle. Evidence exists that negative pressure wound therapy (NPWT) combined with a split thickness skin graft (STSG) can help to heal wounds with FG. However, when the wound spreads to the anal area, it can easily be contaminated by faeces, causing a more extensive wounds; thus, faecal diversion is considered. Here, we report a case of extensive perineum necrotizing fasciitis that spread to near the anus; NPWT combined with STSGs was used to help heal the wound without faecal diversion. CASE PRESENTATION: A 47-year-old male patient was admitted with extensive perineum fascia necrosis caused by Pseudomonas aeruginosa that rapidly spread to near the anus. After comprehensive therapy completed wound bed preparation, STSGs from the scalp were grafted to the wound, and NPWT was applied to improve STSGs survival and seal the anus without faecal diversion. After treatment, graft take was 95%, and the exposed testicular and residual wounds were repaired with a local skin flap. At discharge, the wound had decreased to two pea-sized areas. The patient received conventional moist gauze therapy to close the residual wound at the local hospital. A follow-up by telephone 1 month later showed that both wounds had healed and that the patient was satisfied with the outcome. CONCLUSION: NPWT use combined with STSGs to cover the whole wound and the anus without faecal diversion is a safe and effective method to help with wound healing and avoid contamination with excrement.
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Fascitis Necrotizante/terapia , Terapia de Presión Negativa para Heridas , Perineo , Infecciones por Pseudomonas/terapia , Pseudomonas aeruginosa , Trasplante de Piel , Fascitis Necrotizante/patología , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Pseudomonas/patología , Colgajos Quirúrgicos , Cicatrización de HeridasRESUMEN
Natural d-DNA and l-DNA are mirror-image counterparts. However, because of the inherent flexibility and conformation diversity of DNA, it is still not clear how enantiomeric compounds recognize d-DNA and l-DNA. Herein, taking G-quadruplex (G4) DNA as an example that has diverse conformations and distinct biofunctions, the binding of ten pairs of iron triplex metallohelices to d- and l-G4 DNA were evaluated. The Δ-enantiomer binds to d-DNA and the Λ-enantiomer binds to l-DNA, exhibiting almost the same stabilization effect and binding affinity. The binding affinity of the Δ-metallohelix with d-G4 is nearly 70-fold higher than that of Λ-metallohelix binding d-G4. Δ-Metallohelix binding to d-G4 follows a two-step binding process driven by a favorable enthalpy contribution to compensate for the associated unfavorable entropy.
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ADN/química , Compuestos Organometálicos/química , G-Cuádruplex , Cinética , Estructura Molecular , TermodinámicaRESUMEN
Cancer stem cells (CSCs) are responsible for drug resistance, metastasis and recurrence of cancers. However, there is still no clinically approved drug that can effectively eradicate CSCs. Thus, it is crucial and important to develop specific CSC-targeting agents. Chiral molecular recognition of DNA plays an important role in rational drug design. Among them, polymorphic telomeric G-quadruplex DNA has received much attention due to its significant roles in telomerase activity and chromosome stability. Herein, we find that one enantiomer of zinc-finger-like chiral metallohelices, [Ni2L3]4+-P, a telomeric G-quadruplex-targeting ligand, can preferentially reduce cell growth in breast CSCs compared to the bulk cancer cells. In contrast, its enantiomer, [Ni2L3]4+-M, has little effect on both populations. Further studies indicate that [Ni2L3]4+-P can repress CSC properties and induce apoptosis in breast CSCs. This is different to the bulk cancer cells. The inhibition of breast CSC traits is involved in the nuclear translocation of hTERT. The apoptosis is associated with the induction of telomere uncapping, telomere DNA damage and the degradation of 3'-overhang. Moreover, [Ni2L3]4+-P, but not [Ni2L3]4+-M, has the ability to reduce tumorigenesis of breast CSCs in vivo. To our knowledge, this is the first report that chiral complexes show significant enantioselectivity on eradicating CSCs.
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Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Carcinogénesis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN , Diseño de Fármacos , G-Cuádruplex/efectos de los fármacos , Humanos , Células Madre Neoplásicas/enzimología , Células Madre Neoplásicas/metabolismo , Telomerasa/metabolismo , Telómero/efectos de los fármacos , Telómero/genéticaRESUMEN
Stereoselectivity towards substrates is one of the most important characteristics of enzymes. Amino acids, as cofactors of many enzymes, play important roles in stereochemistry. Herein, chiral nanozymes were constructed by grafting a series of d- or l-amino acids onto the surfaces of ceria (cerium oxide) nanoparticles. We selected the most commonly used drug for combating Parkinson's disease, that is, 3,4-dihydroxyphenylalanine (DOPA) enantiomers, as examples for chiral catalysis. Through detailed kinetic studies of cerium oxide nanoparticles (CeNPs) modified with different eight amino acids, we found that phenylalanine-modified CeNP was optimal for the DOPA oxidation reaction and showed excellent stereoselectivity towards its enantiomers. l-Phenylalanine-modified CeNPs showed higher catalytic ability for oxidation of d-DOPA, while d-phenylalanine-modified CeNPs were more effective towards l-DOPA. Taken together, the results indicated that stereoselective nanozyme can be constructed by grafting nanoparticles with chiral molecules. This work may inspire better design of chiral nanozymes.
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Antiparkinsonianos/química , Cerio/química , Coenzimas/química , Dihidroxifenilalanina/química , Nanopartículas del Metal/química , Fenilalanina/química , Catálisis , Humanos , Cinética , Levodopa/química , Oxidación-Reducción , Tamaño de la Partícula , Estereoisomerismo , Propiedades de SuperficieRESUMEN
The objective of this study was to investigate the influence of extracellular polymeric substance (EPS) on the coupling effects between ammonia-oxidizing bacteria (AOB) and anaerobic ammonium-oxidizing (anammox) bacteria for the completely autotrophic nitrogen removal over nitrite (CANON) biofilm formation in a moving bed biofilm reactor (MBBR). Analysis of the quantity of EPS and cyclic diguanylate (c-di-GMP) confirmed that the contents of polysaccharides and c-di-GMP were correlated in the AOB sludge, anammox sludge, and CANON biofilm. The anammox sludge secreted more EPS (especially polysaccharides) than AOB with a markedly higher c-di-GMP content, which could be used by the bacteria to regulate the synthesis of exopolysaccharides that are ultimately used as a fixation matrix, for the adhesion of biomass. Indeed, increased intracellular c-di-GMP concentrations in the anammox sludge enhanced the regulation of polysaccharides to promote the adhesion of AOB and formation of the CANON biofilm. Overall, the results of this study provide new comprehensive information regarding the coupling effects of AOB and anammox bacteria for the nitrogen removal process.
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Amoníaco/metabolismo , Compuestos de Amonio/metabolismo , Bacterias/metabolismo , Biopelículas/crecimiento & desarrollo , GMP Cíclico/análogos & derivados , Nitrógeno/metabolismo , Anaerobiosis , Bacterias/genética , Reactores Biológicos/microbiología , GMP Cíclico/metabolismo , Desnitrificación , Regulación Bacteriana de la Expresión Génica , Nitritos/metabolismo , Oxidación-Reducción , Polisacáridos Bacterianos/metabolismo , Sistemas de Mensajero Secundario , Aguas del Alcantarillado/microbiologíaRESUMEN
Chiral recognition of DNA molecules is important because DNA chiral transition and its different conformations are involved in a series of important life events. Among them, polymorphic human telomere DNA has attracted great interests in recent years because of its important roles in chromosome structural integrity. In this report, we examine the short-term effect of chiral metallo-supramolecular complex enantiomers treatment on tumor cells, and find that a zinc-finger-like alpha helical chiral metallo-supramolecular complex, [Ni2L3](4+)-P enantiomer (NiP), can selectively provoke the rapid telomere uncapping, trigger DNA damage responses at telomere and degradation of G-overhang and the delocalization of telomeric protein from telomeres. Further studies indicate that NiP can induce an acute cellular apoptosis and senescence in cancer cells rather than normal cells. These results are further evidenced by the upregulation of p21 and p16 proteins. Moreover, NiP can cause translocation of hTERT from nuclear to cytoplasm through Tyr 707 phosphorylation. While its enantiomer, [Ni2L3](4+)-M (NiM), has no such mentioned effects, these results clearly demonstrate the compound's chiral selectivity in cancer cells. Our work will shed light on design of chiral anticancer drugs targeting G-quadruplex DNA, and developing telomere and telomerase modulation agents.