RESUMO
The identity of the earliest inhabitants of Xinjiang, in the heart of Inner Asia, and the languages that they spoke have long been debated and remain contentious1. Here we present genomic data from 5 individuals dating to around 3000-2800 BC from the Dzungarian Basin and 13 individuals dating to around 2100-1700 BC from the Tarim Basin, representing the earliest yet discovered human remains from North and South Xinjiang, respectively. We find that the Early Bronze Age Dzungarian individuals exhibit a predominantly Afanasievo ancestry with an additional local contribution, and the Early-Middle Bronze Age Tarim individuals contain only a local ancestry. The Tarim individuals from the site of Xiaohe further exhibit strong evidence of milk proteins in their dental calculus, indicating a reliance on dairy pastoralism at the site since its founding. Our results do not support previous hypotheses for the origin of the Tarim mummies, who were argued to be Proto-Tocharian-speaking pastoralists descended from the Afanasievo1,2 or to have originated among the Bactria-Margiana Archaeological Complex3 or Inner Asian Mountain Corridor cultures4. Instead, although Tocharian may have been plausibly introduced to the Dzungarian Basin by Afanasievo migrants during the Early Bronze Age, we find that the earliest Tarim Basin cultures appear to have arisen from a genetically isolated local population that adopted neighbouring pastoralist and agriculturalist practices, which allowed them to settle and thrive along the shifting riverine oases of the Taklamakan Desert.
Assuntos
Arqueologia , Genoma Humano/genética , Genômica , Migração Humana/história , Múmias/história , Filogenia , Agricultura/história , Animais , Bovinos , China , Características Culturais , Cálculos Dentários/química , Clima Desértico , Dieta/história , Europa (Continente) , Feminino , Cabras , Pradaria , História Antiga , Humanos , Masculino , Proteínas do Leite/análise , Filogeografia , Análise de Componente Principal , Proteoma/análise , Proteômica , Ovinos , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: This study was performed to investigate the clinical efficacy of percutaneous kyphoplasty (PKP) for vertebral compression fractures with different bone mineral densities (BMD). METHODS: We performed a retrospective analysis of 232 patients with single-segment vertebral compression fractures who underwent PKP. Patients were divided into the normal BMD, osteopenia, and osteoporosis groups according to their average lumbar BMD before surgery. The visual analog scale (VAS) was used to compare differences in pain relief before and after surgery in each group. Corrections of the wedge angle and kyphotic angle before and after surgery were observed using anteroposterior and lateral radiographs and compared among the groups, as was the incidence of bone cement leakage. RESULTS: Patients were followed up for 6-12 months, with an average follow-up time of 9.12 ± 1.68 months. The VAS score, wedge angle, and kyphotic angle of the three groups of patients decreased significantly at the end of the follow-up (P < 0.05). The changes in VAS score and wedge angle correction in the osteoporosis group were significantly larger than those in the normal BMD and osteopenia groups (P < 0.05). There were no significant differences among the three groups in terms of kyphotic angle correction or bone cement leakage rates (P > 0.05). CONCLUSIONS: PKP has a positive effect on vertebral compression fractures with different BMD, and is especially suitable for osteoporotic vertebral compression fractures.
Assuntos
Fraturas por Compressão , Cifoplastia , Cifose , Osteoporose , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Humanos , Cifoplastia/efeitos adversos , Estudos Retrospectivos , Fraturas por Compressão/diagnóstico por imagem , Fraturas por Compressão/cirurgia , Fraturas por Compressão/complicações , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/cirurgia , Fraturas da Coluna Vertebral/complicações , Densidade Óssea , Cimentos Ósseos/uso terapêutico , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/cirurgia , Fraturas por Osteoporose/etiologia , Osteoporose/complicações , Resultado do Tratamento , Cifose/diagnóstico por imagem , Cifose/etiologia , Cifose/cirurgiaRESUMO
Interfacial properties of polymeric materials are significantly influenced by their architectural structures and spatial features, while such a study of topologically interesting macromolecules is rarely reported. In this work, we reported, for the first time, the interfacial behavior of catenated poly(l-lactide) (C-PLA) at the air-water interface and compared it with its linear analogue (L-PLA). The isotherms of surface pressure-area per repeating unit showed significant interfacial behavioral differences between the two polymers with different topologies. Isobaric creep experiments and compression-expansion cycles also showed that C-PLA demonstrated higher stability at the air-water interface. Interestingly, when the films at different surface pressures were transferred via the Langmuir-Blodgett method, successive atomic force microscopy imaging displayed distinct nanomorphologies, in which the surface of C-PLA exhibited nanofibrous structures, while that of the L-PLA revealed a smoother topology with less fiber-like structures.
Assuntos
Ar , Água , Microscopia de Força Atômica , Poliésteres/química , Polímeros/química , Propriedades de Superfície , Água/químicaRESUMO
Compared to the equiatomic or near-equiatomic NiTinol alloys, Ni-rich NiTi alloys are suitable to be employed in structural applications as they exhibit higher hardness and are dimensionally stable. This research aimed to process two different grades of Ni-rich NiTi alloys, 58NiTi and 60NiTi, from Ni-Ti powder mixtures having about 58 wt.% and 60 wt.% Ni, respectively. This was performed by a laser powder bed fusion technique. At the first stage of this research, the printability of the used powder mixtures was investigated by applying different sets of printing parameters. Two appropriate sets were then selected to print the samples. Microstructural study of the printed parts revealed the existence of inhomogeneity in the microstructures. In addition, depending on the applied set of parameters, some amounts of cracks and pores were also present in the microstructure of these parts. Postprinting hot isostatic pressing procedures, performed at different temperatures, were developed to cause the reaction of phases, homogenize the parts, and possibly eliminate the existing flaws from the samples. Effects of these applied treatments on the microstructure, phase composition, density, dimensional integrity, and hardness of parts were sequentially studied. In essence, 58NiTi and 60NiTi parts having phase compositions complying with those of the equilibrium phase diagram were obtained in this research. However, the mentioned cracks and pores, formed in the microstructure of as-printed parts, could not be fully removed by postprocessing treatments.
Assuntos
Ligas , Titânio , Ligas/química , Lasers , Pós , Impressão Tridimensional , Titânio/químicaRESUMO
A bacterial strain, Gram-stain negative, rod-shaped, aerobic and cellulose-degrading, designated NEAU-DD11T, was isolated from rhizosphere soil of rice collected from Northeast Agricultural University in Harbin, Heilongjiang Province, North-east China. Base on 16S rRNA gene sequence analysis, strain NEAU-DD11T belongs to the genus Massilia and shared high sequence similarities with Massilia phosphatilytica 12-OD1T (98.46%) and Massilia putida 6NM-7 T (98.41%). Phylogenetic analysis based on the 16S rRNA gene and whole genome sequences indicated that strain NEAU-DD11T formed lineage related to M. phosphatilytica 12-OD1T and M. putida 6NM-7 T. The major fatty acids of the strain were C16:0, C17:0-cyclo and C16:1ω7c. The respiratory quinone was Q-8. The polar lipids profile of the strain showed the presence of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unidentified polar lipid and an unidentified phospholipid. In addition, the digital DNA-DNA hybridization values between strain NEAU-DD11T and M. phosphatilytica 12-OD1T and M. putida 6NM-7 T were 45.4 and 35.6%, respectively, which are lower than the accepted threshold value of 70%. The DNA G + C content of strain NEAU-DD11T was 66.2%. The whole genome analysis showed the strain contained carbohydrate enzymes such as glycoside hydrolase and polysaccharide lyase, which enabled the strain to have the function of degrading cellulose. On the basis of the phenotypic, genotypic and chemotaxonomic characteristics, we conclude that strain NEAU-DD11T represents a novel species of the genus Massilia, for which the name Massilia cellulosiltytica sp. nov. is proposed. The type strain is NEAU-DD11T (= CCTCC AB 2019141 T = DSM 109721 T).
Assuntos
Oryza , Técnicas de Tipagem Bacteriana , Celulose , DNA Bacteriano/genética , Ácidos Graxos , Humanos , Oxalobacteraceae , Filogenia , RNA Ribossômico 16S/genética , Rizosfera , Análise de Sequência de DNA , Solo , Microbiologia do SoloRESUMO
Diffusion MRS of non-water molecules offers great potential in directly revealing various tissue microstructures and physiology at both cellular and subcellular levels. In brain, 1 H diffusion MRS has been demonstrated as a new tool for probing normal tissue microstructures and their pathological changes. In skeletal muscle, 1 H diffusion MRS could characterize slow and restricted intramyocellular lipid diffusion, providing a sensitive marker for metabolic alterations, while 31 P diffusion MRS can measure ATP and PCr diffusion, which may reflect the capacity of cellular energy transport, complementing the information from frequently used 31 P MRS in muscle. In intervertebral disk, 1 H diffusion MRS can directly monitor extracellular matrix integrity by quantifying the mobility of macromolecules such as proteoglycans and collagens. In tumor tissue, 13 C diffusion MRS could probe intracellular glycolytic metabolism, while 1 H diffusion MRS may separate the spectrally overlapped lactate and lipid resonances. In this review, recent diffusion MRS studies of these biologically relevant non-water molecules under normal and diseased conditions will be presented. Technical considerations for diffusion MRS experiments will be discussed. With advances in MRI hardware and diffusion methodology, diffusion MRS of non-water molecules is expected to provide increasingly valuable and biologically specific information on tissue microstructures and physiology, complementing the traditional diffusion MRI of small and ubiquitous water molecules. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Biopolímeros/metabolismo , Imagem de Difusão por Ressonância Magnética/métodos , Interpretação de Imagem Assistida por Computador/métodos , Espectroscopia de Ressonância Magnética/métodos , Imagem Molecular/métodos , Processamento de Sinais Assistido por Computador , Algoritmos , Animais , Humanos , Aumento da Imagem/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
From a hydrothermal reaction using CuI, KI, and 3,3'5,5'-tetramethyl-4,4'-bipyrazole (TMBP), the triiodide anion I3(-) has been integrated into the water-stable 2D coordination polymer Cu(TMBP)I3 (1). In contrast with other metal triiodide complexes, 1 features remarkably small distortions in the bond distances associated with the I3(-) units (i.e., the Cu-I and I-I bonds), which effectively link up the copper(I) centers into infinite CuI3 chains. The electronic band gaps and electrical conductivity data are also found to be consistent with the I3(-) ion acting as an effective linker across the copper(I) centers.
Assuntos
Complexos de Coordenação/química , Reagentes de Ligações Cruzadas/química , Polímeros/química , Pontos Quânticos/química , Ânions/química , Cobre/químicaRESUMO
A synthetic strategy is reported for the production of a trefoil knotted polymer from a copper(I)-templated helical knot precursor through ring expansion. The expected changes in the properties of the knotted polymer compared to a linear analogue, for example, reduced hydrodynamic radius and lower intrinsic viscosity, together with an atomic force microscopy (AFM) image of individual molecular knots, confirmed the formation of the resulting trefoil knotted polymer. The strategies employed here could be utilized to enrich the variety of available polymers with new architectures.
Assuntos
Polímeros/química , Cobre/química , Espectroscopia de Ressonância Magnética , Microscopia de Força Atômica , Polímeros/síntese química , ViscosidadeRESUMO
Rab GTPase-activating proteins (RabGAPs), serving as crucial signaling switches, play essential roles in several physiological processes related to plant growth and development. However, despite their importance, information regarding the RabGAP gene family and their biological functions remains unknown in the Rosaceae. In this study, we identified a total of 127 RabGAP genes in seven Rosaceae species, which were divided into five subfamilies. Our findings indicate that whole genome duplication (WGD) events or dispersed duplication events largely contributed to the expansion of RabGAP family members within Rosaceae species. Through tissue-specific expression analyses, we revealed that the PbrRabGAP genes exhibited distinct expression patterns in different pear tissues. Furthermore, by examining the expression pattern during pollen development and employing an antisense oligonucleotide approach, we demonstrated that PbrRabGAP10, located in the cytoplasm, mediates the imbalance of cellulose distribution, thus regulating pollen tube elongation. In conclusion, the present study offers an overview of the RabGAP family in Rosaceae genomes and serves as the basis for further functional studies.
Assuntos
Pyrus , Rosaceae , Celulose , Evolução Molecular , Genoma de Planta/genética , Genômica , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tubo Polínico/genética , Tubo Polínico/metabolismo , Pyrus/genética , Pyrus/metabolismo , Rosaceae/genéticaRESUMO
Despite exhibiting potent anticancer activity, the strong hemolytic properties of melittin (MEL) significantly restrict its delivery efficiency and clinical applications. To address this issue, we have devised a strategy wherein homologous dopamine (DA), an essential component of bee venom, is harnessed as a vehicle for the synthesis of MEL-polydopamine (PDA) nanoparticles (MP NPs). The ingenious approach lies in the fact that MEL is a basic polypeptide, and the polymerization of DA is also conducted under alkaline conditions, indicating the distinctive advantages of PDA in MEL encapsulation. Furthermore, MP NPs are modified with folic acid to fabricate tumor-targeted nanomedicine (MPF NPs). MPF NPs can ameliorate the hemolysis of MEL in drug delivery and undergo degradation triggered by high levels of reactive oxygen species (ROS) within solid tumors, thereby facilitating MEL release and subsequent restoration of anticancer activity. After cellular uptake, MPF NPs induce cell apoptosis through the PI3K/Akt-mediated p53 signaling pathway. The tumor growth inhibitory rate of MPF NPs in FA receptor-positive 4T1 and CT26 xenograft mice reached 78.04% and 81.66%, which was significantly higher compared to that in FA receptor-negative HepG2 xenograft mice (45.79%). Homologous vehicles provide a new perspective for nanomedicine design.
Assuntos
Antineoplásicos , Hemólise , Indóis , Meliteno , Polímeros , Meliteno/química , Meliteno/farmacologia , Animais , Humanos , Indóis/química , Indóis/farmacologia , Polímeros/química , Polímeros/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Camundongos , Hemólise/efeitos dos fármacos , Nanopartículas/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos Nus , Tamanho da PartículaRESUMO
The primary regulators of Rho GTPases are GTPase-activating protein (GAP), guanine nucleotide exchange factor (GEF), and GDP dissociation inhibitor (GDI), which function as signaling switches in several physiological processes involved in plant growth and development. This study compared how the Rho GTPase regulators functioned in seven Rosaceae species. Seven Rosaceae species, divided into three subgroups, had a total of 177 regulators of Rho GTPases. According to duplication analysis, the expansion of GEF, GAP, and GDI families was facilitated by whole genome duplication or a dispersed duplication event. The balance of cellulose deposition to control the growth of the pear pollen tube, as demonstrated by the expression profile and antisense oligonucleotide approach. Moreover, protein-protein interactions indicated that PbrGDI1 and PbrROP1 could directly interact, suggesting that PbrGDI1 regulated the growth of the pear pollen tube through PbrROP1 signaling downstream. These results lay the foundations for future functional characterization of the GAP, GEF, and GDI gene families in Pyrus bretschneideri.
Assuntos
Pyrus , Rosaceae , Rosaceae/genética , Pyrus/genética , Pyrus/metabolismo , Proteínas rho de Ligação ao GTP/genética , Tubo Polínico/genética , Tubo Polínico/metabolismo , Celulose/metabolismo , Genoma de Planta/genética , Fatores de Troca do Nucleotídeo Guanina/genética , GenômicaRESUMO
As a novel antimicrobial material, quaternary phosphonium salts (QPSs) have been drawing close attention because of their excellent antimicrobial capacity with high activity and low bacterial survivability. Polymeric QPSs (PQPSs) also exhibit selectivity and long-term stability, however the polymerization of QPSs is severely challenged by low controllability and narrow selectivity of cation type. In this study, high-conversion RAFT polymerization is employed to prepare innovative phosphonium-functionalized diblock copolymers (PFDCs) with desired molecular weights and particle sizes. The excellent antibacterial activity of the PFDCs achieves lowest MIC values of 40 and 60 µg mL-1 (i.e., 1.4 and 2.2 µmol L-1) against E. coli and S. aureus, respectively. Mixing with an ink, dye, and latex coating does not weaken the antibacterial activity of the PFDCs, which inhibited 99.9% E. coli, showing broad applicability in different media. The effects of the cation type, synthesis medium, crosslinking content, and particle size on the morphology and antibacterial activity are studied. In summary, the RAFT polymerization of QPSs through the versatile design of ionic liquid monomers and the polymerization-induced self-assembly (PISA) method for constructing nano-assemblies with various micromorphology and particle size provides an exceedingly efficient way to build up multifunctional and multi-morphological polymeric nano-objects that open up vast possibilities in the fields of antibiotics, drug delivery, templated synthesis, and catalysis.
Assuntos
Escherichia coli , Staphylococcus aureus , Polímeros , Polimerização , Antibacterianos/farmacologiaRESUMO
In this study, we explored the heavy metal elements in 42 surface sediments from the Malacca Strait in terms of distribution, controlling factors, environmental quality, and primary sources. An analysis of grain size revealed finer sediments near the coast of Malaysia, which gradually thickened toward offshore. In addition, heavy metal elements were abundantly distributed near the coastal area of Malaysia, with a gradual decrease toward the sea; their content increased within waters close to the Perak estuary. Source analysis of heavy metals showed that Cr, Hg, Zn, Cd, and Cu were mostly derived from natural weathering, and their distribution was significantly influenced by sediment grain size. As and Pb were affected by human activities. The environmental quality assessment results showed that Cu, Cr, Cd, and Zn in our study regions were pollution-free. Pb elements showed low-to-moderate pollution, and Hg showed a certain degree of ecological risk due to its high toxicity coefficient. The content of As elements in surface sediments increased significantly when compared to the background value, with several evaluation methods indicating a high-risk index. According to these findings, the area near the mouth of the Perak River is the most polluted, followed by the surrounding coastal areas.
Assuntos
Mercúrio , Metais Pesados , Poluentes Químicos da Água , Cádmio , Monitoramento Ambiental/métodos , Sedimentos Geológicos , Humanos , Chumbo , Mercúrio/análise , Metais Pesados/análise , Medição de Risco , Poluentes Químicos da Água/análiseRESUMO
OBJECTIVE: To test the nickel-titanium (Ni-Ti) shape memory alloys of vertebral body reduction fixator with assisted distraction bar for the treatment of traumatic and osteoporotic vertebral body fracture. METHODS: A Ni-Ti shape memory alloys of vertebral body reduction fixator with assisted distraction bar was implanted into the compressed fracture specimens through vertebral pedicle with the radiographic monitoring to reduce the collapsed endplate as well as distract the compressed vertebral fracture. Radiographic film and computed tomographic reconstruction technique were employed to evaluate the effects of reduction and distraction. A biomechanic test machine was used to measure the fatigue and the stability of deformation of fixation segments. RESULTS: Relying on the effect of temperature shape memory, such an assembly could basically reduce the collapsed endplate as well as distract the compressed vertebral fracture. And when unsatisfied results of reduction and distraction occurred, its super flexibility could provide additional distraction strength. CONCLUSION: A Ni-Ti shape memory alloys of vertebral body reduction fixator with assisted distraction bar may provide effective endplate reduction, restore the vertebral height and the immediate biomechanic spinal stability. So the above assembly is indicated for the treatment of traumatic and osteoporotic vertebral body fracture.
Assuntos
Ligas , Níquel , Próteses e Implantes , Fusão Vertebral/instrumentação , Titânio , Fixação Interna de Fraturas , Humanos , Teste de MateriaisRESUMO
Supramolecular associations provide a promising route to functional materials with properties such as self-healing, easy recyclability or extraordinary mechanical strength and toughness. The latter benefit especially from the transient character of the formed network, which enables dissipation of energy as well as regeneration of the internal structures. However, recent investigations revealed intrinsic limitations in the achievable mechanical enhancement. This manuscript presents studies of a set of telechelic polymers with hydrogen-bonding chain ends exhibiting an extraordinarily high, almost glass-like, rubbery plateau. This is ascribed to the segregation of the associative ends into clusters and formation of an interfacial layer surrounding these clusters. An approach adopted from the field of polymer nanocomposites provides a quantitative description of the data and reveals the strongly altered mechanical properties of the polymer in the interfacial layer. These results demonstrate how employing phase separating dynamic bonds can lead to the creation of high-performance materials.
Assuntos
Nanocompostos , Borracha , Vidro , Ligação de Hidrogênio , Polímeros/químicaRESUMO
DNA studies of endangered or extinct species often rely on ancient or degraded remains. The majority of ancient DNA (aDNA) extraction protocols focus on skeletal elements, with skin and hair samples rarely explored. Similar to that found in bones and teeth, DNA extracted from historical or ancient skin and fur samples is also extremely fragmented with low endogenous content due to natural degradation processes. Thus, the development of effective DNA extraction methods is required for these materials. Here, we compared the performance of two DNA extraction protocols (commercial and custom laboratory aDNA methods) on hair and skin samples from decades-old museum specimens to Iron Age archaeological material. We found that apart from the impact sample-specific taphonomic and handling history has on the quantity and quality of DNA preservation, skin yielded more endogenous DNA than hair of the samples and protocols tested. While both methods recovered DNA from ancient soft tissue, the laboratory method performed better overall in terms of DNA yield and quality, which was primarily due to the poorer performance of the commercial binding buffer in recovering aDNA.
Assuntos
DNA Antigo/análise , Cães , Presbytini , Análise de Sequência de DNA/veterinária , Manejo de Espécimes/veterinária , Animais , Museus , Análise de Sequência de DNA/métodos , Manejo de Espécimes/métodosRESUMO
OBJECTIVE: To study the efficacy of polyporus composite phosphate calcium and rhBMP-2 compounds with laparoscopical lumbar interbody fusion in sheep. METHODS: Fourteen uniform-weight adult sheep were randomly divided into three groups for LA-5 interbody fusion with titanium mesh. Autogenous bone and titanium mesh was applied with open anterior technique in group 1 (n=4). In group 2, 4 sheep were operated with laparoscope technique for LA-5 interbody fusion with composite phosphate calcium (CPC) and titanium mesh. In group 3, 6 sheep underwent laparoscopical L4-5 interbody fusion with titanium mesh as well as polyporus composite phosphate calcium and rhBMP-2 compounds. At Weeks 6 and 12 post-operation, the sheep were sacrificed for imaging, biomechanic and morphological examinations. RESULTS: Although there was no statistical difference between open and laparoscopical interbody fusion group when comparing the remaining disc and endplate decorticated, bone fusion occurred in 3 groups after 3 months. A much larger amount of bony callus was observed earlier in laparoscopical L4-5 interbody fusion group with titanium mesh as well as polyporus composite phosphate calcium and rhBMP-2 compounds than two other groups. CONCLUSION: Polyporus composite phosphate calcium and rhBMP-2 compounds are suitable prosthetic materials for clinical trials. When these materials are utilized with a laparoscopical technique, satisfactory interbody fusion may be achieved.
Assuntos
Proteína Morfogenética Óssea 2/uso terapêutico , Fosfatos de Cálcio/uso terapêutico , Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Alicerces Teciduais , Animais , Substitutos Ósseos/uso terapêutico , Laparoscopia , Masculino , Proteínas Recombinantes/uso terapêutico , Ovinos , Titânio/uso terapêuticoRESUMO
A late Middle Pleistocene mandible from Baishiya Karst Cave (BKC) on the Tibetan Plateau has been inferred to be from a Denisovan, an Asian hominin related to Neanderthals, on the basis of an amino acid substitution in its collagen. Here we describe the stratigraphy, chronology, and mitochondrial DNA extracted from the sediments in BKC. We recover Denisovan mitochondrial DNA from sediments deposited ~100 thousand and ~60 thousand years ago (ka) and possibly as recently as ~45 ka. The long-term occupation of BKC by Denisovans suggests that they may have adapted to life at high altitudes and may have contributed such adaptations to modern humans on the Tibetan Plateau.
Assuntos
Cavernas , DNA Antigo/isolamento & purificação , Sedimentos Geológicos/química , Hominidae/classificação , Hominidae/genética , Animais , DNA Mitocondrial/genética , Humanos , Filogenia , TibetRESUMO
Aberrant expression of thioredoxin 1 (Trx1) plays an important role in cancer initiation and progression and has gained attention as an anticancer drug target. Here we report that the recently discovered natural diterpenoid isoforretin A (IsoA) significantly inhibits Trx1 activity and mediates anticancer effects in multiple preclinical settings. The inhibitory effect of IsoA was antagonized by free radical scavengers polyethylene glycol-catalase, polyethylene glycol superoxide dismutase, thiol-based antioxidants N-acetylcysteine and glutathione. Mass spectrometry analysis revealed that the mechanism of action was based on direct conjugation of IsoA to the Cys32/Cys35 residues of Trx1. This conjugation event attenuated reversible thiol reduction of Trx1, leading to ROS accumulation and a broader degradation of thiol redox homeostasis in cancer cells. Extending these in vitro findings, we documented that IsoA administration inhibited the growth of HepG2 tumors in a murine xenograft model of hepatocellular carcinoma. Taken together, our findings highlight IsoA as a potent bioactive inhibitor of Trx1 and a candidate anticancer natural product. Cancer Res; 77(4); 926-36. ©2016 AACR.
Assuntos
Antineoplásicos/farmacologia , Diterpenos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxinas/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Diterpenos/uso terapêutico , Células Hep G2 , Humanos , MAP Quinase Quinase Quinase 5/fisiologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Superóxido Dismutase/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To improve the tumor therapeutic efficiency and reduce undesirable side effects, ternary FK/p53/PEG-PLL(DA) complexes with a detachable surface shielding layer were designed. The FK/p53/PEG-PLL(DA) complexes were fabricated by coating the folate incorporated positively charged FK/p53 complexes with charge-switchable PEG-shield (PEG-PLL(DA)) through electrostatic interaction. At the physiological pH 7.4 in the bloodstream, PEG-PLL(DA) could extend the circulating time by shielding the positively charged FK/p53 complexes. After the accumulation of the FK/p53/PEG-PLL(DA) complexes in tumor sites, tumor-acidity-triggered charge switch led to the detachment of PEG-PLL(DA) from the FK/p53 complexes, and resulted in efficient tumor cell entry by folate-mediated uptake and electrostatic attraction. Stimulated by the high content glutathione (GSH) in cytoplasm, the cleavage of disulfide bond resulted in the liberation of proapoptosis peptide C-KLA(TPP) and the p53 gene, which exerted the combined tumor therapy by regulating both intrinsic and extrinsic apoptotic pathways. Both in vitro and in vivo studies confirmed that the ternary detachable complexes FK/p53/PEG-PLL(DA) could enhance antitumor efficacy and reduce adverse effects to normal cells. These findings indicate that the tumor-triggered decomplexation of FK/p53/PEG-PLL(DA) supplies a useful strategy for targeting delivery of different therapeutic agents in synergetic anticancer therapy.