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pH-dependent peptide biomaterials hold tremendous potential for cell delivery and tissue engineering. However, identification of responsive self-assembling sequences with specified secondary structure remains a challenge. In this work, An experimental procedure based on the one-bead one-compound (OBOC) combinatorial library is developed to rapidly screen self-assembling ß-sheet peptides at neutral aqueous solution (pH 7.5) and disassemble at weak acidic condition (pH 6.5). Using the hydrophobic fluorescent molecule thioflavin T (ThT) as a probe, resin beads displaying self-assembling peptides show fluorescence under pH 7.5 due to the insertion of ThT into the hydrophobic domain, and are further cultured in pH 6.5 solution. The beads with extinguished fluorescence are selected. Three heptapeptides are identified that can self-assemble into nanofibers or nanoparticles at pH 7.5 and disassemble at pH 6.5. P1 (LVEFRHY) shows a rapid acid response and morphology transformation with pH modulation. Changes in the charges of histidine and hydrophobic phenyl motif of phenylalanine may play important roles in the formation of pH-responsive ß-sheet nanofiber. This high-throughput screening method provides an efficient way to identify pH-dependent ß-sheet self-assembling peptide and gain insights into structural design of such nanomaterials.
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Peptídeos , Concentração de Íons de Hidrogênio , Peptídeos/química , Conformação Proteica em Folha beta , Ensaios de Triagem em Larga Escala/métodos , Nanofibras/química , Interações Hidrofóbicas e Hidrofílicas , Benzotiazóis/químicaRESUMO
Predicting the spatial distribution of species and suitable areas under global climate change could provide a reference for species conservation and long-term management strategies. Macaca thibetana and Macaca arctoides are two endangered species of Chinese macaques. However, limited information is available on their distribution, and their habitat needs lack proper assessment due to complicated taxonomy and less research attention. In recent years, scholars widely used the maximum entropy (MaxEnt) model to predict the impact of global climate and certain environmental factors on species distribution. Therefore, we used the MaxEnt model to predict the spatiotemporal distribution of both macaque species under six climate change scenarios using occurrence and high-resolution ecological data. We identified climatic factors, elevation, and land cover that shape their distribution range and determined shifts in their habitat range. The results demonstrated that temperature range, annual precipitation, forest land cover, and temperature seasonality, including the precipitation of the driest month are the main factors affecting their distribution. Currently, M. thibetana is mainly concentrated in central, eastern, southern, and southwestern China, and M. arctoides is mainly concentrated in three provinces (Yunnan, Guangxi, and Guangdong) in southern China. The MaxEnt model predicted that the suitable habitat for both species will increase with increased greenhouse emission scenarios. We also found that with the further increase in greenhouse emissions M. thibetana is expected to migrate to western China, and M. arctoides is expected to migrate to western or eastern China. This reinterpretation of the distribution of M. thibetana and M. arctoides in China, and predicted potential suitable habitat and possible migration direction, may provide new insights into the future conservation and management of these two species.
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Mudança Climática , Macaca arctoides , Macaca , Animais , China , Ecossistema , Distribuição AnimalRESUMO
Nanomaterials (NMs) inevitably adsorb proteins in blood and form "protein corona" upon intravenous administration as drug carriers, potentially changing the biological properties and intended functions. Inspired by anti-adhesion properties of natural proteins, herein, we employed the one-bead one-compound (OBOC) combinatorial peptide library method to screen anti-adhesion peptides (AAPs) against proteins. The library beads displaying random peptides were screened with three fluorescent-labeled plasma proteins. The nonfluorescence beads, presumed to have anti-adhesion property against the proteins, were isolated for sequence determination. These identified AAPs were coated on gold nanorods (GNRs), enabling significant extension of the blood circulating half-life of these GNRs in mice to 37.8 h, much longer than that (26.6 h) of PEG-coated GNRs. In addition, such AAP coating was found to alter the biodistribution profile of GNRs in mice. The bioinspired screening strategy and resulting peptides show great potential for enhancing the delivery efficiency and targeting ability of NMs.
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Nanoestruturas , Biblioteca de Peptídeos , Camundongos , Animais , Técnicas de Química Combinatória/métodos , Distribuição Tecidual , Peptídeos/farmacologia , Peptídeos/química , Proteínas Sanguíneas , Administração Intravenosa , Ouro , Portadores de FármacosRESUMO
BACKGROUND: Microwave ablation (MWA) is a potentially curative treatment for unresectable patients with hepatocellular carcinoma (HCC) ≤ 3 cm, while its therapeutic efficacy decreases significantly for HCC > 3cm. Previous studies have demonstrated that conventional transarterial chemoembolization (cTACE) combined with MWA (cTACE-MWA) may improve local tumor control rate and reduce the recurrence rate for HCC > 3cm. However, there have been few study designs to analyze the clinical efficacy of cTACE-MWA for medium-sized HCC (3-5cm). Therefore, this study aims to compare the clinical efficacy and safety of cTACE-MWA with cTACE alone for a single medium-sized HCC of 3-5 cm in diameter. METHODS: We retrospectively investigate the data of 90 patients with a single medium-sized HCC who were referred to our hospital and underwent cTACE-MWA or cTACE alone from December 2017 to March 2020. Then, patients were identified with propensity score-matched (1:1). The local tumor response to treatment and time to progression (TTP) were compared using mRECIST criteria between the cTACE-MWA group and the cTACE group. RESULTS: A total of 42 patients were included after matching (cTACE-MWA: 21; cTACE: 21). Comparing with cTACE, cTACE-MWA demonstrate significantly better local tumor control (ORR: 95.2% vs 61.9%, p = 0.02; DCR: 95.2% vs 66.7%, p = 0.045) and TTP (median 19.8 months vs 6.8 months, p < 0.001). The 1- and 2-year cumulative probabilities of OS were 100% and 95% in the cTACE-MWA group, which were significantly higher than those in the cTACE group (95% and 76%) (p = 0.032). Multivariate Cox regression analysis illustrates that cTACE-MWA was associated with better TTP (hazard ratio, 0.28; 95% CI: 0.1, 0.76; p = 0.012), but tumor size was associated with worse TTP (hazard ratio, 1.71; 95% CI: 1.01, 2.89; p = 0.045). CONCLUSIONS: cTACE followed by MWA improved TTP and OS in patients with a single medium-sized HCC, and no major complication was observed in this study.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Terapia Combinada , Humanos , Neoplasias Hepáticas/cirurgia , Micro-Ondas/uso terapêutico , Pontuação de Propensão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Despite recent advances in tumor treatment through cancer immunotherapy, the efficacy of this approach remains to be improved. Looking forward to high rates of objective clinical response, cancer immunotherapy combined with chemotherapy has gained increasing attention recently. Here, we constructed liposomes with matrix metalloproteinases (MMPs) responsive moiety and PD-L1 inhibitor conjugate combine with low dose chemotherapy to achieve enhanced antitumor efficacy. Upon introduction of the pH-responsive polymer to LPDp, the coassembly could be almost stable in physiological conditions and tumor microenvironments and release the loaded cargos at the lysosome. MMP-2 enzyme extracellularly secreted by the B16F10 cells could cleave the cross-linker and liberate the PD-L1 inhibitor effectively disrupting the PD-1/PD-L1 interaction in vitro. Low dose DOX encapsulated in the LPDp was capable of sensitizing B16F10 cells to CTLs by inducing overexpression of M6PR on tumor cell membranes. In comparison with free PD-L1 inhibitor, LPDp improved the biodistribution and on-demand release of the peptide inhibitor in tumor regions following administration. LPDp achieved the optimal tumor suppression efficiency (â¼78.7%), which demonstrated the significantly enhanced antitumor effect ( P < 0.01) than that of LPp (â¼57.5%) as well as that of LD (<40%), attributing to synergistic contribution from the substantial increase in M6PR expression on tumor cells and the blockade of immune checkpoints. This strategy provides a strong rationale for combining standard-of-care chemotherapy with relative nontoxic and high specific immunotherapy.
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Antineoplásicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Lipossomos/química , Metaloproteinases da Matriz/metabolismo , Polímeros Responsivos a Estímulos/química , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Liberação Controlada de Fármacos , Tratamento Farmacológico/métodos , Concentração de Íons de Hidrogênio , Imunoterapia/métodos , CamundongosRESUMO
Au-BP7@SP nanohybrids with active motion under NIR laser irradiation can effectively enhance the temperature of tumor potentially by converting the kinetic energy to thermal energy, enhancing the killing efficiency of the tumor cells compared with Au@SP. The study provides an insight of nanohybrids' effect on photothermal treatment and opens a new avenue to cancer treatment by using self-propulsion Janus nanohybrids.
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Hipertermia Induzida , Raios Infravermelhos , Neoplasias/terapia , Fototerapia , Animais , Sobrevivência Celular , Humanos , Células MCF-7 , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Neoplasias/patologia , TemperaturaRESUMO
BACKGROUND: Subphrenic carcinoma has been identified as a significant risk factor for the thermal ablation of intrahepatic tumors, resulting in a high rate of residual tumor recurrence. Some studies have proposed that combination treatment with transarterial chemoembolization (TACE) followed by radiofrequency ablation is both feasible and safe for tumors in the subphrenic region. However, research specifically examining the therapeutic outcomes of combination therapy using TACE and microwave ablation (TACE-MWA) in subphrenic tumors is lacking. AIM: To evaluate the efficacy and safety of TACE-MWA in patients with subphrenic hepatocellular carcinoma (HCC). METHODS: Between December 2017 and December 2021, 49 patients diagnosed with HCC ≤ 6 cm, who received TACE-MWA, were included in this retrospective cohort study. These patients were classified into subphrenic and non-subphrenic groups based on the distance between the diaphragm and the tumor margin. The rates of local tumor progression (LTP), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Complications were evaluated by using a grading system developed by the Society of Interventional Radiology. RESULTS: After a median follow-up time of 38 mo, there were no significant differences in LTP between the subphrenic and non-subphrenic groups (27.3% and 22.2% at 5 years, respectively; P = 0.66), PFS (55.5% at 5 years in both groups; P = 0.91), and OS (85.0% and 90.9% in the subphrenic and non-subphrenic groups at 5 years; P = 0.57). However, a significantly higher rate of LTP was observed in subphrenic HCC > 3 cm compared to those ≤ 3 cm (P = 0.085). The dosage of iodized oil [hazard ratio (HR): 1.52; 95% confidence interval (CI): 1.11-2.08; P = 0.009] and multiple tumors (HR: 13.22; 95%CI: 1.62-107.51; P = 0.016) were independent prognostic factors for LTP. There were no significant differences in complication rates between the two groups (P = 0.549). CONCLUSION: Combined TACE and MWA was practical and safe for managing subphrenic HCC. The efficacy and safety levels did not vary significantly when tumors outside the subphrenic region were treated.
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To compare and study the decoction and dissolution of active constituents in crude and processed Corni Fructus. HPLC, the traditional Chinese medicine (TCM) decoction method and the dissolution methods were adopted to compare and study the decoction yield and dissolution rate of loganin and morroniside, active constituents in crude and processed Corni Fructus. The results showed that the content of active constituents loganin and morroniside in crude and processed Corni Fructus did not change significantly; compared with crude Corni Fructus, processed Corni Fructus (decoction) contained much higher loganin, with no obvious change in morroniside; compared with crude Corni Fructus, processed Corni Fructus (extracts) showed no significant difference in loganin dissolution, but notable increase in morroniside dissolution in intestinal fluid; in gastric fluid, processed Corni Fructus showed significant increase in loganin and morroniside dissolutions. However, in comprehensive consideration of the decoction dose in clinical administration, and calculated on the basis of the formula of the decoction yield x dissolution rate = decoction-dissolution product, it showed increase in the decoction-dissolution products of both of the active constituents loganin and morroniside, with significant difference. This suggested that processed Corni Fructus is superior to crude Corni Fructus in clinical application. In this article, we proposed to compare the changes in decoction and dissolution of active constituents in crude and processed Corni Fructus, study the decoction-dissolution product, and then apply it in the quality evaluation of crude and processed Corni Fructus.
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Cornus/química , Composição de Medicamentos/métodos , Medicamentos de Ervas Chinesas/química , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacocinética , Humanos , Mucosa Intestinal/metabolismo , Modelos Biológicos , SolubilidadeRESUMO
The One-Bead One-Compound (OBOC) library screening is an efficient technique for identifying targeting peptides. However, due to the relatively large bead size, it is challenging for the OBOC method to be applied for in vivo screening. Herein, we report an in vivo Localized Instillation Beads library (LIB) screening method to discover targeting peptides with the OBOC technique. Inspired by localized instillation, we constructed a cavity inside of a transplanted tumor of a mouse. Then, the OBOC heptapeptide library was injected and incubated inside the tumor cavity. After an efficient elution process, the retained beads were gathered, from which three MDA-MB-231 tumor-targeting heptapeptides were discovered. It was verified that the best peptide had 1.9-fold higher tumor accumulation than the commonly used targeting peptide RGD in vivo. Finally, two targeting proteins were discovered as potential targets of our targeting peptide to the MDA-MB-231 tumor. The in vivo LIB screening method expands the scope of OBOC peptide screening applications to discover targeting peptides in vivo feasibly and reliably.
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Cell function-associated biomolecular condensation has great potential in modulation of molecular activities. We develop a microtubule-trapping peptide that first self-assembles into nanoparticles and then in situ transforms into nanofibers via ligand-receptor interactions when targeted to tubulin. The nanofibers support the increased exposed targets for further adhering to microtubules and induce the self-assembly of microtubules into networks due to multivalent effects. Microtubule condensation with prolonged retention in cells for up to 24 h, which is 6 times longer than that of the non-transformable nanoparticle group, efficiently induces in vitro cell apoptosis and inhibits in vivo tumour growth. These smart transformable peptide materials for targeted protein condensation have the potential for improving retention and inducing cell apoptosis in tumour therapy.
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Microtúbulos , Neoplasias , Humanos , Microtúbulos/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Proteínas/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptídeos/metabolismoRESUMO
The viral spike (S) protein on the surface of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2) receptors on the host cells, facilitating its entry and infection. Here, functionalized nanofibers targeting the S protein with peptide sequences of IRQFFKK, WVHFYHK and NSGGSVH, which are screened from a high-throughput one-bead one-compound screening strategy, are designed and prepared. The flexible nanofibers support multiple binding sites and efficiently entangle SARS-CoV-2, forming a nanofibrous network that blocks the interaction between the S protein of SARS-CoV-2 and the ACE2 on host cells, and efficiently reduce the invasiveness of SARS-CoV-2. In summary, nanofibers entangling represents a smart nanomedicine for the prevention of SARS-CoV-2.
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COVID-19 , Nanofibras , Humanos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/química , Ligação Proteica , PeptídeosRESUMO
The primary purpose of the Man and the Biosphere Program is the sustainable development of both the economy and nature conservation activities. Although the effectiveness of eco-tourism to reach this goal has been proposed, due to the lack of long-term monitoring data and a model species, there has been no obvious mechanism to evaluate the effectiveness of this policy. This study explored the effectiveness of the sustainable development policy of HMBR based on 30 years data of monitoring the Tibetan macaque, local human population, visitors, and annual ecotourism income in Huangshan by estimating species habitat suitability and the impact of ecotourism. The results showed increases in the income for the local human population, the number of visitors, and annual eco-tourism. Simultaneously, the reserve's Tibetan macaque population size and suitable habitat areas increased. The macaques expanded their habitat to the low-altitude buffer zone (400-800 m), an area with lower eco-tourism disturbance. Scenic spots had a significant negative impact on habitat suitability (the substantially increased contributions of scenic spots from 0.71% to 32.88%). Our results and methods provide a suitable evaluation framework for monitoring the sustainable development and effectiveness of eco-tourism and wildlife conservation in Man and the Biosphere reserves.
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Two novel dysprosium(III) clusters have been prepared and structurally characterized. One has a tetranuclear core with a rare zigzag arrangement, and the other is an unprecedented octanuclear cluster with six triangular Dy(3) units sharing vertices. Both dysprosium(III) clusters possess frequency-dependent on alternating-current magnetic susceptibilities, indicating possible single-molecule magnet behavior.
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Self-assembling peptides have shown tremendous potential in the fields of material sciences, nanoscience, and medicine. Because of the vast combinatorial space of even short peptides, identification of self-assembling sequences remains a challenge. Herein, we develop an experimental method to rapidly screen a huge array of peptide sequences for self-assembling property, using the one-bead one-compound (OBOC) combinatorial library method. In this approach, peptides on beads are N-terminally capped with nitro-1,2,3-benzoxadiazole, a hydrophobicity-sensitive fluorescence molecule. Beads displaying self-assembling peptides would fluoresce under aqueous environment. Using this approach, we identify eight pentapeptides, all of which are able to self-assemble into nanoparticles or nanofibers. Some of them are able to interact with and are taken up efficiently by HeLa cells. Intracellular distribution varied among these non-toxic peptidic nanoparticles. This simple screening strategy has enabled rapid identification of self-assembling peptides suitable for the development of nanostructures for various biomedical and material applications.
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Nanofibras/química , Nanoestruturas/química , Biblioteca de Peptídeos , Peptídeos/química , Dicroísmo Circular , Técnicas de Química Combinatória/métodos , Células HeLa , Ensaios de Triagem em Larga Escala/métodos , Humanos , Ligação de Hidrogênio , Microscopia Eletrônica de Transmissão , Nanofibras/ultraestrutura , Nanoestruturas/ultraestrutura , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Different from chemical (small molecular inhibitor) and biological (monoclonal antibody) drugs, herein, based on angiogenesis-related neuropilin-1 (NRP-1), we develop a biomimetic superstructure drug, i.e. an antibody-like peptidic network (ALPN) to achieve the high-efficient treatment of choroidal neovascularization (CNV). The ALPN in nanoparticulated formulation (ALPN-NPS) can bind NRP-1 through targeting unit and form fibrous peptidic networks trapping NRP-1 on the surface of endothelial cells (ECs), leading to anti-angiogenesis. The ALPN shows high-efficacy against angiogenesis in CNV rat model ascribed to the superstructure-enhanced binding and blockage of NRP-1. The very low dose of ALPN (0.263 µg/Kg) exhibits similar anti-angiogenesis effect comparing with monoclonal antibody bevacizumab (23.5 µg/Kg), which shows potential advantages over traditional monoclonal antibodies.
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Neovascularização de Coroide , Células Endoteliais , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Neovascularização de Coroide/tratamento farmacológico , Neuropilina-1 , Peptídeos/uso terapêutico , RatosRESUMO
Cancer therapeutic strategies based on angiogenesis attract great attention from fundamental and clinical research. Blocking oxygen and nutrition supply to tumor cells could inhibit the growth of tumors based on occlusion of blood vessels in the tumor. Herein, we report a dual-responsive peptide-based nanoparticle, mimicking the laminin fibrillogenesis specifically and highly efficiently in tumor vessels, resulting in the blockage of tumor vessels and the growth inhibition of tumors. The laminin mimic peptide (LMMP) is designed with a fibrillation sequence, a pH-responsive sequence, and a targeting sequence. The LMMP in nanoformulations is delivered to blood vessels in the tumors, where the microenvironment (pH and microthrombus) enable LMMP to process laminin fibrillogenesis, constructing fibrous networks. The laminin-like fibrous networks capture red blood cells etc., forming occlusion specifically in the tumor blood vessels to inhibit the growth of the tumor.
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Nanopartículas , Neoplasias , Humanos , Laminina , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Peptídeos , Microambiente TumoralRESUMO
Using broad-spectrum antibiotics for microbial infection may cause flora disequilibrium, drug-resistance, etc., seriously threatening human health. Here, we design a human defensin-6 mimic peptide (HDMP) that inhibits bacterial invasion in vivo through mimicking the mechanisms of human defensin-6 with high efficiency and precision. The HDMP with ligand and self-assembling peptide sequence recognizes bacteria through ligand-receptor interactions and subsequently traps bacteria by an in situ adaptive self-assembly process and resulting nanofibrous networks; these trapped bacteria are unable to invade host cells. In four animal infection models, the infection rate was markedly decreased. Notably, administration of HDMP (5 mg/kg) nanoparticles increased the survival rate of mice with methicillin-resistant S. aureus bacteremia by as much as 100%, even more than that of vancomycin treatment (5 mg/kg, 83.3%)-treated group, the golden standard of antibiotics. This biomimetic peptide shows great potential as a precise and highly efficient antimicrobial agent.
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Staphylococcus aureus Resistente à Meticilina , Animais , Antibacterianos/farmacologia , Bactérias , Biomimética , Defensinas/farmacologia , Humanos , Ligantes , Camundongos , Vancomicina/farmacologiaRESUMO
Platelets play a critical role in the regulation of coagulation, one of the essential processes in life, attracting great attention. However, mimicking platelets for in vivo artificial coagulation is still a great challenge due to the complexity of the process. Here, we design platelet-like nanoparticles (pNPs) based on self-assembled peptides that initiate coagulation and form clots in blood vessels. The pNPs first bind specifically to a membrane glycoprotein (i.e., CD105) overexpressed on angiogenetic endothelial cells in the tumor site and simultaneously transform into activated platelet-like nanofibers (apNFs) through ligand-receptor interactions. Next, the apNFs expose more binding sites and recruit and activate additional pNPs, forming artificial clots in both phantom and animal models. The pNPs are proven to be safe in mice without systemic coagulation. The self-assembling peptides mimic platelets and achieve artificial coagulation in vivo, thus providing a promising therapeutic strategy for tumors.