Distinct Synergistic Effect Research Articles

The structural, antioxidant and emulsifying properties of cellulose nanofiber-dihydromyricetin mixtures: Effects of composite ratio

In this work, effects of cellulose nanofiber/dihydromyricetin (CNF/DMY) ratio on the structural, antioxidant and emulsifying properties of the CNF/DMY mixtures were investigated. CNF integrated with DMY via hydrogen bonding and the antioxidant capacity of mixtures increased with decreasing CNF/DMY ratio (k). The oxidative stability of emulsions enhanced as the DMY content increased. Emulsions formed at Φ = 0.5 displayed larger size (about 25 μm), better viscoelasticity and centrifugal stability than those at Φ = 0.3 (about 23 μm). The emulsions at k = 17:3 and Φ = 0.5 exhibited the most excellent viscoelasticity. In conclusion, the DMY content in mixtures and the oil phase fraction exhibited distinct synergistic effects on the formation and characteristics of emulsions, and the emulsions could demonstrate superior oxidative and storage stability. These findings could provide a novel strategy to extend the shelf life of cellulose-based emulsions and related products.

Synergistic corrosion effects of magnetite and microorganisms: microbial community dependency

The synergistic corrosion effect of acid-producing bacteria (APB) and magnetite on carbon steel corrosion was assessed using two different microbial consortia. A synergistic corrosion effect was observed exclusively with Consortium 2, which was composed of Enterobacter sp., Pseudomonas sp., and Tepidibacillus sp. When Consortium 2 was accompanied by magnetite, uniform corrosion and pitting rates were one-time higher (0.094 mm/year and 0.777 mm/year, respectively) than the sum of the individual corrosion rates promoted by the consortium and deposit separately (0.084 and 0.648 mm/year, respectively). The synergistic corrosion effect observed exclusively with Consortium 2 is attributed to its microbial community structure. Consortium 2 exhibited higher microbial diversity that benefited the metabolic status of the community. Although both consortia induced acidification of the test solution and metal surface through glucose fermentation, heightened activity levels of Consortium 2, along with increased surface roughness caused by magnetite, contributed to the distinct synergistic corrosion effect observed with Consortium 2 and magnetite.Key points• APB and magnetite have a synergistic corrosion effect on carbon steel.• The microbial composition of APB consortia drives the synergistic corrosion effect.• Magnetite increases carbon steel surface roughness.

Covalent bond enhanced highly stable urea perylene diimide polymer for concurrent photocatalysis-persulfate activation

The self-assembled perylene diimide (SAPDI) connected by hydrogen bonds is limited by the instability of easy disintegration under alkaline conditions. The covalently linked urea PDI (UPDI) was synthesized under air conditions, and concurrent photocatalysis-persulfate activation (CPPA) system was constructed. A distinct synergistic effect was attained when UPDI/peroxymonosulfate (UPDI/PMS, 0.012 min−1) system was combined with photocatalysis (UPDI/PMS/Vis, 0.115 min−1) to degrade iohexol (IOX). The import of the light field can accelerate the electron migration between the electron donor and the acceptor with more reactive oxygen species (ROS) generation. Evidenced by quenching tests, electron paramagnetic resonance, the dominated reactive species in UPDI/PMS system tended to be holes and 1O2. The utilization efficiency of ROS is crucial to improve the performance of CPPA. The stability of the UPDI system is superior to that of previously reported SAPDI and its derivatives or heterojunctions. The higher content of adsorbed oxygen can produce more reactive oxygen species (ROS), which is one of the reasons for the stable activity of UPDI in cyclic experiments. An enhancement for PMS activation on covalently bonded UPDI was observed based on density functional theory calculation. This study provides a new perspective for the application of stable and efficient metal-free water treatment technology.

Gold nanorods-loaded chitosan-based nanomedicine platform enabling an effective tumor regression in vivo

The clinical utility of 7-ethyl-10-hydroxycamptothecin (SN-38) is hampered by its low water solubility and reduced bioactivity at neutral or alkaline conditions. The rational design of an effective drug delivery system that can significantly enhance the therapeutic index of SN-38 and achieve complete tumor regression still remains a challenge. Herein, chitosan-based hybrid nanoparticles system co-loading with chemotherapeutic drug SN-38 and gold nanorods (AuNRs) was engineered for effective combinational photothermal-chemotherapy. To increase the solubility of SN-38, soluble polymeric prodrug poly (l-glutamic acid)-SN38 (l-PGA-SN38) was firstly synthesized and then complexed with chitosan to form stable nanomedicine via a mild and facile way without using any organic solvent or surfactant. Upon introducing AuNRs into chitosan-based nanomedicine by coordination interaction between the amine group of chitosan and AuNRs, the hybrid nanoparticles exhibited distinct synergistic therapeutic effect compared with single chemotherapy or photothermal treatment in vitro and in vivo. Almost complete tumor regression was achieved after 21-day treatment of the developed hybrid nanoparticles and showed no recurrence for at least 60 days.

Design of ZSM-5 encapsulating FeMnK nanocatalysts for light olefins synthesis with enhanced carbon utilization efficiency

Light olefins are important basic chemical materials, and the synthesis of light olefins from syngas via mild and efficient Fischer-Tropsch catalytic process is attractive. However, the application of technology is still plagued by the carbon utilization efficiency in CO conversion to target products. Therefore, both hydrocarbon distribution regulation and CO2 by-products reduction are desirable. Here, FeMnK oxide encapsulated by the hollow mesoporous ZSM-5 zeolite nanostructures with adjustable Si/Al ratio were constructed via a “dissolution-recrystalization” strategy, denoted as FeMnK@HM-Z-5(x), where x represents Si/Al ratio of ZSM-5 (x=∞, noted as FeMnK@HM-S-1). In catalytic performance, FeMnK@HM-Z-5(x) presented controlled regulation on hydrocarbon distribution and CO2 selectivity, compared with the supported or microporous coating structures, due to the distinct synergistic catalytic effect between FeMnK and ZSM-5. Carbon utilization efficiency reaches the maximum over FeMnK@HM-Z-5(200) with a space–time-yield of 22.7 μmol C2-C4∙gFe∙S-1 at similar CO conversion, due to the harmonization of light olefins selectivity improvement and CO2 suppression with the modulation of Si/Al ratio. With the aid of ethylene pulse experiment, C2H4-TPD, H2-TPD, in situ DRIFTS experiment, it confirmed that the change of light olefins and CO2 selectivity is mainly due to the variety of hydrogenation capacity, which is closely related to the Brønsted acid strength of the catalysts. CO2 pulse experiments further verified that the FeMnK@HM-Z-5(x) catalysts were endowed with different CO2 hydrogenation capacity. This study provides a new strategy for the precise regulation of the products distribution in CO / CO2 hydrogenation to enhance the carbon utilization.

Accelerated degradation of groundwater-containing malathion using persulfate activated magnetic Fe3O4/graphene oxide nanocomposite for advanced water treatment

Malathion (MT) is a widely used organophosphate insecticide with a broad spectrum. MT residues in the environment even at low concentrations can have adverse effects on humans, plants, animals, and ecosystems. In this study aimed to investigate the MT degradation yield from groundwater using persulfate activated magnetic Fe3O4/graphene oxide nanocomposite (PS/Fe3O4-GO MNCs). Thus, the effects of MT concentration, the dosage of PS and Fe3O4-GO MNCs, pH value along with reaction time were investigated and further optimized applying Response Surface Method (RSM). This model equation showed a sufficient match with the measured results from the experimental data with the correlation coefficient (R2) of 0.9819 according to the analysis of variance. For the optimal yield, MT concentration of 3.7 mg/L, PS of 2.25 mM, Fe3O4-GO MNCs dosage of 225 mg/L, reaction time of 22 min and pH of 4 were obtained. Moreover, for MT degradation, the estimated optimal degradation efficiency was 96.5 %. Furthermore, a distinct synergistic effect was observed upon the usage of Fe3O4-GO MNCs for PS activation. The MT degradation rate is generally characterized by a pseudo-first-order kinetic model. Besides, experiments with radical scavengers revealed that both OH∙ and SO4-∙radicals had significant functions in MT degradation yields, with sulphate radicals being the dominant species. Conclusively, results revealed that the PS/Fe3O4-GO MNCs degradation process is an effective method for remediating waters that have been polluted with MT and related pesticides.

Origin of synergistic effect between Fe/Mn minerals and biochar for peroxymonosulfate activation

Biochar possesses attractive structural (highly porous) and chemical (abundant functional groups) properties, exhibiting promising future in diverse applications such as soil amendment and environmental remediation. However, the interaction between biochar and soil active minerals, especially the synergistic effect on peroxymonosulfate (PMS) activation is largely unknown. In this study, we focused on the origin of the observed synergistic effect between biochar and two typical soil active minerals, i.e., goethite (α-FeOOH) and birnessite (δ-MnO2) on the activation of PMS by preparing four mineral-biochar composites, i.e., GBC350, BBC350, GBC700, and BBC700. Interestingly, BBC350, BBC700, and GBC700 exhibited distinct synergistic effects for BPA removal, whilst no obvious synergistic effect was observed for GBC350. The theoretical calculations based on density functional theory (DFT) further confirmed the improved PMS adsorption affinity, ascribing to the delocalization of O electrons (in PMS) to the π bond in C-layer. Furthermore, non-radical regime was elucidated to dominate the BPA oxidation. Mineral species could establish an electron channel between oxidant and catalyst, thus accelerating the electron transfer process. The high-valent Mn species (Mn(V)) also contributed to BPA removal in BBC350/PMS process. Overall, this study uncovered the origin of synergistic effect between BC700 and Fe/Mn minerals by exploring the electron transfer regime, which might provide new insights into PMS activation in practical applications.

Applying a novel advanced oxidation process of biochar activated periodate for the efficient degradation of bisphenol A: Two nonradical pathways

Periodate based advanced oxidation processes (PI-AOPs) exhibited promising future for the abatement of emerging contaminants, yet the underlying mechanism of carbon materials for PI activation was still unclear. In this study, a metal-free biochar (BCx, x represents the pyrolysis temperature) catalyzed PI-AOPs system was established and explored for the degradation of bisphenol A (BPA), one of the endocrine disrupting compounds (EDCs) that was ubiquitously detected in natural ecosystems. Biochar catalysts clearly boosted BPA degradation, suggesting a distinct synergistic effect between PI and biochar. Interestingly, BC350 and BC800 exhibited distinct behaviors for PI activation. Specifically, BC350 performed moderate PI activation, which was believed to be a surface hydroxyl group (OH)-induced nonradical pathway. A unique COOIO3 complex was formed and served as the reactive oxidant responsible for the BPA oxidation. On the other hand, BC800 showed a significant PI activation ability, which was preferentially proved to be a carbon-mediated electron-transfer mechanism. A high potential metastable carbon activated PI complexes (C-PI*) was elucidated to be the dominant oxidative species through electrochemical characterizations and galvanic oxidation process (GOP) experiments. The electron-transfer between adsorbed BPA (electron donor) and C-PI* (electron acceptor) was a crucial step in this pathway. Density functional theory (DFT) calculations confirmed that the interaction between PI and carbon surface was probably caused by the van der Waals force and a part of strong attraction between the interface of PI and BCOH. These findings provide new insights into nonradical pathways in biochar catalyzed PI-AOPs and promote the development and application of PI-AOPs in environmental remediation.

Binary Metal Single Atom Electrocatalysts with Synergistic Catalytic Activity toward High‐Rate and High Areal‐Capacity Lithium–Sulfur Batteries

AbstractLithium–sulfur (Li–S) batteries with high theoretical energy density have been long considered as an alternative energy storage device to lithium‐ion batteries. Nevertheless, the polysulfide shuttle effects trigger fast capacity decay and short battery lifespan, severely hampering their practical utilizations. Herein, an efficient electrocatalyst comprising of nitrogen (N)‐coordinated binary metal single atoms (SAs) implanted within a hierarchical porous carbon skeleton (Fe/CoNHPC) is constructed to trap and catalyze polysulfides conversion through a separator coating strategy. It is demonstrated that the introduction of Co atom can enrich the electron number of Fe active center, thereby realizing the distinct synergistic catalytic effect of binary metal SAs and improving the bidirectional catalysis of Li–S redox reaction. As a result, Li–S batteries with the Fe/CoNHPC‐modified separator exhibit outstanding rate capability (740 mAh g−1 at 5.0 C), and superior long‐term cyclic stability (694 mAh g−1 after 600 cycles at 1.0 C). Increasing the sulfur loading to 4.8 mg cm−2, a remarkable areal capacity of 6.13 mAh cm−2 is achieved. Furthermore, in situ X‐ray diffraction and theoretical simulation results verify the catalysis mechanism of binary metal SAs by changing the rate‐determining steps, providing new directions for constructing high‐performance Li–S batteries.

IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern

Monoclonal antibodies are a promising approach to treat COVID-19, however the emergence of SARS-CoV-2 variants has challenged the efficacy and future of these therapies. Antibody cocktails are being employed to mitigate these challenges, but neutralization escape remains a major challenge and alternative strategies are needed. Here we present two anti-SARS-CoV-2 spike binding antibodies, one Class 1 and one Class 4, selected from our non-immune human single-chain variable fragment (scFv) phage library, that are engineered into four, fully-human IgG-like bispecific antibodies (BsAb). Prophylaxis of hACE2 mice and post-infection treatment of golden hamsters demonstrates the efficacy of the monospecific antibodies against the original Wuhan strain, while promising in vitro results with the BsAbs demonstrate enhanced binding and distinct synergistic effects on neutralizing activity against circulating variants of concern. In particular, one BsAb engineered in a tandem scFv-Fc configuration shows synergistic neutralization activity against several variants of concern including B.1.617.2. This work provides evidence that synergistic neutralization can be achieved using a BsAb scaffold, and serves as a foundation for the future development of broadly reactive BsAbs against emerging variants of concern.

Heterogeneous Fenton-like removal of tri(2-chloroisopropyl) phosphate by ilmenite (FeTiO3): Kinetic, degradation mechanism and toxic assessment

Tri(2-chloroisopropyl) phosphate (TCPP), a common organophosphate flame retardant, was frequently detected in the environment and posed threats to human health. In this work, the main component of ilmenite FeTiO3 was synthesized by the sol-gel method and employed as the catalyst for the degradation of TCPP by activating persulfate (PS) under UV irradiation. The degradation processes were fitted by the pseudo-first-order kinetic. The kobs value in UV/FeTiO3/PS system was up to 0.0056 min−1 and much higher than that in UV/PS (0.0014 min−1), UV/FeTiO3 (0.0012 min−1) and FeTiO3/PS (0.0016 min−1) systems, demonstrating a distinct synergistic effect in TCPP removal. The degradation efficiency of TCPP increased with the increase of UV intensity, PS concentration and catalyst dosage, and with the decrease of pH. By quenching experiment and EPR analysis, ·OH was confirmed to be the dominant radical in the reaction of the UV/FeTiO3/PS system. The possible degradation pathways of TCPP were dechlorination, dealkylation, and further oxidation of alkyl groups based on the theoretical calculation of frontier molecular orbits. The toxicity of degradation intermediates evaluated by luminescence inhibition rate of photoluminescence was higher than TCPP. Thus, TCPP can be degraded in the UV/FeTiO3/PS system effectively at the premise of introducing controlling measures to reduce the toxicity of degradation intermediates.

Combined Systemic Drug Treatment with Proton Therapy: Investigations on Patient-Derived Organoids.

Simple SummaryRadiotherapy is part of the standard of care for many solid tumors. In pancreatic ductal adenocarcinoma (PDAC), good responses to radiotherapy can only be observed in a minority of patients. In our study, we used PDAC patient-derived organoids (PDO) to investigate alternative radiotherapy approaches for PDAC, such as proton irradiation and combined radiochemotherapy (RCT). Although only very distinct differences in treatment response could be identified, we show the utility of PDOs in translational proton research and found synergistic effects of combined treatments with chemotherapy and proton irradiation in individual PDOs.To optimize neoadjuvant radiochemotherapy of pancreatic ductal adenocarcinoma (PDAC), the value of new irradiation modalities such as proton therapy needs to be investigated in relevant preclinical models. We studied individual treatment responses to RCT using patient-derived PDAC organoids (PDO). Four PDO lines were treated with gemcitabine, 5-fluorouracile (5FU), photon and proton irradiation and combined RCT. Therapy response was subsequently measured via viability assays. In addition, treatment-naive PDOs were characterized via whole exome sequencing and tumorigenicity was investigated in NMRI Foxn1nu/nu mice. We found a mutational pattern containing common mutations associated with PDAC within the PDOs. Although we could unravel potential complications of the viability assay for PDOs in radiobiology, distinct synergistic effects of gemcitabine and 5FU with proton irradiation were observed in two PDO lines that may lead to further mechanistical studies. We could demonstrate that PDOs are a powerful tool for translational proton radiation research.

Synergistic effects of monocaprin and carvacrol against Escherichia coli O157:H7 and Salmonella Typhimurium in chicken meat preservation

Escherichia coli O157:H7 and Salmonella Typhimurium are both foodborne pathogens commonly found in contaminated chicken meat. In this study, the combined effects of monocaprin and thymol, carvacrol, citral, and cinnamaldehyde against both pathogens were investigated to evaluate their effects in chicken meat preservation. Among the combinations, only the combination of monocaprin and carvacrol exhibited distinct synergistic effects on both pathogens in vitro . This combination showed a stronger synergistic biofilm inhibition and bactericidal effect than monocaprin or carvacrol alone. SEM and TEM microscopy showed that the combined treatment synergistically damaged the morphology of E. coli O157:H7 and S. Typhimurium. DAPI/SYTOX Green double-staining, outer and inner membrane permeability, membrane potential, and reactive oxygen species (ROS) generation experiments were performed to further assess the synergistic action. Results indicated that carvacrol rapidly increased the outer membrane permeability, allowing monocaprin to enter the cell of both pathogens, and damage the plasma membrane, and monocaprin increased the ROS accumulation effect of carvacrol, resulting in cell death. Monocaprin and carvacrol also showed synergistic effect on retarding the growth of E. coli O157:H7 and S. Typhimurium in chicken breast meat during storage at 4 °C. Besides, the results of sensory evaluation, including appearance, odor, firmness and overall acceptance, showed that the combined treatment reduced deterioration of the sensory properties of chicken breast meat. These findings suggest that this combination may be used as a novel approach to the preservation of chicken meat. • Monocaprin and carvacrol exhibited synergistic effect on E. coli O157:H7 and S. typhimurium. • This combination inhibited biofilm formation and rapidly inactivated cell counts. • Carvacrol induces monoocaprin entry into cells by increasing OM permeability. • Monocaprin intensified the ROS accumulation effect of carvacrol. • This combination can be used as a natural alternative for the preservation of chicken meat.

Factors detrimental to work productivity and daily activities in systemic lupus erythematosus patients - Analysis of the German LuLa study.

The aim of this study was to identify factors associated with impaired work productivity and impaired daily activities in patients with systemic lupus erythematosus (SLE). The LuLa study is a longitudinal patient-reported study. Beyond sociodemographic data, work productivity, daily activities and fatigue, several other clinical outcome parameters (e.g. mental health-related quality of life and physical functioning, disease activity, damage and pain) were surveyed with validated questionnaires. The effects of confounders on work productivity (WPAI 2) and daily activity domains (WPAI 4) were studied by multivariate regression analysis. A total of 585 patients completed the questionnaire of whom 259 were employed and analysed. The median impairment in work productivity (WPAI 2) was 20% (Q1-3 0-40), and the median impairment in daily activities (WPAI 4) was 30% (Q1-3 10-50%). Multivariate regression analysis revealed that fatigue, pain, disease activity and health-related quality of life affected WPAI 2 and 4. Furthermore, we observed distinct synergistic effects of fatigue, disease activity and pain on both work productivity and daily activities: a higher impact of fatigue was associated with the reported extent of pain or disease activity. In employed patients with SLE, impaired work productivity and impaired daily activities were frequently reported. Fatigue, pain, disease activity and health-related quality of life demonstrated a detrimental impact, with a synergistic effect of fatigue, disease activity and pain. Hence, both optimized pain management and targeted immunomodulatory therapy are important for preserving active participation in life among patients with fatigue.

Synergistic effects of a combined treatment of PI3K/mTOR dual inhibitor LY3023414 and carboplatin on human endometrial carcinoma

ObjectivesOur study aims to investigate whether PI3K/mTOR dual inhibitor LY3023414 has synergistic effects with carboplatin in suppressing endometrial cancer (EC), and explore the mechanisms and toxicity of combined therapy. MethodsThe effects of combined therapy of LY3023414 and carboplatin on cell viability, long-term survival and cell apoptosis were studied in vitro, and on subcutaneous xenograft model of HEC-1A cells and patient derived xenograft (PDX) models with different PI3K pathway mutational patterns in vivo. The synergistic mechanisms were explored on ATM/Chk2 and PI3K signaling pathway. The toxicity of combined therapy was also observed. ResultsCombined treatment of LY3023414 and carboplatin synergistically inhibited proliferation, colony formation, promoted apoptosis of EC cells, and significantly activated ATM/Chk2 signaling pathway. LY3023414 had synergistic anti-tumor effects with carboplatin in HEC-1A subcutaneous xenograft which harbors PIK3CA mutation. The sensitivity to LY3023414 and carboplatin differed in PDX of EC cases with different mutational patterns of PI3K pathway, and combined therapy exhibited distinct synergistic anti-tumor effects in those harboring different PI3K pathway mutations. No increased drug toxicity in nude mice was seen in combined groups. ConclusionsCombined therapy of PI3K/mTOR dual inhibitor LY3023414 and carboplatin had synergistic anti-tumor effects in EC cell line and some of the PDX EC models, without increasing the toxicity of single drug. Enhanced carboplatin-induced DNA damage response (DDR) and cell apoptosis may be the mechanisms of synergistic effects. The anti-tumor effects may correlate with the mutational pattern of PI3K pathway, which provides experimental basis of individual treatments of ECs in the future.

Analysis of the generation efficiency of disaggregated renewable energy and its spatial heterogeneity influencing factors: A case study of China

The world has witnessed a surge in renewable power installed capacity in recent years, and there is an emerging trend of renewable penetration in electricity production. However, there is a lack of quantitative comparative study on disaggregated renewable power sources concerning their generation efficiency performance, regional heterogeneity, development potential, and influencing mechanism in the existing literature. In the case of China's 30 provinces, this paper evaluates the hydropower, solar power, and wind power generation efficiency by stochastic frontier analysis method, and then reveals the distribution characteristics and deployment potential of different renewable sources. Furthermore, from the perspective of spatial heterogeneity, geographical detector model is utilized to study the influence mechanism of the generation efficiency of different renewable sources. The main results are as follows. Firstly, production inefficiency prevails in hydropower, solar power, and wind power generation industries. The installed capacity, utilized hours, and auxiliary power consumption have positive impacts on the three renewable energy sources. Every 1% increase in auxiliary power consumption leads to 0.16% increase in solar power generation, which is quite larger than the increase in hydropower and wind power. Secondly, on average, hydropower has the highest level of generation efficiency, followed by wind power and solar power. Kernel density curves indicate the generation efficiency of hydropower, solar power, and wind power displays distinct aggregation characteristics. Different energy types show significant regional differences in deployment potential. Thirdly, annual precipitation accounts for 76% of the spatial heterogeneity in hydropower generation efficiency, followed by hydropower technology innovation and power structure. As for solar power generation efficiency, the most important influencing factors are electricity investment and economic development. By contrast, wind power generation efficiency is primarily affected by power structure, electricity investment, and urbanization. Additionally, there exist distinct synergistic effects among different variables. These results provide insightful policy support for the improvement of renewable power generation efficiency. The study can be extended to the global scale using country-level data.

A clinically acceptable strategy for sensitizing anti-PD-1 treatment by hypoxia relief

The hypoxic tumor microenvironment (TME) hinders the effectiveness of immunotherapy. Alleviating tumor hypoxia to improve the efficacy of immune checkpoint inhibitors (ICIs) represented by programmed cell death protein 1 (PD-1) antibody has become a meaningful strategy. In this study, we adopted three methods to alleviate hypoxia, including direct oxygen delivery using two different carriers and an indirect way involving HIF-1α inhibition. Both in vivo and in vitro experiments showed that liposomes modified with perfluorocarbon or hemoglobin (PFC@lipo or Hb@lipo) were able to efficiently load and release oxygen, relieving tumor hypoxia. However, the gas release behavior of PFC@lipo was uncontrollable, which might induce acute hyperoxia side effects during intravenous injection and reduce its biosafety. In contrast, whether administered locally or systemically, Hb@lipo revealed high animal tolerance, and was much safer than commercial HIF-1α inhibitor (PX-478), displaying prospects as a promising oxygen carrier for clinical practice. Pharmacodynamic experiments suggested that Hb@lipo helped PD-1 antibody break the therapeutic bottleneck and significantly inhibited the progression of 4 T1 breast cancer. But in CT26 colon cancer, the combination therapy failed to suppress tumor growth. After in-depth analysis and comparison, we found that the ratio of M1/M2 tumor associated macrophages (TAMs) between these two tumor models were dramatically different. And the lower M1/M2 ratio in CT26 tumors limited the anti-tumor effect of combination therapy. In this study, three methods for alleviating tumor hypoxia were compared from the perspectives of biosafety, efficacy and clinical applicability. Among them, Hb@lipo stood out, and its combined use with PD-1 antibody exhibit a distinct synergistic suppression effect on tumors with more M1 macrophages presented in the microenvironment. Our work provided a good reference for improving the efficacy of PD-1 antibody by alleviating tumor hypoxia.

Simultaneous Activation of Signals Through gp130, c-kit, and Interleukin-3 Receptor Promotes a Trilineage Blood Cell Production in the Absence of Terminally Acting Lineage-Specific Factors

AbstractWe assessed the biologic role of signaling through gp130, a signal-transducing receptor (R) component, in human hematopoiesis in vitro. Although peripheral blood-derived CD34+ cells ubiquitously expressed gp130 and interleukin-3 receptor α (IL-3Rα), IL-6Rα was only detected on 80% of these CD34+ cells. We sorted CD34+IL-6R+ or CD34+IL-6R− cells and studied the effect on hematopoietic colony formation of signaling through gp130 activated by IL-6 or a combination of IL-6 and recombinant soluble human IL-6R (sIL-6R) in the presence or absence of stem cell factor (SCF ) and/or IL-3. Signals activated by SCF, IL-6, or IL-6/sIL-6R complex alone did not induce significant colony formation. However, a combination of IL-3, SCF, and IL-6/sIL-6R complex dramatically induced many neutrophil (colony-forming unit-granulocyte [CFU-G]), erythroid burst (burst-forming unit-erythrocyte [BFU-E]), erythrocyte-containing mixed (CFU-Mix), and megakaryocyte (CFU-Meg) colony formations when CD34+IL-6R− cells were used as the target. CFU-G colony formation induced by the three signals was more evident when CD34+IL-6R+ cells were used as the target. This distinct synergistic effect of the three different signals was confirmed by single-cell clone-sorting experiments. Moreover, colony formation (including CFU-G, BFU-E, CFU-Mix, and CFU-Meg) was observed even in the presence of neutralizing antibodies for granulocyte colony-stimulating factor, erythropoietin, and thrombopoietin (c-Mpl), whereas neutralizing antibodies for gp130, IL-6R, IL-3, and SCF partially or completely blocked the synergistic effect. The maturation of neutrophilic, erythroid, and megakaryocytic cells supported by the three signals in serum-free cultures was confirmed by immunostaining using anti-CD66b, antiglycophorin A, antihemoglobin α, and anti-CD41 monoclonal antibodies, respectively. In contrast, any two of the three signals were insufficient for effective blood cell production in the absence of maturation factors. These results suggest that simultaneous activation of the three signals through gp130, c-kit, and IL-3R can induce in vitro proliferation and differentiation of trilineage hematopoietic progenitors in the absence of terminally acting lineage-specific factors.

Synergistic Antibacterial Activity of Designed Trp-Containing Antibacterial Peptides in Combination With Antibiotics Against Multidrug-Resistant Staphylococcus epidermidis.

Multidrug resistance among various bacterial strains is leading to worldwide resistance to a wide range of antibiotics. Combination therapy involving current antibiotics and other biological or chemical molecules represents an attractive novel strategy. In this study, we investigated the synergistic antibacterial activity of a series of Trp-containing antimicrobial peptides (AMPs) with four classes of traditional chemical antibiotics that are inactive against multidrug-resistant Staphylococcus epidermidis (MRSE) in vitro and in vivo. Among the antibiotics that we studied, penicillin, ampicillin and erythromycin showed a distinct synergistic effect in combination with all of the Trp-containing AMPs, represented by a fractional inhibitory concentration index (FICI) of <0.5. The antibacterial activities were noticeably improved, with 32-to 64-fold reductions in the MIC values for ampicillin and 16- to 32-fold reductions in the MIC values for erythromycin and penicillin. Tetracycline showed synergistic activity with only I1WL5W but additive activity with L11W, L12W, and I4WL5W. Ceftazidime exhibited additive activity with the Trp-containing peptides. In addition, the antibiotics in combination with the peptide significantly inhibited biofilm formation by MRSE 1208. A mechanistic study demonstrated that the Trp-containing peptides, especially I1WL5W and I4WL5W, which contain two tryptophan residues, disrupted bacterial inner and outer membranes, which promoted antibiotic delivery into the cytoplasm and access to cytoplasmic targets; however, L11W and L12W may have increased intracellular antibiotic concentrations by decreasing blaZ, tet(m) and msrA expression. Importantly, strong synergistic activity against the MRSE 1208 strain was observed for the combination of I1WL5W and penicillin in a mouse infection model. Thus, the combination of AMPs and traditional antibiotics could be a promising option for the prevention of acute and chronic infections caused by MRSE.

Polydopamine-Assisted Immobilization of Chitosan Brushes on a Textured CoCrMo Alloy to Improve its Tribology and Biocompatibility.

Due to their bioinert and reliable tribological performance, cobalt chromium molybdenum (CoCrMo) alloys have been widely used for articular joint implant applications. However, friction and wear issues are still the main reasons for the failure of implants. As a result, the improvement of the tribological properties and biocompatibility of these alloys is still needed. Thus, surface modification is of great interest for implant manufacturers and for clinical applications. In this study, a strategy combining laser surface texturing and chitosan grafting (mussel inspired) was used to improve the tribological and biocompatible behaviors of CoCrMo. The microstructure and chemical composition were investigated by atomic force microscopy, scanning electron microscopy, and X-ray photoelectron spectroscopy, respectively. The tribological properties were discussed to determine their synergistic effects. To evaluate their biocompatibility, osteoblast cells were cocultured with the modified surface. The results show that there is a distinct synergistic effect between laser surface texturing and polymer brushes for improving tribological behaviors and biocompatibility. The prepared chitosan brushes on a textured surface are a strong mechanism for reducing friction force. The dimples took part in the hydrodynamic lubrication and acted as the container for replenishing the consumed lubricants. These brushes also promote the formation of a local lubricating film. The wear resistance of the chitosan brushes was immensely improved. Further, the worn process was observed, and the mechanism of destruction was demonstrated. Co-culturing with osteoblast cells showed that the texture and grafting have potential applications in enhancing the differentiation and orientation of osteoblast cells.