Abstract The continued evolution of biomedical nanotechnology has enabled clinicians to better detect, prevent, manage, and treat human disease. In order to further push the limits of nanoparticle ...performance and functionality, there has recently been a paradigm shift towards biomimetic design strategies. By taking inspiration from nature, the goal is to create next-generation nanoparticle platforms that can more effectively navigate and interact with the incredibly complex biological systems that exist within the body. Of great interest are cellular membranes, which play essential roles in biointerfacing, self-identification, signal transduction, and compartmentalization. In this review, we explore the major ways in which researchers have directly leveraged cell membrane-derived biomaterials for the fabrication of novel nanotherapeutics and nanodiagnostics. Such emerging technologies have the potential to significantly advance the field of nanomedicine, helping to improve upon traditional modalities while also enabling novel applications.
Tumor-associated macrophages (TAMs) constitute a large population of glioblastoma and facilitate tumor growth and invasion of tumor cells, but the underlying mechanism remains undefined. In this ...study, we demonstrate that chemokine (C-C motif) ligand 8 (CCL8) is highly expressed by TAMs and contributes to pseudopodia formation by GBM cells. The presence of CCL8 in the glioma microenvironment promotes progression of tumor cells. Moreover, CCL8 induces invasion and stem-like traits of GBM cells, and CCR1 and CCR5 are the main receptors that mediate CCL8-induced biological behavior. Finally, CCL8 dramatically activates ERK1/2 phosphorylation in GBM cells, and blocking TAM-secreted CCL8 by neutralized antibody significantly decreases invasion of glioma cells. Taken together, our data reveal that CCL8 is a TAM-associated factor to mediate invasion and stemness of GBM, and targeting CCL8 may provide an insight strategy for GBM treatment.
Branched‐chain amino acids (BCAAs), including leucine, isoleucine and valine, may potentially influence cancer progression by various mechanisms including its role in insulin resistance. However, the ...association of BCAAs with survival among patients with established colorectal cancer (CRC) remains unclear. We evaluated the associations between postdiagnostic BCAA intake with CRC‐specific mortality and overall mortality among 1674 patients with nonmetastatic CRC in the Nurses' Health Study and the Health Professionals Follow‐up Study. Patients completed a validated food frequency questionnaire. Multivariable hazard ratios (HRs) were calculated using Cox proportional‐hazards regression model after adjustment for tumor characteristics and potential confounding factors. Comparing the highest with the lowest quartile intake of postdiagnostic total BCAA, the multivariable HRs were 1.18 (95% confidence interval CI, 0.75‐1.85, P for trend = .46 across quartiles) for CRC‐specific mortality and 1.30 (95% CI, 1.01‐1.69, P for trend = .04) for all‐cause mortality. The multivariable HRs (the highest vs the lowest quartile) for all‐cause mortality were 1.33 (95% CI, 1.03‐1.73, Ptrend = .02) for valine, 1.28 (95% CI, 0.99‐1.66, P for trend = .05) for leucine and 1.25 (95% CI, 0.96‐1.61, P for trend = .06) for isoleucine. No statistically significant associations with each of the BCAA intake were observed for CRC‐specific mortality (all P for trend > .30). Our findings suggest positive associations between higher intake of dietary BCAAs and risk of all‐cause mortality in CRC patients. These findings need to be confirmed and potential mechanisms underlying this association need to be elucidated.
What's new?
Animal protein sources such as meat and milk are high in branched‐chain amino acids (BCAAs). BCAAs may potentially influence cancer progression by various mechanisms, including providing an energy source for tumor growth, and activation of the mTOR/p70S6K pathway. However, the impact of BCAAs on survival among patients with colorectal cancer (CRC) has been unclear. The results of this study suggest that higher intake of dietary BCAAs is associated with overall mortality risk in CRC patients.
Acidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human ...tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxel + cisplatin regimen in patients with metastatic breast cancer (MBC).
Patients enrolled were randomly assigned to three arms: Arm A, docetaxel 75 mg/m(2) followed by cisplatin 75 mg/m(2) on d4, repeated every 21 days with a maximum of 6 cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80 mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3 days on 4 days off) was maintained up to maximum 66 weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100 mg p.o. bid. The primary endpoint was response rate.
Ninety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5 %, respectively. Median TTP for arm A (n = 32), B (n = 31), C (n = 31) were 8.7, 9.4, and 9.7 months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (67.7 % vs. 46.9 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045) corrected. Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8 months, respectively (p = 0.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2 months, p = 0.090). No additional toxicity was observed with PPI.
The results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial.
Clinicaltrials.gov identifier: NCT01069081 .
Background
The spinal phosphodiesterase‐4 (PDE4) plays an important role in chronic pain. Inhibition of PDE4, an enzyme catalyzing the hydrolysis of cyclic adenosine monophosphate AMP (cAMP), ...produces potent antinociceptive activity. However, the antinociceptive mechanism remains largely unknown. Connexin43 (Cx43), a gap junction protein, has been shown to be involved in controlling pain transduction at the spinal level; restoration of Cx43 expression in spinal astrocytes to the normal levels reduces nerve injury‐induced pain. Here, we evaluate the novel mechanisms involving spinal cAMP‐Cx43 signaling by which PDE4 inhibitors produce antinociceptive activity.
Methods
First, we determined the effect of PDE4 inhibitors rolipram and roflumilast on partial sciatic nerve ligation (PSNL)‐induced mechanical hypersensitivity. Next, we observed the role of cAMP‐Cx43 signaling in the effect of PDE4 inhibitors on PSNL‐induced mechanical hypersensitivity.
Results
Single or repeated, intraperitoneal or intrathecal administration of rolipram or roflumilast significantly reduced mechanical hypersensitivity in mice following PSNL. In addition, repeated intrathecal treatment with either of PDE4 inhibitors reduced PSNL‐induced downregulation of cAMP and Cx43, and upregulation of proinflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interleukin‐1β. Furthermore, the antinociceptive effects of PDE4 inhibitors were attenuated by the protein kinase A (PKA) inhibitor H89, TNF‐α, or Cx43 antagonist carbenoxolone. Finally, PSNL‐induced upregulation of PDE4B and PDE4D, especially the PDE4B subtype, was reduced by treatment with either of the PDE4 inhibitors.
Conclusions
The results suggest that the antinociceptive effect of PDE4 inhibitors is contributed by increasing Cx43 expression via cAMP‐PKA‐cytokine signaling in the spinal dorsal horn.
The present study provides not only solid demonstration for the analgesic effects of PDE4 inhibitors but also valued clues on the novel mechanism of cAMP‐PKA‐cytokine signaling whereby PDE4 inhibitors produce analgesic activity. The findings will aid in the development of novel antinociceptive agents.
Genetic analyses for bipolar disorder (BD) have achieved prominent success in Europeans in recent years, whereas its genetic basis in other populations remains relatively less understood. We herein ...report that the leading risk locus for BD in European genome-wide association studies (GWAS), the single-nucleotide polymorphism (SNP) rs9834970 near TRANK1 at 3p22 region, is also genome-wide significantly associated with BD in a meta-analysis of four independent East Asian samples including 5748 cases and 65,361 controls (p = 2.27 × 10
, odds ratio = 1.136). Expression quantitative trait loci (eQTL) analyses and summary data-based Mendelian randomization (SMR) analyses in multiple human brain samples suggest that lower TRANK1 mRNA expression is a principal BD risk factor explaining its genetic risk signals at 3p22. We also identified another SNP rs4789 in the 3' untranslated region (3'UTR) of TRANK1 showing stronger eQTL associations as well as genome-wide significant association with BD. Despite the relatively unclear neuronal function of TRANK1, our mRNA expression analyses in the human brains and in rat primary cortical neurons reveal that genes highly correlated with TRANK1 are significantly enriched in the biological processes related to dendritic spine, synaptic plasticity, axon guidance and circadian entrainment, and are also more likely to exhibit strong associations in psychiatric GWAS (e.g., the CACNA1C gene). Overall, our results support that TRANK1 is a potential BD risk gene. Further studies elucidating its roles in this illness are needed.
To better constrain the Ca isotopic composition of the Bulk Silicate Earth (BSE) and explore the Ca isotope fractionation in the mantle, we determined the Ca isotopic composition of 28 peridotite ...xenoliths from Mongolia, southern Siberia and the Siberian craton. The samples are divided in three chemical groups: (1) fertile, unmetasomatized lherzolites (3.7–4.7 wt.% Al2O3); (2) moderately melt-depleted peridotites (1.3–3.0 wt.% Al2O3) with no or very limited metasomatism (LREE-depleted cpx); (3) strongly metasomatized peridotites (LREE-enriched cpx and bulk rock) further divided in subgroups 3a (harzburgites, 0.1–1.0% Al2O3) and 3b (fertile lherzolites, 3.9–4.3% Al2O3). In Group 1, δ44/40Ca of fertile spinel and garnet peridotites, which experienced little or no melting and metasomatism, show a limited variation from 0.90 to 0.99‰ (relative to SRM 915a) and an average of 0.94 ± 0.05‰ (2SD, n=14), which defines the Ca isotopic composition of the BSE. In Group 2, the δ44/40Ca is the highest for three rocks with the lowest Al2O3, i.e. the greatest melt extraction degrees (average 1.06±0.04‰, i.e. ∼0.1‰ heavier than the BSE estimate). Simple modeling of modal melting shows that partial melting of the BSE with 103lnαperidotite-melt ranging from 0.10 to 0.25 can explain the Group 2 data. By contrast, δ44/40Ca in eight out of nine metasomatized Group 3 peridotites are lower than the BSE estimate. The Group 3a harzburgites show the greatest δ44/40Ca variation range (0.25–0.96‰), with δ44/40Ca positively correlated with CaO and negatively correlated with Ce/Eu. Chemical evidence suggests that the residual, melt-depleted, low-Ca protoliths of the Group 3a harzburgites were metasomatized, likely by carbonate-rich melts/fluids. We argue that such fluids may have low (≤0.25‰) δ44/40Ca either because they contain recycled crustal components or because Ca isotopes, similar to trace elements and their ratios, may be fractionated by kinetic and/or chromatographic effects of melt percolation in the mantle. The δ44/40Ca in Group 3b lherzolites (0.83–0.89‰) are lower than in the BSE as well, but the effects of metasomatism on δ44/40Ca are smaller, possibly because of the high Ca contents in their protoliths and/or smaller δ44/40Ca differences between the protoliths and metasomatic agents. The BSE estimates based on fertile peridotites in this study fall in the δ44/40Ca ranges for oceanic and continental basalts, various meteorites (achondrites; carbonaceous, ordinary and enstatite chondrites), Mars, and the Moon. These results provide benchmarks for the application of Ca isotopes to planet formation, mantle evolution, and crustal recycling.
•We report δ44/40Ca for peridotites with variable degrees of metasomatism.•Unmetasomatized lherzolites define δ44/40Ca of BSE as 0.94 ± 0.05‰ (2SD, n=14).•Melt-depleted peridotites have average δ44/40Ca of 1.06 ± 0.04‰ (2SD, n=3).•δ44/40Ca of metasomatized peridotites range from 0.25‰ to 0.96‰.
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•Ultrasonication was successfully used to prepare the composite PVDF/GO membranes.•Largely enhanced hydrophilicity was achieved for the composite membranes.•The composite membrane ...exhibited excellent adsorption ability toward MB.•The composite membrane showed good regeneration ability and adsorption stability.
In this work, ultrasonication-assisted deposition technology was used to prepare the composite poly(vinylidene fluoride) (PVDF)/graphene oxide (GO) membrane with regarding to organic dyes removal. The electrospun PVDF fibrous membrane, which was first obtained through electrospinning technology, was immersed into the GO aqueous solution, and then the mixture was ultrasonically treated at power of 100 W for different time. Microstructure characterizations and hydrophilicity measurements confirmed that many GO platelets were incorporated into the PVDF membrane. The adsorption ability toward methylene blue (MB) by the composite PVDF/GO membrane was then systematically investigated. The results showed that the ultrasonication time and the concentration of GO in the aqueous solution determined the content of GO in the composite membrane, which also determined the adsorption capacity of the composite membrane. Studies on adsorption kinetics and adsorption isotherms showed that the adsorption behavior of the composite PVDF/GO membrane could be well described by the pseudo second-order model, and the maximum adsorption capacity of MB was 621.1 mg g−1. Furthermore, the composite PVDF/GO membrane exhibited excellent regeneration ability. This work demonstrates that the composite PVDF/GO membrane may be a promising adsorbent to remove organic dyes from wastewater.
Aqueous Zn–iodine (Zn–I2) batteries have been regarded as a promising energy‐storage system owing to their high energy/power density, safety, and cost‐effectiveness. However, the polyiodide shuttling ...results in serious active mass loss and Zn corrosion, which limits the cycling life of Zn–I2 batteries. Inspired by the chromogenic reaction between starch and iodine, a structure confinement strategy is proposed to suppress polyiodide shuttling in Zn–I2 batteries by hiring starch, due to its unique double‐helix structure. In situ Raman spectroscopy demonstrates an I5−‐dominated I−/I2 conversion mechanism when using starch. The I5− presents a much stronger bonding with starch than I3−, inhibiting the polyiodide shuttling in Zn–I2 batteries, which is confirmed by in situ ultraviolet–visible spectra. Consequently, a highly reversible Zn–I2 battery with high Coulombic efficiency (≈100% at 0.2 A g−1) and ultralong cycling stability (>50 000 cycles) is realized. Simultaneously, the Zn corrosion triggered by polyiodide is effectively inhibited owing to the desirable shuttling‐suppression by the starch, as evidenced by X‐ray photoelectron spectroscopy analysis. This work provides a new understanding of the failure mechanism of Zn–I2 batteries and proposes a cheap but effective strategy to realize high‐cyclability Zn–I2 batteries.
Inspired by the significant chromogenic reaction between starch and iodine, the shuttle effect of Zn–I2 batteries is effectively addressed by using starch, which strongly anchors polyiodide anions due to its unique double‐helix structure. Benefiting from this structure confinement, a Coulombic efficiency of almost 100% and an ultralong life of 50 000 cycles are realized in Zn–I2 batteries.
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