Fabrication of deoxycholic acid-modified polymeric micelles and their transmembrane transport

Oral administration is the best way for the most patients due to the good compliance,and intestinal epithelium is the main barrier of oral drug absorption.In order to overcome the small intestine epithelial barrier to orally deliver water-insoluble drugs,deoxycholic acid(DA),a substrate of the intestinal bile acid transporters,conjugated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide)(DA-PEOz-PLA)was designed and synthesized,and deoxycholic acid-modified polymeric micelles composed of DA-PEOz-PLA and mPEG-PLA were fabricated to encapsulate model drug coumarin 6(C6)based on intestinal bile acid pathway.The structure of DA-PEOz-PLA was confirmed using 1 H NMR and TLC,and the molecular weight measured by GPC was 10034 g/mol with a PDI of 1.51.The C6-loaded polymeric micelles with drug loading content of 0.085%were characterized to have 40.11 nm in diameter and uniform spherical morphology observed by TEM.Furthermore,the deoxycholic acid-modified polymeric micelles were demonstrated to further enhance the transmembrane transport efficiency.The mechanic study evidenced that anchorage of deoxycholic acid onto the micelles surface enriched their transcellular transport pathway.Therefore,the designed deoxycholic acid-modified polymeric micelles might have a promising potential for oral delivery of water-insoluble drugs.

Design of Lipophilic Split Aptamers as Artificial Carriers for Transmembrane Transport of Adenosine Triphosphate

Transmembrane transport plays an important role in many physiological functions,and mimicking this biological process in artificial systems has potential applications in biosensing,drug delivery,and bionic science.Here,a lipophilic split aptamer was developed as a novel transmembrane carrier for adenosine triphosphate(ATP)transport.The ATP carrier comprises two split aptamer fragments and cholesterol tags,with the split aptamers acting as targetrecognition domains to enhance their specific binding capability and the cholesterol tags as hydrophobic domains to facilitate membrane penetration.Giant unilamellar vesicle experiments demonstrated that the ATP carrier-mediated transmembrane transport was concentration-and time-dependent and showed high transport selectivity.Moreover,the artificial carriers were applicable to living cells and facilitated rapid cell internalization of fluorescencelabeled ATP.Furthermore,carrier-mediated ATP transport into ATP-deficient cells enabled recovery of cellular ATP levels and improved cell viability.This study demonstrated the efficacy of an aptamer nanostructure for designing DNA-based synthetic carriers with high selectivity and flexibility.

BcSDR1 is involved in regulation of glucose transport and cAMP and MAPK signaling pathways in Botrytis cinerea

Botrytis cinerea is a typical necrotrophic pathogenic fungus that causes severe diseases in a wide range of plant species, leading to significant economic losses. Our previous study showed that BcSDR1 positively regulates growth,development, and pathogenicity of B. cinerea. However, the regulation mechanism of BcSDR1 and the relationship between BcSDR1 and cAMP and MAPK signaling pathways are not well understood. In this study, transcriptome data showed that BcSDR1 is involved in glucose transmembrane transport, signal transduction, secondary metabolism, and other biological processes. BcSDR1 mutant(BCt41) showed remarkably weak sensitivity to cAMP and MAPK signaling pathways specific inhibitors, SQ22536 and U0126, and significantly decreased cAMP content. The key genes of cAMP and MAPK signaling pathways, BcGB1, BcBTP1, BcBOS1, BcRAS1, and BcBMP3 were significantly upregulated,whereas BcPLC1, BcBCG1, BcCDC4, BcSAK1, BcATF1, and BcBAP1 were significantly downregulated(P<0.05).BcSDR1 was obviously upregulated in BcBCG2, BcBCG3, BcPKA1, and BcPKAR RNA interference(RNAi) mutants, but significantly downregulated in BcPKA2, BcBMP1, and BcBMP3 RNAi mutants. Thus, BcBCG2, BcBCG3, BcPKA1, and BcPKAR negatively regulate BcSDR1 expression, whereas BcPKA2, BcBMP1, and BcBMP3 positively regulate BcSDR1expression.

Unimolecular artificial transmembrane channel with terminal dihydrogen phosphate groups showing transport selectivity for ammonium

A new artificial transmembrane channel molecule bearing dihydrogen phosphate groups has been synthesized.The terminal dihydrogen phosphate groups enable the channel to be highly negatively charged at both ends of the channel structures.The artificial channel could incorporate into the lipid bilayer efficiently under low concentration.The channel displays high NH4+/K+selectivity due to the electrostatic interaction and hydrogen bonding between NH4+and the terminal dihydrogen phosphate groups.

Physical principles at bio-nano interfaces with active matter

Active matter is characterized by out-of-equilibrium behaviors,offering an attractive,alternative route for revolutionizing disease diagnostics and therapy.A better understanding of how active matter interacts with cell membranes is critical to elucidating the underlying physical mechanisms and broadening the potential biomedical applications.This review provides a conceptual framework on the physiochemical mechanisms underlying active matter-biomembrane interactions.We briefly introduce the physical models of active matter and lipid membranes,and summarize the typical phenomena emerging from various active matter,including artificial active particles,cellular cytoskeletons,bacteria,and membrane proteins.Moreover,the remaining challenges and future perspectives of such non-equilibrium systems in living organisms are discussed.The findings and fundamental principles discussed in this review shed light on the rational design of activity-mediated cellular interaction,and could trigger better strategies to design and develop novel functional systems and materials toward advantageous biomedical applications.

Attenuated retinoic acid signaling is among the early responses in mouse uterus approaching embryo attachment

The uterus is transiently receptive for embryo implantation.It remains to be understood why the uterus does not reject a semi-allogeneic embryo(to the biological mother)or an allogeneic embryo(to a surrogate)for implantation.To gain insights,we examined uterine early response genes approaching embryo attachment on day 3 post coitum(D3)at 22 hours when blue dye reaction,an indication of embryo attachment,had not manifested in mice.C57BL/6 pseudo-pregnant(control)and pregnant mouse uteri were collected on D3 at 22 hours for microarray analysis.The self-assembling-manifold(SAM)algorithm identified 21,858 unique probesets.Principal component analysis indicated a clear separation between the pseudo-pregnant and pregnant groups.There were 106 upregulated and five downregulated protein-coding genes in the pregnant uterus with fold change(fc)>1.5 andq value<5%.Gene ontology(GO)analysis of the 106 upregulated genes revealed 38 significant GO biological process(GOBP)terms(P<0.05),and 32(84%)of them were associated with immune responses,with a dominant natural killer(NK)cell activation signature.Among the top eight upregulated protein-coding genes,Cyp26a1 inactivates retinoic acid(RA)whileLrat promotes vitamin A storage,both of which are expected to attenuate RA bioavailability;Atp6v0d2 andGjb2 play roles in ion transport and transmembrane transport;Gzmb,Gzmc,andIl2rb are involved in immune responses;andTdo2 is important for kynurenine pathway.Most of these genes or their related pathways have functions in immune regulations.RA signaling has been implicated in immune tolerance and immune homeostasis,and uterine NK cells have been implicated in immunotolerance at the maternal-fetal interface in the placenta.The mechanisms of immune responses approaching embryo attachment remain to be elucidated.The coordinated effects of the early response genes may hold the keys to the question of why the uterus does not reject an implanting embryo.

Responsive Polymers with Contraction-arisen Helicity and Biomimetic Membrane-spanning Transport Functions

Responsive polymers have attracted increasing attention for prospective design of smart materials.The development of multifunctional responsive materials is very dependent on polymeric structures that can be manipulated with the change of microenvironment at the molecular level.Herein,we report a type of responsive coordination polymers(RCPs)consisting of dual phenanthroline-oxadiazole(DPO)units and metal Zn^(2+)ions,which can contract from linear structure into topologically helical structure driven by hydrophobic effect while changing the microenvironment from nonpolar solvent to aqueous media.The symmetry breaking of RCPs was confirmed by circular dichroism(CD)spectra and atomic force microscope(AFM)images,clearly demonstrating the intramolecularly contraction-arisen helicity.Moreover,RCPs can intelligently adapt different microenvironments by changing their conformations,as evidenced by a demonstration of biomimetic lipid bilayer-based vesicle experiments.Furthermore,RCPs show significant concentration-dependent transmembrane transport functions,implying that RCPs are able to span cellular membranes to form channels inside the hydrophobic lipid bilayers.At the same time,the electrophysiological conductance experiments further underpin the biomimetic transport functions and channel-based conduction mechanism of RCPs.This study demonstrates an important paradigm of responsive polymers performing microenvironment-induced conformational change and thereof unique functions,and thus provides valuable insights on the development of functional responsive materials.

Controlling microbiological interfacial behaviors of hydrophobic organic compounds by surfactants in biodegradation process

Bioremediation of hydrophobic organic compounds （HOCs） contanlinated soils involves several physicochemical and microbiological interracial processes among the soil-water-microorganism interfaces. The participation of surfactants facilitates the mass transport of HOCs in both the physicochemical and microbiological interfaces by reducing the interfacial tension. The effects and underlying mechanisms of surfactants on the physi-cochemical desorption of soil-sorbed HOCs have been widely studied. This paper reviewed the progress made in understanding the effects of surfactant on microbiological interlhcial transport of HOCs and the underlying mechanisms, which is vital for a better understanding and control of the mass transfer of HOCs in the biodegradation process. In summary, surfactants affect the microbiological interfacial behaviors of HOCs during three consecutive processes： the soil solution-microorganism sorption, the transmembrane process, and the intracellular metabolism. Surfactant could promote cell sorption of HOCs depending on the compatibility of surfactant hydrophile hydrophilic balance （HLB） with cell surface properties; while the dose ratio between surfactant and biologic mass （membrane lipids） determined the transmembrane processes. Although surfactants cannot easily directly affect the intracellular enzymatic metabolism of HOCs due to the steric hindrace, the presence of surfactants can indirectly enhanced the metabolism by increasing the substrate concentrations.