Self-Assembly of Sulfate-Containing Peptides Sequesters VEGF for Inhibiting Cancer Cell Invasion.

Heparan sulfate proteoglycans (HSPGs) play a crucial role in regulating cancer growth and migration by mediating interactions with growth factors. In this study, we developed a self-assembling peptide (S1) containing a sulfate group to simulate the contiguous sulfated regions (S-domains) in heparan sulfate for growth factor binding, aiming to sequester growth factors like VEGF. Spectral and structural studies as well as simulation studies suggested that S1 self-assembled into nanostructures similar to the heparan sulfate chains and effectively bound to VEGF. On cancer cell surfaces, S1 self-assemblies sequestered VEGF, leading to a reduction in VEGF levels in the medium, consequently inhibiting cancer cell growth, invasion, and angiogenesis. This study highlights the potential of self-assembling peptides to emulate extracellular matrix functions, offering insights for future cancer therapeutic strategies.

Pyrene-Based Self-Assembling Peptide for Ratiometric Detection of Heparin.

Heparin is a commonly used anticoagulant in clinical practice; however, excessive heparin can cause serious adverse reactions. Convenient and accurate detection of heparin levels is thus very important. In this research, a pyrene-based self-assembling fluorescent peptide PyFFRRR was designed for simple, selective, and efficient heparin detection. The guanidine groups in the arginine residues of PyFFRRR bind tightly with heparin, which is highly sulfated, through electrostatic interactions. Charge neutralization facilitated the self-assembly of PyFFRRR, resulting in its spectral response changing from deep blue monomer fluorescence to green excimer fluorescence. PyFFRRR exhibited excellent sensitivity and selectivity for ratiometric detection of heparin. The binding mechanism was investigated by using spectral and simulation tools, and structural observation. Finally, PyFFRRR was employed in human serum samples for ratiometric detection of heparin.

Constructing ECM-like Structure on the Plasma Membrane via Peptide Assembly to Regulate the Cellular Response.

This feature article introduces the design of self-assembling peptides that serve as the basic building blocks for the construction of extracellular matrix (ECM)-like structure in the vicinity of the plasma membrane. By covalently conjugating a bioactive motif, such as membrane protein binding ligand or enzymatic responsive building block, with a self-assembling motif, especially the aromatic peptide, a self-assembling peptide that retains bioactivity is obtained. Instructed by the target membrane protein or enzyme, the bioactive peptides self-assemble into ECM-like structure exerting various stimuli to regulate the cellular response via intracellular signaling, especially mechanotransduction. By briefly summarizing the properties and applications (e.g., wound healing, controlling cell motility and cell fate) of these peptides, we intend to illustrate the basic requirements and promises of the peptide assembly as a true bottom-up approach in the construction of artificial ECM.

Microtubule-Targeted Self-Assembly Triggers Prometaphase-Metaphase Oscillations Suppressing Tumor Growth.

Microtubules are highly strategic targets of cancer therapies. Small molecule antimitotic agents are so far the best chemotherapeutic medication in cancer treatment. However, the high rate of neuropathy and drug resistance limit their clinical usage. Inspired by the multicomponent-targeting feature of molecular self-assembly (MSA) overcoming drug resistance, we synthesized peptide-based rotor molecules that self-assemble in response to the surrounding environment to target the microtubule array. The MSAs self-adjust morphologically in response to the pH change and viscosity variations during Golgi-endosome trafficking, escape trafficking cargos, and eventually bind to the microtubule array physically in a nonspecific manner. Such unrefined nano-bio interactions suppress regional tubulin polymerization triggering atypical prometaphase--metaphase oscillations to inhibit various cancer cells proliferating without inducing obvious neurotoxicity. The MSA also exerts potent antiproliferative effects in the subcutaneous cervix cancer xenograft tumor model equivalent to Cisplatin, better than the classic antimitotic drug Taxol.

Lipid-Raft-Targeted Molecular Self-Assembly Inactivates YAP to Treat Ovarian Cancer.

The Yes-associated protein (YAP) is a major oncoprotein responsible for cell proliferation control. YAP's oncogenic activity is regulated by both the Hippo kinase cascade and uniquely by a mechanical-force-induced actin remodeling process. Inspired by reports that ovarian cancer cells specifically accumulate the phosphatase protein ALPP on lipid rafts that physically link to actin cytoskeleton, we developed a molecular self-assembly (MSA) technology that selectively halts cancer cell proliferation by inactivating YAP. We designed a ruthenium-complex-peptide precursor molecule that, upon cleavage of phosphate groups, undergoes self-assembly to form nanostructures specifically on lipid rafts of ovarian cancer cells. The MSAs exert potent, cancer-cell-specific antiproliferative effects in multiple cancer cell lines and in mouse xenograft tumor models. Our work illustrates how basic biochemical insights can be exploited as the basis for a nanobiointerface fabrication technology which links nanoscale protein activities at specific subcellular locations to molecular biological activities to suppress cancer cell proliferation.

Robust Packing of a Self-Assembling Iridium Complex via Endocytic Trafficking for Long-Term Lysosome Tracking.

Live cell imaging of lysosome positioning and motility is critical to studying lysosome status and function for pharmacological interventions. To create a super stable lysosomal probe for long-term live cell imaging, we have designed and synthesized an aromatic-peptide-conjugated cyclometalated iridium(III) complex that emits light via π-π stacking oriented self-assembly in water at extremely low concentration. Through endocytic trafficking, self-assemblies are transformed from nanoparticles into sturdily packed networks that are stabilized in lysosomal acidic environment. Upon short time/low dose treatment of the iridium complex at passage 0, live cell lysosomal tracking is applicable beyond the 14th passage of cells with high labelling rate and a mild decline in luminescence intensity. The illuminated lysosomes are trackable using super-resolution imaging to study their response to cellular processes.

Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Drug Resistant Cancer Cells.

Although lipids contribute to cancer drug resistance, it is challenging to target diverse range of lipids. Here, we show enzymatically inserting exceedingly simple synthetic lipids into membranes for increasing membrane tension and selectively inhibiting drug resistant cancer cells. The lipid, formed by conjugating dodecylamine to d-phosphotyrosine, self-assembles to form micelles. Enzymatic dephosphorylation of the micelles inserts the lipids into membranes and increases membrane tension. The micelles effectively inhibit a drug resistant glioblastoma cell (T98G) or a triple-negative breast cancer cell (HCC1937), without inducing acquired drug resistance. Moreover, the enzymatic reaction of the micelles promotes the accumulation of the lipids in the membranes of subcellular organelles (e.g., endoplasmic reticulum (ER), Golgi, and mitochondria), thus activating multiple regulated cell death pathways. This work, in which for the first time membrane tension is increased to inhibit cancer cells, illustrates a new and powerful supramolecular approach for antagonizing difficult drug targets.

Self-Assembly-Directed Cancer Cell Membrane Insertion of Synthetic Analogues for Permeability Alteration.

Inspired by the metamorphosis of pore-forming toxins from soluble inactive monomers to cytolytic transmembrane assemblies, we developed self-assembly-directed membrane insertion of synthetic analogues for permeability alteration. An expanded π-conjugation-based molecular precursor with an extremely high rigidity and a long hydrophobic length that is comparable to the hydrophobic width of plasma membrane was synthesized for membrane-inserted self-assembly. Guided by the cancer biomarker expression in vitro, the soluble precursors transform into hydrophobic monomers  forming assemblies inserted into the fluid phase of the membrane exclusively. Membrane insertion of rigid synthetic analogues destroys the selective permeability of the plasma membrane gradually. It eventually leads to cancer cell death, including drug resistant cancer cells.

Interfering with DNA High-Order Structures using Chiral Ruthenium(II) Complexes.

In this work, it was found that DNA can undergo B-Z transformational changes and compaction in the presence of DNA intercalators such as ruthenium(II) polypyridyl complexes. The link between B-Z transition and condensation is weak but can be strengthened under certain circumstances with slight alterations to the structures of the ruthenium(II) complexes. Here, following on from previous research, this work reports a series of ruthenium(II) complexes with imidazophenanthroline ligands, which vary in size and planarity. The complexes exhibit distinct effects on DNA structures, ranging from little impact to the transformation of DNA secondary structures to the formation of higher-order DNA structures. Further studies on DNA morphological changes induced by chiral ruthenium(II) complexes are observed by atomic force microscopy and transmission electron microscopy.

Iridium(III) Anthraquinone Complexes as Two-Photon Phosphorescence Probes for Mitochondria Imaging and Tracking under Hypoxia.

In the present study, four mitochondria-specific and two-photon phosphorescence iridium(III) complexes, Ir1-Ir4, were developed for mitochondria imaging in hypoxic tumor cells. The iridium(III) complex has two anthraquinone groups that are hypoxia-sensitive moieties. The phosphorescence of the iridium(III) complex was quenched by the functions of the intramolecular quinone unit, and it was restored through two-electron bioreduction under hypoxia. When the probes were reduced by reductase to hydroquinone derivative products under hypoxia, a significant enhancement in phosphorescence intensity was observed under one- (λ=405 nm) and two-photon (λ=720 nm) excitation, with a two-photon absorption cross section of 76-153 GM at λ=720 nm. More importantly, these probes possessed excellent specificity for mitochondria, which allowed imaging and tracking of the mitochondrial morphological changes in a hypoxic environment over a long period of time. Moreover, the probes can visualize hypoxic mitochondria in 3D multicellular spheroids and living zebrafish through two-photon phosphorescence imaging.

[Levels and evaluations of physical activity using 5-A counseling model in patients with stable schizophrenia].

OBJECTIVE: To explore the levels and evaluations of physical activity (PA) using 5-A counseling model in patients with stable schizophrenia. METHODS: A total of 258 patients with stable schizophrenia during February-August in 2014 were selected as research group while 214 healthy subjects as control group. A self-formulated questionnaire was used to assess the PA levels of participants. And a 5-A counseling model (assess, advise, agree, assist and arrange) was used to evaluate the experiences and qualities of PA counseling. RESULTS: There were significantly fewer people physically active in research group than those in control group (20.1% vs 35.9%). According to the results of PA counseling experience in research group, only 29.5% patients received PA counseling. And the strategies of "advising on personal benefits and principles of intensified PA" were most frequently used while other strategies seldom used. CONCLUSION: Most patients with stable schizophrenia are physically inactive and they should receive more PA counseling.

Causal role of immune cells in hypertension: a bidirectional Mendelian randomization study.

Background: Although Hypertension (HTN) is considered to be a cardiovascular disease caused by multiple factors, the cause of it is still unknown. In this study, we aim to find out whether circulating immune cell characteristics have an impact on susceptibility to HTN. Methods: This study employed a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the causal association between immune cell characteristics and HTN. Utilizing publicly accessible genetic data, we examined the causal relationship between HTN and the susceptibility to 731 immune cell signatures. To ensure the reliability and validity of the findings, a comprehensive sensitivity analysis was conducted to assess heterogeneity, confirm the robustness of the results and evaluate the presence of horizontal pleiotropy. Results: After FDR correction, immune phenotype had an effect on HTN. In our study, one immunophenotype was identified as being positively associated with HTN risk significance: HLA DR on CD33- HLA DR+. In addition, we examined 8 immune phenotype with no statistically significant effect of HTN, but it is worth mentioning that they had an unadjusted low P-value phenotype. Conclusions: Our MR study by genetic means demonstrated the close relationship between HTN and immune cells, thus providing guidance for future clinical prediction and subsequent treatment of HTN.

Acid-assisted self-assembly of pyrene-capped tyrosine ruptures lysosomes to induce cancer cell apoptosis.

Induced lysosomal membrane permeabilization (LMP) by peptide self-assembly has emerged as an effective platform for lysosome-targeted cancer therapy. In this study, we shift this strategical paradigm and present an innovative approach to LMP induction through amino acid-based self-assembly. Pyrene-capped tyrosine (Py-Tyr), as a proof-of-concept molecule, is designed with acidity-responsive self-assembly. Under acidic conditions (pH 4), Py-Tyr is protonated with reduced charge repulsion, and self-assembles into micrometer-scaled aggregates, which exceed the biological size of lysosomes. Cell experiments showed that Py-Tyr specifically accumulates in lysosomes and induces lysosome rupture, leading to the release of cathepsin B into the cytoplasm for subsequent apoptosis activation in cancer cells. This study capitalizes on the concept of amino acid assembly for efficient LMP induction, providing a simple and versatile platform for precise and effective therapeutic interventions in cancer therapy.

An ALP-responsive, anionic iridium complex for specific recognition of osteosarcoma cells.

Poor cellular permeability greatly hampers the utilization of anionic Ir(III) complexes, though efficiently emissive and remarkably stable, in cell-based diagnosis. To overcome this barrier, we present the development of an alkaline phosphatase (ALP)-responsive, anionic, and aggregation-induced emission (AIE)-active Ir(III) complex (Ir1) for specific recognition of osteosarcoma cells. Containing phosphate moieties, Ir1 exhibits a net -1 charge, enabling charge repulsion from the cell membrane and resulting in low cellular uptake and good biocompatibility in normal osteoblast cells. Upon ALP-mediated hydrolysis of phosphate groups, the resulting dephosphorylated product, Ir2, demonstrates a positive charge and increased lipophilicity, promoting cellular uptake and activating its AIE properties for specific recognition of osteosarcoma cells that express elevated levels of ALP. This study elucidates the role of ALP as an ideal trigger for enhancing the cellular permeability of phosphate ester-containing Ir(III) complexes, thus expanding the potential of anionic Ir(III) complexes for biomedical applications.

Formulate Adaptive Biphasic Scaffold via Sequential Protein-Instructed Peptide Co-Assembly.

To ensure compositional consistency while mitigating potential immunogenicity for stem cell therapy, synthetic scaffolds have emerged as compelling alternatives to native extracellular matrix (ECM). Substantial progress has been made in emulating specific natural traits featuring consistent chemical compositions and physical structures. However, recapitulating the dynamic responsiveness of the native ECM involving chemical transitions and physical remodeling during differentiation, remains a challenging endeavor. Here, the creation of adaptive scaffolds is demonstrated through sequential protein-instructed molecular assembly, utilizing stage-specific proteins, and incorporating in situ assembly technique. The procedure is commenced by introducing a dual-targeting peptide at the onset of stem cell differentiation. In response to highly expressed integrins and heparan sulfate proteoglycans (HSPGs) on human mesenchymal stem cell (hMSC), the peptides assembled in situ, creating customized extracellular scaffolds that adhered to hMSCs promoting osteoblast differentiation. As the expression of alkaline phosphatase (ALP) and collagen (COL-1) increased in osteoblasts, an additional peptide is introduced that interacts with ALP, initiating peptide assembly and facilitating calcium phosphate (CaP) deposition. The growth and entanglement of peptide assemblies with collagen fibers efficiently incorporated CaP into the network resulting in an adaptive biphasic scaffold that enhanced healing of bone injuries.

Specific discrimination and efficient elimination of gram-positive bacteria by an aggregation-induced emission-active ruthenium (II) photosensitizer.

The infections caused by Gram-positive bacteria (G+) have seriously endangered public heath due to their high morbidity and mortality. Therefore, it is urgent to develop a multifunctional system for selective recognition, imaging and efficient eradication of G+. Aggregation-induced emission materials have shown great promise for microbial detection and antimicrobial therapy. In this paper, a multifunctional ruthenium (II) polypyridine complex Ru2 with aggregation-induced emission (AIE) characteristic, was developed and used for selective discrimination and efficient extermination of G+ from other bacteria with unique selectivity. The selective G+ recognition benefited from the interaction between lipoteichoic acids (LTA) and Ru2. Accumulation of Ru2 on the G+ membrane turned on its AIE luminescence and allowed specific G+ staining. Meanwhile, Ru2 under light irradiation also possessed robust antibacterial activity for G+in vitro and in vivo antibacterial experiments. To the best of our knowledge, Ru2 is the first Ru-based AIEgen photosensitizer for simultaneous dual applications of G+ detection and treatment, and inspires the development of promising antibacterial agents in the future.

Duration and dosing of systemic corticosteroids for acute exacerbation of COPD, protocol for a systematic review with meta-analysis of randomized trials and cohort studies.

PURPOSE: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a leading cause of deterioration in patients with otherwise stably controlled COPD. Treatments of AECOPD often require the use of corticosteroid therapy in conjunction with bronchodilators and antibiotics. However, the duration and dosage of corticosteroids still remain unclear. We propose to perform this systematic review and meta-analysis of all available randomized control trials (RCTs) and observational cohort studies to comprehensively assess the efficacy and safety of different corticosteroid duration and dosing regimen in the current body of evidence. METHODS: We will search MEDLINE, EMBASE, CENTRAL via Ovid as well as CINAHL and Web of Science for available literature comparing different corticosteroid duration and dosage in the treatment of AECOPD. We will perform title and full text screening in duplicate, then extract relevant data using a pre-piloted extraction form. We will define short duration as less than 14-day duration of treatment and long duration as greater than 14-day treatment. We will report mortality difference as our primary outcome, with additional comparisons in incidence of re-exacerbation, hospital length of stay, lung function, incidence of hyperglycemia and infection. We will perform risk of bias assessment using the ROB2.0 and ROBINS-I tool, as well as the GRADE assessment to assess the quality of evidence. RESULTS: We will publish the full results of our systematic review and meta-analysis in a peer-reviewed journal. DISCUSSIONS: To our knowledge, this represents an updated and most comprehensive review of the literature comparing different duration and dosing regimen of corticosteroid treatments in AECOPD, as we will include both RCTs and observational studies without date or language restrictions. We aim to validate prior meta-analyses and study findings on the efficacy of short duration corticosteroid therapy over longer treatments and to inform future research directions in dosing regimens.

Succinic Ester-Based Shape Memory Gelatin Sponge for Noncompressible Hemorrhage without Hindering Tissue Regeneration.

Shape memory sponges are very promising in stopping the bleeding from noncompressible and narrow entrance wounds. However, few shape memory sponges have fast degradable properties in order to not hinder tissue healing. In this work, based on cryopolymerization, a succinic ester-based sponge (Ssponge) is fabricated using gelatin and bi-polyethylene glycol-succinimidyl succinate (Bi-PEG-SS). Compared with the commercially available gelatin sponge (Csponge), Ssponge possesses better water/blood absorption ability and higher mechanical pressure over the surrounding tissues. Moreover, in the models of massive liver hemorrhage after transection and noncompressive liver wounds by penetration, Ssponge exhibits a better hemostasis performance than Csponge. Furthermore, in a liver regeneration model, Ssponge-treated livers shows higher regeneration speed compared with Csponge, including a lower injury score, more cavity-like tissues, less fibrosis and enhanced tissue regeneration. Overall, it is shown that Ssponge, with a fast degradation behavior, is not only highly efficient in stopping bleeding but also not detrimental for tissue healing, possessing promising clinical translational potential.

Stimuli-responsive platinum and ruthenium complexes for lung cancer therapy.

Lung cancer is the most common cause of cancer-related deaths worldwide. More efficient treatments are desperately needed. For decades, the success of platinum-based anticancer drugs has promoted the exploration of metal-based agents. Four ruthenium-based complexes have also entered clinical trials as candidates of anticancer metallodrugs. However, systemic toxicity, severe side effects and drug-resistance impeded their applications and efficacy. Stimuli-responsiveness of Pt- and Ru-based complexes provide a great chance to weaken the side effects and strengthen the clinical efficacy in drug design. This review provides an overview on the stimuli-responsive Pt- and Ru-based metallic anticancer drugs for lung cancer. They are categorized as endo-stimuli-responsive, exo-stimuli-responsive, and dual-stimuli-responsive prodrugs based on the nature of stimuli. We describe various representative examples of structure, response mechanism, and potential medical applications in lung cancer. In the end, we discuss the future opportunities and challenges in this field.

Cohesion Design-Led Tough Sealants with Controllably Dissolvable Properties.

Leakage is a common complication of surgeries and injuries, causing pain and increasing the economic burden on patients. Although there are commercially available sealants for leakage prevention, few of them are entirely satisfactory due to disease transmission, high cost, and poor biocompatibility. In addition, none of them can be controllably removed for further healthcare. In this paper, by using cohesion design, a sealant based on amino-modified gelatin (AG) and bi-polyethylene glycol N-hydroxysuccinimide active ester (Bi-PEG-SS) was fabricated. To increase the bursting pressure, the cohesion strength was enhanced by increasing the cross-linking density of the sealant. To endow the sealant with controllably dissolvable properties, the smart succinic ester units were introduced into the cohesion network. Both the in vitro and in vivo experiments showed that this sealant processed high bursting pressure with efficient hemorrhage control. Moreover, no side effects were observed after 7 days of in vivo sealing, including little inflammation and fibrogenesis. These results, together with the easy availability of the raw materials, revealed that this sealant might be a promising alternative for leakage sealing.