A Strong and Highly Transparent Ionogel Electrolyte Enabled by In Situ Polymerization-Induced Microphase Separation for High-Performance Electrochromic Devices.

Electrochromic devices built with ionogel electrolytes are seen as a pivotal step toward the future of quasi-solid electrochromic devices, due to their striking properties like exceptional safety and high ionic conductivity. Yet, the poor mechanical strength of electrolyte of these devices remains a constraint that hampers their advancement. As a resolution, this research explores the use of a robust, transparent ionogel electrolyte, which is designed using an in situ microphase separation strategy. The ionogels are highly transparent and robust and exhibit excellent physicochemical stability, including a wide electrochemical window and high temperature tolerance. Benefitting from these properties, a high-performance electrochromic device is fabricated through in situ polymerization with the ionogels, PPRODOT as the electrochromic layer, and PEDOT: PSS as the ion storage layer, achieving high transmittance contrast (43.1%), fast response (1/1.7 s), high coloring efficiency (1296.4 cm2 C-1), and excellent cycling endurance (>99.9% retention after 2000 cycles). In addition, using ITO-poly(ethylene terephthalate) as flexible substrates, a deformable electrochromic device displaying high stability is realized, highlighting the potential use in functional wearables.

Precisely Detecting the Telomerase Activities by an AIEgen Probe with Dual Signal Outputs after Cell-Cycle Synchronization.

By maintaining the telomere lengths, telomerase can make the tumor cells avoid the apoptosis, thus, achieving the cell immortalization. In the past, a series of telomerase detection systems have been developed through utilizing the unique characteristic of telomerase extended primer. However, fluctuation of telomerase activity, along with the cell cycle progression, leads to ambiguous detection results. Here, we reported a dual signal output detection strategy based on cell-cycle synchronization for precisely detecting telomerase activities by using a new AIEgen probe SSNB. Experimental and simulating calculation results demonstrated that positively charged SSNB could interact with DNA through the electrostatic interaction and π-π interaction, as well as the hydrogen bonds. The aggregation of SSNB caused by the extended template strand primer (TP) could be observed in tumor cells, thus, indicating the telomerase activity in various cell lines. Furthermore, after cell cycle synchronization, it was found that the telomerase activity in the S phase was the highest, no matter from the fluorescence intensity or the ROS generation situation. Dual signal outputs of SSNB verified the significance and necessity of cell-cycle synchronization detection for telomerase activity. This strategy could open a new window for the biotargets of which activity is variational in time dimension.

Modular Design of Peptide- or DNA-Modified AIEgen Probes for Biosensing Applications.

Fluorophore probes are widely used for bioimaging in cells, tissues, and animals as well as for monitoring of multiple biological processes in complex environments. Such imaging properties allow scientists to make direct visualizations of pathological events and cellular targets. Conventional fluorescent molecules have been developed for several decades and achieved great successes, but their emissions are often weakened or quenched at high concentrations that might suffer from the aggregation-caused quenching (ACQ) effect, which reduces the efficiencies of their applications. In contrast to the ACQ effect, aggregation-induced emission (AIE) luminogens (AIEgens) display much higher fluorescence in aggregated states and possess various advantages such as low background, long-term tracking ability, and strong resistance to photobleaching. Therefore, AIEgens are employed as unique fluorescence molecules and building blocks for biosensing applications in the fields of ions, amino acids, carbohydrates, DNAs/RNAs, peptides/proteins, cellular organelles, cancer cells, bacteria, and so on. Quite a few of the above biosensing missions are accomplished by modular peptide-modified AIEgen probes (MPAPs) or modular DNA-modified AIEgen probes (MDAPs) because of the multiple capabilities of peptide and DNA modules, including solubility, biocompatibility, and recognition. Meanwhile, both electrostatic interactions and coupling reactions could provide efficient methods to construct different MPAPs and MDAPs, finally resulting in a large variety of biosensing probes. Those probes exhibit leading features of detecting nucleic acids or proteins and imaging mass biomolecules. For example, under modular design, peptide modules possessing versatile recognition abilities enable MPAPs to detect numerous targets, such as integrin αvß3, aminopeptidase N, MMP-2, MPO, H2O2, and so forth; MDAP could allow the imaging of mRNA in cells and tissue chips, suggesting the diagnostic functions of MDAP in clinical samples. Modular design offers a novel strategy to generate AIEgen-based probes and expedites functional biomacromolecules research. In this vein, here we review the progress on MPAPs and MDAPs in the most recent 10 years and highlight the modular design strategy as well as their advanced biosensing applications including briefly two aspects: (1) detection and (2) imaging. By the use of MPAPs/MDAPs, multiple bioanalytes can be efficiently analyzed at low concentrations and directly visualized through high-contrast and luminous imaging. Compared with MPAPs, the quantities of MDAPs are limited because of the difficult synthesis of long-length DNA strands. In future work, multifunctional of DNA sequences are needed to explore varieties of MDAPs for diverse biosensing purposes. At the end of this Account, some deficiencies and challenges are mentioned for briging more attention to accelerate the development of AIEgen-based probes.

Concentration-induced spontaneous polymerization of protic ionic liquids for efficient in situ adhesion.

The advancement of contemporary adhesives is often limited by the balancing act between cohesion and interfacial adhesion strength. This study explores an approach to overcome this trade-off by utilizing the spontaneous polymerization of a protic ionic liquid-based monomer obtained through the neutralization of 2-acrylamide-2-methyl propane sulfonic acid and hydroxylamine. The initiator-free polymerization process is carried out through a gradual increase in monomer concentration in aqueous solutions caused by solvent evaporation upon heating, which results in the in-situ formation of a tough and thin adhesive layer with a highly entangled polymeric network and an intimate interface contact between the adhesive and substrate. The abundance of internal and external non-covalent interactions also contributes to both cohesion and interfacial adhesion. Consequently, the produced protic poly(ionic liquid)s exhibit considerable adhesion strength on a variety of substrates. This method also allows for the creation of advanced adhesive composites with electrical conductivity or visualized sensing functionality by incorporating commercially available fillers into the ionic liquid adhesive. This study provides a strategy for creating high-performance ionic liquid-based adhesives and highlights the importance of in-situ polymerization for constructing adhesive composites.

Adhesive Zwitterionic Poly(ionic liquid) with Unprecedented Organic Solvent Resistance.

The resistance of adhesives to organic solvents is of paramount importance in diverse industries. Unfortunately, many currently available adhesives exhibit either weak intermolecular chain interactions, resulting in insufficient resistance to organic solvents, or possess a permanent covalent crosslinked network, impeding recyclability. This study introduces an innovative approach to address this challenge by formulating zwitterionic poly(ionic liquid) (ZPIL) derivatives with robust dipole-dipole interactions, incorporating sulfonic anions and imidazolium cations. Due to its unique dynamic and electrostatic self-crosslinking structure, the ZPIL exhibits significant adhesion to various substrates and demonstrates excellent recyclability even after multiple adhesion tests. Significantly, ZPIL exhibits exceptional adhesion stability across diverse nonpolar and polar organic solvents, including ionic liquids, distinguishing itself from nonionic polymers and conventional poly(ionic liquid)s. Its adhesive performance remains minimally affected even after prolonged exposure to soaking conditions. The study presents a promising solution for the design of highly organic solvent-resistant materials for plastics, coatings, and adhesives.

Plasmon-enhanced fluorescence and electrochemical aptasensor for SARS-CoV-2 Spike protein detection.

In this work, we combined plasmon-enhanced fluorescence and electrochemical (PEF-EC) transduction mechanisms to realize a highly sensitive dual-transducer aptasensor. To implement two traducers in one biosensor, a novel large-scale nanoimprint lithography process was introduced to fabricate gold nanopit arrays (AuNpA) with unique fringe structures. Light transmitting through the AuNpA samples exhibited a surface plasmon polariton peak overlapping with the excitation peak of the C7 aptamer-associated fluorophore methylene blue (MB). We observed a five and seven-times higher average fluorescence intensity over the AuNpA and fringe structure, respectively, in comparison to a plane Au film. Furthermore, the MB fluorophore was simultaneously utilized as a redox probe for electrochemical investigations and is described here as a dual transduction label for the first time. The novel dual transducer system was deployed for the detection of SARS-CoV-2 Spike protein via a C7 aptamer in combination with a strand displacement protocol. The PEF transducer exhibited a detection range from 1 fg/mL to 10 ng/mL with a detection limit of 0.07 fg/mL, while the EC traducer showed an extended dynamic range from 1 fg/mL to 100 ng/mL with a detection limit of 0.15 fg/mL. This work provides insights into an easy-to-perform, large-scale fabrication process for nanostructures enabling plasmon-enhanced fluorescence, and the development of an advanced but universal aptasensor platform.

Gender differences in pancreatic neuroendocrine neoplasms: A retrospective study based on the population of Hubei Province, China.

Objective: The aims of the present study were to investigate gender differences in the clinicopathological features, distant metastasis and prognosis of pancreatic neuroendocrine neoplasms (pNENs) in a Chinese population, and to identify any important gaps in the classification and management of pNENs relative to gender. Methods: Retrospective collection of the clinicopathological data of 193 patients with pathologically confirmed pNENs were analyzed and follow up was extended to observe the prognosis of the disease. Differences between genders in basic characteristics, clinical symptoms, comorbidities, and tumor parameters were analyzed. Results: There was no significant difference in females and males, however, moderately higher for females (52.8% vs. 47.2%), with the largest subgroup being 40~60 years of age (54.9%). Age at onset (P=0.002) and age at diagnosis (P=0.005) were both younger in females compared to males. Males lived more in urban areas and females lived more in rural areas (P=0.047). The proportion of smokers and alcohol drinkers was significantly higher in males than in females (P < 0.001). Non-functional pNENs were more frequent in males and functional pNENs in females (P=0.032). In women, functional status of the tumor was significantly associated with metastatic outcome (P=0.007) and functional tumors proved to be a protective factor compared to non-functional tumors (OR=0.090,95% CI: 0.011~ 0.752). There were no gender differences in tumor size, location, grade, stage or prognosis. Conclusions: Gender differences in some clinicopathological features, and distant metastasis in patients with pNENs were identified, which suggested certain management details that justified emphasis based on gender.

Predictive value of the preoperative prognostic nutritional index for postoperative progression in patients with pancreatic neuroendocrine neoplasms.

Objective: The preoperative nutritional status of cancer patients is closely related to prognosis. The prognostic nutritional index (PNI) has been shown to predict the prognosis of a variety of tumors, but its study in pancreatic neuroendocrine neoplasms (pNENs) is lacking. The aim of the present study is to investigate the predictive value of the preoperative PNI for postoperative progression in patients with pNENs. Methods: The medical records of 181 patients with pNENs, who underwent surgery, were retrospectively analyzed. A time-dependent receiver operating characteristic (ROC) curve was plotted to determine the optimal cut-off value of the preoperative PNI. Correlations between the preoperative PNI and clinicopathological parameters were analyzed using multiple linear regression. A Kaplan-Meier curve was applied to assess the progression-free survival (PFS) rate, which was tested using a log rank. Univariate and multivariate Cox proportional risk regression models were used to analyze the predictive value of the preoperative PNI on prognosis. Results: The optimal cut-off value of the preoperative PNI was 48.275. The patients were divided into a high PNI group (PNI > 48.275, n = 92) and a low PNI group (PNI ≤ 48.275, n = 89). The proportion of patients with tumor progression after surgery was significantly higher in the low PNI group compared with that in the high PNI group (P = 0.004). The Kaplan-Meier curve showed that the PFS rate after surgery was significantly lower in the low PNI group compared with that in the high PNI group (P = 0.026). The preoperative PNI was an independent predictor of PFS (HR: 2.727, 95% CI: 1.174∼6.333, P = 0.020). Conclusion: The preoperative PNI has a predictive value for postoperative progression in patients with pNENs.

Src Activation Aggravates Podocyte Injury in Diabetic Nephropathy via Suppression of FUNDC1-Mediated Mitophagy.

Background and purpose: Mitophagy plays a significant role in the progression of diabetic nephropathy (DN), although the regulatory mechanisms remain unclear. Recently, accumulating evidence demonstrated that impaired mitochondrial function and mitophagy are involved in DN. Here, we are aimed to explore the role of c-Src (Src) and FUNDC1-related mitophagy in the development of DN. Methods: The db/db mice were used to establish a DN mice model. The mice accepted PP2 (Src inhibitor) treatment to study the role of Src in DN. Kidney function was measured via biochemical testing. Renal histopathology and morphometric analysis were conducted via hematoxylin-eosin (HE), periodic acid-Schiff (PAS), Masson's staining, and transmission electron microscopy (TEM). We measured degree of apoptosis in kidney by TUNEL assay. Indices of mitophagy (LC3 and p62) were evaluated by Western blotting and immunofluorescence. Complementary in vitro assays were conducted using human podocytes subjected to high glucose in combination with PP2 treatment or FUNDC1 small interfering RNAs (siRNAs). Flow cytometry was used to detect the apoptotic cells. Mitochondrial function was evaluated by JC-1 staining. Double immunofluorescence labeling of LC3 and TOMM20 used to assess the degree of mitophagy. Results: Increased Src activation was detected in the kidneys of db/db mice, and its expression was positively correlated with mitochondrial damage, podocyte apoptosis, and renal dysfunction. Inhibition of Src activation with PP2 protected against mitochondrial damage and podocyte apoptosis. In vitro experiments in podocytes established that high glucose increased Src activation, promoting FUNDC1 phosphorylation and inhibiting mitophagy. Consistent with the mouse model, inhibiting Src activity protected podocytes against mitochondrial damage. FUNDC1 silencing negated the actions of PP2, indicating that FUNDC1-mediated mitophagy is downstream pathway of Src. Conclusion: In summary, our data indicated that Src is a culprit factor in diabetic renal damage via suppression of FUNDC1-mediated mitophagy, promoting the development of DN.

Nanococktail Based on AIEgens and Semiconducting Polymers: A Single Laser Excited Image-Guided Dual Photothermal Therapy.

Semiconducting polymers (SPs)-based dual photothermal therapy (PTT) obtained better therapeutic effect than single PTT due to its higher photothermal conversion efficiency. However, most dual PTT need to use two lasers for heat generation, which brings about inconvenience and limitation to the experimental operations. Herein, we report the development of "nanococktail" nanomaterials (DTPR) with 808 nm-activated image-guided dual photothermal properties for optimized cancer therapy. Methods: In this work, we co-encapsulated AIEgens (TPA-BDTO, T) and SPs (PDPPP, P) by using maleimide terminated amphiphilic polymer (DSPE-PEG2000-Mal, D), then further conjugated the targeting ligands (RGD, R) through "click" reaction. Finally, such dual PTT nanococktail (termed as DTPR) was constructed. Results: Once DTPR upon irradiation with 808 nm laser, near-infrared fluorescence from T could be partially converted into thermal energy through fluorescence resonance energy transfer (FRET) between T and P, coupling with the original heat energy generated by the photothermal agent P itself, thus resulting in image-guided dual PTT. The photothermal conversion efficiency of DTPR reached 60.3% (dual PTT), much higher as compared to its inherent photothermal effect of only 31.5% (single PTT), which was further proved by the more severe photothermal ablation in vitro and in vivo upon 808 nm laser irradiation. Conclusion: Such smart "nanococktail" nanomaterials could be recognized as a promising photothermal nanotheranostics for image-guided cancer treatment.

Anti-inflammatory and metabolic reprogramming effects of MENK produce antitumor response in CT26 tumor-bearing mice.

Methionine enkephalin (MENK), an endogenous opioid peptide, has a role in nervous system, immune system, and anticancer therapy. Inflammation, metabolism and cancer are closely intertwined with each other. This study is to identify the correlation of the antitumor effects of MENK with systemic inflammation, liver metabolism, and immune cells as myeloid-derived suppressor cells (MDSCs). We established a subcutaneous CT26 colon carcinoma model and a cyclophosphamide-induced immunosuppressive model subjected to MENK. AML12 and MDSCs were used as in vitro models. The results showed that MENK treatment degraded tumor growth and inhibited proinflammatory cytokines both in tumor tissues and serum. The MENK-treated tumor mice showed normalized liver function with glycolipid metabolic homeostasis. No inhibitory effect on CT26 tumor cell in vitro, but only reduced lipid synthesis in AML12 were presented by MENK. Meanwhile, MENK invigorated immune response in both two animal models by markedly suppressing MDSCs and enhancing T cells response. In vitro MENK-treated MDSCs showed reduced glycolysis and less ROS production, which was mediated by PI3K/AKT/mTOR pathway. Opioid receptor antagonist naltrexone reversed most of the regulation. These results illustrate that MENK preventing development of colon carcinoma might be correlated with the suppression of inflammation, improving metabolism in liver as well as in MDSCs partly through opioid receptor, which brings new elements supporting the adjuvant therapy for tumor by MENK.

Modular DNA-Incorporated Aggregation-Induced Emission Probe for Sensitive Detection and Imaging of DNA Methyltransferase.

DNA adenine methylation (Dam) MTase serves a very important epigenetic process that transfers a methyl group on an adenine residue including N6-methyladenosine (m6A). A variety of evidence have demonstrated that m6A methylation plays a significant role in modulating genes in human disease and development. Hence, a modular DNA-incorporated AIEgen probe (TPE-Py-DNA) was specifically developed for detection and imaging of Dam MTase. TPE-Py-DNA consisted of two modules: a "turn-on" fluorescent AIEgen (TPE-Py) and a DNA sequence (Alk-DNA) involved in specific recognition of the targeted strand. The TPE-Py-DNA probe was dispersed and almost nonfluorescent in an aqueous environment. On the contrary, the TPE-Py-DNA molecule was digested based on the target-recycling strategy in assistance with exonuclease III (Exo III) when Dam MTase was presented, finally releasing aggregated AIEgens to produce a remarkably increased fluorescence signal. Therefore, the detection limit toward Dam MTase was as low as 3.1 × 10-5 U mL-1, and the fluorescent signal could be used to detect Dam MTase activities in real samples and screen its inhibitors. More importantly, the Dam MTase expression was visualized in E. coli cells via CLMS imaging and confirmed in E. coli cell-bearing tissues. In this vein, our results demonstrated that the TPE-Py-DNA probe is a potent tool for the Dam MTase detection and imaging as well as offers an efficient biosensing platform for further investigation of disease pathway and carcinogenesis.

MnO2-DNAzyme-photosensitizer nanocomposite with AIE characteristic for cell imaging and photodynamic-gene therapy.

Photodynamic therapy (PDT) was considered as an effective treatment. Whereas only PDT is not enough to achieve effective therapy on account of irradiation intensity decreases as depth increases as well as tumor hypoxia. Combination with gene therapy and photodynamic therapy have emerged as an effective strategy to improve therapeutic effectiveness. In the present study, a GSH responsive MnO2 was employed to delivery TB and DNAzyme for cancer imaging and PDT-gene combination treatment. TB, a photosensiters with aggregation-induced emission characteristic, was employed for photodynamic therapy, while DNAzyme, acting as catalysts for the degradation of EGR-1 mRNA, was exploited for gene silencing. All of the results of tumor treatment in vitro have implied that MnO2-DNAzyme-TB nanocomposite (MDT) can internalize into cells. Subsequently, MDT could decrease the expression of EGR-1 by gene silencing that enabling inhibition of cell growth. In addition, the singlet oxygen which was generated by the aggregated TB were able to further suppress cell growth. Combination therapy of photodynamic as well as gene therapy greatly enhanced antitumor efficiencies. Furthermore, in vivo tumor treatment experiments demonstrated that MDT under illumination can effectively inhibit the tumor growth of MCF-7 tumor-bearing mice by photodynamic and gene silencing combination therapy.

Absorption Characteristics of Novel Compound Calcium Carbonate Granules: Effects of Gastric Acid Deficiency and Exogenous Weak Acids.

Calcium carbonates are commonly administered as supplements for conditions of calcium deficiency. We report here pharmacokinetic characteristics of a novel formulation, calcium carbonate compound granules (CCCGs), forming complexes of calcium carbonate and calcium citrate in water. CCCGs were compared to a kind of commonly-used calcium carbonate D3 preparation (CC) in the market in 5-week-old mice that had been treated with omeprazole, to suppress gastric acid secretion, and in untreated control mice. The results showed that: (1) CCCGs had better water solubility than CC in vitro; (2) In control mice, calcium absorption rates after CCCGs administration were comparable to those after CC administration; (3) Inhibition of gastric acid secretion did not affect calcium absorption after CCCGs, but moderately decreased it after CC; (4) The presence of phytic acid or tannin did not affect calcium absorption rates after CCCGs but did for CC; and (5) In normal mice, CCCGs did not inhibit gastric emptying and intestinal propulsion, and did not alter the gastrointestinal hormones. The results suggest that CCCGs may be therapeutically advantageous over more commonly used calcium supplement formulations, particularly for adolescents, because of their stable calcium absorption characteristics and their relatively favorable adverse effect profile.

Exploring the Mechanism of Dangguiliuhuang Decoction Against Hepatic Fibrosis by Network Pharmacology and Experimental Validation.

Dangguiliuhuang decoction (DGLHD) has been demonstrated to be effective in treating inflammatory, hepatic steatosis, and insulin resistance. In the study, we tried to elucidate the pharmacological efficacy and mechanism of DGLHD against liver fibrosis and predicate potential active ingredients and targets via network analysis and experimental validation. In the formula, we totally discovered 76 potential active ingredients like baicalein, berberine, and wogonin, and 286 corresponding targets including PTGS (prostaglandin-endoperoxide synthase) 2, PPAR (peroxisome proliferator-activated receptors) -γ, and NF-κB (nuclear factor-κB). Pathway and functional enrichment analysis of these putative targets indicated that DGLHD obviously influenced NF-κB and PPAR signaling pathway. Consistently, DGLHD downregulated levels of ALT (alanine transaminase) and AST (aspartate transaminase), reduced production of proinflammatory cytokines-TNF (tumor necrosis factor) -α and IL (Interleukin) -1ß in serum and liver from mice with hepatic fibrosis, and inhibited hepatic stellate cell (HSC)-T6 cells proliferation. DGLHD decreased TGF (transforming growth factor) -ß1 and α-SMA (smooth muscle actin) expression as well, maintained MMP (matrix metalloprotein) 13-TIMP (tissue inhibitor of metalloproteinases) 1 balance, leading to mitigated ECM (extracellular matrix) deposition in vivo and in vitro. Moreover, our experimental data confirmed that the alleviated inflammation and ECM accumulation were pertinent to NF-κB inhibition and PPAR-γ activation. Overall, our results suggest that DGLHD aims at multiply targets and impedes the progression of hepatic fibrosis by ameliorating abnormal inflammation and ECM deposition, thereby serving as a novel regimen for treating hepatic fibrosis in clinic.