A Coupling-Induced Assembly Strategy for Constructing Artificial Shell on Mitochondria in Living Cells.

The strategy of in vivo self-assembly has been developed for improved enrichment and long-term retention of anticancer drug in tumor tissues. However, most self-assemblies with non-covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling-induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation-responsive peptide-porphyrin conjugate P1 is synthesized, which self-assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2-fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria-targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies.

Effect of Supplementary Light with Different Wavelengths on Anthocyanin Composition, Sugar Accumulation and Volatile Compound Profiles of Grapes.

Protected cultivation is currently one of the main cultivation modes for grape production, but the long-term use of plastic film will have a certain negative impact on the light environment in vineyards, which in turn causes poor colouring, low sugar content and a lack of aroma in some red grape varieties. Supplementing light can be an effective way to mitigate these problems. In this study, vines of three red table grape varieties ('Summer Black', 'Xinyu' and 'Queen Nina') cultivated in a plastic greenhouse were supplemented with red, blue, white and red-blue light from veraison to harvest. All four supplemental light treatments increased the content of anthocyanins, sugars and volatile compounds in three grape varieties compared to CK (no supplemental lighting). Red-blue light treatment was the most favourable for the accumulation of anthocyanins and sugars, and the grapes treated with blue light had the highest content of volatile compounds. The grapes treated with red-blue light all obtained the highest composite scores via principal component analysis. For most of the sensory properties, the highest scores were obtained by the red-blue light-treated grapes. The results of this study will be useful in improving the colouring, sugar, and aroma content of grapes under protected cultivation.

Performance Evaluation and Formation Mechanism of Viscoelastic Surfactant Fracturing Fluids with Moderate Interfacial Activity Enhanced by Janus-SiO2 Nanoparticles.

Nanoparticles (NPs) exhibit great potential to improve various properties of viscoelastic surfactant (VES) fracturing fluids in the development of low-permeability reservoirs. In the present study, the amphiphilic Janus NPs (JANPs) were fabricated via the Pickering emulsion method and employed to construct the novel JA12C (JANPs with dodecyl hydrophobic carbon chains)-assisted VES fracturing fluid (JAVES). The successful fabrication of JANPs was confirmed via Fourier transform infrared spectroscopy (FTIR) measurements and water contact angle tests. The rheology behavior of the VES fracturing fluid incorporating various SiO2 NPs including hydrophilic SiO2 NPs (HLNPs), JA8C (JANPs with octyl hydrophobic carbon chains), and JA12C was systematically investigated. It was revealed that the additional JA12C significantly improved the tolerance and proppant suspension properties. To explore the subsequent oil recovery performance of various gel breaking liquids, the formation wettability and the oil-water interfacial tension (IFT) were studied after the evaluation of breaking properties and formation damage properties of various fracturing fluids. The results suggested that the JAVES gel breaking liquid showed remarkable wettability alternation capability and moderate oil-water IFT reduction ability, which can partially reduce the impact on reservoir permeability. Moreover, the formation mechanism of the JAVES was proposed by molecular dynamics simulations at the molecular level, which was further visually verified via the cryo-TEM images. The improved viscoelasticity of developed the JAVES with moderate interfacial activity is advantageous to enhance subsequent oil recovery.

Research progress on vestibular dysfunction and visual-spatial cognition in patients with Alzheimer's disease.

Alzheimer's disease (AD) or vestibular dysfunction may impair visual-spatial cognitive function. Recent studies have shown that vestibular dysfunction is increasingly common in patients with AD, and patients with AD with vestibular impairment show more visual-spatial cognitive impairment. By exploring the relationship and interaction mechanism among the vestibular system, visual-spatial cognitive ability, and AD, this study aims to provide new insights for the screening, diagnosis, and rehabilitation intervention of patients with AD. In contrast, routine vestibular function tests are particularly important for understanding the vestibular function of patients with AD. The efficacy of vestibular function test as a tool for the early screening of patients with AD must also be further studied. Through the visual-spatial cognitive ability test, the "spatial impairment" subtype of patients with AD, which may be significant in caring for patients with AD to prevent loss and falls, can also be determined. Additionally, the visual-spatial cognitive ability test has great benefits in preventing and alleviating cognitive decline of patients with AD.

Corrigendum: Vestibular dysfunction is an important contributor to the aging of visuospatial ability in older adults-Data from a computerized test system.

[This corrects the article DOI: 10.3389/fneur.2022.1049806.].

Vestibular cognition assessment system: Tablet-based computerized visuospatial abilities test battery.

Introduction: The vestibular system is anatomically connected to extensive regions of the cerebral cortex, hippocampus, and amygdala. However, studies focusing on the impact of vestibular impairment on visuospatial cognition ability are limited. This study aimed to develop a mobile tablet-based vestibular cognitive assessment system (VCAS), enhance the dynamic and three-dimensional (3D) nature of the test conditions, and comprehensively evaluate the visuospatial cognitive ability of patients with vestibular dysfunction. Materials and methods: First, the VCAS assessment dimensions (spatial memory, spatial navigation, and mental rotation) and test content (weeding, maze, card rotation, and 3D driving tests) were determined based on expert interviews. Second, VCAS was developed based on Unity3D, using the C# language and ILruntime hot update framework development technology, combined with the A* algorithm, prime tree algorithm, and dynamic route rendering. Further, the online test was built using relevant game business logic. Finally, healthy controls (HC) and 78 patients with vertigo (VP) were recruited for the VCAS test. The validity of VCAS was verified using the test results of random controls. Results: In the weeding test, the HC group had a significantly longer span and faster velocity backward than did the VP group. In the 12 × 12 maze, statistically significant differences in step and time were observed between the two groups, with VP taking longer time and more steps. In the mental rotation task, no significant difference was observed between the two groups. Similarly, no significant difference was found in the performance of the two groups on maps 2, 3, and 4 in the 3D driving task. Discussion: Thus, impaired visuospatial cognition in patients with vestibular dysfunction is primarily related to spatial memory and navigation. VCAS is a clinically applicable visuospatial cognitive ability test for VP.

Vestibular dysfunction is an important contributor to the aging of visuospatial ability in older adults-Data from a computerized test system.

Background: A convergence of research supports a key role of the vestibular system in visuospatial ability. However, visuospatial ability may decline with age. This work aims to elucidate the important contribution of vestibular function to visuospatial ability in old adults through a computerized test system. Methods: Patients with a clinical history of recurrent vertigo and at least failed one vestibular test were included in this cross-sectional study. Healthy controls of three age groups: older, middle-aged, and young adults were also involved. Visuospatial cognitive outcomes including spatial memory, spatial navigation, and mental rotation of all the groups were recorded. Comparing the performance of the visuospatial abilities between patients and age-matched controls as well as within the controls. Results: A total of 158 individuals were enrolled. Results showed that patients performed worse than the age-matched controls, with the differences in the forward span (p < 0.001), the time of the maze 8 × 8 (p = 0.009), and the time of the maze 12 × 12 (p = 0.032) being significant. For the differences in visuospatial cognitive outcomes within the controls, the younger group had a significantly better performance than the other groups. The older group and the middle-aged group had comparable performances during all the tests. Conclusions: Older patients with vestibular dysfunction had more difficulties during visuospatial tasks than age-matched controls, especially in spatial memory and spatial navigation. Within the controls, younger adults did much better than other age groups, while older adults behaved similarly to middle-aged adults. It is a valuable attempt to computerize the administration of tests for visuospatial ability.

CCN1 Promotes Inflammation by Inducing IL-6 Production via α6ß1/PI3K/Akt/NF-κB Pathway in Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with unknown etiology. CCN1, an extracellular matrix-associated protein, is associated with carcinoma, inflammation, liver fibrosis, and even autoimmune diseases. However, the role that CCN1 plays in AIH has remained undetermined. In this study, expression of CCN1 in liver was detected by real-time PCR, western blot and immunohistochemistry (IHC). CCN1 level in serum was detected by ELISA. Diagnostic value of CCN1 was determined by receiver operating characteristic (ROC) curve analysis. CCN1 conditional knockout (CCN1 fl/fl Cre+) mice were generated by mating CCN1 fl/fl C57BL/6J and CAG-Cre-ERT C57BL/6J mice. Autoimmune hepatitis mice model was induced by concanavalin A (ConA). IKKα/ß, IκBα, NF-κB p65 and Akt phosphorylation were determined by western blot. NF-κB p65 nuclear translocation was examined by immunofluorescence. Here, we found that CCN1 was over-expressed in hepatocytes of AIH patients. CCN1 level also increased in serum of AIH patients compared to healthy controls (HC). ROC curve analysis results showed that serum CCN1 was able to distinguish AIH patients from HD. In ConA induced hepatitis mice model, CCN1 conditional knockout (CCN1 fl/fl Cre+) attenuated inflammation by reducing ALT/AST level and IL-6 expression. In vitro, CCN1 treatment dramatically induced IL-6 production in LO2 cells. Moreover, the production of IL-6 was attenuated by CCN1 knockdown. Furthermore, we showed that CCN1 could activate IL-6 production via the PI3K/Akt/NF-κB signaling pathway by binding to α6ß1 receptor. In summary, our results reveal a novel role of CCN1 in promoting inflammation by upregulation of IL-6 production in AIH. Our study also suggests that targeting of CCN1 may represent a novel strategy in AIH treatment.

Skin-like wound dressings with on-demand administration based on in situ peptide self-assembly for skin regeneration.

Burn injuries without the normal skin barrier usually cause skin wound infections, and wound dressings are necessary. Although various dressings with antibacterial ability have already been developed, the biosafety and administration mode are still bottleneck problems for further application. Herein, we designed skin-like wound dressings based on silk fibroin (SF), which are modified with the gelatinase-cleavable self-assembled/antibacterial peptide (GPLK) and epidermal growth factor (EGF). When a skin wound is infected, the gelatinase over-secreted by bacteria can cut the GPLK peptides, leading to the in situ self-assembly of peptides and the resultant high-efficiency sterilization. Compared with the commercial antibacterial dressing, the SF-GPLK displayed a faster wound healing rate. When a skin wound is not infected, the GPLK peptides remain in the SF, realizing good biosafety. Generally, the EGF can be released to promote wound healing and skin regeneration in both cases. Therefore, skin-like SF-GPLK wound dressings with on-demand release of antibacterial peptides provide a smart administration mode for clinical wound management and skin regeneration.

Multifunction Sandwich Structure Based on Diffusible 2-Chloroethylamine for High-Efficiency and Stable Tin-Lead Mixed Perovskite Solar Cells.

Low-bandgap tin-lead mixed perovskites (PVKs) are necessary for all-perovskite tandem solar cells. This work proposes a multifunctional sandwich structure with 2-chloroethylamine (CEA) as the top and bottom interface layer and perovskite as the core layer. The sandwich structured CEA allows large ClCH2CH2NH3+ and small Cl- to diffuse into the crystal lattice and grain boundaries of perovskites, endowing an excellent antioxidation property by forming Sn(0), coordinating with SnI2, and controlling the perovskite crystallization process. Moreover, the energy level alignment at the interface of the perovskite and transport layer becomes more matched. As a result, the CEA-modified champion device acquires a power conversion efficiency of 18.13% with an open-circuit voltage of 0.82 V and a short-circuit current density of 30.06 mA cm-2. Meanwhile, the environmental stability of CEA-modified devices is substantially enhanced. This work introduces a new strategy for improving the performance and stability of tin-lead mixed perovskite solar cells.

Intracellular Self-Immolative Polyprodrug with Near-Infrared Light Guided Accumulation and in Vivo Visualization of Drug Release.

The selective accumulation and real-time monitoring of drug release at tumor site are the key bottlenecks to the clinical translation of polyprodrug. Herein, an intracellular self-immolative polyprodrug (PMTO) is exploited, which not only shows the enhanced cellular internalization and selective accumulation in tumor site under the mild hyperthermia triggered by laser irradiation, but also possesses the self-monitoring drug release ability in vivo. The polyprodrug amphiphiles are synthesized by sequential esterification reaction, and hydrophilic poly(ethylene glycol) serves as blocking agent. On account of the mild hyperthermia produced by PMTO under the laser irradiation at tumor site, the cell membranous permeability increases, resulting in the enhanced cellular internalization and drug accumulation in tumor. After internalized by cells, the self-immolative PMTO nanoparticles can release free mitoxantrone (MTO) in intracellular reductive environment, and ratiometric photoacoustic imaging based on distinct signals between MTO and PMTO is presented to trace the drug release in vivo. Finally, this self-monitoring polyprodrug presents significant tumor suppression efficacy, which exhibits great potential for guiding the clinical medication in cancer treatment.

In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization.

Therapeutic peptides have been widely concerned, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK]2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP), KYp can be dephosphorylated and self-assembles in situ, which induces the aggregation of ALP and the protein-lipid phase separation on cell membrane. Consequently, KYp internalization is 2-fold enhanced compared to non-responsive peptide, and IC50 value of KYp is approximately 5 times lower than that of free peptide. Therefore, the in vivo self-assembly induced phase separation on cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.

Precise magnetic resonance imaging-guided sonodynamic therapy for drug-resistant bacterial deep infection.

The precise treatment of drug-resistant deep bacterial infections remains a huge challenge in clinic. Herein, a polymer-peptide-porphyrin conjugate (PPPC), which can be real-time monitored in infectious site, is developed for accurate and deep sonodynamic therapy (SDT) based on "in vivo self-assembly" strategy. The PPPC contains four moieties, i.e., a hyperbranched polymer backbone, a self-assembled peptide linked with an enzyme-cleavable peptide-poly (ethylene glycol) terminal, a bacterial targeting peptide, and a porphyrin sonosensitizer (MnTCPP) segment. Once PPPC nanoparticles reach the infectious area, the protecting PEG layers are removed due to the over-expressed gelatinase, leading to the secondary assembly into large nanoaggregates and resultant enhanced accumulation of sonosensitizer. The nanoaggregates exhibit enhanced interaction with bacterial membrane and decrease the minimum inhibitory concentration (MIC) significantly. Meanwhile, compared with free MnTCPP, the concentration of which can not be accurately quantified, the accumulation amount of MnTCPP in PPPCs at infectious site can be in situ monitored by magnetic resonance imaging (MRI) using T1 combined with T2. When the concentration of PPPC-1 reaches MIC, the drug-resistant bacterial infection area is exposed to ultrasound irradiation, causing the precise and efficient elimination of bacteria. Therefore, the MRI-guided SDT system shows extraordinary tissue penetration depth, drug concentration monitoring, morphology-transformation induced accumulation and improved treatment capacity toward drug-resistant bacteria.

Stromal cells promote chemoresistance of acute myeloid leukemia cells via activation of the IL-6/STAT3/OXPHOS axis.

BACKGROUND: Bone marrow stromal cells (BMSCs) are known to promote chemoresistance in acute myeloid leukemia (AML) cells. However, the molecular basis for BMSC-associated AML chemoresistance remains largely unexplored. METHODS: The mitochondrial oxidative phosphorylation (OXPHOS) levels of AML cells were measured by a Seahorse XFe24 cell metabolic analyzer. The activity of total or mitochondrial signal transducer and transcription activator 3 (STAT3) in AML cells was explored by flow cytometry and Western blotting. Real-time quantitative PCR, Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to analyze expression of interleukin 6 (IL-6) in the human BMSC line HS-5, and IL-6 was knocked out in HS-5 cells by CRISPR/Cas9 system. RESULTS: In this study, we observed that co-culturing with BMSCs heightened OXPHOS levels in AML cells, thus promoting chemoresistance in these cells. HS-5 cell-induced upregulation of OXPHOS is dependent on the activation of STAT3, especially on that of mitochondrial serine phosphorylated STAT3 (pS-STAT3) in AML cells. The relationship among pS-STAT3, OXPHOS, and chemosensitivity of AML cells induced by BMSCs was demonstrated by the STAT3 activator and inhibitor, which upregulated and downregulated the levels of mitochondrial pS-STAT3 and OXPHOS, respectively. Intriguingly, AML cells remodeled HS-5 cells to secrete more IL-6, which augmented mitochondrial OXPHOS in AML cells and stimulated their chemoresistance. IL-6 knockout in HS-5 cells impaired the ability of these cells to activate STAT3, to increase OXPHOS, or to promote chemoresistance in AML cells. CONCLUSIONS: BMSCs promoted chemoresistance in AML cells via the activation of the IL-6/STAT3/OXPHOS pathway. These findings exhibit a novel mechanism of chemoresistance in AML cells in the bone marrow microenvironment from a metabolic perspective.

Recent progress of therapeutic peptide based nanomaterials: from synthesis and self-assembly to cancer treatment.

Peptides have shown great potential in cancer treatment due to their good biocompatibility and low toxicity. However, the bioavailability and adverse immune response of peptides limit their further translation from bench to bedside. Over the past few decades, various peptide-based nanomaterials have been developed for drug delivery and cancer treatment. Compared with therapeutic peptides alone, self-assembled peptide nanomaterials have obvious advantages, such as improved stability and biodistribution for high-performance cancer therapy. In this review, we have described the synthesis, self-assembly and the anti-cancer application of therapeutic peptides and their conjugates, particularly polymer-peptide conjugates (PPCs).

Ultrasound-Activated Cascade Effect for Synergistic Orthotopic Pancreatic Cancer Therapy.

In some malignant tumor, especially for pancreatic tumor, poor solid-tumor penetration of nanotherapeutics impedes their treatment efficacy. Herein, we develop a polymer-peptide conjugate with the deep tissue penetration ability, which undergoes a cascade process under ultrasound (US), including (1) the singlet oxygen 1O2 is generated by P18, (2) the thioketal bond is cleaved by the 1O2, (3) the departure of PEG chains leads to the in situ self-assembly, and (4) the resultant self-assembled PK nanoparticles show considerable cellular internalization. Owing to the synergistic effect of US on increasing the membrane permeability, the endocytosis and lysosome escape of PK nanoparticles are further enhanced effectively, resulting in the improved therapeutic efficacy. Thanks to the high tissue-penetrating depth and spatial precision of US, PTPK presents enhanced tumor inhibition in an orthotopic pancreatic tumor model. Therefore, the US-activated cascade effect offers a novel perspective for precision medicine and disease theranostics.

Near-Infrared Laser-Triggered In Situ Dimorphic Transformation of BF2-Azadipyrromethene Nanoaggregates for Enhanced Solid Tumor Penetration.

The shape of a drug delivery system impacts its in vivo behavior such as circulation time, accumulation, and penetration. Considering the advantages of functional dyes in bioapplications, we synthesize a class of nanoaggregates based on BF2-azadipyrromethene (aza-BODIPY) dyes, which can realize long blood circulation and deep tumor penetration simultaneously in vivo through morphological transformation modulated by a near-infrared (NIR) laser. First, when the temperature increases, the wormlike nanofibers of the aza-BODIPY-1 aggregate, possessing a long blood circulation time, can be transformed into spherical nanoparticles, which are conducive to increasing the penetration in the solid tumor. Second, without any postmodification, the nanofibers exhibit an outstandingly narrow absorption band in the NIR spectral range, so that they possess ideal photothermal properties. Through 655 nm laser irradiation, the intrinsic photothermal effect causes a local temperature increase to ∼48 °C, realizing the transformation of 1-NFs to 1-NPs. Third, the morphological transformation is real-time detected by photoacoustic (PA) imaging. By monitoring the change of the PA signal at a specific wavelength, the in vivo deformation process of nanomaterials can be traced. Consequently, the in situ morphology transformation of aza-BODIPY-based nanomaterials can simultaneously realize long blood circulation and deep penetration, resulting in the enhanced antitumor outcome.

Photothermal-Promoted Morphology Transformation in Vivo Monitored by Photoacoustic Imaging.

The in situ construction of the nanoassembly has been demonstrated to improve the performance of bioactive molecules, but the control of the morphology of nanomaterials in vivo still remains a tremendous challenge. Herein, a photothermal-promoted morphology transformation (PMT) strategy is developed to accelerate the formation of nanomaterials for improving the biological performance of drug molecules. Compared with the spontaneous process, the rate of transformation increases by ∼4 times in the PMT process. Owing to increased assembly rate, the tumor accumulation of drugs is ∼2-fold than that without photo irradiation, which inhibits tumor growth effectively. More importantly, the chemical reassembly process in vitro and in vivo is monitored by the advanced ratiometric photoacoustic image, confirming the photoinduced transformation acceleration. Through the noninvasively artificial control on assembly dynamics in vivo, the PMT strategy provides a new insight for developing the intelligent theranostics.

Site-Specific Construction of Long-Term Drug Depot for Suppression of Tumor Recurrence.

Local tumor recurrence after surgical resection is a critical concern in cancer therapy, and the current treatments, such as postsurgical chemotherapy, still show undesired side effects. Here a nonimplant strategy (transformation induced localization, TIL) is presented to in situ construct long-term retentive drug depots, wherein the sustained drug release from fibrous drug depots results in highly efficient suppression of postsurgical local tumor relapse. The peptide-based prodrug nanoparticles show favorable tumor targeting and instantly reorganize into fibrous nanostructures under overexpressed enzyme, realizing the construction of long-term drug depot in the tumor site. After the resection surgery, the remnant cancer cells are still inhibited by the sustained drug release from the fibrous prodrug depot, effectively preventing postsurgical local recurrences. This TIL strategy shows great potential in cancer recurrence therapy and offers a novel perspective for constructing functional biomaterials in vivo.

Endogenous Reactive Oxygen Species-Triggered Morphology Transformation for Enhanced Cooperative Interaction with Mitochondria.

The morphology controlled molecular assemblies play vital roles in biological systems. Here we present endogenous reactive oxygen species (ROS)-triggered morphology transformation of polymer-peptide conjugates (PPCs) for cooperative interaction with mitochondria, exhibiting high tumor therapeutic efficacy. The PPCs are composed of (i) a ß-sheet-forming peptide KLVFF conjugated with poly(ethylene glycol) through ROS-cleavable thioketal, (ii) a mitochondria-targeting cytotoxic peptide KLAK, and (iii) a poly(vinyl alcohol) backbone. The self-assembled PPCs nanoparticles can enter cells and target mitochondria. Because of overgenerated ROS around mitochondria in most cancer cells, the thioketal linker can be cleaved, leading to transformation from nanoparticles to fibrous nanostructures. As a result, the locational nanofibers with exposure of KLAK exhibit enhanced multivalent cooperative interactions with mitochondria, which causes selective cytotoxicity against cancer cells and powerful tumor suppression efficacy in vivo. As the first example of ROS-triggered intracellular transformation, the locational assembly strategy in vivo may provide a new insight for disease diagnosis and therapy through enhanced interaction with targeting site.