Vitamin K2 ameliorates osteoarthritis by suppressing ferroptosis and extracellular matrix degradation through activation GPX4's dual functions.

Vitamin K2 (VK2) is an effective compound for anti-ferroptosis and anti-osteoporosis, and Semen sojae praeparatum (Dandouchi in Chinese) is the main source of VK2. Chondrocyte ferroptosis and extracellular matrix (ECM) degradation playing a role in the pathogenesis of osteoarthritis (OA). Glutathione peroxidase 4 (GPX4) is the intersection of two mechanisms in regulating OA progression. But no studies have elucidated the therapeutic effects and mechanisms of VK2 on OA. This study utilized an in vivo rat OA model created via anterior cruciate ligament transection (ACLT) and an in vitro chondrocyte oxidative damage model induced by TBHP to investigate the protective effects and mechanisms of action of VK2 in OA. Knee joint pain in mice was evaluated using the Von Frey test. Micro-CT and Safranin O-Fast Green staining were employed to observe the extent of damage to the tibial cartilage and subchondral bone, while immunohistochemistry and PCR were used to examine GPX4 levels in joint cartilage. The effects of VK2 on rat chondrocyte viability were assessed using CCK-8 and flow cytometry assays, and chondrocyte morphology was observed with toluidine blue and alcian blue staining. The impact of VK2 on intracellular ferroptosis-related markers was observed using fluorescent staining and flow cytometry. Protein expression changes were detected by immunofluorescence and Western blot analysis. Furthermore, specific protein inhibitors were applied to confirm the dual-regulatory effects of VK2 on GPX4. VK2 can increase bone mass and cartilage thickness in the subchondral bone of the tibia, and reduce pain and the OARSI score induced by OA. Immunohistochemistry results indicate that VK2 exerts its anti-OA effects by regulating GPX4 to delay ECM degradation. VK2 can inhibit the activation of the MAPK/NFκB signaling pathway caused by reduced expression of intracellular GPX4, thereby decreasing ECM degradation. Additionally, VK2 can reverse the inhibitory effect of RSL3 on GPX4, increase intracellular GSH content and the GSH/GSSG ratio, reduce MDA content, and rescue chondrocyte ferroptosis. The protective mechanism of VK2 may involve its dual-target regulation of GPX4, reducing chondrocyte ferroptosis and inhibiting the MAPK/NFκB signaling pathway to decelerate the degradation of the chondrocyte extracellular matrix.

A Novel Mechanism of hPRL-G129R, a Prolactin Antagonist, Inhibits Human Breast Cancer Cell Proliferation and Migration.

Prolactin (PRL) and its receptor, PRLR, are closely related to the occurrence and development of breast cancer. hPRL-G129R, an hPRLR antagonist, has been found to induce apoptosis in breast cancer cells via mechanisms currently unknown. Recent studies have indicated that PRLR exhibits dual functions based on its membrane/nucleus localization. In that context, we speculated whether hPRL-G129R is a dual-function antagonist. We studied the internalization of the hPRLR-G129R/PRLR complex using indirect immunofluorescence and Western blot assays. We found that hPRL-G129R not only inhibited PRLR-mediated intracellular signaling at the plasma membrane, but also blocked nuclear localization of the receptor in T-47D and MCF-7 cells in a time-dependent manner. Clone formation and transwell migration assays showed that hPRL-G129R inhibited PRL-driven proliferation and migration of tumor cells in vitro. Further, we found that increasing concentrations of hPRL-G129R inhibited the nuclear localization of PRLR and the levels of signal transducer and activator of transcription (STAT) 5 in tumor-bearing mice and hPRL-G129R also exerted an antiproliferative effect in vivo. These results indicate that hPRL-G129R is indeed a dual-function antagonist. This study lays a foundation for exploring and developing highly effective agents against the proliferation and progression of breast malignancies.

Dissecting transcription of the 8q24-MYC locus in prostate cancer recognizes the equilibration between androgen receptor direct and indirect dual-functions.

BACKGROUND: Androgen receptor (AR) activation and repression dual-functionality only became known recently and still remains intriguing in prostate cancer (PCa). MYC is a prominent oncogene that functionally entangles with AR signaling in PCa. Further exploration of AR regulatory mechanisms on MYC gene transcription bears clinical and translation significance. METHODS: Bioinformatics analysis of PCa cell line and clinical RNA-Seq and ChIP-Seq (chromatin immunoprecipitation-sequencing) datasets to anchor interactions of AR and MYC transcriptional networks. ChIP-qPCR and 3C (chromosome conformation capture) analyses to probe MYC distal regulation by AR binding sites (ABSs). CRISPR/Cas9-mediated genome-editing to specify functions of ABS within the 8q24-MYC locus on androgen-mediated MYC transcription. Global FoxA1 and HoxB13 distribution profiling to advance AR transcriptional mechanisms. RESULTS: Here we recognize AR bi-directional transcription mechanisms by exploiting the prominent 8q24-MYC locus conferring androgen hyper-sensitivity. At ~ 25 Kb downstream of the MYC gene, we identified an undefined ABS, P10. By chromatin analyses, we validated androgen-dependent spatial interaction between P10 and MYC-Promoter (MYC-Pro) and temporal epigenetic repression of these MYC-proximal elements. We next designed a CRISPR/Cas9-mediated double genomic knock-out (KO) strategy to show that P10-KO slightly lessened androgen-elicited MYC transrepression in LNCaP-AR cells. In similar genomic editing assays, androgen-mediated MYC repression became slightly deepened upon KO of P11, an ABS in the PVT1 gene locus highly enriched in AR-binding motifs and peaks. We also investigated multiple ABSs in the established PCAT1 super-enhancer that distally interacts with MYC-Pro for transactivation, with each KO pool consistently shown to relieve androgen-elicited MYC repression. In the end, we systemically assessed androgen effects in the 8q24-MYC locus and along PCa genome to generalize H3K27ac and BRD4 re-distribution from pioneer factors (FoxA1 and HoxB13) to AR sites. CONCLUSION: Together, we reconciled these observations by unifying AR dual-functions that are mechanistically coupled to and equilibrated by co-factor redistribution.

Androgen receptor and MYC transcriptomes are equilibrated in multilayer regulatory circuitries in prostate cancer.

BACKGROUND: The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region. METHODS: RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites. RESULTS: In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site. CONCLUSION: Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.

Flexible Wearable Electronic Fabrics with Dual Functions of Efficient EMI Shielding and Electric Heating for Triboelectric Nanogenerators.

Traditional conductive fabrics are prepared by the synthesis of conductive polymers and the coating modification of metals or carbon black conductive materials. However, the conductive fabrics cause a significant decline in performance after washing or mechanical wear, which limits their application. Moreover, the single function of the traditional conductive fabric is also the reason that limits its wide application. In order to prepare a wearable, stable, high-performance, washable, multifunctional conductive fabric, we have carried out related research. In this work, polydopamine was used as a bonding layer, an adsorption reduction layer, and a protective layer to improve the bonding between silver nanoparticles and carbon nanotubes (CNTs) on the polyester fabric surface so as to prepare a multifunctional conductive fabric with a high-stability "sandwich" structure, in which a Ag-NPS@CNT structure acting as an intermediate conductive layer formed on the inner layer PDA@CNT by electroless silver plating and the outermost layer PDA@CNT coated on the surface of the intermediate conductive layer by the impregnation-drying method. The sheet resistance of an E-Fabric can reach 2.11 Ω/□ due to the uniform and dense conductive path formed by the special structure Ag-NPs@CNT. At a low voltage of 1.5 V, the E-Fabric can reach 117 °C in 50 s and remain stable. The electrical conductivity and current heating properties of the E-Fabric remain good even after multiple washing or bending tests. Due to its stable and outstanding electrical conductivity, the E-Fabric has an electromagnetic shielding efficiency (SET) of 35.3 dB in the X-band (8.2-12.4 GHz). In addition, E-Fabric-based spin-coated poly(methyl methacrylate) or polydimethylsiloxane electrodes exhibit excellent performance in nanogenerators. Through the low-frequency friction of the human body, transient voltages up to 4 V can be generated from a 2 cm × 2 cm electrode sample. The output power of a single generator can reach about 12 nW/cm2. Therefore, an E-Fabric is considered to have great potential in the fields of electric heating, electromagnetic shielding, and smart wearable devices.

Development of novel hydrogen sulfide depletion aided platform for photodynamic therapy with enhanced anticancer performance.

Hydrogen sulfide (H2S) as a key fundamental gasotransmitter regulates various biological processes, and the incontrollable H2S is essentially associated with the occurrence and development of multiple diseases, including cancers. Photodynamic therapy (PDT), as an invasive tumor treatment technology, has also attracted great attentions. Due to the key role of elevated H2S in cancers, integrating H2S depletion/recognition and PDT should be an effective strategy to enhance anticancer performance. In this work, we report a H2S depletion aided PDT platform (3RAX-NBD) by the chemical ligation of 3RAX and NBD. 3RAX-NBD can react rapidly with H2S and generate a novel 3RAX derivative compound 3 with increased fluorescence in vitro and in vivo. More notably, 3RAX-NBD can effectively kill multiple cancer cells through in situ irradiation, and 3RAX-NBD also has prominent anticancer effects on 4 T1 tumor-bearing BALB/c female mice with no notably toxic side effects. We believe that our H2S depletion aided PDT platform may provide a powerful tool for studying the key roles of H2S in diseases, and also give another promising candidate for cancer treatment.

New insights into MAIT cells in autoimmune diseases.

Mucosal-associated invariant T (MAIT) cells are resident T cells that express semi-invariant TCR chains and are restricted by monomorphic major histocompatibility complex (MHC) class I-related molecules (MR1). MAIT cells can be activated by microbial-specific metabolites (MR1-dependent mode) or cytokines (MR1-independent mode). Activated MAIT cells produce chemokines, cytotoxic molecules (granzyme B and perforin), and proinflammatory cytokines (IFN-γ, TNF-α, and IL-17), to clear pathogens and target infected cells involved in the pro-inflammatory, migratory, and cytolytic properties of MAIT cells. MAIT cells produce pro-inflammatory cytokines in the target organs of autoimmune diseases and contribute to the development and progression of autoimmune diseases. This article reviews the biological characteristics, activation mechanism, dynamic migration, and dual functions of MAIT cells, and focuses on the mechanism and potential application of MAIT cells in the early diagnosis, disease activity monitoring, and therapeutic targets of autoimmune diseases, to lay a foundation for future research.

A novel ratiometric nanoprobe based on copper nanoclusters and graphitic carbon nitride nanosheets using Ce(III) as crosslinking agent and aggregation-induced effect initiator for sensitive detection of hydrogen peroxide and glucose.

Herein, glutathione-capped copper nanoclusters (CuNCs) and graphitic carbon nitride nanosheets (g-C3N4 NSs) were synthesized by a facile one-pot chemical reduction and directly thermal pyrolysis following ultrasonic exfoliation approaches, respectively. The introduction of Ce(III) (Ce3+) played dual functions in constructing a fluorescence-enhanced ratiometric nanoprobe (g-C3N4 NSs-Ce3+-CuNCs), i.e., triggering aggregation-induced emission of CuNCs and conjugating g-C3N4 NSs with CuNCs by virtue of electrostatic and coordination interactions. The as-fabricated nanohybrid displayed 460 and 625 nm dual-emitting peaks, attributing to the emission of g-C3N4 NSs and CuNCs, respectively. Upon addition of H2O2, the 625 nm emission was dramatically quenched, whereas the 460 nm emission remained nearly unchanged, thereby causing obvious color changes from purple to blue under a 365-nm UV lamp. A ratiometric fluorescent assay, based on g-C3N4 NSs-Ce3+-CuNCs, was devised for sensitive and visual detection of H2O2, which spanned the linear range of 2-100 µM with a detection limit of 0.6 µM. In the presence of glucose oxidase, the ratiometric nanoprobe could be simultaneously employed to detect glucose across the linear range of 1.6-320 µM with a detection limit of 0.48 µM. In milk and human serum samples, the fortified recoveries for H2O2 and glucose by the nanoprobe were in the range of 95.5-103.6% with RSDs <3.8%. The real detection levels for glucose are consistent with those by a standard glucometer. As such, the ratiometric nanoprobe offers a promising methodology for several practical applications, such as point-of-care diagnosis and workplace health evaluations.

Dual roles of the caspase-11 non-canonical inflammasome in inflammatory bowel disease.

Inflammation is a two-step process comprising the first priming step that prepares inflammatory responses and the second triggering step that activates inflammatory responses. The key feature of the triggering step is the activation of inflammasomes and intracellular inflammatory protein complexes that provide molecular platforms to activate inflammatory signal transduction cascades. Although canonical inflammasomes have been well demonstrated to be actively involved in numerous human diseases, the roles of the recently identified non-canonical inflammasomes are largely unknown. However, recent studies have demonstrated the emerging roles of the caspase-11 non-canonical inflammasome in various human inflammatory diseases, ultimately providing strong evidence that the caspase-11 non-canonical inflammasome is a key player in the pathogenesis of various human diseases. Here, we comprehensively reviewed the regulatory roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory bowel disease (IBD) and its underlying mechanisms. Overall, this review highlights the current understanding of the regulatory roles of the caspase-11 non-canonical inflammasome in IBD and may provide insight into new strategies for preventing and treating IBD and caspase-11 non-canonical inflammasome-driven diseases.

Origins and evolution of the dual functions of strigolactones as rhizosphere signaling molecules and plant hormones.

Strigolactones (SLs) play roles as a class of plant hormones and rhizosphere signaling chemicals that induce hyphal branching of arbuscular mycorrhizal fungi and seed germination of parasitic plants. Therefore, SLs have dual functions. Recent progress in genome sequencing and genetic studies of bryophytes and algae has begun to shed light on the origin and evolution of these two functions of SLs.

One-step zwitterionization and quaternization of thick PDMAEMA layer grafted through subsurface-initiated ATRP for robust antibiofouling and antibacterial coating on PDMS.

In this work, we demonstrate the grafting of thick poly((2-dimethylamino) ethyl methacrylate) (PDMAEMA) layer on PDMS via subsurface-initiated atom transfer radical polymerization (SSI-ATRP). The self-migration of DMAEMA monomers into the subsurface of PDMS is proven to be the dominant factor for the success of SSI-ATRP. The as-prepared thick microscale graft layer on PDMS shows much better abrasion resistance than nanoscale graft layer obtained by conventional surface-initiated atom transfer radical polymerization (SI-ATRP) under identical condition. Taking advantage of the tertiary amines of PDMAEMA, the simultaneous zwitterionization and quaternization of the PDMAEMA thick layer is realized through a facile one-step process. The effect of zwitterionization and quaternization degree on the antibiofouling and antibacterial properties is investigated. The results show that a relatively high zwitterionization degree (75 mol%) and a low quaternization degree (25 mol%) exhibit a good well-balanced effect on both fouling repellence and bactericidal activity. This work may lead to the development of robust bifunctional antibiofouling and antibacterial surfaces via SSI-ATRP strategy.

A Full-Spectrum Metal-Free Porphyrin Supramolecular Photocatalyst for Dual Functions of Highly Efficient Hydrogen and Oxygen Evolution.

A full-spectrum (300-700 nm) responsive porphyrin supramolecular photocatalyst with a theoretical solar spectrum efficiency of 44.4% is successfully constructed. For the first time, hydrogen and oxygen evolution (40.8 and 36.1 µmol g-1 h-1 ) is demonstrated by a porphyrin photocatalyst without the addition of any cocatalysts. The strong oxidizing performance also presents an efficient photodegradation activity that is more than ten times higher than that of g-C3 N4 for the photodegradation of phenol. The high photocatalytic reduction and oxidation activity arises from a strong built-in electric field due to molecular dipoles of electron-trapping groups and the nanocrystalline structure of the supramolecular photocatalyst. The appropriate band structure of the supramolecular photocatalyst adjusted via the highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels of the porphyrin gives rise to thermodynamic driving potential for H2 and O2 evolution under visible light irradiation. Controlling the energy band structure of photocatalysts via the ordered assembly of structure-designed organic molecules could provide a novel approach for the design of organic photocatalysts in energy and environmental applications.

Hydroxyapatite nanowires modified polylactic acid membrane plays barrier/osteoinduction dual roles and promotes bone regeneration in a rat mandible defect model.

Periodontitis is an inflammatory disease leading to tooth loss, alveolar bone absorption and disorder of masticatory function. Guided tissue regeneration (GTR) is one of the most common strategies for regeneration of lost periodontium. During surgical process, barrier membranes, and osteoinductive/osteoconductive materials should be placed, respectively, which may increase risks of infection, bleeding, and difficulty of operation. Here, we introduced a new kind of hydroxyapatite (HAp) nanowires modified polylactic acid (PLA) membrane to achieve barrier/osteoinduction dual functions. The physicochemical property measurements suggested the two sides of the composite membrane did not change after composition. Then a rat mandibular defect model was established to investigate barrier and osteoinductive effects of this composite membrane. After implantation, effects of functional cells engraftment and osteoinduction were detected by scanning electron microscope (SEM), histomorphometric measurement, immunohistochemical staining, and Micro-CT scanning. SEM images showed HAp side engrafted more cells than PLA side. The result of immunohistochemical staining suggested HAp/PLA promoted the expression of bone-related markers. Moreover, there were more newly formed bones with better quality in HAp/PLA group. Therefore, this composite membrane would be a promising biomaterial in tissue engineering for bone regeneration due to its barrier/osteoinduction dual functions. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3099-3110, 2018.

Ion-Selective Polyamide Acid Nanofiber Separators for High-Rate and Stable Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries have attracted great attention because of their high energy density and high theoretical capacity. However, the "shuttle effect" caused by the dissolution of polysulfides in liquid electrolytes severely hinders their practical applications. Herein, we originally propose a carboxyl functional polyamide acid (PAA) nanofiber separator with dual functions for inhibiting polysulfide transfer and promoting Li+ migration via a one-step electrospinning synthesis method. Especially, the functional groups of -COOH in PAA separators provide an electronegative environment, which promotes the transport of Li+ but suppresses the migration of negative polysulfide anions. Therefore, the PAA nanofiber separator can act as an efficient electrostatic shield to restrict the polysulfide on the cathode side, while efficiently promoting Li+ transfer across the separator. As a result, an ultralow decay rate of only 0.12% per cycle is achieved for the PAA nanofiber separator after 200 cycles at 0.2 C, which is less than half that (0.26% per cycle) of the commercial Celgard separator.

Hydroxyapatite nanobelt/polylactic acid Janus membrane with osteoinduction/barrier dual functions for precise bone defect repair.

Controllable osteoinduction maintained in the original defect area is the key to precise bone repair. To meet the requirement of precise bone regeneration, a hydroxyapatite (HAp) nanobelt/polylactic acid (PLA) (HAp/PLA) Janus membrane has been successfully prepared in this study by coating PLA on a paper-like HAp nanobelt film by a casting-pervaporation method. The Janus membrane possesses dual functions: excellent osteoinduction from the hydrophilic HAp nanobelt side and barrier function originating from the hydrophobic PLA film. The cell viability and osteogenic differentiation ability of human adipose-derived stem cells (hADSCs) on the Janus membrane were assessed. The in vitro experimental results prove that the HAp nanobelt side presents high cell viability and efficient osteoinduction without any growth factor and that the PLA side can prohibit cell attachment. The in vivo repair experiments on a rat mandible defect model prove that the PLA side can prevent postoperative adhesion between bone and adjacent soft tissues. Most importantly, the HAp side has a strong ability to promote defect repair and bone regeneration. Therefore, the HAp/PLA Janus membrane will have wide applications as a kind of tissue engineering material in precise bone repair because of its unique dual osteoinduction/barrier functions, biocompatibility, low cost, and its ability to be mass-produced. STATE OF SIGNIFICANCE: Precise bone defect repair to keeping tissue integrity and original outline shape is a very important issue for tissue engineering. Here, we have designed and prepared a novel HAp/PLA Janus membrane using a casting-pervaporation method to form a layer of PLA film on paper-like HAp nanobelt film. HAp nanobelt side of the Janus membrane can successfully promote osteogenic differentiation. PLA side of the Janus membrane exhibits good properties as a barrier for preventing the adhesion of cells in vitro. Mandible repair experiments in vivo have shown that the HAp/PLA Janus membrane can promote rat mandible repair on the HAp side and can successfully prevent postoperative adhesion on the PLA side at the same time. Therefore, the HAp/PLA Janus membrane with its osteoinduction/barrier dual functions can be applied to repair bone defect precisely.

Thermo-Magnetoresponsive Dual Function Nanoparticles: An Approach for Magnetic Entrapable-Releasable Chitosan.

Magnetic polymeric nanoparticles can be used for selective binding in a magnetic field. However, as the magnetic nanoparticles (MAG) are stabilized with polymers, the separation of the MAG from the polymer chains after use is difficult. This work proposes a combination of a thermoresponsive polymer with MAG allows for the as-desired simple removal of MAG from the polymer chains. For this, chitosan (CS) was conjugated with thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) and antibody (Ab) together with the physisorbed MAG as a thermo-magneto dual functional material. The key synthesis steps are (i) radical polymerization of NIPAM in the presence of mercaptoacetic acid so that the PNIPAM obtained contains terminal carboxylic acid groups (PNIPAM-COOH), (ii) the CS-N-hydroxysuccinamide water-based system that allows conjugation of CS with PNIPAM-COOH in water at room temperature, and (iii) the weak interaction between MAG and the CS chain. As a model application, CS is conjugated with the antirecombinant Leptospirosis Ab (rLipL32) to allow the selective binding and collection of the target antigen under the dual functions. This is the first demonstration of a simple but effective solution for MAG exclusion from the target molecules and will be practical for diverse applications, such as diagnosis, sensors, filtration, etc.

Autophagy as an emerging therapy target for ovarian carcinoma.

Autophagy is a conserved cellular self-digestion pathway for maintenance of homeostasis under basal and stressed conditions. Autophagy plays pivotal roles in the pathogenesis of many diseases, such as aging-related diseases, autoimmune diseases, cardiovascular diseases, and cancers. Of special note is that accumulating data suggest an intimate relationship between autophagy and ovarian carcinoma. Autophagy is well identified to act as either as a tumor-suppressor or as a tumor-promoter in ovarian carcinoma. The exact function of autophagy in ovarian carcinoma is highly dependent on the circumstances of cancer including hypoxic, nutrient-deficient, chemotherapy and so on. However, the mechanism underlying autophagy associated with ovarian carcinoma remains elusive, the precise role of autophagy in ovarian carcinoma also remains undetermined. In this review, we tried to sum up and discuss recent research achievements of autophagy in ovarian cancer. Moreover, waves of novel therapies ways for ovarian carcinoma based on the functions of autophagy were collected.