Indoxyl sulphate-TNFα axis mediates uremic encephalopathy in rodent acute kidney injury.

Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.

Electrospun fibers based anisotropic silk fibroin film with photodynamic antibacterial therapy for S. aureus infected wound healing.

Bacterial infection has been regarded as a life-threatening problem in clinic. In addition to screening of new antibiotics, it is important to develop highly effective antibacterial materials against antibiotic resistance with capacities on modulating chronic inflammation. Herein, aligned Chlorin e6 (Ce6) conjugated silk fibroin electrospun fibers were successfully fabricated on silk fibroin based film via electrospining to achieve effective photodynamic antibacterial activities under near infrared (NIR) irradiation. The aligned electrospun fiber based film composite (SFCF@Film) exhibited good mechanical properties and desirable hemocompatibility. SFCF@Film provided a promising guidance cue for directing cell orientation and promoting cell growth. Significantly, SFCF@Film effectively generated ROS under NIR irradiation to kill S. aureus for treating wound infections within 10 min and promoted M2 polarization of macrophages for wound healing at later stage. Therefore, we believed that this engineered bioscaffold can be a powerful strategy for handling wound infection.

Exosome inspired photo-triggered gelation hydrogel composite on modulating immune pathogenesis for treating rheumatoid arthritis.

Although exosome therapy has been recognized as a promising strategy in the treatment of rheumatoid arthritis (RA), sustained modulation on RA specific pathogenesis and desirable protective effects for attenuating joint destruction still remain challenges. Here, silk fibroin hydrogel encapsulated with olfactory ecto-mesenchymal stem cell-derived exosomes (Exos@SFMA) was photo-crosslinked in situ to yield long-lasting therapeutic effect on modulating the immune microenvironment in RA. This in situ hydrogel system exhibited flexible mechanical properties and excellent biocompatibility for protecting tissue surfaces in joint. Moreover, the promising PD-L1 expression was identified on the exosomes, which potently suppressed Tfh cell polarization via inhibiting the PI3K/AKT pathway. Importantly, Exos@SFMA effectively relieved synovial inflammation and joint destruction by significantly reducing T follicular helper (Tfh) cell response and further suppressing the differentiation of germinal center (GC) B cells into plasma cells. Taken together, this exosome enhanced silk fibroin hydrogel provides an effective strategy for the treatment of RA and other autoimmune diseases.

Chitosan Lactate Particles for Non-Compression Hemostasis on Hepatic Resection.

The liver is the most complex vascular anatomy of all human organs, with extremely rich blood flow and fragile texture. Massive liver bleeding usually occurs after traumatic liver injury, causing severe systematic issues. Thus, bleeding control is critical in hindering mortality rates and complications in patients. In this study, non-compression hemostasis materials based on chitosan lactate particles (CLP) were developed for handling liver bleeding after injuries. CLP showed good blood biocompatibility and antibacterial performance against S. aureus. Taking advantage of the vital capacity of CLP to promote red blood cell and platelet adhesion, CLP exhibited in vivo homeostasis properties as non-compression hemostasis materials for traumatic liver injury, both in SD rats, New Zealand rabbits, or in beagles. Whereas CLP has better hemostasis than the commercial hemostatic agent Celox™.

Progress in methods for evaluating Schwann cell myelination and axonal growth in peripheral nerve regeneration via scaffolds.

Peripheral nerve injury (PNI) is a neurological disorder caused by trauma that is frequently induced by accidents, war, and surgical complications, which is of global significance. The severity of the injury determines the potential for lifelong disability in patients. Artificial nerve scaffolds have been investigated as a powerful tool for promoting optimal regeneration of nerve defects. Over the past few decades, bionic scaffolds have been successfully developed to provide guidance and biological cues to facilitate Schwann cell myelination and orientated axonal growth. Numerous assessment techniques have been employed to investigate the therapeutic efficacy of nerve scaffolds in promoting the growth of Schwann cells and axons upon the bioactivities of distinct scaffolds, which have encouraged a greater understanding of the biological mechanisms involved in peripheral nerve development and regeneration. However, it is still difficult to compare the results from different labs due to the diversity of protocols and the availability of innovative technologies when evaluating the effectiveness of novel artificial scaffolds. Meanwhile, due to the complicated process of peripheral nerve regeneration, several evaluation methods are usually combined in studies on peripheral nerve repair. Herein, we have provided an overview of the evaluation methods used to study the outcomes of scaffold-based therapies for PNI in experimental animal models and especially focus on Schwann cell functions and axonal growth within the regenerated nerve.

The success of biomaterial-based tissue engineering strategies for peripheral nerve regeneration.

Peripheral nerve injury is a clinically common injury that causes sensory dysfunction and locomotor system degeneration, which seriously affects the quality of the patients' daily life. Long gapped defects in large nerve are difficult to repair via surgery and limited donor source of autologous nerve greatly challenges the successful nerve repair by transplantation. Significantly, remarkable progress has been made in repairing the peripheral nerve injury using artificial nerve grafts and a variety of products for peripheral nerve repair have emerged been approved globally in recent years. The raw materials of these commercial products includes natural/synthetic polymers, extracellular matrix. Despite a lot of effort, the desirable functional recovery still remains great challenges in long gapped nerve defects. Thus this review discusses the recent development of tissue engineering products for peripheral nerve repair and the design of bionic grafts improving the local microenvironment for accelerating nerve regeneration against locomotor disorder, which may provide potential strategies for the repair of long gaps or thick nerve defects by multifunctional biomaterials.

Recent advances in NIR-II fluorescence based theranostic approaches for glioma.

Gliomas are among the most common malignant tumors in the central nervous system and lead to poor life expectancy. However, the effective treatment of gliomas remains a considerable challenge. The recent development of near infrared (NIR) II (1000-1700 nm) theranostic agents has led to powerful strategies in diagnosis, targeted delivery of drugs, and accurate therapy. Because of the high capacity of NIR-II light in deep tissue penetration, improved spatiotemporal resolution can be achieved to facilitate the in vivo detection of gliomas via fluorescence imaging, and high contrast fluorescence imaging guided surgery can be realized. In addition to the precise imaging of tumors, drug delivery nano-platforms with NIR-II agents also allow the delivery process to be monitored in real-time. In addition, the combination of targeted drug delivery, photodynamic therapy, and photothermal therapy in the NIR region significantly improves the therapeutic effect against gliomas. Thus, this mini-review summarizes the recent developments in NIR-II fluorescence-based theranostic agents for glioma treatment.

Regenerative Role of T Cells in Nerve Repair and Functional Recovery.

The immune system is essential in the process of nerve repair after injury. Successful modulation of the immune response is regarded as an effective approach to improving treatment outcomes. T cells play an important role in the immune response of the nervous system, and their beneficial roles in promoting regeneration have been increasingly recognized. However, the diversity of T-cell subsets also delivers both neuroprotective and neurodegenerative functions. Therefore, this review mainly discusses the beneficial impact of T-cell subsets in the repair of both peripheral nervous system and central nervous system injuries and introduces studies on various therapies based on T-cell regulation. Further discoveries in T-cell mechanisms and multifunctional biomaterials will provide novel strategies for nerve regeneration.

Silk-inspired fiber implant with multi-cues enhanced bionic microenvironment for promoting peripheral nerve repair.

Successful repair and desirable functional recovery of large-gap nerve injuries using artificial nerve implants remains a significant clinical challenge. The beneficial bionic microenvironment within scaffolds can significantly promote the outgrowth of newborn nerve tissues after implantation. Herein, we developed an aligned silk-inspired fiber scaffold (RGD@ASFFs) with a synergistic effect of an extracellular matrix mimicking physical cues and RGD (Arg-Gly-Asp) signals to provide an enhanced cell-friendly microenvironment for repairing large-gap peripheral nerve injuries. The topographic alignment of the methacrylated silk fibroin electrospun fibers effectively facilitated axonal guidance and oriented Schwann cell growth. Importantly, the mechanical cue combined with cell adhesion signals provided by RGD peptides further triggered enriched myelination of Schwann cells by nuclear translocation of Yes-associated protein 1 (YAP) to secrete neurotrophins to support axonal growth. Moreover, benefiting from improved neuronal extension and re-myelination, promising motor function recovery in vivo was achieved by RGD@ASFFs, which is comparable to that of autografts. Thus, the design of this engineered bionic scaffold is a powerful strategy for peripheral nerve defect repair.

Brain-Targeted Dual Site-Selective Functionalized Poly(ß-Amino Esters) Delivery Platform for Nerve Regeneration.

Brain injuries are devastating central nervous system diseases, resulting in cognitive, motor, and sensory dysfunctions. However, clinical therapeutic options are still limited for brain injuries, indicating an urgent need to investigate new therapies. Furthermore, the efficient delivery of therapeutics across the blood-brain barrier (BBB) to the brain is a serious problem. In this study, a facile strategy of dual site-selective functionalized (DSSF) poly(ß-amino esters) was developed using bio-orthogonal chemistry for promoting brain nerve regeneration. Fluorescence colocalization studies demonstrated that these proton-sponge DSSF poly(ß-amino esters) targeted mitochondria through electrostatic interactions. More importantly, this delivery system could effectively accumulate in the injured brain sites and accelerate the recovery of the injured brain. Finally, this DSSF poly(ß-amino esters) platform may provide a new methodology for the construction of dual regioselective carriers in protein/peptide delivery and tissue engineering.

Anisotropic Silk-Inspired Nerve Conduit with Peptides Improved the Microenvironment for Long-Distance Peripheral Nerve Regeneration.

A lack of effective bioactivity to create a desirable microenvironment for peripheral nerve regeneration has been challenging in successful treatment of long-distance injuries using nerve guidance conduits (NGCs) clinically. Herein, we developed a silk-inspired phototriggered gelation system combining dual therapeutic cues of anisotropic topography and adhesive ligands for improving peripheral nerve regeneration. Importantly, enhanced cell recruitment and myelination of Schwann cells were successfully achieved by the Arg-Gly-Asp (RGD)-peptide-immobilized hydrogel scaffolds to promote axon growth. Moreover, as the orientated growth of Schwann cells and rapid axon growth were facilitated by aligned grooved micropatterns, this multifunctional bioactive system provides remarkable nerve regeneration with function recovery for long-distance nerve injury. Therefore, this bioengineered silk-inspired nerve guidance conduit delivers a platform for desirable peripheral nerve repair.

Light-Triggered Adhesive Silk-Based Film for Effective Photodynamic Antibacterial Therapy and Rapid Hemostasis.

Successful control of massive hemorrhage in deep wounds with irregular shape and low elasticity still remains great challenges in the clinic. As the wound sites are usually at risk of bacterial infection, it is necessary to design an ideal hemostatic agent with rapid hemostasis and excellent antibacterial activity. In this study, we developed a light responsive hemostatic film for effective handling of liver bleeding with promising photodynamic therapy against S. aureus onnear infrared (NIR) irradiation. Based on silk fibroin, the film exhibited desirable biocompatibility and mechanical property as a hemostat tape. Significantly, the film tape achieved excellent tissue adhesion and hemostasis in vivo within 2 min of UV exposure, which would have a great potential as a multifunctional biomedical material in the field of tissue repair such as wound healing, bone repair, and nerve regeneration.

Stable antibacterial polysaccharide-based hydrogels as tissue adhesives for wound healing.

Adhesion to the surface of moist, dynamic, biological tissues is important in many fields. Currently, tissue adhesives commonly used in clinical practice remain far from ideal, exhibiting either poor tissue compatibility or weak tissue adhesion. Here, we designed biocompatible hydrogels comprising polysaccharides with polyacrylamide and exhibiting promising cytocompatibility, antibacterial activity, and excellent tissue adhesion. Alginate/chitosan-based hydrogels covalently cross-linked to the tissue surface in order to achieve admirable tissue adhesion. Additionally, the mechanical properties of the hydrogels were significantly enhanced with the addition of polyacrylamide, which synergistically promoted their enhanced adhesion. Importantly, the hydrogels exhibited good biocompatibility and reasonable antibacterial activity that promoted wound recovery during use as wound dressings. These results suggested the efficacy of the developed tissue adhesives for applications in biomedical fields, as well as broadening potential hydrogel use in tissue engineering.

Freestanding Hyaluronic Acid/Silk-Based Self-healing Coating toward Tissue Repair with Antibacterial Surface.

Developing coatings with multifunctional and biocompatible properties to enhance tissue wound regeneration is preferably applied clinically. Consequently, the freestanding and self-healing coatings were formed with the employment of the layer-by-layer (LbL) self-assembly. The coatings comprise beta-cyclodextrin-modified silk fibroin (SCD) and adamantane-modified hyaluronic acid (HAD) on the basis of the interactions between the host and the guest. The self-healing and freestanding capabilities allow the coatings to easily and repeatedly repair external mechanical damage and could be pulled off substrate. More importantly, the coatings have admirable antibacterial activity and biocompatibility. Moreover, the proliferation of cells and the myelination of Schwann cells are enhanced. Thus, we believe that the multifunctional coatings will have great potential in tissue engineering, especially for nerve regeneration.

Investigation of the Viscoelastic Behavior Variation of Glass Mat Thermoplastics (GMT) in Compression Molding.

Compression molding is a lightweight technology that allows to preserve fiber length and retain better mechanical properties compared to injection molding. In compression molding development, a suitable material such as glass fiber mat thermoplastics (GMT) is often used. However, because of the complicated micro-structure of the fibers and the fiber⁻resin matrix interactions, it is still quite challenging to understand the mechanism of compression molding and it is very difficult to obtain a uniformly compressed GMT product. In this study, we propose a method to measure the rheological properties of GMT through a compression system. Specifically, we utilized a compression molding system to record the relation between the loading force and the displacement. This quantitative information was used to estimate the power-law index and viscoelastic parameters and predict viscosity. Moreover, the estimated viscoelastic parameters of GMT were implemented into Moldex3D to evaluate the flow behavior under compression. The results showed that the trend of the loading force variation was consistent in numerical simulation and experiments. However, at the final stage of compression molding, the experimental loading force was much higher than that estimated by simulation. To find out the mechanism causing this deviation, a series of studies were performed. Through TGA measurement, we found that the fiber content of the center portion of the compressed part increased from 63% to 85% during compression. This was expected, as a result of the fiber⁻polymer matrix separation effect. This fiber⁻polymer matrix separation effect influenced the power-law index and rheological parameters of GMT, making them fluctuate. Specifically, the power-law index changed from 1.0 to 0.62. These internal changes of the rheological properties further induced a much higher loading force in the real experimental GMT system. We further verified the rheological properties variation using pure polyamide (PA) and found that since there is no fiber⁻polymer matrix interactions the power-law index and curve-fitting rheological parameters were almost constant. The mechanism causing the deviation was therefore validated.

Population analysis to increase the robustness of molecular computational identification and its extension into the near-infrared for substantial numbers of small objects.

The first population analysis is presented for submillimetric polymer beads which are tagged with five multi-valued logic gates, YES, 2YES + PASS 1, YES + PASS 1, YES + 2PASS 1 and PASS 1 with H+ input, 700 nm near-infrared fluorescence output and 615 nm red excitation light as the power supply. The gates carry an azaBODIPY fluorophore and an aliphatic tertiary amine as the H+ receptor where necessary. Each logic tag has essentially identical emission characteristics except for the H+-induced fluorescence enhancement factors which consistently map onto the theoretical predictions, after allowing for bead-to-bead statistical variability for the first time. These enhancement factors are signatures which identify a given bead type within a mixed population when examined with a 'wash and watch' protocol under a fluorescence microscope. This delineates the scope of molecular computational identification (MCID) for encoding objects which are too small for radiofrequency identification (RFID) tagging.

[Effect of long-term treatment of Wuzhi tablet on the expression and activity of cytochrome P450 3A in rats].

The study aims to evaluate the effect of long-term pretreatment of the rat with Wuzhi tablet（WZ） on hepatic and intestinal CYP3A mRNA and protein expression and activity. Male Sprague-Dawley rats were orally administered of midazolam (2 mg·kg-1) with or without 14 days of pretreatment of WZ (0.25 g·kg-1) to determine CYP3A activity. Meanwhile, RNA and protein of rats liver and intestine samples were prepared 24 h after the last dose of 14 days of WZ treatment to determine CYP3A mRNA and protein expression. Long-term treatment of WZ increased the mRNA expression of hepatic Cyp3a1, Cyp3a9 and intestinal Cyp3a9 by 54.6%, 188.3%（P < 0.05） and 48.2%（P < 0.05）, respectively; and increased the protein expression of hepatic CYP3A by 43.2%. However, after long-term treatment of WZ, the AUC of orally administered of midazolam in the WZ group was increased 29.9%（WZ pretreatment group） and 154.2%（WZ coadministered group） compared to that of control group. In conclusion, long-term treatment of WZ increased the m RNA and protein expression of CYP3A, while could inhibit the activity of CYP3A.

Effect of long-term treatment of Wuzhi tablet on the expression and activity of cytochrome P450 3A in rats / 药学学报

The study aims to evaluate the effect of long-term pretreatment of the rat with Wuzhi tablet (WZ) on hepatic and intestinal CYP3A mRNA and protein expression and activity. Male Sprague-Dawley rats were orally administered of midazolam (2 mg·kg-1) with or without 14 days of pretreatment of WZ (0.25 g·kg-1) to determine CYP3A activity. Meanwhile, RNA and protein of rats liver and intestine samples were prepared 24 h after the last dose of 14 days of WZ treatment to determine CYP3A mRNA and protein expression. Long-term treatment of WZ increased the mRNA expression of hepatic Cyp3a1, Cyp3a9 and intestinal Cyp3a9 by 54.6%, 188.3% (PP<0.05), respectively;and increased the protein expression of hepatic CYP3A by 43.2%. However, after long-term treatment of WZ, the AUC of orally administered of midazolam in the WZ group was increased 29.9% (WZ pretreatment group) and 154.2% (WZ coadministered group) compared to that of control group. In conclusion, long-term treatment of WZ increased the mRNA and protein expression of CYP3A, while could inhibit the activity of CYP3A.

Fluorescent logic systems for sensing and molecular computation: structure-activity relationships in edge-detection.

Molecular logic-based computation continues to throw up new applications in sensing and switching, the newest of which is the edge detection of objects. The scope of this phenomenon is mapped out by the use of structure-activity relationships, where several structures of the molecules and of the objects are examined. The different angles and curvatures of the objects are followed with good fidelity in the visualized edges, even when the objects are in reverse video.

Building pH sensors into paper-based small-molecular logic systems for very simple detection of edges of objects.

Genetically engineered bacteria and reactive DNA networks detect edges of objects, as done in our retinas and as also found within computer vision. We now demonstrate that simple molecular logic systems (a combination of a pH sensor, a photo acid generator, and a pH buffer spread on paper) without any organization can achieve this relatively complex computational goal with good fidelity. This causes a jump in the complexity achievable by molecular logic-based computation and extends its applicability. The molecular species involved in light dose-driven "off-on-off" fluorescence is diverted in the "on" state by proton diffusion from irradiated to unirradiated regions where it escapes a strong quencher, thus visualizing the edge of a mask.