Owing to the insufficient guidance of new bone formation in orthopedic and craniomaxillofacial surgery, construction of a guided bone regeneration membrane to support vascularized bone regeneration remains a challenge. Herein, an electrospun asymmetric double-layer polycaprolactone/collagen (PCL/Col) membrane modified by metal-organic framework (MOF) crystals is developed. The optimization of the PCL/Col weight ratio (1:1 and 1:1.5) enables the composite membrane with a balanced tensile strength (only fell by 49.9% in wet conditions) and a controlled degradation rate (completely degraded at 12 weeks). The MOF crystals can provide a pH-responsive release of Zn2+ ions. In vitro experiments indicate that the barrier layer functions to prevent the infiltration of fibrous connective tissue. The MOF crystal layer functions to enhance osteogenesis and angiogenesis in vitro. Using a rat calvarial defect model, the MOF crystals exhibit a sign of osteoinductivity along with blood vessel formation after 8 weeks post-surgery. Strikingly, when assessed in a chick chorioallantoic membrane model, the MOF modified membrane demonstrates a significant angiogenic response, which can be envisaged as its outstanding merits over the commercially Col membrane. Therefore, the MOF crystals represent an exciting biomaterial option, with neovascularization capacity for bone tissue engineering and regenerative medicine.
Abstract Every year, over 12 million people are enduring the persistent pain resulting from wound infections. In these chronic wounds, concealed infections may be covered up by scabs or granulation, which impeding accurate diagnosis and treatment. To address such clinical challenges, inspired by corals, a biomimetic microneedle patch (HepMi‐PCL) is developed to indicate and treat infections within wound. Relying on high‐precision 3D printing technology, each polycaprolactone microneedle own an equally sized porous shell and cavity with heparin‐based functional hydrogel filling in. After penetrating through the scab, HepMi‐PCL can absorb exudate in wound through surficial guide grooves and pores microstructure on its microneedle, thereby indicating whether anti‐infection is needed. Upon the identification of a positive chronic infection, HepMi‐PCL will smartly activate to release drugs rapidly. Subsequently, when the infection is effectively managed and the exudate progressively decreases, the drug delivery will correspondingly slow down or cease altogether. By leveraging autonomous response and therapeutic capabilities, HepMi‐PCL demonstrates the potential to expedite the diagnosis and treatment of infections, resulting in an enhancement of healing speed for infected wounds by over 200%. Thus, the integration of diagnostic and therapeutic functions of the microneedle patch is anticipated to offer novel approaches in addressing the management of chronic wounds.
Wound treatment is a long-lasting clinical issue. Poor angiogenesis leading to delayed wound closure causes huge challenges for healing. Functional electrospun membranes have been established as an efficient strategy to promote wound recovery by protecting and improving vascular regeneration. Here, we aimed to investigate the effect of tazarotene, an active drug for angiogenesis, loaded in aligned electrospun nanofibrous barrier on a soft tissue wound. This aligned membrane was arranged in a single direction, and tazarotene could be released from its nanofibers sustainably. The in vitro study demonstrated that compared with the random drug-loaded or other control groups, the aligned tazarotene-loaded membranes [poly-caprolactone (PCL)/AT] could stimulate proliferation, migration, angiogenesis, and vascular endothelial growth factor secretion and its gene expression of human umbilical vein endothelial cells. Furthermore, the in vivo model showed that the prepared tazarotene-loaded aligned membrane significantly accelerated the speed of healing, improved the neovascularization and re-epithelialization, and inhibited the inflammatory reaction in the wound area. All these results above indicated that the PCL/AT nanofibrous dressing, which could promote angiogenesis because of both stimulation of structure and chemical signals, is a promising wound-caring material.
Objective To investigate the effects of the calmodulin inhibitor W-7 on the expression of the key marker of ERS GRP78 and neuronal apoptosis in the immature rat hippocampus after status convulsion(SC).Methods One hundred and seventeen male Sprague-Dawley rats aged 19-21 days were randomly divided into three groups:normal saline control(control),SC with and without W-7 pretreatment.Each of the 3 groups was further subdivided into subgroups sacrificed at 4,24 and 48 hrs.SC model was prepared using lithium-pilocarpine.GRP78 mRNA expression in the hippocampus was detected by semiquantitative reverse transcription-polymerase chain reaction(RT-PCR).GRP78 protein was ascertained by immunohistochemistry.Neuronal apoptosis was observed with TdT-mediated dUTP nick end labeling(TUNEL).Results The expression of GRP78 mRNA was significantly increased in the non-pretreated SC group compared with the control group 24 hrs after injection of saline or lithium-pilocarpine(P0.01),and the expression of GRP78 protein also increased markedly in the seizure group compared with the control group 24 and 48 hrs after the injection(P0.01).The expression of GRP78 mRNA and protein in the W-7 pretreatment group was significantly higher than both the control and the non-pretreated seizure groups 24 and 48 hrs after injection.The TUNEL positive cells in the hippocampus CA1 in the non-pretreated SC group 24 and 48 hrs after injection(21.0±2.5 and 29.4±2.8,respectively) were increased compared to the control group(7.1±1.4 and 7.3±1.6,respectively;P0.01).W-7 pretreatment decreased TUNEL positive cells to 15.0±2.5 and 20.0±2.9 at 24 and 48 hrs after injection compared to the non-pretreated seizure group(P0.01),but the number of TUNEL positive cells in the W-7 pretreatment group remained significantly greater than in the control group(P0.01).Conclusions W-7 may up-regulate the expression of GRP78 and reduce the number of apoptotic neurons,thus provides a neuroprotective effect against brain damage following SC.
To observe the effects of moxibustion on blood lipid metabolism, pathological morphology of thoracic aorta, and the expression of silent information regulator 1 (SIRT1) and forkhead box transcription factor O3a (FOXO3a) in ApoE
Abstract Epidermal growth factor receptor (EGFR) signalling results in a variety of cell behaviours, including cell proliferation, migration and apoptosis, which depend on cell context. Here we have explored how the Rab5GEF, Rme-6, regulates EGFR signalling by modulating endocytic flux. We demonstrate that Rme-6, which acts early in the endocytic pathway, regulates EGFR trafficking through an endocytic compartment that is competent for ERK1/2 signalling. While overexpression of Rme-6 results in enhanced ERK1/2 nuclear localisation and c-Fos activation, loss of Rme-6 results in aberrant ERK1/2 signalling with increased cytoplasmic ERK1/2 phosphorylation (Thr202/Tyr204) but decreased ERK1/2 nuclear translocation and c-Fos activation, the latter leading to decreased cell proliferation. Phosphorylation of ERK1/2 by protein kinase 2 (CK2) is required for its nuclear translocation and our data support a model whereby Rme-6 provides a scaffold for a population of CK2 which is required for efficient nuclear translocation of ERK1/2. Rme-6 is itself a substrate for CK2 on Thr642 and Ser996 and phosphorylation on these sites can activate its Rab5GEF activity and endocytic trafficking of EGFR. Together our results indicate that Rme-6 co-ordinates EGFR trafficking and signalling to regulate the assembly and disassembly of an ERK1/2 signalosome. Summary statement Here we demonstrate how Rme-6, a Rab5GEF, co-ordinates trafficking and signalling of EGFR on the early endocytic pathway to ensure appropriate regulation of downstream ERK1/2 signalling.
Bisphosphonates
(BPs) are routinely administered for the treatment
of turnover bone diseases. To avoid the undesirable adverse effects
of long-term usage of bisphosphonates and improve their bioavailability
in the bone microenvironment, we initially encapsulated risedronate
(RIS) molecules inside nanoscale zeolitic imidazolate framework-8
particles (nZIF-8) by a one-step synthesis method to generate RIS@ZIF-8
nanoparticles. RIS@ZIF-8 nanoparticles displayed high loading encapsulation
efficiency (64.21 ± 2.48%), good biocompatibility, controlled
drug release capacity, and dual effects for bone regeneration. This
work explored the potential of RIS@ZIF-8 nanoparticles, which could
not only enhance ATP production, induce extracellular matrix (ECM)
mineralization, and upregulate the expression levels of osteogenic
genes but also effectively inhibit the formation of multinucleated
giant osteocasts and decrease the Rankl/Opg ratio. Overall, RIS@ZIF-8
nanoparticles could be a very promising approach to synergistically
enhance osteogenic and antiresorptive properties for bone regeneration,
which could be utilized for the local treatment of bone defects.
Piezoelectric biomaterials are advantageous in terms of easy generation of transduced bioelectrical signals to skeleton systems in response to body movements or external stimulations. In the bone formation process, the coupling of angiogenesis-osteogenesis is crucial but the effect of piezoelectric biomaterials on angiogenesis and mechanism of stress-transformed electrical signals affecting vascular cells remain elusive. In this work, hierarchically architected polyvinylidene fluoride (PVDF) foam fabricated by solid-state shearing milling was further decorated with ZIF-8 nanocrystals. The unique hierarchical porous structure realizes stable voltage outputs up to 10 V without polarization. The electric potential of piezoelectric PVDF affected molecular trajectory of Zn 2+ released from ZIF-8, leading to Zn 2+ enrichment around the PVDF surface. Under piezoelectric condition, PVDF/ZIF-8 foams promoted both in-vitro angiogenic and osteogenic activity. Upon calvarium and femur defect repair, PVDF/ZIF-8 piezoelectric foams also guided vascularized bone regeneration through micro-current stimulation and Zn 2+ enrichment. RNA-seq demonstrated PVDF/ZIF-8 piezoelectric foam mainly up-regulated ATP coupled cation transmembrane transportation in vascular endothelial cells, which enhanced cellular uptake of Zn 2+ , indicating the synergistic effect of piezoelectric PVDF and bioactive ZIF-8. This work offers a preliminary explanation for mechanism of angiogenesis-osteogenesis coupling of PVDF/ZIF-8 foam nanogenerator and provides a valuable complement to clinical treatment strategies for bone defect repair.
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