Engineering and functional analysis of yeast with a monotypic 40S ribosome subunit.

Emerging evidence reveals that ribosomes are not monolithic but dynamic machines with heterogeneous protein compositions that can reshape ribosomal translational abilities and cellular adaptation to environmental changes. Duplications of ribosomal protein (RP) genes are ubiquitous among organisms and are believed to affect cell function through paralog-specific regulation (e.g., by generating heterogeneous ribosomes) and/or gene dose amplification. However, direct evaluations of their impacts on cell function remain elusive due to the highly heterogeneous cellular RP pool. Here, we engineered a yeast with homogeneous 40S RP paralog compositions, designated homo-40S, by deleting the entire set of alternative duplicated genes encoding yeast 40S RP paralogs. Homo-40S displayed mild growth defects along with high sensitivity to the translation inhibitor paromomycin and a significantly increased stop codon readthrough. Moreover, doubling of the remaining RP paralogous genes in homo-40S rescued these phenotypes markedly, although not fully, compared to the wild-type phenotype, indicating that the dose of 40S RP genes together with the heterogeneity of the contents was vital for maintaining normal translational functionalities and growth robustness. Additional experiments revealed that homo-40S improved paromomycin tolerance via acquisition of bypass mutations or evolved to be diploid to generate fast-growing derivatives, highlighting the mutational robustness of engineered yeast to accommodate environmental and genetic changes. In summary, our work demonstrated that duplicated RP paralogs impart robustness and phenotypic plasticity through both gene dose amplification and paralog-specific regulation, paving the way for the direct study of ribosome biology through monotypic ribosomes with a homogeneous composition of specific RP paralogs.

Dynamic regulation of phosphorylation of NMDA receptor GluN2B subunit tyrosine residues mediates ketamine rapid antidepressant effects.

The rapid antidepressant effects of ketamine depend on the N-methyl-D-aspartate (NMDA) receptor containing 2B subunit (NR2B), whose function is influenced by its phosphorylated regulation and distribution within and outside synapses. It remains unclear if ketamine's rapid onset of antidepressant effects relies on the dynamic phosphorylated regulation of NR2B within and outside synapses. Here, we show that ketamine rapidlyalleviated depression-like behaviors and normalized abnormal expression of pTyr1472NR2B and striatal-enriched protein tyrosine phosphatase (STEP) 61 within and outside synapses in the medial prefrontal cortex (mPFC) induced by chronic unpredictable stress (CUS) and conditional knockdown of STEP 61, a key phosphatase of NR2B, within 1 hour after administration Together, our results delineate the rapid initiation of ketamine's antidepressant effects results from the restoration of NR2B phosphorylation homeostasis within and outside synapses. The dynamic regulation of phosphorylation of NR2B provides a new perspective for developing new antidepressant strategies.

Large-scale pathway reconstruction and colorimetric screening accelerate cellular metabolism engineering.

The capability to manipulate and analyze hard-wired metabolic pathways sets the pace at which we can engineer cellular metabolism. Here, we present a framework to extensively rewrite the central metabolic pathway for malonyl-CoA biosynthesis in yeast and readily assess malonyl-CoA output based on pathway-scale DNA reconstruction in combination with colorimetric screening (Pracs). We applied Pracs to generate and test millions of enzyme variants by introducing genetic mutations into the whole set of genes encoding the malonyl-CoA biosynthetic pathway and identified hundreds of beneficial enzyme mutants with increased malonyl-CoA output. Furthermore, the synthetic pathways reconstructed by randomly integrating these beneficial enzyme variants generated vast phenotypic diversity, with some displaying higher production of malonyl-CoA as well as other metabolites, such as carotenoids and betaxanthin, thus demonstrating the generic utility of Pracs to efficiently orchestrate central metabolism to optimize the production of different chemicals in various metabolic pathways. Pracs will be broadly useful to advance our ability to understand and engineer cellular metabolism.

Budesonide-liposomes inclusion complex in thermosensitive gel alleviates DSS-induced ulcerative colitis in mice.

PURPOSE: A novel formulation for Ulcerative Colitis (UC) treatment by rectal administration with budesonide liposomes (Bud Lip) and thermosensitive gel (Gel) was developed for future clinical use. To evaluate the anti-inflammatory activity and colon mucosal protection of this novel formulation compared with the other three in mice. METHODS: Bud Lip was prepared by reverse evaporation method and then dispersed in solutions with PL407 and PL188 by a cold method. Male mice were induced to UC by dextran sulfate sodium (DSS) and were treated for 14 days by rectal administration, as follows: Bud enema (a conventional suspension formulation); Bud Lip; Bud Gel; Bud Lip-Gel; saline. And a negative control without colitis was also used. Disease activity index (DAI), and macroscopic and microscopic damage scores in colon tissues were used to evaluate the effect of therapy. The levels of IL-6 and IL-10 in serum and the concentrations of TNF-α and IL-10 and myeloperoxidase (MPO) activity in colon tissue were also introduced. RESULTS: In UC mice model, Bud Lip-Gel showed inflammation was alleviated significantly, and the treatment was highly associated with lower DAI, less macroscopic and microscopic colonic damage and downregulation of pro-inflammatory cytokines TNF-α, IL-6 and MPO. Bud Lip-Gel had advantages over Bud, Bud Lip, Bud Gel in the treatment of active UC. CONCLUSION: Novel Bud liposomes complex in thermosensitive Gel effectively mitigated symptoms, alleviated macroscopic and microscopic colon damage, and reduced inflammatory reaction in UC mice, which might be a potential strategy for UC treatment.

Incidence of posterior vitreous detachment after congenital cataract surgery: an ultrasound evaluation.

BACKGROUND: To investigate the incidence of developing posterior vitreous detachment (PVD) in children after congenital cataract surgery. METHODS: This is a prospective study which recruited 131 children with congenital cataracts who underwent cataract surgery between June 1, 2015, and September 1, 2018. The patients were divided into two groups depending on their post-operation phakic status (with or without IOL implantation). Infants aged from 6 to 12 months from two groups were analyzed as subgroups, respectively. B-scan ultrasonography was performed before the procedure and at 1, 3, 6, 9, and 12-month follow-ups, respectively, after the operation. RESULTS: Of the 131 eyes included in the analyses, 74 were aphakic, and 57 were pseudophakic after surgery. The postoperative rate of PVD in all analyzed eyes was 6.9% (9 of 131 eyes). After 12 months, PVD was significantly more prevalent in the eyes that underwent cataract surgery with IOL implantation (10.5%, 6 of 57 eyes) compared to the eyes without IOL implantation (4.1%, 1 of 74 eyes, P < 0.05); however, the eyes in the aphakic group were significantly younger than the eyes in the pseudophakic group, while the mean axial length (AL) of the pseudophakic eyes (21.11 ± 2.07 mm) was significantly higher than that of the aphakic eyes (18.93 ± 1.86 mm) (P < 0.01). In patients between the ages of 6 and 12 months of age from the two groups, the AL of patients with IOL implantation continued to be significantly increased compared to the group without IOL implantation (20.44 ± 1.68 mm vs. 19.78 ± 1.52 mm, P < 0.01). At the follow-up appointments, two patients with PVD were observed among the 14 eyes that had undergone cataract surgery with IOL implantation, while one eye was observed to have developed PVD among the 15 eyes without IOL implantation. CONCLUSIONS: PVD occurs with greater frequency after congenital cataract surgery, particularly in eyes that have undergone IOL implantation. We suggest that PVD should be carefully monitored in children after congenital cataract surgery to avoid subsequent ocular pathologies such as retinal detachment. Future studies are needed to determine other potential risk factors that have not been as thoroughly explored, as opposed to better-known factors such as older age, longer axial length, and IOL implantation.

Iridocorneal Angle and Anterior Segment Structure of Eyes in Children with Cataract.

OBJECTIVE: To evaluate the morphology of iridocorneal angle and anterior segment in eyes of children with cataract. METHODS: In this prospective cross-sectional study, we included eyes of children with bilateral cataract as well as unilateral cataract and fellow eyes. The iridocorneal angle was evaluated using gonioscopy. We compared the preoperative structures of iridocorneal angle and anterior segment between cataractous eyes and fellow eyes. The grading of iridocorneal angle and anatomical changes were analyzed. RESULTS: We finally recruited 55 eyes of 55 children with bilateral cataract and 41 cataractous eyes and 33 fellow eyes of 41 children with unilateral cataract. The fellow eyes were used as a control group. The iridocorneal angle was open in eyes with pediatric cataract when compared to control eyes. The eyes with cataract exhibited more pigments on the trabecular meshwork than control eyes did (unilateral cataract vs. control, p = 0.013; bilateral cataract vs. control, p = 0.002). The eyes with cataract exhibited a smaller cornea than control eyes (unilateral cataract vs. control, p = 0.031; bilateral cataract vs. control, p < 0.001). CONCLUSIONS: The iridocorneal angle is open in the eyes of children with cataract. Eyes with increased pigments on the trabecular meshwork need to be carefully monitored and surgeons should to be on the alert for postoperative glaucoma.

EpCAM Aptamer-Functionalized Cationic Liposome-Based Nanoparticles Loaded with miR-139-5p for Targeted Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide. MicroRNAs (miRNAs) play a vital role in a variety of biology processes. Our previous work identified miR-139-5p as a tumor suppressor gene overexpressed in CRC that assisted in inhibiting progression of cancer. The main challenge of miRNAs as therapeutic agents is their rapid degradation in plasma, poor uptake, and off-target effects. Therefore, the development of miRNA-based therapies is necessary. In this study, we developed a cationic liposome-based nanoparticle loaded with miR-139-5p (miR-139-5p-HSPC/DOTAP/Chol/DSPE-PEG2000-COOH nanoparticles, MNPs) and surface-decorated with epithelial cell adhesion molecule (EpCAM) aptamer (Apt) (miR-139-5p-EpCAM Apt-HSPC/DOTAP/Chol/DSPE-PEG2000-COOH nanoparticles, MANPs) for the targeted treatment of CRC. The size of MANPs was 150.3 ± 8.8 nm, which had a round-shaped appearance and functional dispersion capabilities. It also showed negligible hemolysis in the blood. MANPs markedly inhibited the proliferation, migration, and invasion of one or more CRC cell lines in vitro. Furthermore, we demonstrated the uptake and targeting ability of MANPs in vivo and in vitro. MANPs inhibit the growth of HCT8 cells in vitro and have a significant tumor suppressive effect on subcutaneous HCT8 colorectal tumor mice. Our results demonstrated that MANPs were an effective carrier approach to deliver therapeutic miRNAs to CRC.

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.

Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50 = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.

Angular Rate Sensing with GyroWheel Using Genetic Algorithm Optimized Neural Networks.

GyroWheel is an integrated device that can provide three-axis control torques and two-axis angular rate sensing for small spacecrafts. Large tilt angle of its rotor and de-tuned spin rate lead to a complex and non-linear dynamics as well as difficulties in measuring angular rates. In this paper, the problem of angular rate sensing with the GyroWheel is investigated. Firstly, a simplified rate sensing equation is introduced, and the error characteristics of the method are analyzed. According to the analysis results, a rate sensing principle based on torque balance theory is developed, and a practical way to estimate the angular rates within the whole operating range of GyroWheel is provided by using explicit genetic algorithm optimized neural networks. The angular rates can be determined by the measurable values of the GyroWheel (including tilt angles, spin rate and torque coil currents), the weights and the biases of the neural networks. Finally, the simulation results are presented to illustrate the effectiveness of the proposed angular rate sensing method with GyroWheel.

Targeting metabolism to improve CAR-T cells therapeutic efficacy.

ABSTRACT: Chimeric antigen receptor T (CAR-T) cell therapy achieved advanced progress in the treatment of hematological tumors. However, the application of CAR-T cell therapy for solid tumors still faces many challenges. Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy's low effectiveness. Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment, which is characterized by increased interstitial fluid pressure, low pH level, hypoxia, accumulation of immunosuppressive metabolites, and mitochondrial dysfunction. These factors are important contributors to restriction of T cell proliferation, cytokine release, and suppression of tumor cell-killing ability. This review provides an overview of how different metabolites regulate T cell activity, analyzes the current dilemmas, and proposes key strategies to reestablish the CAR-T cell therapy's effectiveness through targeting metabolism, with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.

Astroglial morphological changes in periaqueductal grey in different pain and itch mice models.

BACKGROUND: The periaqueductal gray (PAG) plays a well-established pivotal role in the descending pain modulatory circuit. The objective of this study was to investigate morphological changes in the astroglia in models that are commonly used in pain and itch studies. METHODS: Five different mouse models of pain, as well as two models of chronic itch, were established using complete Freund's adjuvant (CFA), spared nerve injury (SNI), bone cancer pain (BCP), cisplatin (CIS), and paclitaxel (PTX) for pain, and diphenylcyclopropenone (DCP) and acetone and diethyl ether followed by water (AEW) for chronic itch. von Frey tests and video recordings were employed to assess pain and itching behaviors. The immunofluorescence of S100ß, pSTAT3, and glial fibrillary acidic protein (GFAP) was examined. Two- and three-dimensional studies were used to evaluate changes in astrocyte morphology. RESULTS: Significant scratching was caused by DCP and AEW, whereas the administration of CFA, SNI, BCP, CIS, and PTX produced clear mechanical allodynia. The expression of GFAP in the lPAG/vlPAG was upregulated in CFA, SNI, BCP, CIS, PTX, and DCP mice but decreased in AEW mice. According to Sholl analysis, CFA, SNI, PTX, and BCP mice showed substantially higher astrocyte intersections in the vlPAG, whereas CFA, SNI, BCP, CIS, and DCP mice presented longer peak lengths. In three-dimensional analysis, CFA, SNI, PTX, and DCP mice showed increased astrocyte surface areas, while CIS and AEW mice showed both reduced surface areas and/or volumes of astrocytes. CONCLUSION: The findings showed that different pain and itching conditions have different astrocyte morphologies, and these variations in morphological changes help to explain the pathophysiology of these conditions.

CAR T cells engineered to secrete IFN-κ induce tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis.

Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T cell therapy. In this study, we demonstrated that IFN-κ influenced the induction of ferroptosis. IFN-κ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFN-κ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFN-κ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen negative) both in vitro and in vivo. We conclude that IFN-κ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.

Effectiveness and safety of second-generation antipsychotics for psychiatric disorders apart from schizophrenia: A systematic review and meta-analysis.

Second-generation antipsychotics (SGAs) are widely used in treating schizophrenia and related disorders, also other mental disorders. However, the efficacy and safety of SGAs for treating other mental disorders is unclear. A systematic literature search for randomized, placebo-controlled trials of 11 SGAs for treating 18 mental disorders apart from schizophrenia were carried out from database inception to April 3, 2022. The primary outcome was the mean change in the total score for different mental disorders. The secondary outcome was the odds ratio (OR) of response, remission rates and risk ratio (RR) of adverse events (AEs). A total of 181 studies (N = 65,480) were included. All SGAs showed significant effects in treating other mental disorders compared with placebo, except autistic disorder and dementia. Aripiprazole is the most effective treatment for bipolar mania [effect size = -0.90, 95% CI: -1.59, -0.21] and Tourette's disorder [effect size = -0.80, 95% CI: -1.14, -0.45], olanzapine for bipolar depression [effect size = -0.86, 95% CI: -1.32, -0.39] and post-traumatic stress disorder [effect size = -0.98, 95% CI: -1.55, -0.41], lurasidone for depression [effect size = -0.66, 95% CI: -0.82, -0.50], quetiapine for anxiety [effect size = -1.20, 95% CI: -1.96, -0.43], sleep disorders [effect size = -1.2, 95% CI: -1.97, -0.58], and delirium [effect size = -0.36, 95% CI: -0.70, -0.03], and risperidone for obsessive-compulsive disorder [effect size = -2.37, 95% CI: -3.25, -1.49], respectively. For safety, AE items for each SGAs was different. Interestingly, we found that some AEs of OLZ, QTP, RIS and PALI have significant palliative effects on some symptoms. Significant differences in the efficacy and safety of different SGAs for treatment of other mental disorders should be considered for choosing the drug and for the balance between efficacy and tolerability for the specific patient.

An EIT image reconstruction method based on DenseNet with multi-scale convolution.

Electrical impedance tomography (EIT) is an imaging technique that non-invasively acquires the electrical conductivity distribution within a field. The ill-posed and nonlinear nature of the image reconstruction process results in lower quality of the obtained images. To solve this problem, an EIT image reconstruction method based on DenseNet with multi-scale convolution named MS-DenseNet is proposed. In the proposed method, three different multi-scale convolutional dense blocks are incorporated to replace the conventional dense blocks; they are placed in parallel to improve the generalization ability of the network. The connection layer between dense blocks adopts a hybrid pooling structure, which reduces the loss of information in the traditional pooling process. A learning rate setting achieves reduction in two stages and optimizes the fitting ability of the network. The input of the constructed network is the boundary voltage data, and the output is the conductivity distribution of the imaging area. The network was trained and tested on a simulated dataset, and it was further tested using actual measurement data. The images reconstructed via this method were evaluated by employing root mean square error, structural similarity index measure, mean absolute error and image correlation coefficient in comparison with conventional DenseNet and Gauss-Newton. The results show that the method improves the artifact and edge blur problems, achieves higher values on the image metrics and improves the EIT image quality.

Matrix stiffness-induced platelet activation determines immunomodulation of macrophages.

Although various bone defect repair materials have been used clinically, the influence of the material properties on bone repair and regeneration as well as the underlying mechanisms are not fully understood. We hypothesize that the material stiffness affects initial platelet activation during hemostasis phase, which in turn mediates subsequent osteoimmunomodulation of macrophages, finally determining clinical outcomes. To verify the hypothesis, the present work used polyacrylamide hydrogels with different stiffness (10, 70, and 260 kPa) as model materials to investigate matrix stiffness induced platelet activation behavior and its mediation on osteoimmunomodulation of macrophages. The results showed that the matrix stiffness was positively related with activation degree of platelets. However, the extracts of platelets incubated on middle-stiff matrix polarized macrophages to pro-healing M2 phenotype when compared with that on soft and stiff matrixes. ELISA results showed when compared with that on soft and stiff matrixes, the platelets incubated on middle-stiff matrix released more TGF-ß and PGE2, both of which could polarize macrophages to M2 phenotype. The M2 macrophages could promote angiogenesis of endothelial cells and osteogenesis of bone marrow mesenchymal stem cells, two important and coupled processes involved in bone repair and regeneration. These findings suggest bone repair materials with 70 kPa stiffness can mediate proper platelet activation, which can polarize macrophages to pro-healing M2 phenotype, potentially contributing to bone repair and regeneration.

An Anisotropic Hydrogel by Programmable Ionic Crosslinking for Sequential Two-Stage Actuation under Single Stimulus.

As one of the most important anisotropic intelligent materials, bi-layer stimuli-responsive actuating hydrogels have proven their wide potential in soft robots, artificial muscles, biosensors, and drug delivery. However, they can commonly provide a simple one-actuating process under one external stimulus, which severely limits their further application. Herein, we have developed a new anisotropic hydrogel actuator by local ionic crosslinking on the poly(acrylic acid) (PAA) hydrogel layer of the bi-layer hydrogel for sequential two-stage bending under a single stimulus. Under pH = 13, ionic-crosslinked PAA networks undergo shrinking (-COO-/Fe3+ complexation) and swelling (water absorption) processes. As a combination of Fe3+ crosslinked PAA hydrogel (PAA@Fe3+) with non-swelling poly(3-(1-(4-vinylbenzyl)-1H-imidazol-3-ium-3-yl)propane-1-sulfonate) (PZ) hydrogel, the as-prepared PZ-PAA@Fe3+ bi-layer hydrogel exhibits distinct fast and large-amplitude bidirectional bending behavior. Such sequential two-stage actuation, including bending orientation, angle, and velocity, can be controlled by pH, temperature, hydrogel thickness, and Fe3+ concentration. Furthermore, hand-patterning Fe3+ to crosslink with PAA enables us to achieve various complex 2D and 3D shape transformations. Our work provides a new bi-layer hydrogel system that performs sequential two-stage bending without switching external stimuli, which will inspire the design of programmable and versatile hydrogel-based actuators.

Fabrication and characterization of biodegradable Zn scaffold by vacuum heating-press sintering for bone repair.

Bone repair materials with excellent mechanical properties are highly desirable, especially in load-bearing sits. However, the currently used ceramic- and polymer-based ones mainly show poor mechanical properties. Recently, biodegradable metals have attracted extensive attention due to their reliable mechanical strength and degradability. As biodegradable metals, zinc-based materials are promising due to their suitable degradation rate and good biocompatibility. Here, we fabricated biodegradable porous Zn scaffolds with relatively high mechanical properties by vacuum heating-press sintering using NaCl particles as space holders. The microstructure, actual porosity, compressive mechanical properties, in vitro degradation behavior and the vitality of osteoblasts of porous Zn scaffolds were tested and investigated. The results show the porosities of the prepared porous Zn scaffolds are ranging from 11.3 % to 63.3 %, and the pore sizes are similar to the size range of the screened NaCl particles (200-500 µm). Compressive yield strength of 14.2-73.7 MPa and compressive elastic modulus of 1.9-6.7 GPa are shown on porous Zn scaffolds, some of which approach to that of cancellous bone (2-12 MPa and 0.1-5 GPa). Compared to bulk Zn, although the porous structures cause a partial loss of strength, the reliable mechanical properties are still retained. In addition, the porous structures not only greatly increase the degradation rate, but also promote the proliferation of osteoblasts. Based on these results, biodegradable porous Zn scaffolds (porosity in the 40 %-50 %) fabricated by vacuum heating-press sintering method show high application potential for clinical bone repair.

Resveratrol promotes osteogenesis and angiogenesis through mediating immunology of senescent macrophages.

Orthopedic implants have been used clinically to restore the functions of the compromised bone tissues, but there is still a relatively high risk of failure for elderly people. A critical reason is pro-inflammatory immune microenvironment created by senescent macrophages with homeostasis imbalance impairs osteogenesis and angiogenesis, two major processes involved in implant osseointegration. The present work proposes to use resveratrol as an autophagy inducing agent to upregulate the autophagy level of senescent macrophages to restore homeostasis, consequently generating a favorable immune microenvironment. The results show 0.1-1 µM of resveratrol can induce autophagy of senescent macrophages, promote cell viability and proliferation, reduce intracellular reactive oxygen species level, and polarize the cells to pro-healing M2 phenotype. The immune microenvironment created by senescent macrophages upon resveratrol stimulation can promote osteogenesis and angiogenesis, as manifested by upregulated proliferation, alkaline phosphatase activity, type I collagen secretion, and extracellular matrix mineralization of senescent osteoblasts as well as nitric oxide production, migration, andin vitroangiogenesis of senescent endothelial cells. In addition, resveratrol-loaded silk fibroin coatings can be fabricated on titanium surface through electrophoretic co-deposition and the coatings show beneficial effects on the functions of senescent macrophages. Our results suggest resveratrol can be used as surface additive of titanium implants to promote osseointegration of elderly people though regulating immunology of senescent macrophages.

The role of nanopores constructed on the micropitted titanium surface in the immune responses of macrophages and the potential mechanisms.

The delayed transition of macrophages (MΦs) from pro-inflammatory M1 to the pro-healing M2 state on implant surfaces is one of the most important reasons for poor osseointegration. This work reports the construction of closely packed nanopores with a small diameter on the micropitted titanium (Ti) surface by two-step acid etching to promote the M1-to-M2 transition of MΦs and pays special attention to the potential mechanisms by which the nanopores decorating the micropits exert immunomodulatory effects. The results show that the structure composed of hybrid nanopores (10-25 nm) and micropits (5-15 µm) can be produced on the Ti surface by a two-step acid etching process. Compared with the unitary micropits, the micropit/nanopore surface could facilitate the switch of MΦs from the pro-inflammatory M1 to the pro-healing M2 phenotype. RNA sequencing reveals that the MAPK, PI3K-AKT and C-type lectin signaling pathways play key roles in the micro/nano-structure-mediated transition. In addition, the micro/nano-structured surface down-regulated CYP1A2 expression, reducing the generation of mitochondrial ROS, in turn restraining the oxidative stress and further attenuating inflammation. This work provides novel insights into the underlying mechanisms of immunomodulation by the nano-structure-decorated micro-structures on the Ti surface, which is significant for designing the surface of orthopedic implants from the perspective of immunomodulation.

Exosomes derived from magnesium ion-stimulated macrophages inhibit angiogenesis.

Angiogenesis, an essential prerequisite to osteogenesis in bone repair and regeneration, can be mediated by immunoregulation of macrophages. Magnesium and its alloys are promising biodegradable bone implant materials and can affect immunoregulation of macrophages by the degradation products (magnesium ions). Nevertheless, the mechanism of macrophage-derived exosomes stimulated by Mg ions in immunoregulation is still not well understood. Herein, 10-50 mM magnesium ions are shown to inhibit the macrophage viability and proliferation in a dose-dependent manner, but a high concentration results in macrophage apoptosis. The exosomes secreted by macrophages from magnesium ion stimulation inhibit angiogenesis of endothelial cells, as manifested by the suppressed cell viability, proliferation, migration, and tube formation, which arise at least partially from exosome-mediated downregulation of endothelial nitric oxide and the vascular endothelial growth factor. The findings reported in this paper suggest that the bio-functionality of biodegradable magnesium alloys must be considered from the perspective of immunoregulation of macrophage-derived exosomes. Our results also suggest potential cancer therapy by inhibiting tumor-associated angiogenesis.