Nanofibrous 3D Scaffolds Capable of Individually Controlled BMP and FGF Release for the Regulation of Bone Regeneration.

The current clinical applications of bone morphogenetic proteins (BMPs) are limited to only a few specific indications. Locally controlled delivery of combinations of growth factors can be a promising strategy to improve BMP-based bone repair. However, the success of this approach requires the development of an effective release system and the correct choice of growth factors capable of enhancing BMP activity. Basic fibroblast growth factor (bFGF, also known as FGF-2) has shown promise in promoting bone repair, although conflicting results have been reported. Considering the complex biological activities of FGF-2, we hypothesized that FGF-2 can promote BMP-induced bone regeneration only if the dosage and kinetic parameters of the two factors are individually tailored. In this study, we conducted systematic in vitro studies on cell proliferation, differentiation, and mineralization in response to factor dose, delivery mode (sequential or simultaneous), and release rate. Subsequently, we designed individually controlled BMP-7 and FGF-2 release poly(lactide-co-glycolide) (PLGA) nanospheres attached to the poly(l-lactic acid) (PLLA) nanofibrous scaffolds. The data showed that BMP-7-induced bone formation was accelerated by a relatively higher FGF-2 dose (100 ng/scaffold) delivered at a faster release rate, or by a relatively lower FGF-2 dose (10 ng/scaffold) at a slower release rate in an in vivo bone regeneration model. In contrast, a very high dose of FGF-2 (1000 ng/scaffold) inhibited bone regeneration under all conditions. In vitro and in vivo data suggest that FGF-2 improved BMP-7-induced bone regeneration by coordinating FGF-2 dosage and release kinetics to enhance stem cell migration, proliferation, and angiogenesis. STATEMENT OF SIGNIFICANCE: Bone morphogenetic proteins (BMPs) are the most potent growth/differentiation factors in bone development and regeneration. However, the clinical applications of BMPs have been limited to only a few specific indications due to the required supraphysiological dosages with the current BMP products and their side effects. Locally controlled delivery of BMPs and additional growth factors that can enhance their osteogenic potency are highly desired. However, different growth factors act with different mechanisms. Here we report a nanofibrous scaffold that mimics collagen in size and geometry and is immobilized with biodegradable nanospheres to achieve local and distinct release profiles of BMP7 and FGF2. Systematic studies demonstrated low dose BMP7 and FGF2 with different temporal release profiles can optimally enhance bone regeneration.

Anti-aging Metabolite-Based Polymeric Microparticles for Intracellular Drug Delivery and Bone Regeneration.

Alpha-ketoglutarate (AKG), a key component of the tricarboxylic acid (TCA) cycle, has attracted attention for its anti-aging properties. Our recent study indicates that locally delivered cell-permeable AKG significantly promotes osteogenic differentiation and mouse bone regeneration. However, the cytotoxicity and rapid hydrolysis of the metabolite limit its application. In this study, we synthesize novel AKG-based polymeric microparticles (PAKG MPs) for sustained release. In vitro data suggest that the chemical components, hydrophilicity, and size of the MPs can significantly affect their cytotoxicity and pro-osteogenic activity. Excitingly, these biodegradable PAKG MPs are highly phagocytosable for nonphagocytic pre-osteoblasts MC3T3-E1 and primary bone marrow mesenchymal stem cells (BMSCs), significantly promoting their osteoblastic differentiation. RNAseq data suggest that PAKG MPs strongly activate Wnt/ß-catenin and PI3K-Akt pathways for osteogenic differentiation. Moreover, PAKG enables poly (L-lactic acid) and poly (lactic-co-glycolic acid) MPs (PLLA & PLGA MPs) for efficient phagocytosis. Our data indicate that PLGA-PAKG MPs-mediated intracellular drug delivery can significantly promote stronger osteoblastic differentiation compared to PLGA MPs-delivered phenamil. Notably, PAKG MPs significantly improve large bone regeneration in a mouse cranial bone defect model. Thus, the novel PAKG-based MPs show great promise to improve osteogenic differentiation, bone regeneration, and enable efficient intracellular drug delivery for broad regenerative medicine.

In-vitro activities of essential antimicrobial agents including aztreonam/avibactam, eravacycline, colistin and other comparators against carbapenem-resistant bacteria with different carbapenemase genes: A multi-centre study in China, 2021.

OBJECTIVE: Carbapenem-resistant bacteria (CRB), including carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA) and carbapenem-resistant Enterobacterales (CRE), pose a considerable threat to public health in China. Eravacycline, aztreonam/avibactam and colistin are important antimicrobial agents for the treatment of serious infections caused by CRB. This study aimed to evaluate the prevalence of CRB strains, and the susceptibility of commonly used clinical antimicrobial agents against strains with different carbapenemase genes. METHODS: In total, 7194 gram-negative bacteria strains were collected from different regions of China, and 924 carbapenem-resistant strains were identified. All strains were from confirmed infections. Antimicrobial susceptibility testing, covering 21 antimicrobial agents including aztreonam/avibactam, eravacycline, colistin and other comparators, was performed using the broth microdilution method. Carbapenemase genes (blaKPC, blaNDM, blaOXA, blaIMP and blaVIM) were screened using polymerase chain reaction amplification and sequence analysis. All statistical analyses were performed using Statistical Package for the Social Sciences Version 23.0. RESULTS: The isolation rates of CRE, CRAB and CRPA were 6.31% (332/5265), 62.95% (440/699) and 15.20% (152/1000), respectively. The predominant carbapenemase in carbapenem-resistant Escherichia coli (CRECO) was NDM, while in carbapenem-resistant Klebsiella pneumoniae (CRKP), it was KPC. All CRAB produced OXA-23, and 85.52% of CRPA did not produce any of the following carbapenemases: NDM, KPC, VIM, IMP and OXA. Aztreonam/avibactam, colistin and eravacycline exhibited high antimicrobial activity against different species producing various carbapenemases. Compared with ceftazidime/avibactam, aztreonam/avibactam demonstrated superior antimicrobial activity, particularly pronounced in CRECO and strains producing metallo-beta-lactamases. In comparisons between tigecycline and eravacycline, the latter maintained higher antimicrobial activity across different species. Antimicrobial agents exhibited varying levels of activity against strains with different resistance mechanisms. CONCLUSIONS: Using aztreonam/avibactam, eravacycline and colistin to treat infections caused by CRB offers significant advantages. These findings will guide clinical practice and optimize antimicrobial administration.

Prognostic analysis of Pneumocystis jirovecii pneumonia in patients with systemic vasculitides: a retrospective cohort study.

OBJECTIVES: Pneumocystis jirovecii pneumonia (PJP) is a serious complication of autoimmune and inflammatory diseases. This study aimed to describe the characteristics of PJP in patients with various systemic vasculitides and explore potential prognostic factors. METHOD: Data on 62 enrolled PJP patients with systemic vasculitis were analyzed. Patients were stratified based on the outcomes. Prognostic factors were investigated using Cox-regression models. Characteristics of patients with and without interstitial lung disease (ILD) were compared. RESULTS: Among 62 vasculitis-PJP patients, 48 had anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), with microscopic polyangiitis (MPA) being the most common subtype (28 patients). MPA (HR 4.33, p = 0.001), concomitant aspergillosis (HR 2.68, p = 0.019), and higher D-dimer at PJP diagnosis (HR 1.07, p = 0.004) were independent adverse prognostic factors for overall survival. Stable disease activity of vasculitis was an independent favorable prognostic factor (HR 0.28, p = 0.027). Patients with MPA were older than non-MPA patients (median age: 69 vs. 58 years, p = 0.001); both ILD and fibrotic ILD were more prevalent in MPA patients (ILD: 78.6% vs. 35.3%, p = 0.001; fibrotic ILD: 57.1% vs. 11.8%, p < 0.001). At the diagnosis of PJP, patients with preexisting ILD had higher counts of white cells, lymphocytes, and neutrophils, as well as higher levels of immunoglobulin (Ig) G and IgA, than patients without preexisting ILD. CONCLUSIONS: MPA was associated with a higher risk of death in patients with vasculitis-PJP, possibly due to a higher prevalence of ILD. In clinical practice, we should pay more attention to the prophylaxis and management of PJP in patients with systemic vasculitis-associated ILD and/or MPA. Key Points • Data from this study showed that MPA was the most common subtype of vasculitis among vasculitis-PJP patients. • Compared with non-MPA patients in this study, patients with MPA were older, had more ILD and fibrotic ILD, and had a poorer prognosis. • In clinical practice, we should pay more attention to the prophylaxis and management of PJP in patients with systemic vasculitis-associated ILD and/or MPA.

Comparison of bloodstream infections due to Corynebacterium striatum, MRSA, and MRSE.

BACKGROUND: Corynebacterium striatum (C. striatum), a common skin and mucosal colonizer, is increasingly considered as an opportunistic pathogen causing bloodstream infections (BSIs). This study aims to investigate the clinical features and outcomes of C. striatum-BSI. METHODS: We included hospitalized cases with C. striatum-positive blood cultures from January 2014 to June 2022 and classified them into C. striatum-BSI group and contamination group; Clinical characteristics, treatments, and outcomes were compared between the C. striatum-BSI group and contamination group, Methicillin-resistant Staphylococcus aureus (MRSA)-BSI and Methicillin-resistant Staphylococcus epidermidis (MRSE)-BSI. RESULTS: Fifty-three patients with positive C. striatum blood cultures were identified. Among them, 25 patients were classified as C. striatum-BSI, with 21 as contamination cases. And 62 cases of MRSA-BSI and 44 cases of MRSE-BSI were identified. Compared to the contaminated group, the C. striatum-BSI group had a shorter time to positivity of blood cultures (27.0 h vs. 42.5 h, P = 0.011). C. striatum-BSI group had a longer time to positivity (27 h) when compared to both the MRSA (20 h) and MRSE groups (19 h) (p < 0.05). Appropriate therapy within 24 h of BSI onset was significantly lower in the C. striatum group (28%) compared to the MRSA (64.5%) and MRSE (65.9%) groups (p < 0.005). The 28-day mortality was higher in the C. striatum group (52.0%) compared to the MRSA (25.8%) and MRSE (18.2%) groups.  CONCLUSIONS: Given the distinct characteristics of C. striatum-BSI, including a longer time to positivity than other Gram-positive bacteria and higher mortality rates, we suggest prescribing early appropriate antibiotics if C. striatum-BSI is suspected.

Prognostic analysis of concurrent Pneumocystis jirovecii pneumonia in patients with systemic lupus erythematosus: a retrospective study.

BACKGROUND: Systemic lupus erythematosus (SLE) has been less deadly since the advent of corticosteroid-sparing medications. SLE patients still have a higher mortality rate than the general population. Infectious disease is reported as one of the major causes of death in patients with SLE. Although bacteria are the most often isolated pathogens from patients with SLE, Pneumocystis jirovecii pneumonia (PJP) is more deadly than bacterial infection. METHODS: We retrospectively enrolled consecutive patients with SLE concurrent with PJP (SLE-PJP) in our center between January 2014 and December 2022. The participants were classified into two groups: survivors and non-survivors. Cox regression models and Kaplan‒Meier survival analyses were conducted to explore prognostic factors for survival. RESULTS: There were 57 patients with SLE (42.0 ± 15.8 years old, 78.9% female) complicated with PJP, 22 (38.6%) of whom died. Compared with the survival group, the non-survival group had more patients with hyperglycemia or diabetes mellitus, invasive ventilation (p < 0.01), respiratory failure, intensive care unit admission, non-invasive ventilation, and hospital-acquired pneumonia (p < 0.05). The non-survival group showed a higher neutrophil percentage, lactate dehydrogenase, D-dimer (p < 0.001), urea, high-sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), and ferritin (p < 0.05). It also had lower minimal albumin, hemoglobin (p < 0.001), immunoglobulin G, complement 3, peripheral lymphocyte count, platelet, NK cell count, and CD4+ T-cell count (p < 0.05). Multivariate analysis indicated that hyperglycemia or diabetes mellitus (HR = 4.25, p < 0.01, 95% CI: 1.51-11.97), thrombocytopenia (HR = 4.22, p < 0.01, 95% CI: 1.63-10.91) and lower complement 3 (C3) (HR = 4.06, p < 0.01, 95% CI: 1.60-10.33) were independent risk factors for the survival of SLE-PJP patients. CONCLUSIONS: The mortality rate of patients with SLE-PJP is still high. Hyperglycemia, decreased C3, and thrombocytopenia are independent survival risk factors.

Reactive oxygen-scavenging polydopamine nanoparticle coated 3D nanofibrous scaffolds for improved osteogenesis: Toward an aging in vivo bone regeneration model.

Tissue engineered scaffolds aimed at the repair of critical-sized bone defects lack adequate consideration for our aging society. Establishing an effective aged in vitro model that translates to animals is a significant unmet challenge. The in vivo aged environment is complex and highly nuanced, making it difficult to model in the context of bone repair. In this work, 3D nanofibrous scaffolds generated by the thermally-induced self-agglomeration (TISA) technique were functionalized with polydopamine nanoparticles (PD NPs) as a tool to improve drug binding capacity and scavenge reactive oxygen species (ROS), an excessive build-up that dampens the healing process in aged tissues. PD NPs were reduced by ascorbic acid (rPD) to further improve hydrogen peroxide (H2O2) scavenging capabilities, where we hypothesized that these functionalized scaffolds could rescue ROS-affected osteoblastic differentiation in vitro and improve new bone formation in an aged mouse model. rPDs demonstrated improved H2O2 scavenging activity compared to neat PD NPs, although both NP groups rescued the alkaline phosphatase activity (ALP) of MC3T3-E1 cells in presence of H2O2. Additionally, BMP2-induced osteogenic differentiation, both ALP and mineralization, was significantly improved in the presence of PD or rPD NPs on TISA scaffolds. While in vitro data showed favorable results aimed at improving osteogenic differentiation by PD or rPD NPs, in vivo studies did not note similar improvements in ectopic bone formation an aged model, suggesting that further nuance in material design is required to effectively translate to improved in vivo results in aged animal models.

Sodium alginate-based coaxial fibers synergistically integrate moisture actuation, length tracing, humidity sensing, and electric heating.

The development of wearable electronics has driven the need for smart fibers with advanced multifunctional synergy. In this paper, we present a design of a multifunctional coaxial fiber that is composed of a biopolymer-derived core and an MXene/silver nanowire (AgNW) sheath by wet spinning. The fiber synergistically integrates moisture actuation, length tracing, humidity sensing, and electric heating, making it highly promising for portable devices and protective systems. The biopolymer-derived core provides deformation for moisture-sensitive actuation, while the MXene/AgNW sheath with good conductivity enables the fiber to perform electric heating, humidity sensing, and self-sensing actuation. The coaxial fiber can be programmed to rapidly desorb water molecules to shrink to its original length by using the MXene/AgNW sheath as an electrical heater. We demonstrate proof-of-concept applications based on the multifunctional fibers for thermal physiotherapy and wound healing/monitoring. The sodium alginate@MXene-based coaxial fiber presents a promising solution for the next-generation of smart wearable electronics.

Heterogeneous organophotocatalytic HBr oxidation coupled with oxygen reduction for boosting bromination of arenes.

Developing mild photocatalytic bromination strategies using sustainable bromo source has been attracting intense interests, but there is still much room for improvement. Full utilization of redox centers of photocatalysts for efficient generation of Br+ species is the key. Herein we report heterogenous organophotocatalytic HBr oxidation coupled with oxygen reduction to furnish Br2 and H2O2 for effective bromination of arenes over Al2O3 supported perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA). Mechanism studies suggest that O-vacancy in Al2O3 can provide Lewis-acid-type anchoring sites for O2, enabling unexpected dual-electron transfer from anchored photoexcited PTCDA to chemically bound O2 to produce H2O2. The in-situ generated H2O2 and Br2 over redox centers work together to generate HBrO for bromination of arenes. This work provides new insights that heterogenization of organophotocatalysts can not only help to improve their stability and recyclability, but also endow them with the ability to trigger unusual reaction mode via cooperative catalysis with supports.

Giant Spin-Orbit Torque in Antiferromagnetic-Coupled Pt/[Co/Gd]N Multilayers with Suppressed Spin Dephasing and Robust Thermal Stability.

Manipulating magnetization via power-efficient spin-orbit torque (SOT) has garnered significant attention in the field of spin-based memory and logic devices. However, the damping-like SOT efficiency (ξDL) in heavy metal (HM)/ferromagnetic metal (FM) bilayers is relatively small due to the strong spin dephasing accompanied by additional spin polarization decay. Furthermore, the perpendicular magnetic anisotropy (PMA) originating from the HM/FM interface is constrained by the thickness of FM, which is unfavorable for thermal stability in practical applications. Consequently, it is valuable to develop systems that not only exhibit large ξDL but also balance thermal stability. In this work, we designed antiferromagnetic-coupled [Co/Gd]N multilayers, where staggered Co and Gd magnetic moments effectively suppress the spin dephasing and additional spin polarization decay. The ordered Co-Gd arrangements along the out-of-plane direction provide bulk PMA, endowing Pt/[Co/Gd]N high thermal stability. The SOT of Pt/[Co/Gd]N was systematically studied with N, demonstrating a significantly large ξDL of up to 0.66. The ξDL of Pt/[Co/Gd]N is greater than those of Pt/Co and Pt/ferrimagnetic alloys. This significant enhancement relies on the effective suppression of spin dephasing in [Co/Gd]N. Our work highlights that the antiferromagnetic-coupled [Co/Gd]N multilayer is a promising candidate for low-consumption and high-density spintronic devices.

Greater prosociality toward other human drivers than autonomous vehicles: Human drivers' discriminatory behavior in mixed traffic.

The development of autonomous vehicles (AVs) has rapidly evolved in recent years, aiming to gradually replace humans in driving tasks. However, road traffic is a complex environment involving numerous social interactions. As new road users, AVs may encounter different interactive situations from those of human drivers. This study therefore investigates whether human drivers show distinct degrees of prosociality toward AVs or other human drivers and whether AV behavioral patterns exert a relevant influence. Sixty-two drivers participated in the driving simulation experiment and interacted with other human drivers and different kinds of AVs (conservative, human-like, aggressive). The results show that human drivers are more willing to yield to other human drivers than to all kinds of AVs. Their braking reaction time is longer when yielding to AVs and their distance to AVs is shorter when choosing not to yield. AVs of different behavioral patterns do not significantly differ in yielding rate, but the braking reaction time of human-like AVs is longer than conservative AVs and shorter than aggressive AVs. These findings suggest that human drivers show more prosocial behaviors toward other human drivers than toward AVs. And human drivers' yielding behavior changes as the behavioral patterns of AVs changes. Accordingly, this study improves the understanding of how human drivers interact with nonliving road users such as AVs and how the former accept AVs with different driving styles on the road.

Immobilization of Perylenetetracarboxylic Dianhydride on Al2O3 for Efficiently Photocatalytic Sulfide Oxidation.

Perylenetetracarboxylic dianhydride (PTCDA) derivatives have received significant attention as molecule photocatalysts. However, the poor recyclability of molecule-type photocatalysts hinders their widespread applications. Herein, immobilization of PTCDA on Al2O3 was achieved by simply physical mixing, which not only dramatically improved their recyclability, but also surprisingly improved the reactivity. A mechanism study suggested that the photo-exited state (PTCDA*) of PTCDA could promote the oxidation of thioanisole to generate PTCDA•-, which sequentially reduces oxygen to furnish superoxide radicals to achieve the catalytic cycle. Herein, the immobilization support Al2O3 was able to facilitate the strong adsorption of thioanisole, thereby boosting the photocatalytic activity. This work provides a new insight that the immobilization of organic molecular photocatalysts on those supports with proper adsorption sites could furnish highly efficient, stable, and recyclable molecular-based heterogeneous photocatalysts.

Genomic epidemiology reveals multiple mechanisms of linezolid resistance in clinical enterococci in China.

BACKGROUND: Infections caused by linezolid-resistant enterococci (LRE) are clinically difficult to treat and threaten patient health. However, there is a lack of studies on long time-span LRE strains in China. For this reason, our study comprehensively revealed the resistance mechanisms of LRE strains collected in a Chinese tertiary care hospital from 2011 to 2022. METHODS: Enterococcal strains were screened and verified after retrospective analysis of microbial data. Subsequently, 65 LRE strains (61 Enterococcus faecalis and 4 Enterococcus faecium, MIC ≥ 8 µg/ml), 1 linezolid-intermediate Enterococcus faecium (MIC = 4 µg/ml) and 1 linezolid-susceptible Enterococcus faecium (MIC = 1.5 µg/ml) were submitted for whole-genome sequencing (WGS) analysis and bioinformatics analysis. RESULTS: The optrA gene was found to be the most common linezolid resistance mechanism in our study. We identified the wild-type OptrA and various OptrA variants in 98.5% of LRE strains (61 Enterococcus faecalis and 3 Enterococcus faecium). We also found one linezolid-resistant Enterococcus faecium strain carried both optrA and cfr(D) gene, while one linezolid-resistant Enterococcus faecium only harbored the poxtA gene. Most optrA genes (55/64) were located on plasmids, with impB-fexA-optrA, impB-fexA-optrA-erm(A), fexA-optrA-erm(A), and fexA-optrA segments. A minority of optrA genes (9/64) were found on chromosomes with the Tn6674-like platform. Besides, other possible linezolid resistance-associated mechanisms (mutations in the rplC and rplD genes) were also found in 26 enterococcal strains. CONCLUSIONS: Our study suggested that multiple mechanisms of linezolid resistance exist among clinical LRE strains in China.

LncRNA Gm15834 Aggravates Cardiac Hypertrophy by Interacting with Sam68 and Activating NF-κB Mediated Inflammation.

BACKGROUND: Cardiac hypertrophy is the common pathological process of multiple cardiovascular diseases. However, the molecular mechanisms of cardiac hypertrophy are unclear. Long non-coding RNA (lncRNA), a newly discovered type of transcript that has been demonstrated to function as crucial regulators in the development of cardiovascular diseases. This study revealed a novel regulatory pathway of lncRNA in cardiac hypertrophy. METHODS: The cardiac hypertrophy models were established by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) in HL-1 cardiomyocytes. Adeno-associated virus 9 (AAV9) in vivo and lncRNA Gm15834 and shRNA plasmids in vitro were used to overexpress and knock down lncRNA Gm15834. The myocardial tissue structure, cardiomyocyte area, cardiac function, protein expressions, and binding of lncRNA Gm15834 and Src-associated substrate during mitosis of 68 KDa (Sam68) were detected by hematoxylin and eosin (HE) staining, immunofluorescence staining, echocardiography, western blot and RNA immunoprecipitation (RIP), respectively. RESULTS: In cardiac hypertrophy models, inhibiting lncRNA Gm15834 could decrease Sam68 expression and nuclear factor kappa-B (NF-κB) mediated inflammatory activities in vivo and in vitro, but overexpressing lncRNA Gm15834 showed the opposite results. RIP experiments validated the binding activities between lncRNA Gm15834 and Sam68. Overexpression of Sam68 could counteract the anti-hypertrophy effects of lncRNA Gm15834 knockdown. Meanwhile, in vivo inhibition of lncRNA Gm15834 could inhibit Sam68 expression, reduce NF-κB mediated inflammatory activity and attenuate cardiac hypertrophy. CONCLUSION: Our study revealed a novel regulatory axis of cardiac hypertrophy, which comprised lncRNA Gm15834/Sam68/NF-κB/inflammation, shedding a new light for identifying therapy target of cardiac hypertrophy in clinic.

Can Human Growth Hormone Accelerate Tendon and Ligament Injury Recovery?

BACKGROUND: Studies involving human fibroblasts and use of human growth hormone (HGH) administration for injury recovery are limited. It is plausible that if the administration of HGH to human cells increased cellular proliferation and differentiation, then HGH might be able to assist in accelerating recovery from injury. HYPOTHESIS: HGH will increase proliferation and differentiation of human tendon and ligament fibroblasts in vitro based on both a single-dose and a sustained-dose model of HGH administration. STUDY DESIGN: Basic science cellular study. METHODS: Human tendon and ligament tissue were harvested from 24 patients. Tissue samples were digested with type I collagenase to isolate the target cell types. HGH was administered directly to isolated cells at doses ranging from 100 pg/mL to 10 µg/mL, either in a single-dose or a sustained-dose model. Proliferation was analyzed at days 4 and 7. Differentiation of ligament and tendon fibroblasts was assessed at day 14. RESULTS: Administration of a single-dose of HGH to both cell types demonstrated similar or inferior cellular proliferation compared with controls after 7 days. For the sustained-dosing model of ligament fibroblasts, only the 100 ng/mL concentration demonstrated at least statistically similar or improved proliferation compared with controls. When examining the 100 ng/mL HGH concentration with larger sample sizes, cellular proliferation was not improved over controls for any cell type for the single- or sustained-dosing models. Proliferation for tendon fibroblasts was either similar or inferior to the control group at all concentrations of HGH. There was no clear dose-response relationship demonstrating enhanced collagen production with administration of HGH to suggest it enhances injury recovery. CONCLUSION: HGH administered to human tendon and ligament fibroblasts does not appear to positively affect cellular proliferation and differentiation. CLINICAL RELEVANCE: This study does not support the use of HGH for accelerating recovery from injury.

MicroRNA-200c Release from Gelatin-Coated 3D-Printed PCL Scaffolds Enhances Bone Regeneration.

The fabrication of clinically relevant synthetic bone grafts relies on combining multiple biodegradable biomaterials to create a structure that supports the regeneration of defects while delivering osteogenic biomolecules that enhance regeneration. MicroRNA-200c (miR-200c) functions as a potent osteoinductive biomolecule to enhance osteogenic differentiation and bone formation; however, synthetic tissue-engineered bone grafts that sustain the delivery of miR-200c for bone regeneration have not yet been evaluated. In this study, we created novel, multimaterial, synthetic bone grafts from gelatin-coated 3D-printed polycaprolactone (PCL) scaffolds. We attempted to optimize the release of pDNA encoding miR-200c by varying gelatin types, concentrations, and polymer crosslinking materials to improve its functions for bone regeneration. We revealed that by modulating gelatin type, coating material concentration, and polymer crosslinking, we effectively altered the release rates of pDNA encoding miR-200c, which promoted osteogenic differentiation in vitro and bone regeneration in a critical-sized calvarial bone defect animal model. We also demonstrated that crosslinking the gelatin coatings on the PCL scaffolds with low-concentration glutaraldehyde was biocompatible and increased cell attachment. These results strongly indicate the potential use of gelatin-based systems for pDNA encoding microRNA delivery in gene therapy and further demonstrate the effectiveness of miR-200c for enhancing bone regeneration from synthetic bone grafts.

Triptolide attenuates cardiac remodeling by inhibiting pyroptosis and EndMT via modulating USP14/Keap1/Nrf2 pathway.

Background: Cardiac remodeling is a common pathological feature in many cardiac diseases, characterized by cardiac hypertrophy and fibrosis. Triptolide (TP) is a natural compound derived from Tripterygium wilfordii Hook F. However, the related mechanism of it in cardiac remodeling has not been fully understood. Methods and results: Transverse aortic constriction (TAC)-induced cardiac hypertrophic mouse model and angiotensin II (Ang II)-induced cardiomyocytes hypertrophic model were performed. Firstly, the results indicate that TP can improve cardiac function, decreased cardiomyocyte surface area and fibrosis area, as well as lowered the protein expressions of brain natriuretic peptide (BNP), ß-major histocompatibility complex (ß-MHC), type I and III collagen (Col I and III). Secondly, TP suppressed cardiac pyroptosis, and decreased the levels of Interleukin-1ß (IL-1ß), Interleukin-18 (IL-18) by Enzyme-linked immunosorbent assay (ELISA), and pyroptosis-associated proteins. Furthermore, TP enhanced the expressions of Nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase 1 (HO-1). Interestingly, when Nrf2 was silenced by siRNA, TP lost its properties of reducing pyroptosis and cardiac hypertrophy. In addition, in the Transforming Growth Factor ß1 (TGF-ß1)-induced primary human coronary artery endothelial cells (HCAEC) model, TP was found to inhibit the process of endothelial-to-mesenchymal transition (EndMT), characterized by the loss of endothelial-specific markers and the gain of mesenchymal markers. This was accompanied by a suppression of Slug, Snail, and Twist expression. Meanwhile, the inhibitory effect of TP on EndMT was weakened when Nrf2 was silenced by siRNA. Lastly, potential targets of TP were identified through network pharmacology analysis, and found that Ubiquitin-Specific Protease 14 (USP14) was one of them. Simultaneously, the data indicated that decrease the upregulation of USP14 and Kelch-like ECH-Associated Protein 1 (Keap1) caused by cardiac remodeling. However, Keap1 was decreased and Nrf2 was increased when USP14 was silenced. Furthermore, CoIP analysis showed that USP14 directly interacts with Keap1. Conclusion: TP can observably reduce pyroptosis and EndMT by targeting the USP14/Keap1/Nrf2 pathway, thereby significantly attenuating cardiac remodeling.

Biomimetic Therapeutics for Bone Regeneration: A Perspective on Antiaging Strategies.

Advances in modern medicine and the significant reduction in infant mortality have steadily increased the population's lifespan. As more and more people in the world grow older, incidence of chronic, noncommunicable disease is anticipated to drastically increase. Recent studies have shown that improving the health of the aging population is anticipated to provide the most cost-effective and impactful improvement in quality of life during aging-driven disease. In bone, aging is tightly linked to increased risk of fracture, and markedly decreased regenerative potential, deeming it critical to develop therapeutics to improve aging-driven bone regeneration. Biomimetics offer a cost-effective method in regenerative therapeutics for bone, where there are numerous innovations improving outcomes in young models, but adapting biomimetics to aged models is still a challenge. Chronic inflammation, accumulation of reactive oxygen species, and cellular senescence are among three of the more unique challenges facing aging-induced defect repair. This review dissects many of the innovative biomimetic approaches research groups have taken to tackle these challenges, and discusses the further uncertainties that need to be addressed to push the field further. Through these research innovations, it can be noted that biomimetic therapeutics hold great potential for the future of aging-complicated defect repair.