Assembly and comparative analysis of the complete mitochondrial and chloroplast genome of Cyperus stoloniferus (Cyperaceae), a coastal plant possessing saline-alkali tolerance.

BACKGROUND: Cyperus stoloniferus is an important species in coastal ecosystems and possesses economic and ecological value. To elucidate the structural characteristics, variation, and evolution of the organelle genome of C. stoloniferus, we sequenced, assembled, and compared its mitochondrial and chloroplast genomes. RESULTS: We assembled the mitochondrial and chloroplast genomes of C. stoloniferus. The total length of the mitochondrial genome (mtDNA) was 927,413 bp, with a GC content of 40.59%. It consists of two circular DNAs, including 37 protein-coding genes (PCGs), 22 tRNAs, and five rRNAs. The length of the chloroplast genome (cpDNA) was 186,204 bp, containing 93 PCGs, 40 tRNAs, and 8 rRNAs. The mtDNA and cpDNA contained 81 and 129 tandem repeats, respectively, and 346 and 1,170 dispersed repeats, respectively, both of which have 270 simple sequence repeats. The third high-frequency codon (RSCU > 1) in the organellar genome tended to end at A or U, whereas the low-frequency codon (RSCU < 1) tended to end at G or C. The RNA editing sites of the PCGs were relatively few, with only 9 and 23 sites in the mtDNA and cpDNA, respectively. A total of 28 mitochondrial plastid DNAs (MTPTs) in the mtDNA were derived from cpDNA, including three complete trnT-GGU, trnH-GUG, and trnS-GCU. Phylogeny and collinearity indicated that the relationship between C. stoloniferus and C. rotundus are closest. The mitochondrial rns gene exhibited the greatest nucleotide variability, whereas the chloroplast gene with the greatest nucleotide variability was infA. Most PCGs in the organellar genome are negatively selected and highly evolutionarily conserved. Only six mitochondrial genes and two chloroplast genes exhibited Ka/Ks > 1; in particular, atp9, atp6, and rps7 may have undergone potential positive selection. CONCLUSION: We assembled and validated the mtDNA of C. stoloniferus, which contains a 15,034 bp reverse complementary sequence. The organelle genome sequence of C. stoloniferus provides valuable genomic resources for species identification, evolution, and comparative genomic research in Cyperaceae.

Total hip arthroplasty with porous tantalum trabecular metal pads in patients with Crowe IV developmental dysplasia of the hip: a midterm followup study.

PURPOSE: Crowe IV developmental dysplasia of the hip (DDH) is a catastrophic hip disease. Moreover, obtaining ideal clinical efficacy in conventional total hip arthroplasty (THA) is often difficult. In this study, we aimed to assess the mid-term clinical results of THA with porous tantalum trabecular metal (TM) pads for acetabular reconstruction in the treatment of Crowe IV DDH. METHODS: A cohort of 28 patients (32 hips) diagnosed with Crowe type IV DDH who underwent acetabular reconstruction during THA using TM pads with scheduled follow-up between 2011 and 2018, were included in this study. Eight cases were men and 24 were women, with a mean age of 48.4 years (range, 36-72 years) and a mean follow-up was 74.3 months (range, 42-132 months). All patients underwent acetabular reconstruction using TM pads and total hip replacement with subtrochanteric osteotomy. RESULTS: At the final follow-up, 28 hips (87.5%) demonstrated mild or no postoperative limping. The Harris Hip Score improved from 58.4 ± 10.6 preoperatively to 85.6 ± 8.9. The mean pain, stiffness, and function scores on the Western Ontario and McMaster University Osteoarthritis index were 86.5 ± 10.2, 87.3 ± 12.4 and 85.4 ± 11.6 respectively. The mean score of patient satisfaction was 90.4 ± 7.6. Additionally, the SF-12 physical summary score was 41.8 ± 5.6 and the SF-12 mental summary score was 51.6 ± 5.4. TM construct survivorship due to all-cause failure was 90.6% at 5 years with 3 hips at risk, 87.5% at 10 years with 4 hips at risk. The survivorship due to failure from aseptic loosening was 96.9% at 5 years with 1hips at risk and 93.75% at 10 years with 2 hips at risk. CONCLUSION: This study demonstrated satisfactory mid-term clinical and radiological results with the application of TM pads for acetabular reconstruction combined with THA in patients with Crowe IV DDH. TRIAL REGISTRATION NUMBER: ChiCTR1800014526, Date: 18/01/2018.

Hypoxia conduces the glioma progression by inducing M2 macrophage polarization via elevating TNFSF9 level in a histone-lactylation-dependent manner.

Hypoxia is a critical factor contributing to a poor prognosis and challenging glioma therapy. Previous studies have indicated that hypoxia drives M2 polarization of macrophages and promotes cancer progression in various solid tumors. However, the more complex and diverse mechanisms underlying this process remain to be elucidated. Here, we aimed to examine the functions of hypoxia in gliomas and preliminarily investigate the underlying mechanisms of M2 macrophage polarization caused by hypoxia. We found that hypoxia significantly enhances the malignant phenotypes of U87 and U251 cells by regulating glycolysis. In addition, hypoxia-mediated accumulation of the glycolysis product (lactic acid, LA), which is subsequently absorbed by macrophages to induce its M2 polarization, and this process is reverted by both the glycolysis inhibitor and silenced monocarboxylate transporter (MCT-1) in macrophages, indicating that M2 macrophages polarization is associated with the promotion of glycolysis by hypoxia. Interestingly, we also found that hypoxia-mediated LA accumulation in glioma cells upon uptake by macrophages upregulates H3K18La expression and promotes tumor necrosis factor superfamily member 9 (TNFSF9) expression in a histone-lactylation-dependent manner based on the results of ChIP-seq enrichment analysis. Subsequent in vitro and in vivo experiments further indicated that TNFSF9 facilitated glioma progression. Mechanistically, hypoxia-mediated LA accumulation in glioma cells is taken up by macrophages and then induces its M2 macrophage polarization by regulating TNFSF9 expression via MCT-1/H3K18La signaling, thus facilitating the malignant progression of gliomas.

Comparison of the Efficacy of Different Combined Therapies Based on Modified Core Decompression for the Treatment of Early-stage Nontraumatic Osteonecrosis of the Femoral Head: A Retrospective Clinical Study.

OBJECTIVE: Osteonecrosis of the femoral head (ONFH) is a severe orthopedic disease, which may cause severe hip dysfunction in later stage. Therefore, it is necessary to treat nontraumatic ONFH during the early stages. The aim of this study was to evaluate the clinical efficacy and survival rates of different combined therapies based on modified core decompression (CD) for early-stage nontraumatic ONFH. METHODS: This retrospective cohort study assessed 397 hips with ONFH who underwent different combined therapies based on modified CD in our institution between January 2010 and December 2017. Patients were classified into six groups based on treatment modalities, and were followed up at 1 year and 5 years postoperatively. Clinical outcomes, including Harris hip score (HHS) and Western Ontario and McMaster Universities osteoarthritis index (WOMAC), were compared to evaluate the hip function and quick rehabilitation effect. Radiographic progression of ONFH and the incidence of total hip arthroplasty were analyzed to evaluate the survival rate of ONFH postoperatively. Statistical analyses were mainly performed with Kruskal-Wallis test, chi-square test and Kaplan-Meier method. RESULTS: HHS increased significantly in all groups but showed no significant differences among the six groups in the first years. The nonvascularized allogeneic fibula with bone grafting (NVAF + BG) and percutaneous femoral neck-head fenestration with bone grafting via the direct anterior approach (DAA + BG) groups had significantly higher HHS (p = 0.010; p = 0.025) and WOMAC function score (p < 0.001; p = 0.012) than the CD group 5 years postoperatively. Compared with the CD group, all the other groups showed statistically significant differences in radiographic progression (p < 0.001) and a higher survival rate with no significant difference (p = 0.569). CONCLUSION: Our study demonstrates the potential use of NVAF + BG and DAA + BG, may serve as a promising combined therapy for the treatment of early-stage nontraumatic ONFH.

Exploring optimal pathways for enterprise procurement management systems based on fast neural modeling and semantic segmentation.

Corporate procurement management assumes a pivotal role within the contemporary business landscape, yet confronts an array of challenges as markets continue to evolve and globalize. Conventional procurement management systems frequently grapple with issues of inefficiency, resource depletion, and noncompliance, necessitating the exploration of innovative avenues for optimization. This paper delves into the realm of risk mitigation associated with collusion behavior in the administration of intelligent procurement systems, presenting a novel procurement collusion identification model founded on a convolutional neural network (CNN) with reinforcement learning techniques. This framework commences with the application of a CNN and Long Short-Term Memory (LSTM) network for in-depth feature analysis and initial identification of historical procurement data, subsequently leveraging reinforcement learning methodologies to enhance the model's autonomy and intelligence for the purpose of optimization. Throughout the experimental phase, diverse domains of procurement data were meticulously selected for analysis. The empirical findings unequivocally demonstrate the model's proficiency, with an average recognition accuracy of 95.1% across five publicly available datasets. This performance surpasses existing machine learning methodologies employed in contemporary research and common recognition networks, thereby offering a pioneering reference point for the intelligent administration and optimization of future procurement systems.

Will advancement in technologies bring fear and damage human employment? Evidence from China's manufacturing industry.

Advancement in technologies such as robotic industries and artificial intelligence bring fear among human being that jobs will be substituted by robots. Base on the panel data of 28 China's manufacturing industries, this research analyzed the impact of technical progress bias on employment. First, we calculate the technical progress bias index of 28 industries base on the stochastic frontier model with transcendental logarithm function found 16 industries were toward the skilled labor while the remaining 12 industries were toward the unskilled labor. Second, the empirical results show that technical progress bias has a positive impact on the total manufacturing employment and significant positive effect on the unskilled labor, while no significant impact on skilled labor employment. Third, the threshold effect test proves that if taking industry value-added per capita or R&D capital stock as threshold variable, the threshold about the impact exist, making the impact on skilled labor was insignificant.

Molecular mechanisms of circular RNA in breast cancer: a narrative review.

Background and Objective: Breast cancer is presently the most prevalent cancer and the leading cause of cancer-related deaths in women worldwide. Circular RNA (circRNA) is a class of closed circRNAs lacking a 5'-end cap structure and a 3'-end polyA tail, which is highly stable and widely involved in a variety of pathophysiological processes such as cell proliferation, differentiation, and apoptosis. In recent years, accumulating studies have shown that circRNAs play an important role in the development and prognosis of breast cancer, but there are fewer literature reviews on their intrinsic molecular mechanisms which is the aim of this study. Methods: This review synthesizes the findings of literature retrieved from searches of PubMed and Google Scholar databases, hand searches, and authoritative texts. Citations mainly originate from the past 3 years. The articles need to describe the role of circRNA in breast cancer; no language restrictions were imposed. Key Content and Findings: This review summarizes the latest relevant literature and systematically reviews the four main mechanisms of circRNA in breast cancer from the perspective of circRNA function. At the same time, we describe the formation mechanism, characterization, and biological functions of circRNAs. Conclusions: We reviewed the status of actual knowledge about circRNA biogenesis and functions and summarized novel findings regarding the molecular mechanism of circRNA in breast cancer. Meanwhile, this review explores the possibility of circRNAs for becoming new biodiagnostic indicators and therapeutic targets in breast cancer.

The synergetic effect of alginate-derived hydrogels and metal-phenolic nanospheres for chronic wound therapy.

Management of diabetic wounds presents a global health challenge due to elevated levels of ROS in the wound microenvironment, persistent dysregulation of inflammation modulation, and limitations in commercially available dressings. Addressing this issue, we have developed a pH-responsive and glucose-sensitive multifunctional hydrogel dressing that dynamically responds to the wound microenvironment and enables on-demand drug release. The dressing incorporates a matrix material based on aminophenylboronic acid-functionalized alginate and a polyhydroxy polymer, alongside an enhancer phase consisting of self-assembled metal-phenol coordination nanospheres formed by tannic acid and iron ions. Using the dynamic borate ester bonds and catechol-metal ion coordination bonds, the dressing exhibits remarkable shape adaptability, self-healing capability, tissue adhesiveness, antioxidant activity, and photothermal responsiveness, without additional curatives or crosslinking agents. As a wound dressing, it elicits macrophage polarization towards an anti-inflammatory phenotype while maintaining long-lasting antimicrobial effects. In a diabetic mouse model of full-thickness wound infections, it effectively mitigated inflammation and vascular damage, significantly expediting the wound healing process with a commendable 97.7% wound closure rate. This work provides a new direction for developing multifunctional smart hydrogel dressings that can accelerate diabetic wound healing for human health.

Nanotexture and crystal phase regulation for synergistic enhancement in re-endothelialization on medical pure titanium surface.

Re-endothelialization has been recognized as a promising strategy to address the tissue hyperplasia and subsequent restenosis which are major complications associated with vascular implant/interventional titanium devices. However, the uncontrollable over-proliferation of smooth muscle cells (SMCs) limits the clinical application of numerous modified strategies. Herein, a novel modified strategy involving with a two-step anodic oxidation and annealing treatment was proposed to achieve rapid re-endothelialization function regulated by regular honeycomb nanotexture and specific anatase phase on the titanium surface. Theoretical calculation revealed that the presence of nanotexture reduced the polar component of surface energy, while the generation of anatase significantly enhanced the polar component and total surface energy. Meanwhile, the modified surface with regular nanotexture and anatase phase produced positive effect on the expression of CD31, VE-Cadherin and down-regulated α-SMA proteins expression, indicating excellent capacity of pro-endothelial regeneration and inhibition of SMCs proliferation and migration. One-month in vivo implantation in rabbit carotid arteries further confirmed that modified tube implant surface effectively accelerated confluent endothelial monolayer formation and promoted native-like endothelium tissue regeneration. By contrast, original titanium tube implant induced a disorganized tissue proliferation in the lumen with a high risk of restenosis. Collectively, this study opens us an alternative route to achieve the function that selectively promotes endothelial cells (ECs) growth and suppresses SMCs on the medical titanium surface, which has a great potential in facilitating re-endothelialization on the surface of blood-contacting titanium implant.

Immune regulation enhances osteogenesis and angiogenesis using an injectable thiolated hyaluronic acid hydrogel with lithium-doped nano-hydroxyapatite (Li-nHA) delivery for osteonecrosis.

Osteonecrosis is a devastating orthopedic disease in clinic that generally occurs in the femoral head associating with corticosteroid use up to 49 % in patients. In particular, glucocorticoids induced osteonecrosis of the femoral head is closely related to the local immune response that characterized by abnormal macrophage activation and inflammatory cell infiltration at the necrotic site, forming a pro-inflammatory microenvironment dominated by M1 macrophages, and thus leads to failure of bone repair and regeneration. Here, we report a bone regeneration strategy that constructs an immune regulatory biomaterial platform using an injectable thiolated hyaluronic acid hydrogel with lithium-doped nano-hydroxyapatite (Li-nHA@Gel) delivery for osteonecrosis treatment. Li-nHA@Gel achieved a sustain and longterm release of Li ions, which might enhance M2 macrophage polarization through the activation of the JAK1/STAT6/STAT3 signaling pathway, and the following induced pro-repair immune microenvironment mediated the enhancement of the osteogenic and angiogenic differentiation. Moreover, both in vitro and in vivo studies indicated that Li-nHA@Gel enhanced M2 macrophage polarization, osteogenesis, and angiogenesis, and thus promoted the bone and blood vessel formation. Taken together, this novel bone immunomodulatory biomaterial platform that promotes bone regeneration by enhancing M2 macrophage polarization, osteogenesis, and angiogenesis could be a promising strategy for osteonecrosis treatment.

Dipterocarpoidae genomics reveal their demography and adaptations to Asian rainforests.

Dipterocarpoideae species form the emergent layer of Asian rainforests. They are the indicator species for Asian rainforest distribution, but they are severely threatened. Here, to understand their adaptation and population decline, we assemble high-quality genomes of seven Dipterocarpoideae species including two autotetraploid species. We estimate the divergence time between Dipterocarpoideae and Malvaceae and within Dipterocarpoideae to be 108.2 (97.8‒118.2) and 88.4 (77.7‒102.9) million years ago, and we identify a whole genome duplication event preceding dipterocarp lineage diversification. We find several genes that showed a signature of selection, likely associated with the adaptation to Asian rainforests. By resequencing of two endangered species, we detect an expansion of effective population size after the last glacial period and a recent sharp decline coinciding with the history of local human activities. Our findings contribute to understanding the diversification and adaptation of dipterocarps and highlight anthropogenic disturbances as a major factor in their endangered status.

Rapamycin Alleviates Neuronal Injury and Modulates Microglial Activation After Cerebral Ischemia.

Neurons and microglia are sensitive to cerebral microcirculation and their responses play a crucial part in the pathological processes, while they are also the main target cells of many drugs used to treat brain diseases. Rapamycin exhibits beneficial effects in many diseases; however, whether it can affect neuronal injury or alter the microglial activation after global cerebral ischemia remains unclear. In this study, we performed global cerebral ischemia combined with rapamycin treatment in CX3CR1GFP/+ mice and explored the effects of rapamycin on neuronal deficit and microglial activation. Our results showed that rapamycin reduced neuronal loss, neurodegeneration, and ultrastructural damage after ischemia by histological staining and transmission electron microscopy (TEM). Interestingly, rapamycin suppressed de-ramification and proliferation of microglia and reduced the density of microglia. Immunofluorescence staining indicated that rapamycin skewed microglial polarization toward an anti-inflammatory state. Furthermore, rapamycin as well suppressed the activation of astrocytes. Meanwhile, quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed a significant reduction of pro-inflammatory factors as well as an elevation of anti-inflammatory factors upon rapamycin treatment. As a result of these effects, behavioral tests showed that rapamycin significantly alleviated the brain injury after stroke. Together, our study suggested that rapamycin attenuated neuronal injury, altered microglial activation state, and provided a more beneficial immune microenvironment for the brain, which could be used as a promising therapeutic approach to treat ischemic cerebrovascular diseases.

Reduced Graphene Oxide/Cellulose Sodium Aerogel-Supported Eutectic Phase Change Material Gel Demonstrating Superior Energy Conversion and Storage Capacity toward High-Performance Personal Thermal Management.

By virtue of their capacity to absorb and release energy during the phase change process, phase change materials (PCMs) are ideal for personal thermal management (PTM). The combination of reduced graphene oxide/cellulose sodium aerogel (rGCA) and lauric acid/myristic acid binary eutectic phase change gel (LMG) creates a composite phase change material that possesses outstanding photothermal conversion capabilities, electro-thermal conversion capabilities, energy storage capabilities, and shape-stable performance. The results showed that rGCA had a maximum adsorption efficiency of 99.7% with a melting latent heat of 124.6 J g-1. The high absorption rate of rGCA to LMG is a result of the capillary force, pore characteristics, hydrogen bonding, and the π-π interaction. Notably, rGCA and LMG composite material (rGCG) exhibited an excellent photothermal conversion efficiency of 96.5% and electro-thermal conversion of 82.3%. Results indicate that binary eutectic phase change materials are more suitable for temperature regulation than single phase change materials, making them more suitable for PTM. It is anticipated that the innovative thermal comfort solution, which provides thermal shielding, thermal energy storage, self-supporting characteristics, and wearability, will offer new possibilities for the next generation of wearable PTMs.

Nuclear PARP1-Targeted Photosensitizer as a Dual-Mode DNA-Damaging Agent and Immune Activator for Tumor Ablation.

Photodynamic therapy is a promising cancer therapeutic method that can damage DNA via photoinduced reactive oxygen species production. However, tumor cells can initiate DNA repair pathways to resist oxidative damage. In this study, a nuclear-targeted photosensitizer PARP-PS with a poly (ADP-ribose) polymerase 1 (PARP1) inhibitory effect is developed based on the reported PARP1 inhibitor, rucaparib. As a dual-mode DNA-damaging agent, PARP-PS damages DNA upon photoirradiation and enhances oxidative DNA damage by blocking the DNA repair pathway via PARP1 inhibition and degradation. Both in vitro and in vivo investigations demonstrate that PARP-PS exhibits high antitumor activity with few side effects in breast cancer. In addition, PARP-PS can act as an immunogenic cell death inducer to activate immune responses characterized by the promotion of cytotoxic T lymphocyte activation and tumor infiltration. Therefore, PARP-PS is a potential multimodal antitumor agent with synergistic phototherapeutic, chemotherapeutic, and immunotherapeutic effects.

Molecular Biology Mechanisms and Emerging Therapeutics of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is conventionally characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), accounting for approximately 15-20% of all breast cancers. Compared to other molecular phenotypes, TNBC is typically associated with high malignancy and poor prognosis. Cytotoxic agents have been the mainstay of treatment for the past few decades due to the lack of definitive targets and limited therapeutic interventions. However, recent developments have demonstrated that TNBC has peculiar molecular classifications and biomarkers, which provide the possibility of evolving treatment from basic cytotoxic chemotherapy to an expanding domain of targeted therapies. This review presents a framework for understanding the current clinical experience surrounding molecular biology mechanisms in TNBC (Figure 1). Including immunotherapy, polymerase (PARP) and PI3K/AKT pathway inhibitors, antibody-drug conjugates, and androgen receptor (AR) blockade. Additionally, the role of miRNA therapeutics targeting TNBC and potential strategies targeting cancer stem cells (CSCs) are discussed and highlighted. As more and more treatments arise on the horizon, we believe that patients with TNBC will have a new sense of hope.

HutZ is required for efficient heme utilization and contributes to the pathogenicity of Avibacterium paragallinarum.

Avibacterium paragallinarum is the pathogen that causes infectious coryza, a highly contagious respiratory disease that brings a serious threat to chickens. Heme utilization systems play an important role in bacterial adversity adaptation and pathogenicity, and our previous report found the presence of heme utilization (HutZ) in Av. paragallinarum. However, little is known about the function of HutZ in Av. paragallinarum. In this study, the HutZ mutant strain of Av. paragallinarum was successfully developed and identified by PCR and western blot analysis. Mutation of HutZ significantly retards bacterial growth under reduced iron conditions, indicating the regulatory role of HutZ on growth and iron acquisition. Notably, the HutZ mutant strain had slower growth than the wild-type strain when heme was provided as the sole source of iron; thus, HutZ is crucial for heme utilization in Av. paragallinarum. Moreover, the HutZ mutant strain exhibited a markedly compromised tolerance to acid stress compared to the wild-type strain. Pathogenicity analysis showed that mutation of HutZ significantly weakened the ability of bacteria to invade and reproduce in host macrophage cells in vitro. Furthermore, the HutZ mutation could significantly decrease the bacterial virulence in chickens, which displayed lower morbidity and milder clinical symptoms. Hence, this is the first study to demonstrate in-depth the essential roles of HutZ on iron homeostasis and pathogenesis of Av. paragallinarum, which provides novel insight into advances of new prophylactic vaccines against this kind of bacteria.ImportanceHeme utilization (HutZ) protein has been characterized as an important heme-degrading enzyme that is critical for the cleavage of heme to biliverdin via verdoheme and can release iron to be used by bacteria. The interaction between HutZ and Av. paragallinarum is still unknown. Here, we unraveled the role of HutZ on the growth, iron acquisition, heme utilization, and resistance to acidic stress in Av. paragallinarum. We also uncovered the importance of HutZ for the success of Av. paragallinarum infection and provided new clues to the pathogenesis strategies of this organism. This work constitutes a relevant step toward an understanding of the role of HutZ protein as a master virulence factor. Therefore, this study is of great importance for understanding the mechanisms underlying Av. paragallinarum virulence and may contribute to therapeutic applications.

Ligand-Directed Photodegradation of Interacting Proteins: Oxidative HER2/HER3 Heterodimer Degradation with a Lapatinib-Derived Photosensitizer.

In this work, we described a photocatalytic approach, termed ligand-directed photodegradation of interacting proteins (LDPIP), for efficient protein-protein heterodimer degradation. This LDPIP approach utilizes a combination of a photosensitizing protein ligand and appropriate light and molecular oxygen to induce oxidative damage to the ligand-binding protein as well as its interacting protein partner. As a showcase study, a photosensitizing HER2 ligand HER-PS-I was rationally designed based on the FDA-approved HER2 inhibitor lapatinib to efficiently degrade HER2 together with its interacting protein partner HER3, which is thought to induce HER2-targeted therapy resistance and difficult to target by small molecules. HER-PS-I exhibited excellent anticancer activity against drug-resistant MDA-MB-453 cells and its three-dimensional multicellular spheroids. We hope that this LDPIP approach would find more applications in degrading proteins that are thought undruggable or difficult to drug.

Engineered Exosome-Functionalized Extracellular Matrix-Mimicking Hydrogel for Promoting Bone Repair in Glucocorticoid-Induced Osteonecrosis of the Femoral Head.

Glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH) is a serious bone disease that often affects young individuals. Bone grafting combined with core decompression is mainly used in the clinic to treat GC-ONFH. However, the outcome is usually not satisfactory, as expected. Here, we report an engineered exosome-functionalized extracellular matrix-mimicking hydrogel for promoting bone repair in GC-ONFH. Compared with Con-Exo, exosomes secreted by bone marrow stem cells (BMSCs) in conventional culture medium, the engineered Li-Exo, exosomes derived from bone marrow stem cells (BMSCs) stimulated by lithium ions, promoted macrophage M2 polarization while inhibiting macrophage M1 polarization. Furthermore, inspired by the fact that hydrogels can serve as desirable carriers of exosomes to facilitate their release in a sustained manner for improved therapeutic efficiency and in vivo application, an extracellular matrix (ECM)-mimicking hydrogel (Lightgel) composed of methacryloylated type I collagen was employed to incorporate Li-Exo/Con-Exo to construct the Lightgel-Li-Exo hydrogel/Lightgel-Con-Exo hydrogel. In vitro studies showed that the Lightgel-Li-Exo hydrogel had the most significant pro-osteogenic and pro-angiogenic activity. Finally, we evaluated the therapeutic effects of the hydrogel in rat models of GC-ONFH. As a result, the Lightgel-Li-Exo hydrogel had the most significant effect on enhancing macrophage M2 polarization, osteogenesis, and angiogenesis to promote bone repair in GC-ONFH. Taken together, this novel engineered exosome-functionalized ECM-mimicking hydrogel could be a promising strategy for osteonecrosis treatment.

Neuroprotective Effects of Vinpocetine Against Ischemia-Reperfusion Injury Via Inhibiting NLRP3 Inflammasome Signaling Pathway.

Ischemic stroke is one of the main causes of serious disability and death worldwide. NLRP3 inflammasome is an intracellular pattern recognition receptor composed of polyprotein complex, which participates in mediating a series of inflammatory responses and is considered as a potential target for the treatment of ischemic stroke. Vinpocetine, a derivative of vincamine, has been widely used in the prevention and treatment of ischemic stroke. However, the therapeutic mechanism of vinpocetine is not clear, and its effect on NLRP3 inflammasome remains to be determined. In this study, we used the mouse model of transient middle cerebral artery occlusion (tMCAO) to simulate the occurrence of ischemic stroke. Different doses of vinpocetine (5, 10, 15 mg/kg/d) were injected intraperitoneally for 3 days after ischemia-reperfusion in mice. The effects of different doses of vinpocetine on the degree of ischemia-reperfusion injury in mice were observed by TTC staining and modified neurological severity score scale, and the optimal dose was determined. Then, based on this optimal dose, we observed the effects of vinpocetine on apoptosis, microglial proliferation and NLRP3 inflammasome. In addition, we compared the effects of vinpocetine and MCC950 (a specific inhibitor of NLRP3 inflammasome) on NLRP3 inflammasome. Our results show that vinpocetine can effectively reduce the infarct volume and promote the recovery of behavioral function in stroke mice, and the maximal beneficial effects were observed at the dose of 10 mg/kg/d. Vinpocetine can effectively inhibit the apoptosis of peri-infarct neurons, promote the expression of Bcl-2, inhibit the expression of Bax and Cleaved Caspase-3, and reduce the proliferation of peri-infarct microglia. In addition, vinpocetine, like MCC950, can reduce the expression of NLRP3 inflammasome. Therefore, vinpocetine can effectively alleviate the ischemia-reperfusion injury in mice, and the inhibition of NLRP3 inflammasome may be an important therapeutic mechanism of vinpocetine.