Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.

Aging skin, vulnerable to age-related defects, is poor in wound repair. Metabolic regulation in accumulated senescent cells (SnCs) with aging is essential for tissue homeostasis, and adequate ATP is important in cell activation for aged tissue repair. Strategies for ATP metabolism intervention hold prospects for therapeutic advances. Here, we found energy metabolic changes in aging skin from patients and mice. Our data show that metformin engineered EV (Met-EV) can enhance aged mouse skin repair, as well as ameliorate cellular senescence and restore cell dysfunctions. Notably, ATP metabolism was remodeled as reduced glycolysis and enhanced OXPHOS after Met-EV treatment. We show Met-EV rescue senescence-induced mitochondria dysfunctions and mitophagy suppressions, indicating the role of Met-EV in remodeling mitochondrial functions via mitophagy for adequate ATP production in aged tissue repair. Our results reveal the mechanism for SnCs rejuvenation by EV and suggest the disturbed energy metabolism, essential in age-related defects, to be a potential therapeutic target for facilitating aged tissue repair.

BMSCs-laden mechanically reinforced bioactive sodium alginate composite hydrogel microspheres for minimally invasive bone repair.

Minimally invasive, efficient, and satisfactory treatment for irregular and lacunar bone defects is still a challenge. Alginate hydrogels serve as promising stem cell (SC) delivery systems for bone regeneration but are limited by low cellular viability, poor osteogenic differentiation, and insufficient mechanical support. Herein, we developed a BMSCs-laden mechanically reinforced bioactive sodium alginate composite hydrogel microspheres (BCHMs) system via a microfluidic method that possesses 1) a uniform size and good injectability to meet clinical bone defects with complex shapes, 2) high cellular viability maintenance and further osteogenic induction capacity, and 3) improved mechanical properties. As the main matrix, the sodium alginate hydrogel maintains the high viability of encapsulated BMSCs and efficient substance exchange. Enhanced mechanical properties and osteogenic differentiation of the BCHMs in vitro were observed with xonotlite (Ca6Si6O17(OH)2, CSH) nanowires incorporated. Furthermore, BCHMs with 12.5 % CSH were injected into rat femoral bone defects, and satisfactory in situ regeneration outcomes were observed. Overall, it is believed that BCHMs expand the application of polysaccharide science and provide a promising injectable bone substitute for minimally invasive bone repair.

Comprehensive analysis of the prognostic value and immunological role of IDO1 gene in pan-cancer.

OBJECTIVE: It has been demonstrated that IDO1, a target of immune checkpoint inhibition, functions as an oncogene in the majority of human malignancies. IDO1's function in human pan-cancers hasn't been thoroughly studied, though. MATERIALS AND METHODS: The Kaplan-Meier (K-M) and COX analyses were applied to the survival analysis. Furthermore, we used Spearman's correlation analysis to examine the associations between IDO1 and microsatellite instability (MSI), DNA methyltransferases (DNMTs), tumor mutational burden (TMB), the associated genes of mismatch repair (MMR), and immune checkpoint biomarkers. Moreover, immunohistochemical analysis and qRT-PCR were used to evaluate IDO1's expression in pan-cancer cells. RESULTS: The findings of this study reveal that IDO1 has abnormal expression in a number of malignancies and is related to the prognosis for UVM, LGG, KIRP, GBM, LAML, OV, READ, MESO, SARC, SKCM, and HNSC. Furthermore, the aberrant IDO1 expression was connected to the TMB, MSI, MMR, drug sensitivity, immune cells infiltrating, and tumor immune microenvironment across a variety of cancer types. The PCR results showed that in contrast to normal cells, IDO1 was found to be significantly highly expressed in breast cancer cells and hepatocellular carcinoma cells, and significantly lowly expressed in gastric cancer cells. CONCLUSION: The clinical treatment of IDO1 is now better supported by a theoretical basis and guidelines provided by our study.

Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway.

BACKGROUND: Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin's clinical application is limited due to its poor water solubility and low bioavailability. RESULTS: In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA--miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. CONCLUSION: In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment.

A xonotlite nanofiber bioactive 3D-printed hydrogel scaffold based on osteo-/angiogenesis and osteoimmune microenvironment remodeling accelerates vascularized bone regeneration.

BACKGROUND: Coordination between osteo-/angiogenesis and the osteoimmune microenvironment is essential for effective bone repair with biomaterials. As a highly personalized and precise biomaterial suitable for repairing complex bone defects in clinical practice, it is essential to endow 3D-printed scaffold the above key capabilities. RESULTS: Herein, by introducing xonotlite nanofiber (Ca6(Si6O17) (OH)2, CS) into the 3D-printed silk fibroin/gelatin basal scaffold, a novel bone repair system named SGC was fabricated. It was noted that the incorporation of CS could greatly enhance the chemical and mechanical properties of the scaffold to match the needs of bone regeneration. Besides, benefiting from the addition of CS, SGC scaffolds could accelerate osteo-/angiogenic differentiation of bone mesenchymal stem cells (BMSCs) and meanwhile reprogram macrophages to establish a favorable osteoimmune microenvironment. In vivo experiments further demonstrated that SGC scaffolds could efficiently stimulate bone repair and create a regeneration-friendly osteoimmune microenvironment. Mechanistically, we discovered that SGC scaffolds may achieve immune reprogramming in macrophages through a decrease in the expression of Smad6 and Smad7, both of which participate in the transforming growth factor-ß (TGF-ß) signaling pathway. CONCLUSION: Overall, this study demonstrated the clinical potential of the SGC scaffold due to its favorable pro-osteo-/angiogenic and osteoimmunomodulatory properties. In addition, it is a promising strategy to develop novel bone repair biomaterials by taking osteoinduction and osteoimmune microenvironment remodeling functions into account.

A multifunctional quercetin/polycaprolactone electrospun fibrous membrane for periodontal bone regeneration.

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Engineering mesoporous bioactive glasses for emerging stimuli-responsive drug delivery and theranostic applications.

Mesoporous bioactive glasses (MBGs), which belong to the category of modern porous nanomaterials, have garnered significant attention due to their impressive biological activities, appealing physicochemical properties, and desirable morphological features. They hold immense potential for utilization in diverse fields, including adsorption, separation, catalysis, bioengineering, and medicine. Despite possessing interior porous structures, excellent morphological characteristics, and superior biocompatibility, primitive MBGs face challenges related to weak encapsulation efficiency, drug loading, and mechanical strength when applied in biomedical fields. It is important to note that the advantageous attributes of MBGs can be effectively preserved by incorporating supramolecular assemblies, miscellaneous metal species, and their conjugates into the material surfaces or intrinsic mesoporous networks. The innovative advancements in these modified colloidal inorganic nanocarriers inspire researchers to explore novel applications, such as stimuli-responsive drug delivery, with exceptional in-vivo performances. In view of the above, we outline the fabrication process of calcium-silicon-phosphorus based MBGs, followed by discussions on their significant progress in various engineered strategies involving surface functionalization, nanostructures, and network modification. Furthermore, we emphasize the recent advancements in the textural and physicochemical properties of MBGs, along with their theranostic potentials in multiple cancerous and non-cancerous diseases. Lastly, we recapitulate compelling viewpoints, with specific considerations given from bench to bedside.

Smart stimuli-responsive strategies for titanium implant functionalization in bone regeneration and therapeutics.

With the increasing and aging of global population, there is a dramatic rise in the demand for implants or substitutes to rehabilitate bone-related disorders which can considerably decrease quality of life and even endanger lives. Though titanium and its alloys have been applied as the mainstream material to fabricate implants for load-bearing bone defect restoration or temporary internal fixation devices for bone fractures, it is far from rare to encounter failed cases in clinical practice, particularly with pathological factors involved. In recent years, smart stimuli-responsive (SSR) strategies have been conducted to functionalize titanium implants to improve bone regeneration in pathological conditions, such as bacterial infection, chronic inflammation, tumor and diabetes mellitus, etc. SSR implants can exert on-demand therapeutic and/or pro-regenerative effects in response to externally applied stimuli (such as photostimulation, magnetic field, electrical and ultrasound stimulation) or internal pathology-related microenvironment changes (such as decreased pH value, specific enzyme secreted by bacterial and excessive production of reactive oxygen species). This review summarizes recent progress on the material design and fabrication, responsive mechanisms, and in vitro and in vivo evaluations for versatile clinical applications of SSR titanium implants. In addition, currently existing limitations and challenges and further prospective directions of these strategies are also discussed.

Early-Responsive Immunoregulation Therapy Improved Microenvironment for Bone Regeneration Via Engineered Extracellular Vesicles.

Overactivated inflammatory reactions hinder the bone regeneration process. Timely transformation of microenvironment from pro-inflammatory to anti-inflammatory after acute immune response is favorable for osteogenesis. Macrophages play an important role in the immune response to inflammation. Therefore, this study adopts TIM3 high expression extracellular vesicles (EVs) with immunosuppressive function to reshape the early immune microenvironment of bone injury, mainly by targeting macrophages. These EVs can be phagocytosed by macrophages, thereby increasing the infiltration of TIM3-positive macrophages (TIM3+ macrophages) and M2 subtypes. The TIM3+ macrophage group has some characteristics of M2 macrophages and secretes cytokines, such as IL-10 and TGF-ß1 to regulate inflammation. TIM3, which is highly expressed in the engineered EVs, mediates the release of anti-inflammatory cytokines by inhibiting the p38/MAPK pathway and promotes osseointegration by activating the Bmp2 promoter to enhance macrophage BMP2 secretion. After evenly loading the engineered EVs into the hydrogel, the continuous and slow release of EVsTIM3OE recruits more anti-inflammatory macrophages during the early stages of bone defect repair, regulating the immune microenvironment and eliminating the adverse effects of excessive inflammation. In summary, this study provides a new strategy for the treatment of refractory wounds through early inflammation control.

The performance tests of three-dimensional printing titanium alloy craniomaxillofacial bone plate: A preliminary preclinical study.

Background/purpose: Because of the complex anatomical structure of the maxillofacial skeleton, bending plates is necessary during surgery. The fast developing three-dimensional printing (3DP) technology has provided a new method for making personalized craniomaxillofacial bone plates. However, the properties of these bone plates remain unknown. This study evaluates the mechanical, fatigue, and morphological properties of these bone plates, which may provide data supporting future clinical applications. Materials and methods: The 3DP bone plate was fabricated by selective laser melting (SLM) and electron beam melting (EBM) technologies. Mechanical, surface, and defect analyses were performed to compare their properties with a standard machined sample. One-way analysis of variance was applied, with p < 0.05 considered significant. Results: The 3DP craniomaxillofacial bone plate had better bending strength than that of the standard machined plate (p < 0.01). Whereas the fatigue resistance of the 3DP bone plate needs to be improved in the future. Surface analysis indicated greater roughness of the 3DP bone plate (p < 0.01). However, the surface roughness could be significantly reduced by polishing the surface, which would meet the needs of clinical application after polishing. Further defect analysis revealed the internal defect inside the plate, which should be avoided to improve the mechanical strength of the printed sample in the future. Conclusion: The 3DP titanium craniomaxillofacial bone plate has good mechanical performance and surface morphology, meeting the requirements of clinical application. However, poorer fatigue resistance and a high number of internal defects should be modified in the future.

Osteogenic differentiation of 3D-printed porous tantalum with nano-topographic modification for repairing craniofacial bone defects.

Introduction: Congenital or acquired bone defects in the oral and cranio-maxillofacial (OCMF) regions can seriously affect the normal function and facial appearance of patients, and cause great harm to their physical and mental health. To achieve good bone defect repair results, the prosthesis requires good osteogenic ability, appropriate porosity, and precise three-dimensional shape. Tantalum (Ta) has better mechanical properties, osteogenic ability, and microstructure compared to Ti6Al4V, and has become a potential alternative material for bone repair. The bones in the OCMF region have unique shapes, and 3D printing technology is the preferred method for manufacturing personalized prosthesis with complex shapes and structures. The surface characteristics of materials, such as surface morphology, can affect the biological behavior of cells. Among them, nano-topographic surface modification can endow materials with unique surface properties such as wettability and large surface area, enhancing the adhesion of osteoblasts and thereby enhancing their osteogenic ability. Methods: This study used 3D-printed porous tantalum scaffolds, and constructed nano-topographic surface through hydrothermal treatment. Its osteogenic ability was verified through a series of in vitro and in vivo experiments. Results: The porous tantalum modified by nano-topographic surface can promote the proliferation and osteogenic differentiation of BMSCs, and accelerate the formation of new bone in the Angle of the mandible bone defect of rabbits. Discussion: It can be seen that 3D-printed nano-topographic surface modified porous tantalum has broad application prospects in the repair of OCMF bone defects.

The Current Progress of Tetrahedral DNA Nanostructure for Antibacterial Application and Bone Tissue Regeneration.

Recently, programmable assembly technologies have enabled the application of DNA in the creation of new nanomaterials with unprecedented functionality. One of the most common DNA nanostructures is the tetrahedral DNA nanostructure (TDN), which has attracted great interest worldwide due to its high stability, simple assembly procedure, high predictability, perfect programmability, and excellent biocompatibility. The unique spatial structure of TDN allows it to penetrate cell membranes in abundance and regulate cellular biological properties as a natural genetic material. Previous studies have demonstrated that TDNs can regulate various cellular biological properties, including promoting cells proliferation, migration and differentiation, inhibiting cells apoptosis, as well as possessing anti-inflammation and immunomodulatory capabilities. Furthermore, functional molecules can be easily modified at the vertices of DNA tetrahedron, DNA double helix structure, DNA tetrahedral arms or DNA tetrahedral cage structure, enabling TDN to be used as a nanocarrier for a variety of biological applications, including targeted therapies, molecular diagnosis, biosensing, antibacterial treatment, antitumor strategies, and tissue regeneration. In this review, we mainly focus on the current progress of TDN-based nanomaterials for antimicrobial applications, bone and cartilage tissue repair and regeneration. The synthesis and characterization of TDN, as well as the biological merits are introduced. In addition, the challenges and prospects of TDN-based nanomaterials are also discussed.

The protection of CoronaVac against the infection of wild-type SARS-CoV-2 (WH-09) or Omicron variant in nude-hACE2 mice.

BACKGROUND: Immunocompromised individuals have an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe outcomes, but we pay less attention to these people. Athymic nude mice are a murine strain with a spontaneous deficiency of the Foxn1 gene, which can result in thymic degeneration or its absence, leading to immunosuppression and a decrease in the number of T cells, and are widely used in preclinical evaluations of disease in immunocompromised populations. METHODS: We investigated the protection of the coronavirus disease 2019 (COVID-19) inactivated vaccine (CoronaVac) against the infection of wild-type SARS-CoV-2 (WH-09) or Omicron variant utilizing a hybrid-type nude-hACE2 mouse model. RESULTS: Compared with nude-hACE2/W mice, the viral load in the brain and lung tissue of nude-hACE2 mice (nude-hACE2/WV) infected with WH-09 after vaccination significantly decreased, and the histopathological changes were also reduced. The viral load in the brain and lung tissue of nude-hACE2 mice (nude-hACE2/OV) infected with the Omicron variant after vaccination was lower than that in nude-hACE2/O, but histopathological symptoms did not improve significantly. CONCLUSION: CoronaVac provides some protection against infection of both WH-09 and the Omicron variant in the nude-hACE2 mice. Our findings aimed to provide a reference for vaccination against SARS-CoV-2 in immunocompromised populations.

Melatonin Engineering M2 Macrophage-Derived Exosomes Mediate Endoplasmic Reticulum Stress and Immune Reprogramming for Periodontitis Therapy.

Periodontitis is a chronic infectious disease caused by bacterial irritation. As an essential component of the host immunity, macrophages are highly plastic and play a crucial role in inflammatory response. An appropriate and timely transition from proinflammatory (M1) to anti-inflammatory (M2) macrophages is indispensable for treating periodontitis. As M2 macrophage-derived exosomes (M2-exos) can actively target inflammatory sites and modulate immune microenvironments, M2-exos can effectively treat periodontitis. Excessive endoplasmic reticulum stress (ER stress) and unfolded protein response (UPR) are highly destructive pathological characteristics during inflammatory periodontal bone loss. Although melatonin has antioxidant and anti-inflammatory effects, studies focusing on melatonin ER stress modulation remain limited. This study fabricates engineered M2-exos loading with melatonin (Mel@M2-exos) for treating periodontitis. As a result, M2-exos drive an appropriate and timely macrophage reprogramming from M1 to M2 type, which resolves chronic inflammation and accelerated periodontal healing. Melatonin released from Mel@M2-exos rescues the osteogenic and cementogenic differentiation capacity in inflammatory human periodontal ligament cells (hPDLCs) by reducing excessive ER stress and UPR. Injectable gelatin methacryloyl (GelMA) hydrogels with sustained-release Mel@M2-exos accelerate periodontal bone regeneration in rats with ligation-induced periodontitis. Taken together, melatonin engineering M2 macrophage-derived exosomes are promising candidates for inflammatory periodontal tissue regeneration.

Functionalized Metal-Organic Framework-Modified Hydrogel That Breaks the Vicious Cycle of Inflammation and ROS for Repairing of Diabetic Bone Defects.

The regeneration of diabetic bone defects remains challenging. Hyperglycemia causes inflammation state and excessive reactive oxygen species (ROS) during bone regeneration period. These two effects reinforce one another and create an endless loop that is also accompanied by mitochondrial dysfunction. However, there is still no effective and inclusive method targeting at the two aspects and breaking the vicious cycle. Herein, nanoparticles-Met@ZIF-8(metformin loaded zeolitic imidazolate frameworks) modified hydrogel that is capable of releasing metformin and Zn elements are constructed. This hydrogel treats hyperglycemia while also controlling mitochondrial function, reducing inflammation, and restoring homeostasis. In addition, the synergetic effect from metformin and Zn ions inhibits ROS-inflammation cascade generation and destroys the continuous progress by taking effects in both ROS and inflammation and further keeping organelles' homeostasis. Furthermore, with the recovery of mitochondria and breakdown of the ROS-inflammation cascade cycle, osteogenesis under a diabetic microenvironment is enhanced in vivo and in vitro. In conclusion, the study provides critical insight into the biological mechanism and potential therapy for diabetic bone regeneration.

Combined photothermal and sonodynamic therapy using a 2D black phosphorus nanosheets loaded coating for efficient bacterial inhibition and bone-implant integration.

Surgical site infection (SSI) remains a major threat for implant failure in orthopedics. Herein, we report a dual-functional coating on Ti implants (named Ti/PDA/BP) with the integration of two-dimensional (2D) photo-sono sensitive black phosphorus nanosheets (BPNSs) and polydopamine (PDA) for efficient bacterial inhibition and bone-implant integration. For the first time, we employ BPNSs as generators of reactive radicals (ROS) under ultrasound (US) stimuli for implant associated infection. Additionally, the application of PDA improves the stability of BPNSs, the biocompatibility and photothermal performance of this hybrid coating. The as-prepared Ti/PDA/BP coating exhibits superior biocompatibility, bioactivity, photothermal and sonodynamic conversion abilities. Owing to the synergistic effect of hyperthermia and ·OH, Ti/PDA/BP damages the membrane and antioxidant system of Staphylococcus aureus, reaching a high antibacterial activity of 96.6% in vitro and 97.3% in vivo with rapid 10 min NIR irradiation and 20 min US treatment. In addition, we firstly unveil the significant effect of Ti/PDA/BP-based sonodynamic therapy (SDT) on bacterial membrane and oxidative stress at the transcriptome level. Moreover, the Ti/PDA/BP coating remarkably promotes osteogenesis in vitro and bone-implant osseointegration in vivo. Overall, development of Ti/PDA/BP bioactive coating provides a new strategy for combating the implant associated infection.

The Antiangiogenic and Antitumor Effects of Scoparasin B in Non-Small-Cell Lung Cancer.

Angiogenesis and vasculogenic mimicry (VM) are crucial for the growth and metastasis of non-small-cell lung cancer (NSCLC). Most tumor angiogenesis inhibitors mainly target endothelial cell-mediated angiogenesis, ignoring tumor-cell-mediated VM and frequently leading to tumor recurrence and metastasis. Thus, development of bioactive molecules interfering with both tumor angiogenesis and VM is necessary. Identifying novel angiogenesis inhibitors from natural products is a promising strategy. Scoparasin B, a pimarane diterpene extracted from a marine-derived fungus, Eutypella sp. F0219, has an antibacterial effect. However, its effect on angiogenesis and VM remains unexplored. In this study, we first certified that scoparasin B showed a strong inhibition effect on angiogenesis and the VM process in vitro and ex vivo. Moreover, scoparasin B prominently impeded tumor growth, angiogenesis, and VM in an NCI-H1299 xenograft model. Further study revealed that scoparasin B restrained tumor angiogenesis and VM by reducing the VEGF-A level and suppressing the VEGF-A/VEGFR2 signaling pathway. This study first demonstrated scoparasin B inhibited tumor angiogenesis, VM, and tumor growth of NSCLC and revealed its underlying mechanism. These new findings further support the potential of scoparasin B as a novel angiogenesis inhibitor and give a hint for further exploring potential angiogenesis inhibitors from natural products.

A sustained-release PDGF-BB nanocomposite hydrogel for DM-associated bone regeneration.

Regeneration of bone tissue in the environment of diabetes mellitus (DM) remains one of the clinical challenges, with malfunction of stem cells in a high-glucose microenvironment being the primary obstacle. We designed an injectable sustained-release PDGF-BB nanocomposite hydrogel. PDGF-BB, a star molecule for treating various complications of DM, was used for the first time for DM-associated bone regeneration, and we showed that it restored stem cell proliferation and migration and facilitated osteogenesis inhibition under high glucose stimulation by activating ERK and AKT pathways. To address the requirements for continuous PDGF-BB release in GelMA while also increasing mechanical strength, nanoclay LAPONITE® was added, which may still exhibit pro-osteogenic activity in diabetic environments by releasing bioactive ions (Si4+, Mg2+, and Li+). This injectable hydrogel heals calvarial lesions successfully in diabetic rats and has the potential to be used as a direct and effective tool for treating diabetic patients.

Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis.

Osteoarthritis (OA) is a highly prevalent whole-joint disease that causes disability and pain and affects a patient's quality of life. However, currently, there is a lack of effective early diagnosis and treatment. Although stem cells can promote cartilage repair and treat OA, problems such as immune rejection and tumorigenicity persist. Extracellular vesicles (EVs) can transmit genetic information from donor cells and mediate intercellular communication, which is considered a functional paracrine factor of stem cells. Increasing evidences suggest that EVs may play an essential and complex role in the pathogenesis, diagnosis, and treatment of OA. Here, we introduced the role of EVs in OA progression by influencing inflammation, metabolism, and aging. Next, we discussed EVs from the blood, synovial fluid, and joint-related cells for diagnosis. Moreover, we outlined the potential of modified and unmodified EVs and their combination with biomaterials for OA therapy. Finally, we discuss the deficiencies and put forward the prospects and challenges related to the application of EVs in the field of OA.

Calycosin protects against oxidative stress-induced cardiomyocyte apoptosis by activating aldehyde dehydrogenase 2.

Myocardial infarction (MI) is the leading cause of death worldwide, and oxidative stress is part of the process that causes MI. Calycosin, a naturally occurring substance with cardioprotective properties, is one of the major active constituents in Radix Astragali. In this study, effect of Calycosin was investigated in vivo and in vitro to determine whether it could alleviate oxidative stress and oxidative stress-induced cardiac apoptosis in neonatal cardiomyocytes (NCMs) via activation of aldehyde dehydrogenase 2 (ALDH2). Calycosin protected against oxidative stress and oxidative stress-induced apoptosis in NCMs. Molecular docking revealed that the ALDH2-Calycosin complex had a binding energy of -9.885 kcal/mol. In addition, molecular docking simulations demonstrated that the ALDH2-Calycosin complex was stable. Using BLI assays, we confirmed that Calycosin could interact with ALDH2 (KD  = 1.9 × 10-4 M). Furthermore, an ALDH2 kinase activity test revealed that Calycosin increased ALDH2 activity, exhibiting an EC50 of 91.79 µM. Pre-incubation with ALDH2 inhibitor (CVT-10216 or disulfiram) reduced the cardio-protective properties Calycosin. In mice with MI, Calycosin therapy substantially reduced myocardial apoptosis, oxidative stress, and activated ALDH2. Collectively, our findings clearly suggest that Calycosin reduces oxidative stress and oxidative stress-induced apoptosis via the regulation of ALDH2 signaling, which supports potential therapeutic use in MI.