InP QDs modified GaAs/PEDOT:PSS hybrid solar cell with efficiency over 15.

GaAs heterojunction solar cells are known as promising substitutions for traditional GaAs solar cells for their low cost and performance potential. Nevertheless, the further performance enhancement is hindered by insufficient spectral absorption and nonradioactive recombination. In this work, an InP quantum dot (QD) modified GaAs/PEDOT:PSS solar cell is designed to enhance spectrum utilization and suppress the nonradioactive carriers loss and the solar cell efficiency at 15.08% is achieved. Furthermore, InP QDs used in this work are synthesized by a novel hydrothermal method. During the synthesis process, ß-cyclodextrin (ß-cyc) was introduced into the reactants and acted as a reaction cell, isolating water and oxygen, enabling the reaction to proceed in ambient air. InP QDs synthesized by this method can achieve band engineering by altering reactant ratios, thereby effectively serving as both a Luminescent Solar Concentrator (LSC) and a Front Surface Field (FSF) in GaAs/PEDOT:PSS solar cells. This work demonstrates an inspiring way to synthesize InP QDs and optimize the performance of GaAs hybrid solar cells.

Engineering Cells for Cancer Therapy.

ConspectusCells, particularly living cells, serve as natural carriers of bioactive substances. Their inherent low immunogenicity and multifunctionality have garnered significant attention in the realm of disease treatment applications, specifically within the domains of cancer immunotherapy and regenerative tissue repair. Nevertheless, several prominent challenges impede their swift translation into clinical applications, including obstacles related to large-scale production feasibility and high utilization costs. To address these issues comprehensively, researchers have proposed the notion of bionic cells that are synthetically generated through chemical or biosynthetic means to emulate cellular functions and behaviors. However, artificial cell strategies encounter difficulties in fully replicating the intricate functionalities exhibited by living cells while also grappling with the complexities associated with design implementation for clinical translation purposes. The convergence of disciplines has facilitated the reform of living cells through a range of approaches, including chemical-, biological-, genetic-, and materials-based methods. These techniques can be employed to impart specific functions to cells or enhance the efficacy of therapy. For example, cells are engineered through gene transduction, surface modifications, endocytosis of drugs as delivery systems, and membrane fusion. The concept of engineered cells presents a promising avenue for enhancing control over living cells, thereby enhancing therapeutic efficacy while concurrently mitigating toxic side effects and ultimately facilitating the realization of precision medicine.In this Account, we present a comprehensive overview of our recent research advancements in the field of engineered cells. Our work involves the application of biological or chemical engineering techniques to manipulate endogenous cells for therapeutics or drug delivery purposes. For instance, to avoid the laborious process of isolating, modifying, and expanding engineered cells in vitro, we proposed the concept of in situ engineered cells. By applying a hydrogel loaded with nanoparticles carrying edited chimeric antigen receptor (CAR) plasmids within the postoperative cavity of glioma, we successfully targeted tumor-associated macrophages for gene editing, leading to effective tumor recurrence inhibition. Furthermore, leveraging platelet's ability to release microparticles upon activation at injury sites, we modified antiprogrammed death 1 (PD-1) antibodies on their surface to suppress postoperative tumor recurrence and provide immunotherapy for inoperable tumors. Similarly, by exploiting bacteria's active tropism toward sites of inflammation and hypoxia, we delivered protein drugs by engineered bacteria to induce cancer cell death through pyroptosis initiation and immunotherapy strategies. In the final section, we summarize our aforementioned research progress while providing an outlook on cancer therapy and the hurdles for clinical translation with potential solutions or future directions based on the concept of engineered cells.

Anodic Reconstructed p+-GaAs/a-InAsN for Stable and Efficient Photoelectrochemical Hydrogen Evolution.

The extremely poor solution stability and massive carrier recombination have seriously prevented III-V semiconductor nanomaterials from efficient and stable hydrogen production. In this work, an anodic reconstruction strategy based on group III-V active semiconductors is proposed for the first time, resulting in 19-times photo-gain. What matters most is that the device after anodic reconstruction shows very superior stability under the protracted photoelectrochemical (PEC) test over 8100 s, while the final photocurrent density does not decrease but rather increases by 63.15%. Using the experiment and DFT theoretical calculation, the anodic reconstruction mechanism is elucidated: through the oxidation of indium clusters and the migration of arsenic atoms, the reconstruction formed p+-GaAs/a-InAsN. The hole concentration of the former is increased by 10 times (5.64 × 1018 cm-1 increases up to 5.95 × 1019 cm-1) and the band gap of the latter one is reduced to a semi-metallic state, greatly strengthening the driving force of PEC water splitting. This work turns waste into treasure, transferring the solution instability into better efficiency.

Betulinic Acid Attenuates Osteoarthritis via Limiting NLRP3 Inflammasome Activation to Decrease Interleukin-1ß Maturation and Secretion.

Introduction: Osteoarthritis (OA) is the most common degenerative joint disorder. Prior studies revealed that activation of NLRP3 inflammasome could promote the activation and secretion of interleukin-1ß (IL-1ß), which has an adverse effect on the progression of OA. Betulinic acid (BA) is a compound extract of birch, whether it can protect against OA and the mechanisms involved are still unknown. Materials and Methods: In vivo experiments, using gait analysis, ELISA, micro-CT, and scanning electron microscopy (SEM), histological staining, immunohistological (IHC) and immunofluorescence (IF) staining, and atomic force microscopy (AFM) to assess OA progression after intraperitoneal injection of 5 and 15 mg/kg BA in an OA mouse model. In vitro experiments, caspase-1, IL-1ß, and the N-terminal fragment of gasdermin D (GSDMD-NT) were measured in bone marrow-derived macrophages (BMDMs) by using ELISA, western blot, and immunofluorescence staining. Results: We demonstrated that OA progression can be postponed with intraperitoneal injection of 5 and 15 mg/kg BA in an OA mouse model. Specifically, BA postponed DMM-induced cartilage deterioration, alleviated subchondral bone sclerosis, and relieved synovial inflammation. In vitro studies, the activated NLRP3 inflammasome produces mature IL-1ß by facilitating the cleavage of pro-IL-1ß, and BA could inhibit the activation of NLRP3 inflammasome in BMDMs. Conclusions: Taken together, our analyses revealed that BA attenuates OA via limiting NLRP3 inflammasome activation to decrease the IL-1ß maturation and secretion.

Pleiotropic Microenvironment Remodeling Micelles for Cerebral Ischemia-Reperfusion Injury Therapy by Inhibiting Neuronal Ferroptosis and Glial Overactivation.

Reperfusion injury presents a significant obstacle to neuronal survival following successful recanalization in ischemic stroke, which is characterized by intricate pathophysiological processes comprising numerous interconnected pathways. Oxidative stress-induced neuronal ferroptosis and the overactivation of glial cells play important roles in this phenomenon. In this study, we developed a targeted cross-linked micelle loaded with idebenone to rescue the ischemic penumbra by inhibiting neuronal ferroptosis and glial overactivation. In rat models, the CREKA peptide-modified micelles accumulate in the damaged brain via binding to microthrombi in the ipsilateral microvessels. Upon reactive oxygen species (ROS) stimulation, diselenide bonds within the micelles are transformed to hydrophilic seleninic acids, enabling synchronized ROS consumption and responsive drug release. The released idebenone scavenges ROS, prevents oxidative stress-induced neuronal ferroptosis, attenuates glial overactivation, and suppresses pro-inflammatory factors secretion, thereby modulating the inflammatory microenvironment. Finally, this micelle significantly reinforces neuronal survival, reduces infarct volume, and improves behavioral function compared to the control groups. This pleiotropic therapeutic micelle provides a proof-of-concept of remodeling the lesion microenvironment by inhibiting neuronal ferroptosis and glial overactivation to treat cerebral ischemia-reperfusion injury.

Hypoxia-cleavable and specific targeted nanomedicine delivers epigenetic drugs for enhanced treatment of breast cancer and bone metastasis.

Breast cancer bone metastasis has become a common cancer type that still lacks an effective treatment method. Although epigenetic drugs have demonstrated promise in cancer therapy, their nontargeted accumulation and drug resistance remain nonnegligible limiting factors. Herein, we first found that icaritin had a strong synergistic effect with an epigenetic drug (JQ1) in the suppression of breast cancer, which could help to relieve drug resistance to JQ1. To improve tumor-targeted efficacy, we developed a hypoxia-cleavable, RGD peptide-modified poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle (termed ARNP) for the targeted delivery of JQ1 and icaritin. The decoration of long cleavable PEG chains can shield RGD peptides during blood circulation and reduce cellular uptake at nonspecific sites. ARNP actively targets breast cancer cells via an RGD-αvß3 integrin interaction after PEG chain cleavage by responding to hypoxic tumor microenvironment. In vitro and in vivo assays revealed that ARNP exhibited good biodistribution and effectively suppressed primary tumor and bone metastasis. Meanwhile, ARNP could alleviate bone erosion to a certain extent. Furthermore, ARNP significantly inhibited pulmonary metastasis secondary to bone metastasis. The present study suggests that ARNP has great promise in the treatment of breast cancer and bone metastasis due to its simple and practical potential.

Association of fat-soluble vitamins (A, D, and E) status with humoral immune response to COVID-19 inactivated vaccination.

Background: Fat-soluble vitamins (A, D, and E) are essential for the proper functioning of the immune system and are of central importance for infection risk in humans. Vitamins A, D, and E have been reported to be associated with the immune response following vaccination; however, their effects on the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination remain unknown. Methods: We measured the neutralizing antibody titers against wild type and omicron within 98 days after the third homologous boosting shot of inactivated SARS-CoV-2 vaccine (BBIBP-CorV or CoronaVac) in 141 healthy adults in a prospective, open-label study. High-performance liquid chromatography-tandem mass spectroscopy was used to determine the concentrations of plasma vitamins A, D, and E. Results: We found that the anti-wide-type virus and anti-omicron variant antibody levels significantly increased compared with baseline antibody levels (P < 0.001) after the third vaccination. 25(OH)D3 was significantly negatively associated with the baseline anti-wide-type virus antibody concentrations [beta (95% CI) = -0.331 (-0.659 ~ -0.003)] after adjusting for covariates. A potentially similar association was also observed on day 98 after the third vaccination [beta (95% CI) = -0.317 (-0.641 ~ 0.007)]. After adjusting for covariates, we also found that 25(OH)D3 was significantly negatively associated with the seropositivity of the anti-omicron variant antibody at day 98 after the third vaccination [OR (95% CI) = 0.940 (0.883 ~ 0.996)]. The association between plasma 25(OH)D3 with anti-wild-type virus antibody levels and seropositivity of anti-omicron variant antibodies were persistent in subgroup analyses. We observed no association between retinol/α-tocopherol and anti-wide-type virus antibody levels or anti-omicron variant antibody seropositive in our study. Conclusion: The third inactivated SARS-CoV-2 vaccination significantly improved the ability of anti-SARS-CoV-2 infection in the human body. Higher vitamin D concentrations could significantly decrease the anti-wide-type virus-neutralizing antibody titers and anti-omicron variant antibody seropositive rate after the inactivated SARS-CoV-2 vaccination in people with adequate levels of vitamin D, better immune status, and stronger immune response; further studies comprising large cohorts of patients with different nutritional status are warranted to verify our results.

20(R)-ginsenoside Rg3-loaded polyurethane/marine polysaccharide based nanofiber dressings improved burn wound healing potentials.

The management of deep burn injuries is extremely challenging, ascribed to their delayed wound healing rate, susceptibility for bacterial infections, pain, and increased risk of hypertrophic scarring. In our current investigation, a series of composite nanofiber dressings (NFDs) based on polyurethane (PU) and marine polysaccharides (i.e., hydroxypropyl trimethyl ammonium chloride chitosan, HACC and sodium alginate, SA) were accomplished by electrospinning and freeze-drying protocols. The 20(R)-ginsenoside Rg3 (Rg3) was further loaded into these NFDs to inhibit the formation of excessive wound scars. The PU/HACC/SA/Rg3 dressings showed a sandwich-like structure. The Rg3 was encapsulated in the middle layers of these NFDs and slowly released over 30 days. The PU/HACC/SA and PU/HACC/SA/Rg3 composite dressings demonstrated superior wound healing potentials over other NFDs. These dressings also displayed favorable cytocompatibility with keratinocytes and fibroblasts and could dramatically accelerate epidermal wound closure rate following 21 days of the treatment of a deep burn wound animal model. Interestingly, the PU/HACC/SA/Rg3 obviously reduced the excessive scar formation, with a collagen type I/III ratio closer to the normal skin. Overall, this study represented PU/HACC/SA/Rg3 as a promising multifunctional wound dressing, which promoted the regeneration of burn skins and attenuated scar formation.

Gradient tumor microenvironment-promoted penetrating micelles for hypoxia relief and immunosuppression reversion in pancreatic cancer treatment.

The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is the main block for the penetration of chemotherapy. In the tumor microenvironment, a dense matrix composed of fibrin is formed on the exterior, while the interior is featured by high reduction, hypoxia and low pH. How to match the special microenvironment to on-demand drug release is the key to improve chemotherapeutic efficacy. Herein, a microenvironment-responsive micellar system is developed to deepen tumoral penetration. Briefly, the conjugation of a fibrin-targeting peptide to PEG-poly amino acid has been utilized to achieve accumulation of micelles in the tumor stroma. By modification of micelles with hypoxia-reducible nitroimidazole which becomes protonated under acidic conditions, their surface charge is more positive, facilitating deeper penetration into tumors. Paclitaxel was loaded onto the micelles via a disulfide bond to enable glutathione (GSH)-responsive release. Therefore, the immunosuppressive microenvironment is relived through the alleviation of hypoxia and depletion of GSH. Hopefully, this work could establish paradigms by designing sophisticated drug-delivery systems to tactfully employ and retroact the tamed tumoral microenvironment to improve the therapeutic efficacy based on understanding the multiple hallmarks and learning the mutual regulation. STATEMENT OF SIGNIFICANCE: Tumor microenvironment(TME) is an unique pathological feature of pancreatic cancer and an inherent barrier to chemotherapy. Numerous studies regard TME as the targets for drug delivery. In this work, we propose a hypoxia-responsive nanomicellar drug delivery system that aiming hypoxia TME of pancreatic cancer. The nanodrug delivery system could respond to the hypoxic microenvironment and enhance the penetration of the inner tumor at the same time preserving the outer tumor stroma, thus achieving targeted treatment of PDAC by preserving the integrity of the outer stroma. Simultaneously, the responsive group can reverse the degree of hypoxia in TME by disrupting the redox balance in the tumor region, thus achieving precise treatment of PDAC by matching the pathological characteristics of TME. We believe our article would provide new design ideas for the future treatments for pancreatic cancer.

Nanomaterials with dual immunomodulatory functions for synergistic therapy of breast cancer brain metastases.

A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8+ T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.

Generalization of Costly Pain-Related Avoidance Based on Real-Life Categorical Knowledge.

Avoiding activities posing bodily threat is adaptive. However, spreading of avoidance to safe activities may cause functional disability in people with chronic pain. We investigated whether costly pain-related avoidance would generalize from one activity to another on the basis of real-life categorical knowledge in 40 pain-free people (30 female; mean age = 25 years; university students and public of Maastricht, The Netherlands). In a computer task, participants moved a joystick to complete activities from two categories (gardening and cleaning). During activities from the avoidance category, pain could be avoided at the cost of task efficiency by deviating from a short, pain-associated joystick movement. Activities from the safe category were never painful. Subsequently, we tested generalization of avoidance to novel pain-free activities from both categories. Participants generalized avoidance to novel activities from the avoidance category despite the novel activities not being paired with pain and despite avoidance costs, suggesting that costly (pain-related) avoidance generalizes from one activity to another on the basis of category knowledge and can thus be wide reaching, creating detrimental consequences.

ROS/Electro Dual-Reactive Nanogel for Targeting Epileptic Foci to Remodel Aberrant Circuits and Inflammatory Microenvironment.

Medicinal treatment against epilepsy is faced with intractable problems, especially epileptogenesis that cannot be blocked by clinical antiepileptic drugs (AEDs) during the latency of epilepsy. Abnormal circuits of neurons interact with the inflammatory microenvironment of glial cells in epileptic foci, resulting in recurrent seizures and refractory epilepsy. Herein, we have selected phenytoin (PHT) as a model drug to derive a ROS-responsive and consuming prodrug, which is combined with an electro-responsive group (sulfonate sodium, SS) and an epileptic focus-recognizing group (α-methyl-l-tryptophan, AMT) to form hydrogel nanoparticles (i.e., a nanogel). The nanogel will target epileptic foci, release PHT in response to a high concentration of reactive oxygen species (ROS) in the microenvironment, and inhibit overexcited circuits. Meanwhile, with the clearance of ROS, the nanogel can also reduce oxidative stress and alleviate microenvironment inflammation. Thus, a synergistic regulation of epileptic lesions will be achieved. Our nanogel is expected to provide a more comprehensive strategy for antiepileptic treatment.

ROS-removing nano-medicine for navigating inflammatory microenvironment to enhance anti-epileptic therapy.

As a neurological disorder in the brain, epilepsy is not only associated with abnormal synchronized discharging of neurons, but also inseparable from non-neuronal elements in the altered microenvironment. Anti-epileptic drugs (AEDs) merely focusing on neuronal circuits frequently turn out deficient, which is necessitating comprehensive strategies of medications to cover over-exciting neurons, activated glial cells, oxidative stress and chronic inflammation synchronously. Therefore, we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation. In brief, reactive oxygen species (ROS)-sensitive phenylboronic ester was conjugated with poly-ethylene glycol (PEG) to form amphiphilic copolymers. Additionally, dehydroascorbic acid (DHAA), an analogue of glucose, was applied to target glucose transporter 1 (GLUT1) and facilitate micelle penetration across the blood‒brain barrier (BBB). A classic hydrophobic AED, lamotrigine (LTG), was encapsulated in the micelles via self-assembly. When administrated and transferred across the BBB, ROS-scavenging polymers were expected to integrate anti-oxidation, anti-inflammation and neuro-electric modulation into one strategy. Moreover, micelles would alter LTG distribution in vivo with improved efficacy. Overall, the combined anti-epileptic therapy might provide effective opinions on how to maximize neuroprotection during early epileptogenesis.

A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy.

Metastasis accounts for 90% of breast cancer deaths, where the lethality could be attributed to the poor drug accumulation at the metastatic loci. The tolerance to chemotherapy induced by breast cancer stem cells (BCSCs) and their particular redox microenvironment further aggravate the therapeutic dilemma. To be specific, therapy-resistant BCSCs can differentiate into heterogeneous tumor cells constantly, and simultaneously dynamic maintenance of redox homeostasis promote tumor cells to retro-differentiate into stem-like state in response to cytotoxic chemotherapy. Herein, we develop a specifically-designed biomimic platform employing neutrophil membrane as shell to inherit a neutrophil-like tumor-targeting capability, and anchored chemotherapeutic and BCSCs-differentiating reagents with nitroimidazole (NI) to yield two hypoxia-responsive prodrugs, which could be encapsulated into a polymeric nitroimidazole core. The platform can actively target the lung metastasis sites of triple negative breast cancer (TNBC), and release the escorted drugs upon being triggered by the hypoxia microenvironment. During the responsiveness, the differentiating agent could promote transferring BCSCs into non-BCSCs, and simultaneously the nitroimidazole moieties conjugated on the polymer and prodrugs could modulate the tumor microenvironment by depleting nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and amplifying intracellular oxidative stress to prevent tumor cells retro-differentiation into BCSCs. In combination, the BCSCs differentiation and tumor microenvironment modulation synergistically could enhance the chemotherapeutic cytotoxicity, and remarkably suppress tumor growth and lung metastasis. Hopefully, this work can provide a new insight in to comprehensively treat TNBC and lung metastasis using a versatile platform.

Compound Nanoemulsion Combined with Differentiation/Cytotoxicity Drugs for Modulating Breast Cancer Stemness.

Breast cancer stem cells (BCSCs) are the culprit of triple-negative breast cancer invasiveness and are heterogeneous. It is recognized that the combination of chemotherapy and differentiation therapy for killing BCSCs and non-BCSCs simultaneously is a reliable strategy. In this study, an oil-in-water nanoemulsion was prepared by high-pressure homogenization with coencapsulation of all-trans retinoic acid (ATRA) and doxorubicin (DOX). The preparation process was simple, and the production was easy to scale up. The particle size of the nanoemulsion was 127.2 ± 2.0 nm. Cellular toxicity assay showed that the composite index of the ATRA and DOX was less than 1 and exhibited a fine combined effect. In vivo antitumor efficacy showed that the compound nanoemulsion could reduce the proportion of BCSCs to 1.18% by inhibiting the expression of Pin1. In addition, the combination of ATRA and DOX could reduce the cardiotoxicity of DOX and had higher safety. Hopefully, this work can provide a new insight into developing pharmaceutically acceptable technology for treating BCSCs.

Unleashing the healing potential: Exploring next-generation regenerative protein nanoscaffolds for burn wound recovery.

Burn injury is a serious public health problem and scientists are continuously aiming to develop promising biomimetic dressings for effective burn wound management. In this study, a greater efficacy in burn wound healing and the associated mechanisms of α-lactalbumin (ALA) based electrospun nanofibrous scaffolds (ENs) as compared to other regenerative protein scaffolds were established. Bovine serum albumin (BSA), collagen type I (COL), lysozyme (LZM) and ALA were separately blended with poly(ε-caprolactone) (PCL) to fabricate four different composite ENs (LZM/PCL, BSA/PCL, COL/PCL and ALA/PCL ENs). The hydrophilic composite scaffolds exhibited an enhanced wettability and variable mechanical properties. The ALA/PCL ENs demonstrated higher levels of fibroblast proliferation and adhesion than the other composite ENs. As compared to PCL ENs and other composite scaffolds, the ALA/PCL ENs also promoted a better maturity of the regenerative skin tissues and showed a comparable wound healing effect to Collagen spongeⓇ on third-degree burn model. The enhanced wound healing activity of ALA/PCL ENs compared to other ENs could be attributed to their ability to promote serotonin production at wound sites. Collectively, this investigation demonstrated that ALA is a unique protein with a greater potential for burn wound healing as compared to other regenerative proteins when loaded in the nanofibrous scaffolds.

Mouse model of subtalar post-traumatic osteoarthritis caused by subtalar joint instability.

BACKGROUND: Common ankle sprains are often accompanied by injury to the subtalar joint, which eventually leads to subtalar joint instability. Because the clinical manifestations for subtalar joint instability are similar to ankle joint injuries, these are often overlooked. This study aimed to establish an animal model of subtalar joint instability to study post-traumatic osteoarthritis of the subtalar joint caused by long-term subtalar joint instability and to provide a reference for future clinical research on chronic subtalar joint instability. METHODS: In all, 24 C57BL/6 male mice were randomly divided into three groups: Sham, cervical ligament (CL) transection and CL + calcaneofibular ligament (CFL) transection groups. One week after surgical operation, all mice were trained to run in the mouse rotation fatigue machine every day. During this period, a balance beam test was used to evaluate the motor level and coordination ability of the mice before the operation and three days, one week, four weeks, eight weeks, and twelve weeks after operation. Further, post-traumatic osteoarthritis of the subtalar joint was quantified via micro-CT and histological staining. RESULTS: The mice in the partial ligament transection group took significantly longer than those in the Sham group to pass through the balance beam and showed an increased number of hindfoot slips. Micro-CT analysis showed that the subtalar bone volume fraction in the CL + CFL transection group and CL transection group was 5.8% and 2.8% higher than that in the Sham group, respectively. Histological staining showed obvious signs of post-traumatic osteoarthritis (PTOA) in the subtalar joint of the ligament transection group. CONCLUSIONS: The transection of CL and CL + CFL can cause instability of the subtalar joint in mice, resulting in a decrease in motor coordination, and long-term instability of the subtalar joint in mice can cause PTOA of the subtalar joint, which is manifested as destruction and loss of articular cartilage.

A Mouse Model of Ankle-Subtalar Complex Joint Instability.

Ankle sprains are perhaps the most common sports injuries in daily life, often resulting in instability of the ankle-subtalar complex joint (ASCJ), and can eventually lead to post-traumatic osteoarthritis (PTOA) in the long term. However, due to the complexity of the injury mechanism and the clinical manifestations, such as ecchymosis, hematoma, or tenderness in the lateral foot, there is no clinical consensus on diagnosing and treating ASCJ instability. Since the musculoskeletal structure of the bones and ligaments of the mouse hindfoot is comparable to that of humans, an animal model of ASCJ instability in mice was established by the transection of ligaments around the ASCJ. The model was well-validated through a series of behavioral tests and histological analyses, including a balance beam test, a footprint analysis (an assessment of exercise level and balance ability in mice), a thermal nociception assessment (an assessment of foot sensory function in mice), micro-computed tomography (CT) scanning, and section staining of the articular cartilage (an assessment of articular cartilage damage and degeneration in mice). The successful establishment of a mouse model of ASCJ instability will provide a valuable reference for clinical research on the injury mechanism and result in better treatment options for ankle sprain.

A Triple Therapeutic Strategy with Antiexosomal Iron Efflux for Enhanced Ferroptosis Therapy and Immunotherapy.

Ferroptosis is a form of regulated cell death which can not only kill tumor cells but also enhance immunogenicity of tumor cells, and it is evidenced to be involved in a variety of tumor treatments, especially in cancer immunotherapy. Tumor cell-derived exosomes are reported to influence the progression and metastasis process of tumors. In the process of ferroptosis, exosomes are also demonstrated as mediators to export iron under high intracellular iron concentration and resist ferroptosis. Under this regard, the combined application of ferroptosis inducer and the inhibitor of iron-containing exosomes may enhance the ferroptosis. Herein, biocompatible hybrid nanoparticles composed of the iron oxide nanoparticles, polymers with oxaliplatin attached, and siProminin2 are constructed. The siProminin2 mediated exosomal inhibition can restore the intracellular iron concentration, which can also inhibit the secretion of tumor cell-derived exosomes. The combination of immunotherapy with oxaliplatin, ferroptosis-based cancer therapy and inhibition of tumor cell-derived exosomes can enhance the immune activation effects. The nanoparticles represent an excellent triple therapeutic strategy for enhancing ferroptosis-based cancer therapy and immunotherapy.

Propionate and butyrate attenuate macrophage pyroptosis and osteoclastogenesis induced by CoCrMo alloy particles.

BACKGROUND: Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty. Up to now, there is no effective treatment for wear particles-induced osteolysis except for the revision surgery, which is a heavy psychological and economic burden to patients. A metabolite of gut microbiota, short chain fatty acids (SCFAs), has been reported to be beneficial for many chronic inflammatory diseases. This study aimed to investigate the therapeutic effect of SCFAs on osteolysis. METHODS: A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium. After two weeks of intervention, the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by Micro-CT analysis and immunohistochemistry staining. In vitro study, lipopolysaccharide (LPS) primed bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate (C2), propionate (C3), and butyrate (C4). Western blotting, Enzyme-linked immunosorbent assay, and immunofluorescence were used to detect the activation of NLRP3 inflammasome. The effects of SCFAs on osteoclasts were evaluate by qRT-PCR, Western blotting, immunofluorescence, and tartrate-resistant acid phosphatase (TRAP) staining. Additionally, histone deacetylase (HDAC) inhibitors, agonists of GPR41, GPR43, and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis. RESULTS: C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits (P < 0.001), higher level of bone volume to tissue volume (BV/TV, P < 0.001), bone mineral density (BMD, P < 0.001), and a lower total porosity (P < 0.001). C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleation-induced oligomerization, suppressing the cleavage of caspase-1 (P < 0.05) and IL-1ß (P < 0.05) stimulated by CoCrMo alloy particles. C3 and C4 also inhibited the generation of Gasdermin D-N-terminal fragment (GSDMD-NT) to regulate pyroptosis. Besides, C3 and C4 have a negative impact on osteoclast differentiation (P < 0.05) and its function (P < 0.05), affecting the podosome arrangement and morphologically normal podosome belts formation. CONCLUSION: Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.