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.

The ketone body ß-hydroxybutyrate alleviates CoCrMo alloy particles induced osteolysis by regulating NLRP3 inflammasome and osteoclast differentiation.

BACKGROUND: Aseptic Loosening (AL) following periprosthetic osteolysis is the main long-term complication after total joint arthroplasty (TJA). However, there is rare effective treatment except for revision surgery, which is costly and painful to the patients. In recent years, the ketone body ß-hydroxybutyrate (BHB) has attracted much attention and has been proved to be beneficial in many chronic diseases. With respect to the studies on the ketone body ß-hydroxybutyrate (BHB), its anti-inflammatory ability has been widely investigated. Although the ketone body ß-hydroxybutyrate has been applied in many inflammatory diseases and has achieved considerable therapeutic efficacy, its effect on wear particles induced osteolysis is still unknown. RESULTS: In this work, we confirmed that the anti-inflammatory action of ß-hydroxybutyrate (BHB) could be reappeared in CoCrMo alloy particles induced osteolysis. Mechanistically, the ketone body ß-hydroxybutyrate (BHB) deactivated the activation of NLRP3 inflammasome triggered by CoCrMo alloy particles. Of note, this inhibitory action was independent of Gpr109a receptor as well as histone deacetylase (HDAC) suppression. Furthermore, given that butyrate, one kind of short chain fatty acid (SCFA) structurally related to ß-hydroxybutyrate (BHB), has been reported to be an inhibitor of osteoclast, thus we also investigate the effect of ß-hydroxybutyrate (BHB) on osteoclast, which was contributed to bone resorption. It was found that ß-hydroxybutyrate (BHB) did not only affect osteoclast differentiation, but also inhibit its function. Unlike the inflammasome, the effect of ß-hydroxybutyrate (BHB) on osteoclast may mainly rely on histone deacetylase (HDAC) suppression. CONCLUSIONS: In general, our study showed that the alleviation of osteolysis may owe to the effect of ß-hydroxybutyrate (BHB) on inflammasome deactivation and osteoclast.

Melatonin alleviates titanium nanoparticles induced osteolysis via activation of butyrate/GPR109A signaling pathway.

BACKGROUND: Inflammatory osteolysis after total joint replacement (TJR) may cause implant failure, periprosthetic fractures, and be a severe threat to global public health. Our previous studies demonstrated that melatonin had a therapeutic effect on wear-particles induced osteolysis. Gut microbiota is closely related to bone homeostasis, and has been proven to be affected by melatonin. However, whether melatonin could play its anti-osteolysis effects through reprogramming gut microbiota remains elusive. RESULTS: Here, we demonstrated that melatonin could alleviate Ti-particles induced osteolysis, while this therapeutic effect was blocked by antibiotic cocktail treatment. Interestingly, transplantation of fecal microbiota from mice treated with melatonin reappeared the same beneficial effect. Analysis of the 16S rRNA revealed that melatonin could reverse dysbacteriosis triggered by osteolysis, and elevate the relative abundance of some short chain fatty acid (SCFA) producing bacteria. Moreover, butyrate was enriched by exogenous melatonin administration, while acetate and propionate did not show an evident difference. This was consistent with the results of the metagenomic approach (PICRUSt2) analysis, which revealed a general increase in the synthetic enzymes of butyrate. More importantly, direct supplementation of butyrate could also recapitulate the anti-osteolysis effect of melatonin. Further analysis identified that butyrate alleviated osteolysis via activating its receptor GPR109A, and thus to suppress the activation of NLRP3 inflammasome triggered by Ti-particles. CONCLUSIONS: Taken together, our results suggested that the benefits of melatonin mainly depend on the ability of modulating gut microbiota and regulating butyrate production.

Formation and evolution of the unexpected PbI2 phase at the interface during the growth of evaporated perovskite films.

The interface chemistry and evolution of the evaporated perovskite films on ITO, pedot/ITO, Si and glass substrates are studied. As evidenced by X-ray diffraction and X-ray photoemission spectroscopy (XPS) results, the PbI2 phase is found to be inevitably formed at the very initial growth stage, even under the conditions of a MAI-rich environment. The extremely low binding energy of adsorbed MAI particles on all the above substrates, as compared to that of PbI2 particles, is responsible for the presence of the PbI2 phase at the interface. The formation of both hole and electron barriers at the interface of PbI2/MAPbI3, as evidenced by XPS measurements, could block carrier transport into the electrode and thus deteriorate solar cell performance. This result reveals the origin of the poor performance of perovskite solar cells (PSCs) by the vacuum evaporation method, and may help to improve the performance of PSCs made using the vacuum evaporation method.

Time-temperature indicator of hydroxyethyl cellulose ink labels for assessing pork freshness.

Pork is widely consumed worldwide, and many consumers now utilize sensory evaluation techniques to determine the freshness of pork when buying it. A color-changing ink label utilizing bromocresol purple (BCP) and N-hydroxyphthalimide (NHPI) had been created to help consumers better and more rapidly determine the freshness of pork while it is stored. The ink was easy to prepare and could be readily transferred to A4 paper using screen printing technology. This study delved deeper into the impact of hydroxyethyl cellulose (HEC) on the functional properties of inks to enhance printing performance. The experiment demonstrated that a 1 % mass fraction of HEC improved thixotropy and facilitated the even distribution of ink on A4 paper, as confirmed by scanning electron microscopy. Screen-printed labels with varying concentrations displayed distinct color change rates when stored at different temperatures, indicating their capability to assess pork freshness. FT-IR, laboratory, and stability tests verified the ink's exceptional color change capabilities and printing attributes. An analysis using the Arrhenius equation revealed a substantial synergistic effect between BCP and NHPI, resulting in improved sensitivity and accuracy of the ink. This study offers a practical and feasible method to monitor the storage quality of pork effectively.

Development of CO2-sensitive antimicrobial bilayer films based on gellan gum and sodium alginate/sodium carboxymethyl cellulose and its application in strawberries.

To effectively extend the shelf life of fruits meanwhile facilitating consumers to judge their freshness, in this work, a double-layer multifunctional film combining CO2 sensitivity and antibacterial properties was successfully prepared by adding methyl red (MR), bromothymol blue (BTB) into gellan gum (GG) as the sensing inner layer, and doping tannic acid (TA) into sodium alginate with sodium carboxymethyl cellulose (CMC) as the antimicrobial outer layer, which was applied to the freshness indication of strawberries. Microscopic morphology and spectral analysis demonstrated that the bi-layer films were fabricated successfully. The mechanical characteristics, thermal stability, water vapor resistance, and antibacterial capabilities of the bilayer films improved as TA concentration rose. They exhibited noticeable color changes at pH = 2-10 and different concentrations of CO2. Application of the prepared films to strawberries revealed that the GG-MB@SC-6%TA film performed most favorably under 4 °C storage conditions, not only monitoring strawberry freshness but also retaining high soluble solids and titratable acidity, resulting in a slight decrease in hardness and weight loss. Therefore, taking into account all of the physical-functional characteristics, the GG-MB@6%TA film has a broad application prospect for intelligent food packaging.

Development of xanthan gum intelligent oil-in-water ink and its application in pork freshness preservation.

To optimize the stability of oil-based inks and ensure their wide application in freshness indication, new natural indicator inks were prepared using a stable oil-in-water structure. This study selected natural Lycium ruthenicum anthocyanin as the dye and glucose as the pigment carrier. Soybean oil was introduced as a linker and xanthan gum as a thickener, and an oil-in-water ink with the function of freshness indication was successfully developed. In ensuring the safety of ink labels for use on food packaging, particular attention is paid to the origin and properties of the materials used. All ingredients are of food-grade or bio-friendly provenance, thereby ensuring the safety of the product when in direct contact with food. We measured the viscosity, particle size and fineness of the ink for micro characterization and evaluated its macro printing performance by its printing effect on A4 paper. According to the experimental results, when the water-oil ratio of the ink is 10:5, the average particle size of the emulsion system is 822.83 nm, and the fineness reaches 5 µm. These values are relatively low, which indicates that the stability of the ink system is high at this time, and the ink shows excellent rheological and printing characteristics. With this water-to-oil ratio, the ink can show the best results when printed on A4 paper, clearly displaying image details. In addition, in fresh pork applications, inks with a 10: 5 water-to-oil ratio provide an accurate and highly sensitive indication of the freshness of pork. When the freshness of the pork changes, the ink color responds promptly. This high sensitivity makes the ink ideal for use as a food freshness indication tool, providing consumers with an intuitive and reliable reference for pork freshness. As a further innovation, combining this ink-printed label with a WeChat app not only allows consumers to know the freshness of the food in real-time but also tracks the supply chain information of the food, providing a more comprehensive application prospect for freshness-indicating products.

Intelligent double-layer film based on gellan gum/modified anthocyanin/curcumin/sodium alginate/zinc oxide for monitoring shrimp freshness.

In this study, intelligent double-layer films were prepared using modified black rice anthocyanin (MBRA)-curcumin (CUR)-gellan gum (GG) as the inner indicator layer and sodium alginate (ALG)­zinc oxide (ZnO) as the outer antimicrobial layer. The bilayer films were successfully prepared, as revealed by scanning electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction measurements. The mechanical characteristics, moisture content, and water vapor resistance of GG-MBRA/CUR1@ALG-ZnO, GG-MBRA/CUR2@ALG-ZnO, and GG-MBRA/CUR3@ALG-ZnO films showed significant enhancement compared to GG-MBRA/CUR3 and ALG-ZnO films. The bilayer films exhibited excellent pH responsiveness and reacted effectively to ammonia. The outer layer significantly improved the antioxidant and antibacterial properties of the inner layer. When the films were applied to shrimp, it was found that the double-layer films not only monitored the freshness of the shrimp in real-time but also were influential in extending the shelf life of the shrimp by about 1 d. Therefore, the double-layer film demonstrated potential as a smart packaging material for real-time monitoring of meat product freshness.

Growth factor-functionalized titanium implants for enhanced bone regeneration: A review.

Titanium and titanium alloys are widely favored materials for orthopedic implants due to their exceptional mechanical properties and biological inertness. The additional benefit of sustained local release of bioactive substances further promotes bone tissue formation, thereby augmenting the osseointegration capacity of titanium implants and attracting increasing attention in bone tissue engineering. Among these bioactive substances, growth factors have shown remarkable osteogenic and angiogenic induction capabilities. Consequently, researchers have developed various physical, chemical, and biological loading techniques to incorporate growth factors into titanium implants, ensuring controlled release kinetics. In contrast to conventional treatment modalities, the localized release of growth factors from functionalized titanium implants not only enhances osseointegration but also reduces the risk of complications. This review provides a comprehensive examination of the types and mechanisms of growth factors, along with a detailed exploration of the methodologies used to load growth factors onto the surface of titanium implants. Moreover, it highlights recent advancements in the application of growth factors to the surface of titanium implants (Scheme 1). Finally, the review discusses current limitations and future prospects for growth factor-functionalized titanium implants. In summary, this paper presents cutting-edge design strategies aimed at enhancing the bone regenerative capacity of growth factor-functionalized titanium implants-a significant advancement in the field of enhanced bone regeneration.

A double-layer smart film based on gellan gum/modified anthocyanin and sodium carboxymethyl cellulose/starch/Nisin for application in chicken breast.

In order to overcome this challenge of poor stability of natural anthocyanins in intelligent packaging materials, roselle anthocyanin (RA) was first modified by acetic acid, and then a double-layer smart indication antimicrobial film was developed using modified roselle anthocyanin (MRA)-gellan gum (GG) as the inner layer and sodium carboxymethyl cellulose (CMC)-starch (ST)-Nisin as the outer layer. UV spectra revealed that acetic acid was successfully grafted onto RA, which dramatically improved their thermal stability, antioxidant capabilities, photostability, and pH stability. The bilayer films were successfully prepared, as revealed by scanning electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction measurements. In comparison to GG-MRA and CMC-ST-Nisin films, the water content, water solubility, mechanical characteristics, water vapor barrier, oxygen barrier, and hydrophobicity of GG-MRA@CMC-ST-Nisin films were significantly enhanced. The presence of the outer layer films significantly enhanced the UV-vis light barrier, opacity, antioxidant and antibacterial properties of the inner layer films. When the films were applied to chicken breast, it was found that the indicator films not only monitored the freshness of the chicken in real-time but also that the GG-MRA film and the double-layer film were effective in extending the shelf life of the chicken by 1 and 2 days, respectively, compared to the control group.

Preparation and characterization of smart indicator films based on gellan gum/modified black rice anthocyanin/curcumin for improving the stability of natural anthocyanins.

In order to improve the stability of natural anthocyanins in intelligent packaging materials, this work first modified black rice anthocyanins (BRA) by acylation with acetic acid, then modified the acylated BRA by co-coloring with different ratios of curcumin (CUR), and finally added the mixed indicator to gellan gum (GG) to develop intelligent packaging films with good stability. The UV spectroscopy results showed that acetic acid had successfully modified the BRA, while the thermal, photostability and pH stability of the modified black rice anthocyanin (MBRA) were significantly enhanced. The indicators of BRA, MBRA and MBRA mixed with CUR showed excellent pH sensitivity in different buffer solutions. The SEM, FT-IR and XRD results indicated apparent crystalline aggregates on the surface of the films added with a high concentration of CUR. Compared with GG-BRA film, GG-MBRA film improved all properties except for antioxidant performance. Notably, the GG-MBRA/CUR series composite films exhibited significant improvements over the GG-BRA and GG-MBRA films in terms of optical characteristics, mechanical properties, water vapor barrier, oxidation resistance, and color stability; meanwhile, all films exhibited excellent pH sensitivity. Considering all the properties of the films, GG-MBRA/CUR3 film has tremendous potential as a smart indicator film for improving freshness accuracy.

Quercetin alleviates nanoparticle-induced osteolysis via deactivating pyroptosis.

As one of the most successful stories in modern medicine, total joint arthroplasty (TJA) is performed several million times worldwide every year. However, more than 20% of patients will suffer from aseptic loosening (AL) following periprosthetic osteolysis (PPO) in the next few years. Unfortunately, the only effective treatment for PPO, i.e., revision surgery, can cause great surgical trauma. It has been reported that the accumulation of reactive oxidative species (ROS) generated by exposure to wear particles could activate NLRP3 inflammasome in macrophages and accelerate the progress of osteolysis. Given that the conservative treatment is not effective and can be accompanied by apparent side effects, we, therefore, investigated the therapeutic effect of the natural compound quercetin (Que) on wear particle-induced osteolysis. Our results showed that Que could activate nuclear factor erythroid 2-related factor 2 (Nrf2) to remove ROS and deactivate inflammasome activation. Besides, the imbalance between osteoclastogenesis and osteogenesis induced by inflammatory cytokines was also rescued by Que. Collectively, our work demonstrates that Que may be a qualified candidate for the conservative treatment of wear particle-induced osteolysis.

ASPS Exhibits Anti-Rheumatic Effects by Reprogramming Gut Microbiota and Increasing Serum γ-Glutamylcysteine Level.

Rheumatoid arthritis (RA) is an essential cause of labor loss and disability for people worldwide. Acanthopanax senticosus polysaccharide (ASPS) is one of the most important active components from A. senticosus, which exhibits various pharmacological activities such as antioxidation and immunomodulation. However, no studies have reported the application of ASPS in treating RA. This study aims to investigate the therapeutic effect of ASPS on RA and reveal its underlying mechanism. The potential therapeutic effect of ASPS against RA is initially verified in this study using the collagen-induced arthritis model. Moreover, the protective benefits of ASPS are transmitted through the fecal microbiota and blocked by simultaneous antibiotic cocktail treatment, indicating that gut microbiota may be correlated with ASPS. The 16S rRNA sequencing using feces samples and untargeted UPLC-MS metabolomics using serum samples further reveal that ASPS reprograms the arthritic progression triggered dysbiosis, enhances the expression of γ-glutamylcysteine (GGC) synthetase, and enriches the serum concentration of GGC. Furthermore, metabolites GGC is found to be able to effectively interrupt NLRP3 inflammasome activation via inhibiting ASC nucleation and therefore attenuate inflammatory arthritis. Taken together, this work highlights ASPS's therapeutic potential against RA, which mainly exhibits its effects via modulating gut microbiota and regulating GGC production.

A smart film incorporating anthocyanins and tea polyphenols into sodium carboxymethyl cellulose/polyvinyl alcohol for application in mirror carp.

Multifunctional food packaging films were developed based on polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC), tea polyphenol (TP) and black carrot anthocyanin (CA). Results of Zeta potential, scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction showed that CA enhanced the stability of the particle dispersion system through hydrogen bonding and electrostatic interactions, promoted the compatibility between TP and PVA-CMC (PC) substrates, and enhanced the binding between the components of the films. Because of the interaction of TP and CA, PC-TP-CA films had better water resistance and water vapor barrier properties, thermal stability, antioxidant and antimicrobial properties. PC-CA and PC-TP-CA films exhibited excellent UV-blocking properties. They also showed distinct color responsiveness in the pH range of 2-13, significant sensitivity to ammonia vapor in a short period of time and excellent color stability over 20 days of storage under different conditions. When the film was applied to fish, it was found that PC-TP-CA film could extend the shelf life of fish by 1-2 days and successfully monitor the freshness of the fish in real-time. Considering all the physical and functional properties, the non-toxic and biodegradable PC-TP-CA film has excellent potential as a new multifunctional food packaging material in the future.

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.

Interleukin-13 Affects the Recovery Processes in a Mouse Model of Hemorrhagic Stroke with Bilateral Tibial Fracture.

As one form of stroke, intracerebral hemorrhage (ICH) is a fatal cerebrovascular disease, which has high morbidity and mortality and lacks effective medical treatment. Increased infiltration of inflammatory cytokines coupled with pyroptotic cell death is involved in the pathophysiological process of ICH. However, little is known about whether concomitant fracture patients have the same progression of inflammation and pyroptosis. Hence, we respectively established the mouse ICH model and ICH with bilateral tibial fracture model (MI) to explore the potential cross-talk between the above two injuries. We found that MI obviously reversed the expressions of pyroptosis-associated proteins, which were remarkably up-regulated at the acute phase after ICH. Similar results were observed in neuronal expressions via double immunostaining. Furthermore, brain edema was also significantly alleviated in mice who suffered MI, when compared with ICH alone. To better clarify the potential mechanisms that mediated this cross-talk, recombinant mouse interleukin-13 (IL-13) was used to investigate its effect on pyroptosis in the mouse MI model, in which a lower level of IL-13 was observed. Remarkably, IL-13 administration re-awakened cell death, which was mirrored by the re-upregulation of pyroptosis-associated proteins and PI-positive cell counts. The results of hemorrhage volume and behavioral tests further confirmed its critical role in regulating neurological functions. Besides, the IL-13-treated MI group showed poor outcomes of fracture healing. To sum up, our research indicates that controlling the IL-13 content in the acute phase would be a promising target in influencing the outcomes of brain injury and fracture, and meanwhile, provides new evidence in repairing compound injuries in clinics.

Identification of novel rheumatoid arthritis-associated MiRNA-204-5p from plasma exosomes.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by infiltration of immune cells in the synovium. However, the crosstalk of immune cells and synovial fibroblasts is still largely unknown. Here, global miRNA screening in plasma exosomes was carried out with a custom microarray (RA patients vs. healthy controls = 9:9). A total of 14 exosomal miRNAs were abnormally expressed in the RA patients. Then, downregulated expression of exosomal miR-204-5p was confirmed in both the replication (RA patients vs. healthy controls = 30:30) and validation groups (RA patients vs. healthy controls = 56:60). Similar to the findings obtained in humans, a decreased abundance of exosomal miR-204-5p was observed in mice with collagen-induced arthritis (CIA). Furthermore, Spearman correlation analysis indicated that plasma exosomal miR-204-5p expression was inversely correlated with disease parameters of RA patients, such as rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein. In vitro, our data showed that human T lymphocytes released exosomes containing large amounts of miR-204-5p, which can be transferred into synovial fibroblasts, inhibiting cell proliferation. Overexpression of miR-204-5p in synovial fibroblasts suppressed synovial fibroblast activation by targeting genes related to cell proliferation and invasion. In vivo assays found that administration of lentiviruses expressing miR-204-5p markedly alleviated the disease progression of the mice with CIA. Collectively, this study identified a novel RA-associated plasma exosomal miRNA-204-5p that mediates the communication between immune cells and synovial fibroblasts and can be used as a potential biomarker for RA diagnosis and treatment.

SPECT imaging and highly efficient therapy of rheumatoid arthritis based on hyperbranched semiconducting polymer nanoparticles.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease. Although significant progress has been made in clinical treatment, joint inflammation may continue or worsen, and may even progress to the end-stage that requires joint replacement. Traditional therapy using methotrexate (MTX) would cause serious off-target systemic toxicities. Therefore, it is crucial to effectively and specifically deliver MTX to targeted inflamed joints to decrease its adverse systemic toxicities and improve its therapeutic index. Herein, we develop multifunctional nanocarriers for diagnostic radioisotope (99mTc) labeling and therapeutic targeted drug (MTX) delivery by using PEGylated hyperbranched semiconducting polymer nanoparticles (HSP-PEG-NPs) as carriers. Upon intravenous administration, the nanoparticles can extravasate through the turbulent blood-joint barrier and access the inflamed joints. In vivo SPECT/CT imaging shows high accumulation in the inflamed joints of mice with RA after intravenous injection of HSP-PEG-NPs with 99mTc labeling (99mTc-HSP-PEG). In vivo therapeutic evaluations suggest that MTX@HSP-PEG-NPs significantly alleviate RA with a high therapeutic index and relatively low adverse systemic toxicities in comparison with free MTX at the same dose. Our study shows that HSP-PEG-NPs could serve as multifunctional vehicles to deliver radioisotopes for in vivo imaging, and MTX for RA treatment, highlighting the innovative development of the nanoparticle-based RA treatment strategy for clinical applications.

The effect of traumatic brain injury on bone healing from a novel exosome centered perspective in a mice model.

BACKGROUND: In patients with traumatic brain injury (TBI) combined with long bone fracture, the fracture healing is always faster than that of patients with single fracture, which is characterized by more callus growth at the fracture site and even ectopic ossification. Exosomes are nanoscale membrane vesicles secreted by cells, which contain cell-specific proteins, miRNAs, and mRNAs. METHODS: In this study, we used exosomes as the entry point to explore the mechanism of brain trauma promoting fracture healing. We established a model of tibia fracture with TBI in mice to observe the callus growth and expression of osteogenic factors at the fracture site. Blood samples of model mice were further collected, exosomes in plasma were extracted by ultra-centrifugation method, and then identified and acted on osteoblasts cultured in vitro. The effects of exosomes on osteoblast differentiation at the cell, protein and gene levels were investigated by Western Blot and q-PCR, respectively. Furthermore, miRNA sequencing of exosomes was performed to identify a pattern of miRNAs that were present at increased or decreased levels. RESULTS: The results suggested that plasma exosomes after TBI had the ability to promote the proliferation and differentiation of osteoblasts, which might be due to the increased expression of osteoblast-related miRNA in exosomes. They were transmitted to the osteoblasts at the fracture site, so as to achieve the role of promoting osteogenic differentiation. CONCLUSION: The TBI-derived exosomes may have potential applications for promoting fracture healing in future. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Plasma exosomes early after TBI have the ability to promote osteoblast proliferation and differentiation. The mechanism may be achieved by miRNA in exosomes. Plasma exosomes may be used as breakthrough clinical treatment for delayed or non-union fractures.