The design of strut/TPMS-based pore geometries in bioceramic scaffolds guiding osteogenesis and angiogenesis in bone regeneration.

The pore morphology design of bioceramic scaffolds plays a substantial role in the induction of bone regeneration. Specifically, the effects of different scaffold pore geometry designs on angiogenesis and new bone regeneration remain unclear. Therefore, we fabricated Mg/Sr co-doped wollastonite bioceramic (MS-CSi) scaffolds with three different pore geometries (gyroid, cylindrical, and cubic) and compared their effects on osteogenesis and angiogenesis in vitro and in vivo. The MS-CSi scaffolds were fabricated by digital light processing (DLP) printing technology. The pore structure, mechanical properties, and degradation rate of the scaffolds were investigated. Cell proliferation on the scaffolds was evaluated using CCK-8 assays while angiogenesis was assessed using Transwell migration assays, tube formation assays, and immunofluorescence staining. The underlying mechanism was explored by western blotting. Osteogenic ability of scaffolds was evaluated by alkaline phosphatase (ALP) staining, western blotting, and qRT-PCR. Subsequently, a rabbit femoral defect model was prepared to compare differences in the scaffolds in osteogenesis and angiogenesis in vivo. Cell culture experiments showed that the gyroid pore scaffold downregulated YAP/TAZ phosphorylation and enhanced YAP/TAZ nuclear translocation, thereby promoting proliferation, migration, tube formation, and high expression of CD31 in human umbilical vein endothelial cells (HUVECs) while strut-based (cubic and cylindrical pore) scaffolds promoted osteogenic differentiation in bone marrow mesenchymal stem cells and upregulation of osteogenesis-related genes. The gyroid pore scaffolds were observed to facilitate early angiogenesis in the femoral-defect model rabbits while the strut-based scaffolds promoted the formation of new bone tissue. Our study indicated that the pore geometries and pore curvature characteristics of bioceramic scaffolds can be precisely tuned for enhancing both osteogenesis and angiogenesis. These results may provide new ideas for the design of bioceramic scaffolds for bone regeneration.

Correction: Core-shell bioceramic fiber-derived biphasic granules with adjustable core compositions for tuning bone regeneration efficacy.

Correction for 'Core-shell bioceramic fiber-derived biphasic granules with adjustable core compositions for tuning bone regeneration efficacy' by Zhaonan Bao et al., J. Mater. Chem. B, 2023, 11, 2417-2430, https://doi.org/10.1039/D3TB90052E.

Bioceramic scaffolds with triply periodic minimal surface architectures guide early-stage bone regeneration.

The pore architecture of porous scaffolds is a critical factor in osteogenesis, but it is a challenge to precisely configure strut-based scaffolds because of the inevitable filament corner and pore geometry deformation. This study provides a pore architecture tailoring strategy in which a series of Mg-doped wollastonite scaffolds with fully interconnected pore networks and curved pore architectures called triply periodic minimal surfaces (TPMS), which are similar to cancellous bone, are fabricated by a digital light processing technique. The sheet-TPMS pore geometries (s-Diamond, s-Gyroid) contribute to a 3‒4-fold higher initial compressive strength and 20%-40% faster Mg-ion-release rate compared to the other-TPMS scaffolds, including Diamond, Gyroid, and the Schoen's I-graph-Wrapped Package (IWP) in vitro. However, we found that Gyroid and Diamond pore scaffolds can significantly induce osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Analyses of rabbit experiments in vivo show that the regeneration of bone tissue in the sheet-TPMS pore geometry is delayed; on the other hand, Diamond and Gyroid pore scaffolds show notable neo-bone tissue in the center pore regions during the early stages (3-5 weeks) and the bone tissue uniformly fills the whole porous network after 7 weeks. Collectively, the design methods in this study provide an important perspective for optimizing the pore architecture design of bioceramic scaffolds to accelerate the rate of osteogenesis and promote the clinical translation of bioceramic scaffolds in the repair of bone defects.

Core-shell bioceramic fiber-derived biphasic granules with adjustable core compositions for tuning bone regeneration efficacy.

Silicate-based biomaterials-clinically applied fillers and promising candidates-can act as a highly biocompatible substrate for osteostimulative osteogenic cell growth in vitro and in vivo. These biomaterials have been proven to exhibit a variety of conventional morphologies in bone repair, including scaffolds, granules, coatings and cement pastes. Herein, we aim to develop a series of novel bioceramic fiber-derived granules with core-shell structures which have a hardystonite (HT) shell layer and changeable core components-that is, the chemical compositions of a core layer can be tuned to include a wide range of silicate candidates (e.g., wollastonite (CSi)) with doping of functional ions (e.g., Mg, P, and Sr). Meanwhile, it is versatile to control the biodegradation and bioactive ion release sufficiently for stimulating new bone growth after implantation. Our method employs rapidly gelling ultralong core-shell CSi@HT fibers derived from different polymer hydrosol-loaded inorganic powder slurries through the coaxially aligned bilayer nozzles, followed by cutting and sintering treatments. It was demonstrated that the nonstoichiometric CSi core component could contribute to faster bio-dissolution and biologically active ion release in tris buffer in vitro. The rabbit femoral bone defect repair experiments in vivo indicated that core-shell bioceramic granules with an 8% P-doped CSi-core could significantly stimulate osteogenic potential favorable for bone repair. It is worth concluding that such a tunable component distribution strategy in fiber-type bioceramic implants may develop new-generation composite biomaterials endowed with time-dependent biodegradation and high osteostimulative activities for a range of bone repair applications in situ.

Treatment of postoperative non-union with internal fixation loosening of Garden IV femoral neck fracture with teriparatide in a young adult: A case report.

Background: Postoperative non-union of femoral neck fracture often needs secondary operation. We report a case of a postoperative non-union of femoral neck fracture treated with teriparatide. Case presentation: A young male patient with Garden IV femoral neck fracture who showed no obvious signs of healing 3 months after percutaneous hollow nail fixation in which the fracture line was enlarged and the hollow nail was withdrawn. Bone non-union healed after 6 months of continuous subcutaneous injection of teriparatide at a dosage of 20 mg/day after the patient refused a secondary surgery. As far as we know, there have been no relevant reports on this type of fracture yet. Conclusions: Teriparatide is expected to be beneficial in treating young patients with a displaced femoral neck fracture who have difficulty in healing from non-union and who are keen on avoiding secondary surgery.

A new injectable quick hardening anti-collapse bone cement allows for improving biodegradation and bone repair.

The development of injectable cement-like biomaterials via a minimally invasive approach has always attracted considerable clinical interest for modern bone regeneration and repair. Although α-tricalcium phosphate (α-TCP) powders may readily react with water to form hydraulic calcium-deficient hydroxyapatite (CDHA) cement, its long setting time, poor anti-collapse properties, and low biodegradability are suboptimal for a variety of clinical applications. This study aimed to develop new injectable α-TCP-based bone cements via strontium doping, α-calcium sulfate hemihydrate (CSH) addition and liquid phase optimization. A combination of citric acid and chitosan was identified to facilitate the injectable and anti-washout properties, enabling higher resistance to structure collapse. Furthermore, CSH addition (5 %-15 %) was favorable for shortening the setting time (5-20 min) and maintaining the compressive strength (10-14 MPa) during incubation in an aqueous buffer medium. These α-TCP-based composites could also accelerate the biodegradation rate and new bone regeneration in rabbit lateral femoral bone defect models in vivo. Our studies demonstrate that foreign ion doping, secondary phase addition and liquid medium optimization could synergistically improve the physicochemical properties and biological performance of α-TCP-based bone cements, which will be promising biomaterials for repairing bone defects in situations of trauma and diseased bone.

Integrating pore architectures to evaluate vascularization efficacy in silicate-based bioceramic scaffolds.

Pore architecture in bioceramic scaffolds plays an important role in facilitating vascularization efficiency during bone repair or orbital reconstruction. Many investigations have explored this relationship but lack integrating pore architectural features in a scaffold, hindering optimization of architectural parameters (geometry, size and curvature) to improve vascularization and consequently clinical outcomes. To address this challenge, we have developed an integrating design strategy to fabricate different pore architectures (cube, gyroid and hexagon) with different pore dimensions (∼350, 500 and 650 µm) in the silicate-based bioceramic scaffolds via digital light processing technique. The sintered scaffolds maintained high-fidelity pore architectures similar to the printing model. The hexagon- and gyroid-pore scaffolds exhibited the highest and lowest compressive strength (from 15 to 55 MPa), respectively, but the cube-pore scaffolds showed appreciable elastic modulus. Moreover, the gyroid-pore architecture contributed on a faster ion dissolution and mass decay in vitro. It is interesting that both µCT and histological analyses indicate vascularization efficiency was challenged even in the 650-µm pore region of hexagon-pore scaffolds within 2 weeks in rabbit models, but the gyroid-pore constructs indicated appreciable blood vessel networks even in the 350-µm pore region at 2 weeks and high-density blood vessels were uniformly invaded in the 500- and 650-µm pore at 4 weeks. Angiogenesis was facilitated in the cube-pore scaffolds in comparison with the hexagon-pore ones within 4 weeks. These studies demonstrate that the continuous pore wall curvature feature in gyroid-pore architecture is an important implication for biodegradation, vascular cell migration and vessel ingrowth in porous bioceramic scaffolds.

Artificial osteochondral interface of bioactive fibrous membranes mediating calcified cartilage reconstruction.

Calcified cartilage is a mineralized osteochondral interface region between the hyaline cartilage and subchondral bone. There are few reported artificial biomaterials that could offer bioactivities for substantial reconstruction of calcified cartilage. Herein we developed new poly(L-lactide-co-caprolactone) (PLCL)-based trilayered fibrous membranes as a functional interface for calcified cartilage reconstruction and superficial cartilage restoration. The trilayered membranes were prepared by the electrospinning technique, and the fibrous morphology was maintained when the chondroitin sulfate (CS) or bioactive glass (BG) particles were introduced in the upper or bottom layer, respectively. Although 30% BG in the bottom layer led to a significant decrease in tensile resistance, the inorganic ion release was remarkably higher than that in the counterpart with 10% BG. The in vivo studies showed that the fibrous membranes as osteochondral interfaces exhibited different biological performances on superficial cartilage restoration and calcified cartilage reconstruction. All of the implanted host hyaline cartilage enabled a self-healing process and an increase in the BG content in the membranes was desirable for promoting the repair of the calcified cartilage with time. The histological staining confirmed the osteochondral interface in the 30% BG bottom membrane maintained appreciable calcified cartilage repair after 12 weeks. These findings demonstrated that such an integrated artificial osteochondral interface containing appropriate bioactive ions are potentially applicable for osteochondral interface tissue engineering.

Rational design of nonstoichiometric bioceramic scaffolds via digital light processing: tuning chemical composition and pore geometry evaluation.

Bioactive ceramics are promising candidates as 3D porous substrates for bone repair in bone regenerative medicine. However, they are often inefficient in clinical applications due to mismatching mechanical properties and compromised biological performances. Herein, the additional Sr dopant is hypothesized to readily adjust the mechanical and biodegradable properties of the dilute Mg-doped wollastonite bioceramic scaffolds with different pore geometries (cylindrical-, cubic-, gyroid-) by ceramic stereolithography. The results indicate that the compressive strength of Mg/Sr co-doped bioceramic scaffolds could be tuned simultaneously by the Sr dopant and pore geometry. The cylindrical-pore scaffolds exhibit strength decay with increasing Sr content, whereas the gyroid-pore scaffolds show increasing strength and Young's modulus as the Sr concentration is increased from 0 to 5%. The ion release could also be adjusted by pore geometry in Tris buffer, and the high Sr content may trigger a faster scaffold bio-dissolution. These results demonstrate that the mechanical strengths of the bioceramic scaffolds can be controlled from the point at which their porous structures are designed. Moreover, scaffold bio-dissolution can be tuned by pore geometry and doping foreign ions. It is reasonable to consider the nonstoichiometric bioceramic scaffolds are promising for bone regeneration, especially when dealing with pathological bone defects.

Bone tissue regeneration: The role of finely tuned pore architecture of bioactive scaffolds before clinical translation.

Spatial dimension of pores and interconnection in macroporous scaffolds is of particular importance in facilitating endogenous cell migration and bone tissue ingrowth. However, it is still a challenge to widely tune structure parameters of scaffolds by conventional methods because of inevitable pore geometrical deformation and poor pore interconnectivity. Here, the long-term in vivo biological performances of nonstoichiometric bioceramic scaffolds with different pore dimensions were assessed in critical-size femoral bone defect model. The 6% Mg-substituted wollastonite (CSi-Mg6) powders were prepared via wet-chemical precipitation and the scaffolds elaborately printed by ceramic stereolithography, displaying designed constant pore strut and tailorable pore height (200, 320, 450, 600 µm), were investigated thoroughly in the bone regeneration process. Together with detailed structural stability and mechanical properties were collaboratively outlined. Both µCT and histological analyses indicated that bone tissue ingrowth was retarded in 200 µm scaffolds in the whole stage (2-16 weeks) but the 320 µm scaffolds showed appreciable bone tissue in the center of porous constructs at 6-10 weeks and matured bone tissue were uniformly invaded in the whole pore networks at 16 weeks. Interestingly, the neo-tissue ingrowth was facilitated in the 450 µm and 600 µm scaffolds after 2 weeks and higher extent of bone regeneration and remodeling at the later stage. These new findings provide critical information on how engineered porous architecture impact bone regeneration in vivo. Simultaneously, this study shows important implications for optimizing the porous scaffolds design by advanced additive manufacture technique to match the clinical translation with high performance.

Autophagy regulation is an effective strategy to improve the prognosis of chemically induced acute liver injury based on experimental studies.

Acute liver injury (ALI) induced by chemicals in current experimental studies is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long-term outcome and lead to liver failure. In liver cells, different autophagy forms envelop cytoplasm components, including proteins, endoplasmic reticulum (ER), mitochondria and lipids, and they effectively participate in breaking down the cargo enclosed inside lysosomes to replenish cellular energy and contents. In general, autophagy serves as a cell survival mechanism in stressful microenvironments, but it also serves as a destructive mechanism that results in cell death in vitro and in vivo. In experimental animals, multiple chemicals are used to mimic ALI in patients to clarify the potential pathological mechanisms and develop effective strategies in the clinic. In this review, we summarize related publications about autophagy modulation to attenuate chemically induced ALI in vitro and in vivo. We also analysed the underlying mechanisms of autophagy regulators and genetic modifications to clarify how to control autophagy to protect against chemically induced ALI in animal models. We anticipate that selectively controlling the dual effects of hepatic autophagy will help to protect against ALI in various animals, but the detailed mechanisms and effects should be determined further in future studies. In this way, we are more confident that modulating autophagy in liver regeneration can improve the prognosis of ALI.

Seasonal variation and correlation analysis of vitamin D and parathyroid hormone in Hangzhou, Southeast China.

This study aimed to describe the 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) status of Southeast Chinese individuals influenced by season. The secondary aim was to determine the cutoff for sufficient 25(OH)D in a four-season region. From January 2011 to June 2014, a total of 17 646 individuals were evaluated in our study. The serum levels of PTH were detected simultaneously in 5579 cases. A total of 25(OH)D and intact PTH were measured by the electrochemiluminescent immunoassay. The distribution of the concentration, prevalence and seasonal variability of 25(OH)D and PTH were studied. The mean 25(OH)D concentration in our study was 43.00(30.40) nmol/L. The prevalence of insufficiency (25(OH)D < 50 nmol/L) was 62.87% and that of deficiency (<30 nmol/L) was 28.54%. Mean serum 25(OH)D levels revealed a limited sinusoidal profile throughout the year and were significantly higher in Autumn. On the other hand, PTH levels showed an opposite response to seasonal effects relative to 25(OH)D. Age, BMI and daylight were not significantly correlated with 25(OH)D and serum PTH reached a plateau at higher values of serum 25(OH)D of 42.86 nmol/L. This study demonstrated that Vitamin D insufficiency is highly prevalent in Southeast China. The concentration of 25(OH)D in the male group was generally higher than that in the female group. Seasonal variation was an important aspect of 25(OH)D and PTH concentration. This study revealed that the optimal serum threshold of 25(OH)D for bone health should be between 40 and 50 nmol/L for Southeast Chinese individuals.

Effect of Foreign Ion Substitution and Micropore Tuning in Robocasting Single-Phase Bioceramic Scaffolds on the Physicochemical Property and Vascularization.

The inorganic powder slurry extrusion printing technique known as robocasting is an interesting method to fabricate complex porous architectures whereby feedstocks containing organic binders and powders are printed and the resulting scaffolds are subjected to sintering. A major limiting factor of this technique is the simultaneous tailoring of vascularization efficacy and osteogenic activity, usually done by adding the secondary phase in the organic slurry before the writing step. Mechanical mixing of biphasic powders is required to avoid compromising the biological performance and physical defects caused by significantly different physicochemical properties. This study addresses this issue by developing a selective ion doping and microstructure tuning for the production of bioceramic scaffolds with a binozzle robocasting process. Different metal ions (Sr2+, Mg2+) were doped into wollastonite (CaSiO3; CSi) powders considering the mechanical stability and bioactive enhancement of the bioceramic scaffolds. Subsequently, the Mg-doped CSi slurries were used as shell-nozzle feedstocks added with 5, 10, and 15 µm diameter polystyrene microbeads that allowed shell-layer micropore production in pore struts during sintering. Finally, the most promising pore-strut microstructures and mechanical evolution of scaffolds were evaluated, and especially the enhanced fibrovascularization potential was confirmed in dorsal muscle embedding model in rabbits. This study may open an avenue to designing multiproperty-tuned macro- and microporous bioceramics for bone regenerative medicine, especially in challenging bone defect conditions.

Knockdown of miR-372 Inhibits Nerve Cell Apoptosis Induced by Spinal Cord Ischemia/Reperfusion Injury via Enhancing Autophagy by Up-regulating Beclin-1.

To investigate the role of miR-372/Beclin-1 on nerve cell apoptosis induced by spinal cord ischemia/reperfusion injury (SCII). We established in vivo and in vitro SCII model. MiR-372 and Beclin-1 expressions in spinal cord tissues of SCII rats and SCII nerve cells were measured. The cell apoptosis was detected by flow cytometry. MiR-372 inhibitor was used to reduce miR-372 expression. Dual luciferase reporter assay was used to confirm the interaction between miR-372 and Beclin-1. MiR-372 expression in spinal cord tissues of SCII rats and SCII nerve cells was increased, while Beclin-1 expression was decreased. Knockdown of miR-372 could inhibit SCII nerve cell apoptosis. In addition, MiR-372 could negatively regulate Beclin-1 expression. Autophagy inhibitor could inhibit autophagy to promote the apoptosis of SCII nerve cells through decreasing Beclin-1, while interference of miR-372 changed the effect of autophagy inhibitor. Interference of miR-372 could reduce nerve cell apoptosis in SCII via increasing autophagy by up-regulating Beclin-1.

Insight into neural mechanisms underlying discogenic back pain.

Back pain is a common clinical symptom. Degeneration of intervertebral discs is one of the most important factors leading to back pain, namely, discogenic back pain. However, at present, the understanding of lumbar intervertebral discs causing back pain is confined to biomechanical and histological studies. The neuropathological mechanism related to discogenic back pain is still not well understood. Many studies have found that as an intervertebral disc degenerates, the peripheral nerve tissues have corresponding structural reorganization, and a series of nerve cells become involved in progression of discogenic back pain. Therefore, study of neural mechanisms that are involved in progression of discogenic back pain will provide additional assistance for treatment of its symptoms. We review the anatomical structure of intervertebral discs and the related neural mechanisms involved in discogenic back pain. We also discuss the current view of neural mechanisms underlying discogenic back pain.

Nonstoichiometric wollastonite bioceramic scaffolds with core-shell pore struts and adjustable mechanical and biodegradable properties.

Controllable mechanical strength and biodegradation of bioceramic scaffolds is a great challenge to treat the load-bearing bone defects. Herein a new strategy has been developed to fabricate porous bioceramic scaffolds with adjustable component distributions based on varying the core-shell-structured nozzles in three-dimensional (3D) direct ink writing platform. The porous bioceramic scaffolds composed of different nonstoichiometic calcium silicate (nCSi) with 0%, 4% or 10% of magnesium-substituting-calcium ratio (CSi, CSi-Mg4, CSi-Mg10) was fabricated. Beyond the mechanically mixed composite scaffolds, varying the different nCSi slurries through the coaxially aligned bilayer nozzle makes it easy to create core-shell bilayer bioceramic filaments and better control of the different nCSi distribution in pore strut after sintering. It was evident that the magnesium substitution in CSi contributed to the increase of compressive strength for the single-phasic scaffolds from 11.2 MPa (CSi), to 39.4 MPa (CSi-Mg4) and 80 MPa (CSi-Mg10). The nCSi distribution in pore struts in the series of core-shell-strut scaffolds could significantly adjust the strength [e.g. CSi@CSi-Mg10 (58.9 MPa) vs CSi-Mg10@CSi (30.4 MPa)] and biodegradation ratio in Tris buffer for a long time stage (6 weeks). These findings demonstrate that the nCSi components with different distributions in core or shell layer of pore struts lead to tunable strength and biodegradation inside their interconnected macropore architectures of the scaffolds. It is possibly helpful to develop new bioactive scaffolds for time-dependent tailoring mechanical and biological performances to significantly enhance bone regeneration and repair applications, especially in some load-bearing bone defects.

Apoptotic effect of pyrroloquinoline quinone on chondrosarcoma cells through activation of the mitochondrial caspase­dependent and caspase­independent pathways.

Chondrosarcomas are malignant tumors of the bone that exhibit resistance to chemotherapy and radiation. Pyrroloquinoline quinone (PQQ) is a bacterial redox co­factor and antioxidant that has been found to induce apoptosis in various cancer cells. This study investigated the role of PQQ in cell apoptosis of chondrosarcoma cells and the underlying pathways involved. We confirmed that PQQ was cytotoxic to chondrosarcoma SW1353 cells by a cell cytotoxicity assay. Furthermore, flow cytometry showed that the number of apoptotic cells increased in a concentration­dependent and time­dependent manner following PQQ treatment, but this effect was not significant in normal cells. Co­immunoprecipitation assays showed that the binding of Smac to X­linked inhibitor­of­apoptosis protein (XIAP) was significantly increased and the binding of XIAP with caspase­3 was significantly decreased following PQQ treatment. This was accompanied by a decrease in the levels of caspase­1 and procaspase­3, as demonstrated by western blot analysis. Western blotting also showed that the level of cytochrome c in the mitochondria was decreased and its level in the cytoplasm was increased. These findings indicate the role of caspase­dependent apoptotic pathways in the effect of PQQ. Furthermore, the cytoplasmic and nuclear levels of apoptosis­inducing factor (AIF) were increased and its mitochondrial levels were decreased, and similar results were obtained for endonuclease G. Thus, the role of caspase­independent pathways was also demonstrated. Finally, in vivo tumor implantation experiments showed that PQQ was able to inhibit tumor growth in mice with chondrosarcoma. These findings demonstrated that PQQ induced apoptosis in human chondrosarcoma cells by activating mitochondrial caspase­dependent and caspase­independent pathways. Thus, the proteins involved in these pathways may have potential as antitumor treatment targets for chondrosarcoma.

Injection of synthetic mesenchymal stem cell mitigates osteoporosis in rats after ovariectomy.

Osteoporosis is a severe skeletal disorder. Patients have a low bone mineral density and bone structural deterioration. Mounting lines of evidence suggest that inappropriate apoptosis of osteoblasts/osteocytes leads to maladaptive bone remodelling in osteoporosis. It has been suggested that transplantation of stem cells, including mesenchymal stem cells, may alter the trajectory of bone remoulding and mitigate osteoporosis in animal models. However, stem cells needed to be carefully stored and characterized before usage. In addition, there is great batch-to-batch variation in stem cell production. Here, we fabricated therapeutic polymer microparticles from the secretome and membranes of mesenchymal stem cells (MSCs). These synthetic MSCs contain growth factors secreted by MSCs. In addition, these particles display MSC surface molecules. In vitro, co-culture with synthetic MSCs increases the viability of osteoblast cells. In a rat model of ovariectomy-induced osteoporosis, injection of synthetic MSCs mitigated osteoporosis by reducing cell apoptosis and systemic inflammation, but increasing osteoblast numbers. Synthetic MSC offers a promising therapy to manage osteoporosis.

Acamprosate Protects Against Adjuvant-Induced Arthritis in Rats via Blocking the ERK/MAPK and NF-κB Signaling Pathway.

Osteoarthritis is a type of joint disease that results from the breakdown of joint cartilage and underlying bone and is believed to be caused by mechanical stress on the joint and low-grade inflammatory processes. Acamprosate significantly ameliorates the pathological features of experimental autoimmune encephalomyelitis due to its anti-inflammatory effect. The aims of the present study were to investigate the anti-arthritis activities of acamprosate and elucidate the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced by intradermal injection of complete Freund's adjuvant. Male Wistar rats were randomly divided into five groups: (1) sham control group, (2) AIA group, (3) acamprosate 10 mg/kg (AIA + ACA10), (4) acamprosate 30 mg/kg (AIA + ACA30), and (5) acamprosate 100 mg/kg (AIA + ACA100). Paw swelling and the arthritis index were measured, and the production of IL-1ß, IL-6, and TNF-α was detected by ELISA in serum. The expression of inflammation-related molecules, including c-Raf, ERK1/2, and NF-κB, was determined by Western blotting. We found that acamprosate significantly suppressed paw swelling and the arthritis index in AIA rats. Moreover, acamprosate also significantly suppressed the production of TNF-α, IL-1ß, and IL-6 in serum, which is elevated by AIA induction. Finally, acamprosate inhibited p-c-Raf and p-ERK1/2 and NF-κB activation after AIA treatment. These results indicate that acamprosate has an anti-inflammatory effect on adjuvant-induced arthritic rats via inhibiting the ERK/MAPK and NF-κB signaling pathways, and acamprosate may serve as a promising novel therapeutic agent for osteoarthritis.

Therapeutic benefits of CD90-negative cardiac stromal cells in rats with a 30-day chronic infarct.

Cardiac stromal cells (CSCs) can be derived from explant cultures, and a subgroup of these cells is viewed as cardiac mesenchymal stem cells due to their expression of CD90. Here, we sought to determine the therapeutic potential of CD90-positive and CD90-negative CSCs in a rat model of chronic myocardial infarction. We obtain CD90-positive and CD90-negative fractions of CSCs from rat myocardial tissue explant cultures by magnetically activated cell sorting. In vitro, CD90-negative CSCs outperform CD90-positive CSCs in tube formation and cardiomyocyte functional assays. In rats with a 30-day infarct, injection of CD90-negative CSCs augments cardiac function in the infarct in a way superior to that from CD90-positive CSCs and unsorted CSCs. Histological analysis revealed that CD90-negative CSCs increase vascularization in the infarct. Our results suggest that CD90-negative CSCs could be a development candidate as a new cell therapy product for chronic myocardial infarction.