RNA-binding proteins potentially regulate the alternative splicing of apoptotic genes during knee osteoarthritis progression.

BACKGROUND: Alternative splicing (AS) is a principal mode of genetic regulation and one of the most widely used mechanisms to generate structurally and functionally distinct mRNA and protein variants. Dysregulation of AS may result in aberrant transcription and protein products, leading to the emergence of human diseases. Although considered important for regulating gene expression, genome-wide AS dysregulation, underlying mechanisms, and clinical relevance in knee osteoarthritis (OA) remain unelucidated. Therefore, in this study, we elucidated and validated AS events and their regulatory mechanisms during OA progression. RESULTS: In this study, we identified differentially expressed genes between human OA and healthy meniscus samples. Among them, the OA-associated genes were primarily enriched in biological pathways such as extracellular matrix organization and ossification. The predominant OA-associated regulated AS (RAS) events were found to be involved in apoptosis during OA development. The expression of the apoptosis-related gene BCL2L13, XAF1, and NF2 were significantly different between OA and healthy meniscus samples. The construction of a covariation network of RNA-binding proteins (RBPs) and RAS genes revealed that differentially expressed RBP genes LAMA2 and CUL4B may regulate the apoptotic genes XAF1 and BCL2L13 to undergo AS events during OA progression. Finally, RT-qPCR revealed that CUL4B expression was significantly higher in OA meniscus samples than in normal controls and that the AS ratio of XAF1 was significantly different between control and OA samples; these findings were consistent with their expected expression and regulatory relationships. CONCLUSIONS: Differentially expressed RBPs may regulate the AS of apoptotic genes during knee OA progression. XAF1 and its regulator, CUL4B, may serve as novel biomarkers and potential therapeutic targets for this disease.

Cellulose nanofibers embedded chitosan/tannin hydrogel with high antibacterial activity and hemostatic ability for drug-resistant bacterial infected wound healing.

Millions of patients annually suffer life-threatening illnesses caused by bacterial infections of skin wounds. However, the treatment of wounds infected with bacteria is a thorny issue in clinical medicine, especially with drug-resistant bacteria infections. Therefore, there is an increasing interest in developing wound dressings that can efficiently fight against drug-resistant bacterial infections and promote wound healing. In this work, an anti-drug-resistant bacterial chitosan/cellulose nanofiber/tannic acid (CS/CNF/TA) hydrogel with excellent wound management ability was developed by electrospinning and fiber breakage-recombination. The hydrogel exhibited an outstanding antibacterial property exceeding 99.9 %, even for drug-resistant bacteria. This hydrogel could adhere to the tissue surface due to its abundant catechol groups, which avoided the shedding of hydrogel during the movement. Besides, it exhibited extraordinary hemostatic ability during the bleeding phase of the wound and then regulated the wound microenvironment by absorbing water and moisturizing. Moreover, the CS/CNF/TA also promoted the regrowth of vessels and follicles, accelerating the healing of infected wound tissue, with a healing rate exceeding 95 % within a 14-day timeframe. Therefore, the CS/CNF/TA hydrogel opens a new approach for the healing of drug-resistant bacterial infected wounds.

Isolated medial patellofemoral ligament reconstruction improves static bipedal balance control in young patients with recurrent lateral patellar instability.

BACKGROUND: Knee stability can be safely and reliably restored using medial patellofemoral ligament (MPFL) reconstruction, which is widely recognized in patients with recurrent lateral patellar instability. However, the literature regarding its influence on static balance control is limited. Thus, this study aimed to assess the impact of MPFL reconstruction on balance control and determine its functional significance. METHODS: The study comprised 26 patients with recurrent lateral patellar instability, scheduled for MPFL reconstruction, and 26 matched healthy controls who underwent double-leg stance static posturographic tests pre- and postoperatively on a vertical force platform. Four test conditions were performed with their eyes open and closed, without and with foam support to evaluate the balance control of all participants. The International Knee Documentation Committee subjective knee form, Lysholm knee scoring scale, Tampa scale for kinesiophobia, and active range of motion of the affected knee were synchronously obtained and assessed. RESULTS: More postural sway was observed in patients compared to the healthy controls, 11 ± 5 days preoperatively (p < 0.01). However, 374 ± 23 days postoperatively, postural sway between the patients and control subjects was comparable (p > 0.05). Patients following MPFL reconstruction demonstrated better postural stability (p < 0.01). Significant ameliorations were found in all clinical assessments in the study patients postoperatively (p < 0.01). CONCLUSIONS: Patients with recurrent lateral patellar instability have inefficient balance control. Static bipedal balance control can be improved under surface perturbation in these patients one year after isolated MPFL reconstruction that enhances the possibility of normal restoration of postural stability. Structural recovery of the ligament could help restore the sensorimotor efficiency and generate the compensatory and anticipatory balance regulation strategies, thereby improving joint function.

High tibial osteotomy improves balance control in patients with knee osteoarthritis and a varus deformity.

BACKGROUND: Impaired knee stability is observed in patients with medial compartment knee osteoarthritis (OA) and varus malalignment. Although high tibial osteotomy (HTO) is widely used to treat OA-related knee varus deformity, its long-term influence on balance control in OA patients is poorly reported. This study aimed to evaluate the impact of HTO on balance control and assess its biological and functional significance. METHODS: Thirty-two patients with medial compartment knee OA as well as varus deformity who were scheduled for HTO underwent static posturographic tests one month pre- and three months as well as one year postoperatively, respectively, along with forty matched control subjects. Radiographic and clinical evaluations were synchronously carried out on patients pre- and postoperatively. RESULTS: Decreased postural sway was observed in patients one year after HTO. When compared to the control subjects, more postural sway was found in patients one month pre- and three months postoperatively. No difference was observed between the patients and control subjects one year postoperatively. The alignment and joint function of the affected knees significantly improved after HTO. CONCLUSIONS: This study revealed that HTO improves balance control in patients with knee OA and varus deformity. Correct alignment and improved joint function enhance the likelihood of normal postural stability. Hence, this intervention allows the knee joint to recover its corrective compensatory role in postural regulation and should be taken into account for managing knee OA patients.

Effect of autogenous osteochondral mosaicplasty on the balance control of patients with cartilage defects of the knee: a pilot study.

BACKGROUND: Autogenous osteochondral mosaicplasty (AOM) is a widely used optimal surgical technique for cartilage repair in young patients with focal articular cartilage defects. However, the alterations in balance control in these patients after AOM have not been sufficiently investigated. This study aimed to compare different balance control performances between the patients with knee cartilage defects and healthy controls before and after AOM, as well as evaluate the influence of AOM on balance control in these patients. METHODS: Static posturographic tests were performed in twenty-four patients who were scheduled for AOM two weeks pre-, three months, and one year postoperatively, along with thirty matched controls, respectively. All participants underwent posturography under four standing conditions: eyes open and closed, without and with foam support to assess the balance control ability. Subsequently, patient-reported outcome measures (PROMs) were synchronously obtained and analyzed. RESULTS: Compared to the control subjects, less efficient balance control was observed in study patients at three testing phases (p < 0.05), whereas no alterations in postural control were visible in these patients within a year following AOM (p > 0.05). Significant improvements were found in all PROMs such as the International Knee Documentation Committee, the Lysholm Knee Score, and the visual analogue scale in the study patients postoperatively (p < 0.01). CONCLUSION: The results indicated that patients with knee cartilage defects have a prominent balance control deficit compared to healthy individuals. Furthermore, AOM does not improve balance control in these patients for at least one year postoperatively, and more effective approaches for postural regulation are required for the management of cartilage defect patients.

Applications of chitosan-based biomaterials: From preparation to spinal cord injury neuroprosthetic treatment.

Spinal cord injury (SCI)-related disabilities are a serious problem in the modern society. Further, the treatment of SCI is highly challenging and is urgently required in clinical practice. Research on nerve tissue engineering is an emerging approach for improving the treatment outcomes of SCI. Chitosan (CS) is a cationic polysaccharide derived from natural biomaterials. Chitosan has been found to exhibit excellent biological properties, such as nontoxicity, biocompatibility, biodegradation, and antibacterial activity. Recently, chitosan-based biomaterials have attracted significant attention for SCI repair in nerve tissue engineering applications. These studies revealed that chitosan-based biomaterials have various functions and mechanisms to promote SCI repair, such as promoting neural cell growth, guiding nerve tissue regeneration, delivering nerve growth factors, and as a vector for gene therapy. Chitosan-based biomaterials have proven to have excellent potential for the treatment of SCI. This review aims to introduce the recent advances in chitosan-based biomaterials for SCI treatment and to highlight the prospects for further application.

Chitosan-based drug delivery systems: From synthesis strategy to osteomyelitis treatment - A review.

Osteomyelitis is a complex disease in orthopedics mainly caused by bacterial pathogens invading bone or bone marrow. The treatment of osteomyelitis is highly difficult and it is a major challenge in orthopedic surgery. The long-term systemic use of antibiotics may lead to antibiotic resistance and has limited effects on eradicating local biofilms. Localized antibiotic delivery after surgical debridement can overcome the problem of antibiotic resistance and reduce systemic toxicity. Chitosan, a special cationic polysaccharide, is a product extracted from the deacetylation of chitin. It has numerous advantages, such as nontoxicity, biocompatibility, and biodegradability. Recently, chitosan has attracted significant attention in bacterial inhibition and drug delivery. Because chitosan contains many functional bioactive groups conducive to chemical reaction and modification, some chitosan-based biomaterials have been applied as the local antibiotic delivery systems in the treatment of osteomyelitis. This review aims to introduce recent advances in the biomedical applications of chitosan-based drug delivery systems in osteomyelitis treatment and to highlight the perspectives for further studies.

Surgical treatment of diabetic foot ulcers during the COVID-19 pandemic in China.

Diabetic foot ulcers are among the most serious complications of diabetes. If left untreated, these ulcers can lead to severe infection and gangrene; in some instances, they may result in death. Thus, timely treatment of diabetic foot ulcers is extremely important. However, timely patient treatment during the COVID-19 pandemic is particularly challenging, because of the higher volume of patients and the need to ensure safety of medical personnel. This article describes a proposed strategy for diagnosis and treatment of diabetic foot ulcers, based on experiences with infection and control strategies during the COVID-19 pandemic in China.

Anticancer effects and the mechanism underlying 2-methoxyestradiol in human osteosarcoma in vitro and in vivo.

Osteosarcoma (OS) occurs in both children and adolescents and leads to a poor prognosis. 2-methoxyestradiol (2-ME) has a strong antitumor effect and is effective against numerous types of tumor. However, 2-ME has a low level of antitumor effects in OS. The present study investigated the effects of 2-ME on the proliferation and apoptosis of human MG63 OS cells. The potential biological mechanisms by which 2-ME exerts its biological effects were also investigated in the present study. The results of the present study demonstrated that 2-ME inhibited the proliferation of OS cells in a time- and dose-dependent manner, induced G2/M phase cell cycle arrest and early apoptosis. The expression levels of vascular endothelial growth factor (VEGF), Bcl-2 and caspase-3 were measured via western blotting and reverse transcription-quantitative PCR. As the concentration of 2-ME increased, the RNA and protein expression levels of VEGF and Bcl-2 decreased gradually, whereas the expression of caspase-3 increased gradually. In addition, tumor growth in nude mice was suppressed by 2-ME with no toxic side effects observed in the liver or kidney. Immunohistochemistry demonstrated that the expression levels of Bcl-2 and VEGF were significantly lower, and those of caspase-3 were significantly higher in test mice compared with the control group. TUNEL staining of xenograft tumors revealed that with increased 2-ME concentration, the number of apoptotic cells also gradually increased. Thus, 2-ME effectively inhibited the proliferation and induced apoptosis of MG63 OS cells in vitro and in vivo with no obvious side effects. The mechanism of the anticancer effect of 2-ME may be associated with the actions of Bcl-2, VEGF and caspase-3.

Breathing Micelles for Combinatorial Treatment of Rheumatoid Arthritis.

Breathing process involves inhalation and exhalation of different gases in animals. The gas exchange of the breathing process plays a critical role in maintaining the physiological functions of living organisms. Although artificial breathing materials exhibiting volume expansion and contraction upon alternate exposure to different gases have been well explored, those being able to realize the gas exchange remain elusive. Herein, we report breathing micelles (BM) capable of inhaling nitric oxide (NO) and exhaling carbon monoxide (CO), both of which are endogenous gaseous signaling molecules. We demonstrate that BM can simultaneously scavenge overproduced NO and attenuate proinflammatory cytokines in lipopolysaccharide (LPS)-challenged macrophage cells. In vivo studies revealed that BM outperformed conventional nonsteroidal anti-inflammatory drugs such as dexamethasone (Dexa) in treatment of rheumatoid arthritis (RA) in adjuvant-induced arthritis (AIA) rats, likely due to the combinatorial effect of NO depletion, CO-mediated deactivation of inducible NO synthase (iNOS) and activation of heme oxygenase-1 (HO-1). This work provides new insights into artificial BM for potential biomedical applications.

Comparison of subtotal vertebral resection with reconstruction and percutaneous vertebroplasty for treatment of metastasis in the lumbar spine.

Purpose: Tumor metastasis in the spine can cause pain and fractures, leading to deformities, and deficits in movement, sensation, and bowel/bladder function. Percutaneous vertebroplasty (PVP) and subtotal vertebral resection with reconstruction (SVR) are suitable treatments, but their relative clinical efficacy is uncertain. The purpose of this retrospective cohort study was to compare the management and clinical effect of SVR for lumbar metastatic tumor with PVP.Methods: Sixty-seven patients (mean age: 58.6 years) with metastases in the lumbar spine received SVR or PVP at our institution between 2010 and 2013. Thirty-three patients received SVR via a posterior approach, in which vertebrae were resected, with the anterior and lateral walls retained using polymethylmethacrylate (PMMA), followed by reconstruction and pedicle screw fixation. Thirty-four patients received PVP via the vertebral pedicle. Patients were followed for 3-26 months.Results: None of the patients experienced serious complications after surgery, and all patients experienced significant amelioration of pain. Twelve patients (8 in the PVP group and 4 in the SVR group) died during the follow-up, and the survival time was significantly longer in the SVR group. Two patients in the SVR group and 7 patients in the PVP groups experienced recurrence during follow-up, but the groups had no significant difference in local recurrence. Both treatments significantly reduced scores for pain on a visual analog scale (pain-VAS) and disability (Oswestry Disability Index [ODI]), and increased performance status (Karnofsky Performance Status [KPS]). Compared with the PVP group, the SVR group had better ODI score at 1 month and 3 months after surgery and a higher KPS score at 1 month after surgery. The two groups had no significant difference in pain-VAS scores during follow-up.Conclusions: SVR is a reliable treatment for lumbar metastatic tumor and provides good survival rate and satisfying follow-up results.

Surgical treatment of diabetic foot ulcers during the COVID-19 pandemic in China.

Diabetic foot ulcers are among the most serious complications of diabetes. If left untreated, these ulcers can lead to severe infection and gangrene; in some instances, they may result in death. Thus, timely treatment of diabetic foot ulcers is extremely important. However, timely patient treatment during the COVID-19 pandemic is particularly challenging, because of the higher volume of patients and the need to ensure safety of medical personnel. This article describes a proposed strategy for diagnosis and treatment of diabetic foot ulcers, based on experiences with infection and control strategies during the COVID-19 pandemic in China.

Lysozyme/collagen multilayers layer-by-layer deposited nanofibers with enhanced biocompatibility and antibacterial activity.

Biological meshes have always posed a challenge in biological medicine, for which nanocomposites with enhanced biocompatibility and antibacterial activity may be beneficial. In this study, lysozyme (LY) and collagen (Col) were alternately deposited on silk fibroin (SF) and nylon 6 (N6) composite nanofibrous mats using a layer-by-layer (LBL) self-assembly technique. The mechanical properties, biocompatibility, and antibacterial activity of the LBL structured mats were characterized systematically to investigate the impact of the LBL process on the biological properties of SF/N6 nanofibrous mats. Our results showed that the effective deposition of LY and Col may affect the surface topography, mechanical properties, and wetting behavior of the SF/N6 nanofibrous mats. Moreover, LBL structured mats exhibited excellent biocompatibility and antibacterial properties. Among all the tested mats, those coated with 10 bilayers of LY and Col displayed the best biocompatibility, and relatively good mechanical and antibacterial properties. Thus, LBL structured mats, especially those with a 10 bilayer coating, are potentially valuable in clinical therapy for pelvic organ prolapse in the future.

Primary cilia: Versatile regulator in cartilage development.

Cartilage is a connective tissue in the skeletal system and has limited regeneration ability and unique biomechanical reactivity. The growth and development of cartilage can be affected by different physical, chemical and biological factors, such as mechanical stress, inflammation, osmotic pressure, hypoxia and signalling transduction. Primary cilia are multifunctional sensory organelles that regulate diverse signalling transduction and cell activities. They are crucial for the regulation of cartilage development and act in a variety of ways, such as react to mechanical stress, mediate signalling transduction, regulate cartilage-related diseases progression and affect cartilage tumorigenesis. Therefore, research on primary cilia-mediated cartilage growth and development is currently extremely popular. This review outlines the role of primary cilia in cartilage development in recent years and elaborates on the potential regulatory mechanisms from different aspects.

Applications of chitin and chitosan nanofibers in bone regenerative engineering.

Promoting bone regeneration and repairing defects are urgent and critical challenges in orthopedic clinical practice. Research on bone substitute biomaterials is essential for improving the treatment strategies for bone regeneration. Chitin and its derivative, chitosan, are among the most abundant natural biomaterials and widely found in the shells of crustaceans. Chitin and chitosan are non-toxic, antibacterial, biocompatible, degradable, and have attracted significant attention in bone substitute biomaterials. Chitin/chitosan nanofibers and nanostructured scaffolds have large surface area to volume ratios and high porosities. These scaffolds can be fabricated by electrospinning, thermally induced phase separation and self-assembly, and are widely used in biomedical applications such as biological scaffolds, drug delivery, bacterial inhibition, and wound dressing. Recently, some chitin/chitosan-based nanofibrous scaffolds have been found structurally similar to bone's extracellular matrix and can assist in bone regeneration. This review outlines the biomedical applications and biological properties of chitin/chitosan-based nanofibrous scaffolds in bone tissue engineering.

Controlled release of adenosine from core-shell nanofibers to promote bone regeneration through STAT3 signaling pathway.

Adenosine (Ade) has been identified to stimulate bone formation. However, the use of Ade is severely limited by the accompanying side effects and its very short half-life in vivo. This study aimed to fabricate an efficient drug-delivery system to reduce the undesirable side effects and enable the clinical application of Ade for treating large bone defects. The fabricated poly(ε-caprolactone) (PCL)/Ade-polyvinyl alcohol (PVA)(0.3/0.4) nanofibrous mats with 0.3:0.4 (w/w) ratio of Ade and PVA showed a sustained and controlled release of Ade and facilitated the osteogenic differentiation of bone mesenchymal progenitor cells (BMSCs). A larger amount of newly formed bone was observed in vivo in the cranial defects of the PCL/Ade-PVA(0.3/0.4) group compared with those of the non-loaded PCL/PVA nanofibrous mats at 4 and 8 weeks after surgery. Moreover, it is the first time to confirm that Ade mediates the osteogenesis of rat BMSCs through the STAT3 signaling pathway and restrains the osteoclastogenesis of rat bone-marrow macrophages (BMMs). These results suggested that this coaxial drug-delivery system loaded with Ade provided a promising and clinically relevant platform to controlled-release Ade and address large bone defects.

Chitosan-TiO2 microparticles LBL immobilized nanofibrous mats via electrospraying for antibacterial applications.

The antibacterial materials with biodegradable and biocompatible nature have unveiled novel prospects to combat the bacterial infection, which has always been a troubling and challenging issue in the biomedical field. In this study, chitosan (CS) and Titanium dioxide (TiO2) microparticles were well immobilized on polylactic acid (PLA) mats by electrospinning-electrospraying hybrid technique. The surface morphology, chemical composition and characteristic group of the mats were characterized. The results indicated that CS/TiO2 microparticles were successfully immobilized on the surface of PLA mats. In addition, the antibacterial activity and cytotoxicity of the composite mats were investigated to confirm that the layer-by-layer immobilization of CS/TiO2 microparticles via electrospraying could enhance the antibacterial effect and biocompatibility of the mats. At the same time, the PLA-(CS/TiO2-1.5%)1.5 mats exhibited the best performance in antibacterial effect (up to about 95%) and cell viability (nearly 92% and 95% at 3 d and 5 d). The composite mats have great potential as an effective antibacterial material for the biomedical applications.

LBL deposition of chitosan and silk fibroin on nanofibers for improving physical and biological performance of patches.

Pelvic floor dysfunction diseases (PFD) become more prevalent with the increase of elderly population, and complications of pelvic floor reconstructive surgery (e.g. infection and exposure of mesh) have been troubling to patients and gynecologists. In this study, the nanofibrous mats were prepared by alternately depositing chitosan (CS) and silk fibroin (SF) on Nylon6 (N6) nanofibrous mats via layer-by-layer (LBL) technique. The as-prepared mats were characterized. The results showed that CS and SF molecules were successfully assembled on the nanofibers. Additionally, after LBL modification, the hydrophilicity of the nanofibrous mats was reduced and the mechanical properties were improved. Furthermore, the antibacterial activity of the LBL-structured mats reached >95% inhibiting Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The in vitro cell co-culture experiments indicated that LBL-structured mats had smaller toxic effects and more excellent biocompatibility to L929 fibroblasts, especially the mats with 15 bilayers coated films. Hence, the LBL-structured mats are promising materials for pelvic floor reconstruction to reduce postoperative pelvic complication rates.

Synergistic effect of docetaxel combined with cisplatin on inhibiting human osteosarcoma in nude mice.

Cisplatin (CDDP) has been shown to be a promising anticancer drug that is effective against many types of cancer, which include osteosarcoma (OS). However, its therapeutic application is restricted by its toxicity in normal tissues, side effects caused in patients, and chemotherapy resistance. Thus, to further improve patients' treatment, the development of novel, more effective and well tolerated therapeutic approaches against OS in clinical is urgent and important. In the present study, nude mice were inoculated subcutaneously with injections of HOS8603 cells, CDDP and docetaxel (DTX) were administered intraperitoneally respectively. The inhibitive effects and the side effects were observed. Tumor weights and volumes were significantly lower and the tumor inhibition rate was significantly higher in the combination group than those of either drug alone or vehicle. The cell density in the tumor tissue was significantly decreased, apoptotic and necrotic cell death was significantly increased in the combination group, as compared with those of either drug alone or vehicle. In addition, there was no obvious side effect happening besides the appearance of erythema and papules in some mice. These results suggest that the combined effects of CDDP and DTX on the growth of human OS in vivo were superior to the single effects. CDDP combined with DTX had synergistic effects at lower concentrations and promoted apoptosis, but did not increase the side effects of chemotherapy.

Tacolimus postconditioning alleviates apoptotic cell death in rats after spinal cord ischemia-reperfusion injury via up-regulating protein-serine-threonine kinases phosphorylation.

The effects of tacrolimus postconditioning on protein-serine-threonine kinases (Akt) phosphorylation and apoptotic cell death in rats after spinal cord ischemia-reperfusion injury were investigated. Ninety male SD rats were randomly divided into sham operation group, ischemia-reperfusion group and tacrolimus postconditioning group. The model of spinal cord ischemia was established by means of catheterization through femoral artery and balloon dilatation. The spinal cord was reperfused 20 min after ischemia via removing saline out of balloon. The corresponding spinal cord segments were excised and determined for Akt activity in spinal cord tissue by using Western blotting at 5, 15, and 60 min after reperfusion respectively. Spinal cord tissue sections were stained immunohistochemically for detection of the phosphorylated Akt expression at 15 min after reperfusion. Flow cytometry was applied to assess apoptosis of neural cells, and dry-wet weights method was employed to measure water content in spinal cord tissue at 24 h after reperfusion. The results showed that the activities of Akt in tarcolimus postconditioning group were significantly higher than those in ischemia-reperfusion group at 5, 15, and 60 min after reperfusion (P<0.05, P<0.01). The Akt activities reached the peak at 15 min after reperfusion in ischemia-reperfusion group and tacrolimus postconditioning group. The percentage of apoptotic cells and water content in spinal cord tissue were significantly reduced (P<0.01) in tacrolimus postconditioning group as compared with those in ischemia-reperfusion group at 24 h after reperfusion. It is concluded that tacrolimus post-conditioning can increase Akt activity in spinal cord tissue of rats, inhibit apoptosis of neural cells as well as tissue edema, and thereby alleviate spinal cord ischemia-reperfusion injury.