C/EBPε and its acetylation in PMN enhance the tolerance to trauma.

Severe trauma can lead to numerous serious complications, threating the well-being and vitality of the afflicted. The quantity and functionality of PMNs undergo rapid transformations in response to severe trauma, playing a pivotal role in the trauma response. The absence of CCAAT/enhancer-binding protein ε (C/EBPε) profoundly impairs the functionality of polymorphonuclear neutrophils (PMNs), a function of paramount importance in trauma. In this study, by generating mice with C/EBPε knocked out or overexpressed, we substantiate that C/EBPε ensures the restoration of PMN function, enhancing the expression of antimicrobial proteins and thereby promoting trauma recovery. Furthermore, diminished expression of C/EBPε is observed in trauma patients, with levels displaying a negative correlation with ISS and APACHE II scores, suggesting its potential as a prognostic indicator for clinical treatment. Mechanistically, we uncover the upregulation of SIRT1 and the inhibition of P300 participating in the suppression of C/EBPε acetylation, consequently reducing the resilience of mice to trauma. As therapeutic interventions, whether through the sole administration of PMN, NAM treatment, or their combination, all result in an increased survival rate in traumatic mice. In conclusion, our study elucidates the role of C/EBPε in enhancing the resilience to trauma and identifies C/EBPε acetylation as a critical regulatory mechanism, offering potential therapeutic approaches involving PMN transfusion and NAM treatment.

16S rRNA seq-identified Corynebacterium promotes pyroptosis to aggravate diabetic foot ulcer.

BACKGROUND: Diabetic foot ulcer (DFU) is one of the main chronic complications caused by diabetes, leading to amputation in severe cases. Bacterial infection affects the wound healing in DFU. METHODS: DFU patients who met the criteria were selected, and the clinical data were recorded in detail. The pus exudate from the patient's foot wound and venous blood were collected for biochemical analysis. The distribution of bacterial flora in pus exudates of patients was analyzed by 16S rRNA sequencing, and the correlation between DFU and pathogenic variables, pyroptosis and immunity was analyzed by statistical analysis. Then, the effects of key bacteria on the inflammation, proliferation, apoptosis, and pyroptosis of polymorphonuclear leukocytes were investigated by ELISA, CCK-8, flow cytometry, RT-qPCR and western blot. RESULTS: Clinical data analysis showed that Wagner score was positively correlated with the level of inflammatory factors, and there was high CD3+, CD4+, and low CD8+ levels in DFU patients with high Wagner score. Through alpha, beta diversity analysis and species composition analysis, Corynebacterium accounted for a large proportion in DFU. Logistics regression model and Person correlation analysis demonstrated that mixed bacterial infections could aggravate foot ulcer, and the number of bacteria was closely related to inflammatory factors PCT, PRT, immune cells CD8+, and pyroptosis-related proteins GSDMD and NLRP3. Through in vitro experiments, Corynebacterium inhibited cell proliferation, promoted inflammation (TNF-α, PCT, CRP), apoptosis and pyroptosis (IL-1ß, LDH, IL-18, GSDMD, NLRP3, and caspase-3). CONCLUSION: Mixed bacterial infections exacerbate DFU progression with a high predominance of Corynebacterium, and Corynebacterium promotes inflammation, apoptosis and pyroptosis to inhibit DFU healing.

Effects of glucagon­like peptide­1 receptor agonists on fracture healing in a rat osteoporotic model.

Osteoporosis is a common disease characterized by reduced bone mass, microstructural deterioration, fragility and consequent fragility fractures and is particularly prevalent among the elderly population. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have positive effects on bones, their role in the prevention of osteoporotic fractures remains to be elucidated. The present study assigned female Sprague Dawley rats with osteoporotic fractures into variectomized osteoporosis (OVX), OVX + liraglutide (LIRA) (50 µg/kg/day subcutaneous LIRA) and control groups. At 3 and 6 weeks postoperatively, X-ray, tartrate-resistant acid phosphatase (TRAP) staining, histological and biomechanical assays and assessment of femoral bone mineral density (BMD) were performed. Compared with the OVX group, GLP-1 RA treatment improved the formation of calluses and osseous union. TRAP staining showed significantly fewer osteoclasts in the OVX + LIRA group compared with the OVX group. In the osteoporotically fractured rats, LIRA improved bone strength at the femoral diaphysis, stiffness, ultimate load and femoral trabecular BMD Compared with the OVX group. GLP-1 RA treatment inhibited osteoclast formation and improved trabecular bone architecture and mass in osteoporotic fracture model rats, leading to improved biomechanical strength. GLP-1 RAs may be used as novel anti-osteoporotic fracture agents.

Repairing tendon-exposed wounds by combing the Masquelet technique with dermoplasty.

Background: Wound repair is a new field that has emerged in China in the last 5 years. Exposed tendon wounds are one of the most common problems faced in wound treatment today, as the poor blood supply leads to low survival rates of skin grafts. This paper explores the feasibility of applying the Masquelet technique to repair tendon-exposed wounds. Method: We examined 12 patients with tendon-exposed wounds, 5 males and 7 females, from January 2021 to November 2021, including 2 patients with post-traumatic wounds, 8 diabetic patients with dorsal wounds, and 2 patients with various chronic infections. The Masquelet technique was employed to treat these wounds. The wound surface was sealed with antibiotic bone cement to form an induction membrane, the cement was removed after 3-4 weeks, and the wound was repaired with skin grafts to observe survival, appearance, texture, healing, and related functions. Results: All wounds were covered with antibiotic bone cement, and after 3-4 weeks, an induction membrane was applied, and in 10 out of 12 patients, full-thickness skin grafts were applied, and the patients survived. However, in 2 patients, the skin became partially necrotic, but these patients recovered by changing medications. Conclusion: The current study found that direct skin grafting may effectively treat exposed tendon wounds once the Masquelet approach generates the induction membrane. Further, this method is less difficult, less expensive, and easier to care for the procedure that deserves to be used more frequently.

Current opinions on the mechanism, classification, imaging diagnosis and treatment of post-traumatic osteomyelitis.

Post-traumatic osteomyelitis (PTO) is a worldwide problem in the field of orthopaedic trauma. So far, there is no ideal treatment or consensus-based gold standard for its management. This paper reviews the representative literature focusing on PTO, mainly from the following four aspects: (1) the pathophysiological mechanism of PTO and the interaction mechanism between bacteria and the body, including fracture stress, different components of internal fixation devices, immune response, occurrence and development mechanisms of inflammation in PTO, as well as the occurrence and development mechanisms of PTO in skeletal system; (2) clinical classification, mainly the etiological classification, histological classification, anatomical classification and the newly proposed new classifications (a brief analysis of their scope and limitations); (3) imaging diagnosis, including non-invasive examination and invasive examination (this paper discusses their advantages and disadvantages respectively, and briefly compares the sensitivity and effectiveness of the current examinations); and (4) strategies, including antibiotic administration, surgical choices and other treatment programs. Based on the above-mentioned four aspects, we try to put forward some noteworthy sections, in order to make the existing opinions more specific.

Targeting Cell Death: Pyroptosis, Ferroptosis, Apoptosis and Necroptosis in Osteoarthritis.

New research has shown that the development of osteoarthritis (OA) is regulated by different mechanisms of cell death and types of cytokines. Therefore, elucidating the mechanism of action among various cytokines, cell death processes and OA is important towards better understanding the pathogenesis and progression of the disease. This paper reviews the pathogenesis of OA in relation to different types of cytokine-triggered cell death. We describe the cell morphological features and molecular mechanisms of pyroptosis, apoptosis, necroptosis, and ferroptosis, and summarize the current research findings defining the molecular mechanisms of action between different cell death types and OA.

Biomimetic and osteogenic 3D silk fibroin composite scaffolds with nano MgO and mineralized hydroxyapatite for bone regeneration.

Artificial bioactive materials have received increasing attention worldwide in clinical orthopedics to repair bone defects that are caused by trauma, infections or tumors, especially dedicated to the multifunctional composite effect of materials. In this study, a weakly alkaline, biomimetic and osteogenic, three-dimensional composite scaffold (3DS) with hydroxyapatite (HAp) and nano magnesium oxide (MgO) embedded in fiber (F) of silkworm cocoon and silk fibroin (SF) is evaluated comprehensively for its bone repair potential in vivo and in vitro experiments, particularly focusing on the combined effect between HAp and MgO. Magnesium ions (Mg2+) has long been proven to promote bone tissue regeneration, and HAp is provided with osteoconductive properties. Interestingly, the weak alkaline microenvironment from MgO may also be crucial to promote Sprague-Dawley (SD) rat bone mesenchymal stem cells (BMSCs) proliferation, osteogenic differentiation and alkaline phosphatase (ALP) activities. This SF/F/HAp/nano MgO (SFFHM) 3DS with superior biocompatibility and biodegradability has better mechanical properties, BMSCs proliferation ability, osteogenic activity and differentiation potential compared with the scaffolds adding HAp or MgO alone or neither. Similarly, corresponding meaningful results are also demonstrated in a model of distal lateral femoral defect in SD rat. Therefore, we provide a promising 3D composite scaffold for promoting bone regeneration applications in bone tissue engineering.

Research Progress on Diagnosis and Treatment of Chronic Osteomyelitis.

We review the representatives literatures on chronic osteomyelitis, sum up the new insights in recent years into diagnostic options and treatment regimens, analyze the advantages and disadvantages of various diagnostic approaches and treatment strategies, and propose areas of interest to make current diagnostic and treatment strategies more specific.

Diazoxide ameliorates severity of experimental osteoarthritis by activating autophagy via modulation of the osteoarthritis-related biomarkers.

Accumulating evidence suggests that autophagy plays a protective role in chondrocytes and prevents cartilage degeneration in osteoarthritis (OA). The objective of this study was to investigate the effect of diazoxide on chondrocyte death and cartilage degeneration and to determine whether these effects are correlated to autophagy in experimental OA. In this study, a cellular OA model was established by stimulating SW1353 cells with interleukin 1ß. A rat OA model was generated by transecting the anterior cruciate ligament combined with the resection of the medial menisci, followed by treatment with diazoxide or diazoxide combination with 3-methyladenine. The percentage of viable cells was evaluated using calcein-acetoxymethyl/propidium iodide double staining. The messenger RNA expression levels of collagen type II alpha 1 chain (COL2A1), matrix metalloproteinase 13 (MMP-13), TIMP metallopeptidase inhibitor 1 (TIMP-1), and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) were determined using quantitative real-time polymerase chain reaction. The cartilage thickness and joint space were evaluated using ultrasound. SW1353 cell degeneration and autophagosomes were observed using transmission electron microscopy. The expression levels of microtubule-associated protein 1 light chain 3 (LC3), beclin-1, P62, COL2A1, and MMP-13 were evaluated using immunofluorescence staining and Western blot analysis. Diazoxide significantly attenuated articular cartilage degeneration and SW1353 cell death in experimental OA. The restoration of autophagy was observed in the diazoxide-treated group. The beneficial effects of diazoxide were markedly blocked by 3-methyladenine. Diazoxide treatment also modulated the expression levels of OA-related biomarkers. These results demonstrated that diazoxide exerted a chondroprotective effect and attenuated cartilage degeneration by restoring autophagy via modulation of OA-related biomarkers in experimental OA. Diazoxide treatment might be a promising therapeutic approach to prevent the development of OA.

Diazoxide prevents H2O2-induced chondrocyte apoptosis and cartilage degeneration in a rat model of osteoarthritis by reducing endoplasmic reticulum stress.

Osteoarthritis (OA) is a common disease affecting elderly individuals. Its incidence rises sharply with age, and chondrocyte apoptosis plays a vital role in its pathogenesis. Diazoxide opens mitochondrial ATP-sensitive potassium (mitoKATP) channels and exerts multiple pharmacological effects, including reductions in blood pressure and blood sugar levels. It also exerts anti-apoptotic activities, but the cellular and molecular mechanisms by which diazoxide inhibits chondrocyte apoptosis are unknown, as is whether apoptosis is related to endoplasmic reticulum stress (ERS). In the present study, we explored the mechanism underlying the chondroprotective effect of diazoxide on hydrogen peroxide (H2O2)-stimulated chondrocyte apoptosis in rats with surgically induced OA. A cell counting kit-8 (CCK-8) assay showed that the viability of H2O2-stimulated chondrocytes was enhanced in a dose-dependent manner. However, at a concentration ≥400µM, diazoxide had other, negative effects. The protective effect of diazoxide in vitro included inhibition of the ERS response and of mitochondrial dysfunction induced by H2O2 stimulation. These responses were related to activation of the PERK1/2 and ERK1/2 signaling pathways; the prevention of chondrocyte apoptosis; the down-regulation of caspase-3, Bax, ATF-6 and C/EBP-homologous protein (CHOP) expression; and the up-regulation of Bcl-2 and Col II. In vivo, histological and immunohistochemical analyses of caspase-3 and CHOP expression revealed that diazoxide ameliorated cartilage degeneration in a rat model of OA, as revealed by histological and immunohistochemical analyses of caspase-3 and CHOP expression. Diazoxide suppressed H2O2-triggered chondrocyte apoptosis, and ameliorated cartilage degeneration, by inhibiting the development of ERS.

Research progress on osteoarthritis treatment mechanisms.

Osteoarthritis is a common disease and is frequently encountered in the older population; the incidence rises sharply with age. It is estimated that more than 360 million people suffer from OA. However, the pathogenesis of osteoarthritis remains unclear, and we cannot effectively prevent the progression of OA. The aim of this review was to explore the molecular markers and signaling pathways that induce chondrocyte apoptosis in OA. We searched, using the key words osteoarthritis, chondrocyte apoptosis, autophagy, endoplasmic reticulum stress, molecular targets, and biomarkers, in PubMed, Web of Science, and Google Scholar from 1994 to 2017. We also reviewed the signaling pathways and molecular markers associated with chondrocyte apoptosis and approaches aimed at inhibiting the apoptosis-inducing mechanism to at least delay the progression of cartilage degeneration in OA. This article provides an overview of targeted therapies and the related signaling pathways in OA.