搜索结果：destruction

Toll-like receptor 4 (TLR4) activation within the bone marrow (BM) microenvironment regulates proinflammatory cytokines and chemokines, which influence immune activity and bone remodeling. However, the immune cell factors mediating TLR4-dependent cross-talk in the bone/BM microenvironment remain insufficiently defined. We provide a transcriptomic analysis of significant cellular and immune changes in total BM cells of wild-type mice following lipopolysaccharide (LPS)-induced TLR4 activation in vivo compared with TLR4 knockout (KO) mice. To obtain direct evidence that interleukin (IL)-22 contributes to TLR4-driven bone destruction, we analyzed their bone phenotypes following LPS injection into IL-22 KO mice. In addition, co-culture of pre-osteoblasts (OBs) and BM cells was conducted to evaluate the effect of IL-22 in osteoclast (OC) formation in a pre-OB-dependent manner. Differentially expressed gene analysis from BM cells of wild-type (WT) mice revealed an increase in IL-22-producing cells, along with increased IL-22 production in a TLR4-dependent manner. Flow cytometry confirmed that LPS enhanced the number of CD4+IL-22+ cells in the BM and decreased in TLR4-deficient BM. LPS also enhanced the differentiation of CD4+IL-22+ T cells and promoted IL-22 induction in T cells. IL-22 KO mice showed minimal LPS-induced bone loss, whereas WT mice exhibited severe bone destruction with increased formation of tartrate-resistant acid phosphatase-positive OCs. Interestingly, while IL-22 did not directly affect OC differentiation, IL-22 enhanced OC differentiation only when BM cells were co-cultured with pre-OBs through the elevation of the receptor activator of nuclear factor-κB ligand (RANKL) in pre-OBs during osteogenesis. Mechanistically, IL-22 induced cyclooxygenase-2 in pre-OBs through extracellular signal-regulated kinase and p38 signaling, driving prostaglandin E2 production and subsequent RANKL induction. TLR4 activation enhanced IL-22 production in T cells, which stimulates RANKL production in pre-OBs to further induce OC formation. These results support that IL-22 acts as a TLR4-driven mediator to shift bone remodeling toward catabolic bone degeneration.

Type 1 diabetes is a disease caused by the autoimmune destruction of insulin-secreting pancreatic beta cells. The replacement of beta cells according to the Edmonton protocol has opened new therapeutic avenues for restoring physiological regulation of insulin secretion and reducing comorbidities. Current advancements in stem cell differentiation and transplantation hold promise for overcoming the limitations of the Edmonton protocol and improving disease remission. This review analyzes clinical data, highlighting the benefits and challenges of these approaches, twenty-five years after their implementation. Le protocole de transplantation d’Edmonton, 25 ans plus tard : vers la rémission du diabète de type 1 ? Le diabète de type 1 est une maladie chronique due à la destruction auto-immune des cellules bêta du pancréas qui produisent de l’insuline. La transplantation de ces cellules, selon le protocole d’Edmonton, offre de nouvelles perspectives pour restaurer une production physiologique d’insuline et réduire les risques de comorbidités. Les progrès dans la différenciation et la transplantation de cellules souches sont prometteurs pour surmonter les défis liés au protocole d’Edmonton et améliorer la probabilité de rémission. Dans cette revue, nous analysons les données cliniques afin de présenter les avantages et les défis de ce protocole, vingtcinq ans après sa mise en place.

Periodontitis is a chronic inflammatory disease characterized by progressive destruction of periodontal supporting tissues, yet the molecular mechanisms underlying its pathogenesis remain incompletely defined. This study aimed to identify key genes associated with periodontitis through an integrative bioinformatics strategy combined with experimental validation. Two independent transcriptomic datasets (GSE16134 and GSE10334) were analyzed to identify differentially expressed genes. Weighted gene co-expression network analysis, protein-protein interaction network construction, and machine-learning approaches, including random forest and support vector machine algorithms, were employed to screen for candidate hub genes. Gene set enrichment analysis was performed to investigate potential biological functions. A ligature-induced rat periodontitis model and human periodontal tissue samples were used for validation through micro-computed tomography, histological analysis, immunohistochemistry, and quantitative real-time PCR. CD48 and CXCR4 were identified as key genes consistently selected across datasets and analytical methods. Both genes were significantly upregulated in periodontitis samples and demonstrated robust diagnostic performance. Functional enrichment analysis indicated that these genes were closely associated with immune-inflammatory pathways. Experimental validation further confirmed increased expression of CD48 and CXCR4 at both mRNA and protein levels in rat and human periodontal tissues. CD48 and CXCR4 are potential biomarkers associated with periodontitis and may be involved in the regulation of immune-inflammatory processes, particularly those related to inflammatory cell recruitment and periodontal tissue destruction, thereby providing additional insight into disease pathogenesis and offering promising molecular candidates for future translational investigation.

Penetrating chest injuries are associated with high mortality because visceral and vascular structures are situated close together, and injury to these can be devastating due to the limited time for resuscitation. Such injuries often cause massive hemorrhage, tension pneumothorax, hemothorax, cardiac tamponade, or direct penetration of the heart and great vessels. Survival in penetrating chest injuries involving the heart, especially with delayed hospital presentation, is very uncommon. The mechanism of penetration significantly influences the diagnostic approach and necessary interventions. Bedside POCUS protocols, such as eFAST, RUSH, and BLUE, enable immediate resuscitation before further investigations. High-velocity injuries like gunshots and crossbow bolts are linked to high mortality due to rapid tissue destruction caused by kinetic energy transfer. Certain pathological conditions, such as cardiac tamponade or effusion, may sometimes be beneficial in these injuries. We present a case of an accidental penetrating arrow injury to the chest, piercing the heart, yet the patient survived after more than three days of delayed transfer to higher care with hemopneumothorax and mediastinal involvement. Survival after a penetrating chest injury through the heart is very rare. Prompt, rapid resuscitation with a multidisciplinary approach can improve outcomes. However, the prognosis depends on factors such as the type and location of the injury, the speed of medical response, the presence of cardiac tamponade, and the patient's pre-existing clinical condition.

Immune thrombocytopenia (IT) is an autoimmune disorder characterized by isolated thrombocytopenia resulting from increased platelet destruction and impaired production. Although most cases are idiopathic, secondary causes, including malignancies, should be considered, particularly in atypical or treatment-resistant presentations. Non-Hodgkin lymphomas (NHL) may rarely present with autoimmune cytopenias, leading to diagnostic challenges. We report the case of a 77-year-old male patient presenting with fatigue, weight loss, severe thrombocytopenia, anemia, and leukopenia who was initially managed as having IT. Lack of response to corticosteroids and intravenous immunoglobulin (IVIG) prompted further evaluation. Peripheral smear findings, PET/CT imaging, splenomegaly, and myelophthisic features raised suspicion for lymphoma. The initial bone marrow biopsy was inconclusive; however, platelet counts transiently improved following rituximab therapy. Repeat bone marrow biopsy confirmed diffuse large B-cell lymphoma (DLBCL), and the patient was subsequently treated with R-mini-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone administered at reduced doses) chemotherapy, resulting in normalization of platelet counts and significant clinical improvement. This case highlights the importance of reconsidering secondary causes in refractory IT and emphasizes the diagnostic value of repeated bone marrow evaluation in suspected lymphoproliferative disorders.

Staphylococcus pasteuri is a rare coagulase-negative staphylococcus that is infrequently identified as a causative agent in infective endocarditis. Its clinical virulence and embolic potential are not well characterized in current literature. A 57-year-old man with a history of mitral valve prolapse presented with a 2-month history of constitutional symptoms and hematuria. Investigations revealed S pasteuri bacteremia and a large mitral valve vegetation with severe regurgitation. His clinical course was marked by recurrent ST-segment elevation myocardial infarctions and mycotic aneurysm, subacute embolic strokes with hemorrhagic transformation. He ultimately underwent successful bioprosthetic mitral valve replacement after neurologic stabilization. This case highlights the aggressive nature of S pasteuri in native valve endocarditis. The organism produced large, friable vegetations, leading to a high embolic burden and affecting both coronary and cerebral vasculatures. S pasteuri is a virulent pathogen capable of causing significant endocardial destruction and should not be dismissed as a contaminant. Large vegetations associated with this organism carry an exceptionally high risk for recurrent embolic events, including rare coronary septic embolization. Early multidisciplinary consultation is vital to navigate the timing of surgery when embolic risk and intracranial hemorrhage coexist.

Restoration of structurally compromised endodontically treated teeth with extensive coronal destruction and subgingival margins remains a significant restorative challenge. Contemporary biomimetic restorative approaches emphasize preservation of the remaining tooth structure through adhesive reinforcement strategies that improve biomechanical performance while minimizing additional radicular dentin removal. This case report describes the biomimetic rehabilitation of a previously root canal-treated maxillary canine with severe coronal destruction and subgingival palatal and proximal margins. Following laser gingivectomy and margin exposure, complete caries excavation was performed using caries detector dye guidance, followed by immediate dentin sealing using Prime & Bond NT (Dentsply DeTrey GmbH, Konstanz, Germany). Deep margin elevation was carried out using the doughnut technique with SDR Flow + Flowable Composite (Dentsply Sirona, Charlotte, NC, USA). Conservative post-space preparation was subsequently performed, and a polyethylene fiber-reinforced post and composite core buildup were completed using dual-cure resin cement under adhesive protocol. Definitive rehabilitation was achieved using a monolithic zirconia crown fabricated from Cercon XT zirconia (Dentsply Sirona, Bensheim, Germany), conditioned according to the APC (air-particle abrasion, primer application, and composite resin cementation) protocol prior to adhesive cementation. Clinical and radiographic follow-up at one month demonstrated satisfactory esthetic and functional rehabilitation with healthy periodontal response, satisfactory marginal adaptation, and absence of clinical symptoms. Within the limitations of a single case report and short-term follow-up, polyethylene fiber-reinforced post and core systems combined with adhesive biomimetic restorative protocols such as immediate dentin sealing and deep margin elevation may represent a conservative treatment option for rehabilitation of structurally compromised endodontically treated teeth with compromised ferrule and subgingival defects.

This study describes the results of a phytochemical and pharmacological study of Lippia dulcis Trevir, grown in southern Ecuador, where the plant, commonly known by the name buscapina, is widely used by the local population for its therapeutic properties in the treatment of gastrointestinal disorders, mainly colic and spasms. Steam distillation of the aerial parts afforded an essential oil (EO) characterized by GC-MS/FID as a sesquiterpene-rich chemotype (96.89%). β-caryophyllene (18.89%), δ-selinene (11.78%), δ-cadinene (11.07%), β-cubebene (10.51%), and bicyclogermacrene (8.14%) were the predominant constituents of the oil. On the contrary, the hydrolate resulting from the distillation mainly contained oxygenated degradation products of the intensely sweet chemical hernandulcin and was biologically inert. Functional assessment using NIH/3T3 fibroblasts revealed a concentration-time dependent biphasic response. At 0.5-0.75 μL/mL and ≤ 6 h exposure, the EO significantly accelerated wound closure in scratch assays without compromising cell membrane integrity, while simultaneously inducing a moderate increase in intracellular reactive oxygen species (ROS) (6.9-11.0 times compared to the control). Prolonged exposure (24 h) to concentrations ≥ 0.5 μL/mL of the EO led to marked cytotoxicity (IC₅₀ = 0.45 μL/mL), characterized by metabolic impairment, membrane destruction, and massive oxidative stress (30 times increase in intracellular ROS compared to the control). In conclusion, the EO of L. dulcis from southern Ecuador exhibits a potential therapeutic window separating pro-migratory effects on fibroblasts from cytotoxic activity.

Primary bone diffuse large B-cell lymphoma (DLBCL) is a rare subtype of extranodal non-Hodgkin lymphoma that predominantly involves long bones, particularly the metaphyseal regions. We report the case of a 23-year-old man presenting with painful swelling of the right knee. Imaging revealed an osteolytic lesion of the distal right femur with cortical destruction and soft tissue extension. Staging contrast-enhanced computed tomography of the chest, abdomen, and pelvis showed no nodal or visceral involvement, consistent with localized (limited-stage) disease. Histopathological examination of the biopsy specimen demonstrated diffuse sheets of large atypical lymphoid cells, and immunohistochemical analysis confirmed DLBCL with a non-germinal center B-cell phenotype. The patient received six cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), resulting in rapid clinical improvement and complete metabolic remission on post-treatment positron emission tomography, consistent with a complete response. This case underscores the importance of including lymphoma in the differential diagnosis of destructive bone lesions in young adults and highlights the favorable prognosis of localized primary bone DLBCL with appropriate chemoimmunotherapy.

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects bone in the pediatric population, with the skull being one of the most frequent sites of involvement. Local complications following diagnostic procedures in this context are exceptionally rare and poorly described. We report the case of a 14-year-old male with unifocal cranial LCH who developed aggressive local progression after a diagnostic biopsy, characterized by progressive bone destruction, soft tissue involvement, surgical wound dehiscence, and exposure of tumor tissue. Given the rapid evolution of the lesion and the limitations for conventional surgical management, intralesional and perilesional triamcinolone infiltration (40 mg) was performed. A prompt clinical response was observed, with a significant reduction in lesion volume within 4 days. Follow-up magnetic resonance imaging at that time demonstrated a 50-70% decrease in the soft tissue component. During subsequent follow-up, progressive skin healing and early signs of bone repair were noted. This case highlights an uncommon local complication following biopsy of pediatric cranial LCH and suggests that local corticosteroid infiltration may represent a minimally invasive and potentially useful therapeutic alternative in selected cases with aggressive local progression and limited surgical options.

Burn injuries are among the most frequent traumas associated with human activity and primarily affect the skin. Unlike other forms of tissue injury, burns produce a unique combination of extensive tissue destruction, rapid release of damage-associated signals, and profound alterations in cutaneous architecture. These injury-specific features generate a robust inflammatory environment and early neuroimmune activation that can transition into neuropathic pain. Together, they drive marked peripheral sensitization and, in some cases, evolve into pain chronification, substantially affecting long-term quality of life in burn survivors. This review synthesizes current evidence on how thermal injury reshapes the function of key cutaneous cell populations, including keratinocytes, epidermal stem cells, melanocytes, fibroblasts, and immune cells, and how these changes modulate nociceptor activity through inflammatory, neurotrophic, and neuroimmune pathways. Furthermore, we describe how burn-induced cellular dysregulation contributes to peripheral sensitization across the continuum of wound healing, from acute inflammation to tissue repair. By integrating emerging mechanistic insights, this review highlights therapeutic targets aimed at minimizing subacute pain and preventing or mitigating chronic pain after burn injury.

Mucormycosis, a disease encompassing life-threatening fungal infections by members of the Mucorales group, is characterized by significant heterogeneity, poor clinical outcomes, and globally rising incidences. Although showing clear outbreak potential, the disease remains poorly understood. Mucorales infections are characterized by rapid progression and extensive tissue destruction, often requiring disfiguring surgical interventions. Moreover, intrinsic resistance and high drug tolerance limit antifungal effectiveness, contributing to the disease's high mortality. To overcome the challenges associated with these infections, a deeper understanding of mucormycosis is urgently needed. Valuable translational insights traditionally derive from in vivo host models. However, current systems are limited by single-endpoint invasive analysis, offering only a narrow view of infection progression and treatment effects. To address these critical shortcomings and enhance experimental models, bioluminescent Mucor lusitanicus reporter strains were generated to establish models that allow for real-time, longitudinal monitoring of infection in individual animals. Codon optimization, targeted integration of the firefly luciferase gene, and control of expression using highly active promoters resulted in the successful establishment of two mucormycosis models: Galleria mellonella larvae as an intermediate infection model and a translational mouse model. In the murine model, the integration of micro-CT imaging further enhanced the characterization of host-pathogen interactions by enabling noninvasive assessment of tissue responses over time. Overall, our approach enables enhanced temporal resolution for quantitative assessment of fungal burden and host responses. Using M. lusitanicus as a model organism, this methodology establishes a foundation and technical expertise for application toward clinically relevant Mucorales infection and antifungal research.

Hierakonpolis was a major population and political center in Upper Egypt during the Predynastic era (c. 3800-3100 BC). Its ancient remains are preserved mainly as negative archeological features (i.e., structural cuts that disrupt the natural soil), such as postholes and foundation trenches for buildings of wood. One of these constructions is a large palisade wall, of which over 50 m of its length has been uncovered by archaeologists. To trace the buried continuation of this structure without excavation, researchers conducted a ground-penetrating radar (GPR) survey using a high-frequency (900 MHz) antenna. Despite subtle physical contrasts between the remains and the soil, the arid conditions allowed the GPR to detect the foundation trench as a lateral discontinuity within the Nile silt layer that extends across the entire study area. GPR scans revealed that the wall continues westward along the same trajectory as its excavated segments for an additional 18 m before the signal terminated. Analysis of GPR facies suggests that repeated flooding from an ancient Nile channel compromised the site's stability, likely resulting in the destruction of the wall in the northwestern sector. Archaeological findings indicate the wall demarcated a large ceremonial and administrative complex, while the survey results also suggest it had a broader functional role as a defensive barrier against Nile floodwaters and other natural threats.

Gorham-Stout disease (GSD) is a rare idiopathic osteolytic disorder, and its diagnosis depends on a comprehensive evaluation of clinical, imaging, and pathological findings, alongside the systematic exclusion of other diseases. We report a case of GSD characterized by progressive clavicular bone destruction and resorption following low-energy trauma. Monitoring biochemical markers related to bone turnover is essential for early diagnosis and disease assessment, which is critical for controlling disease progression. The early administration of osteoclast activity inhibitors, combined with active vitamin D supplementation, can improve prognosis. Treatment plans should be individualized based on the lesion site, the patient's age, and specific needs. In clinical practice, the routine internal fixation of fractures without a definitive diagnosis may lead to severe consequences.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a crippling orthopedic disease. While glucocorticoids are a well-established etiological factor, the molecular framework driving the cascading tissue destruction remains elusive. Endoplasmic reticulum stress (ERS) has emerged as a central pathogenic hub. This review comprehensively synthesizes current evidence on how ERS orchestrates the multi-dimensional pathological network in SONFH, focusing on specific signaling paradoxes and translational barriers. Mechanistically, ERS drives irreversible osteoblast apoptosis via the PERK-CHOP axis and impairs endothelial regeneration by suppressing mTOR signaling. Notably, ERS exhibits profound microenvironmental heterogeneity: in articular chondrocytes, it aberrantly stabilizes HIF-1α to precipitate matrix degradation-a stark contrast to its canonical vasculoprotective role. Furthermore, ERS exacerbates intraosseous ischemia through a positive feedback loop with lipid metabolism. Importantly, we identify the "ischemic island" effect (a physical sclerotic barrier) and inherent biomechanical discrepancies in quadrupedal animal models as primary bottlenecks hindering the clinical translation of potent ERS inhibitors. To bridge this translational chasm, we propose combinatorial interventions coupling ERS modulators with advanced bone-targeted delivery systems (e.g., Asp8-modified nanocarriers) to breach the ischemic barrier, offering a pivotal strategy for future precision joint-preserving therapies.