Osteoclasts and osteoblasts play critical roles in bone remodeling, and their dysregulation leads to pathological bone loss. However, the precise mechanisms underlying the regulation of differentiation remain unclear. This study investigated the role of the transcriptional regulator Zinc Finger Matrin-Type 1 (Zmat1) in both osteoclastogenesis and osteoblastogenesis. Zmat1 deficiency resulted in decreased osteoclast activity, and bone resorption. Mechanistically, ZMAT1 was significantly upregulated during osteoclast differentiation and acted as a transcriptional repressor of the E3 ubiquitin ligase TRIM46, which regulates YAP1 degradation via K48-linked ubiquitination. Furthermore, Zmat1 deficiency enhanced osteoblast activity and bone formation. These findings highlight a novel ZMAT1/TRIM46/YAP1 axis, providing new insights into the transcriptional regulation of both osteoclast and osteoblast differentiation, and present potential therapeutic targets for osteoporosis.

The healing of infected tendons is hindered by mechanical dysfunction, tissue adhesion, bacterial colonization, and immune imbalance. Inspired by the biphasic “adhesion-lubrication” structure of tendon sheaths, we developed a Janus hydrogel, named HAPP@H-EXO, for spatiotemporal repair. The material exhibits antifatigue properties and redistributes mechanical stress through a dynamic network formed by norbornylated PVA and boronic acid-modified hyaluronic acid-PVA. Its high-adhesion side integrates tissue via borate and hydrogen bonds, whereas the lotus leaf-induced low-adhesion side prevents postsurgical adhesion. The incorporation of oligo-polyethyleneimine and phenylboronic acid groups traps and kills bacteria, overcoming resistance. The pH-responsive release of hypoxic tendon stem cell exosomes reprogrammes macrophages via inhibition of the NF-κB pathway, reducing inflammation and promoting regeneration. In an infected Achilles tendon model, HAPP@H-EXO eliminated MRSA, suppressed early inflammation, and enhanced regeneration. Within 8 weeks, it significantly improved biomechanical strength, prevented adhesion, and restored motor function, establishing a mechanoimmunotherapeutic strategy for infected tissue regeneration. Healing of infected tendons is hindered by mechanical dysfunction, tissue adhesion, and immune imbalance. Here, Li et al. develop a multifunctional Janus hydrogel with asymmetric adhesion, antibacterial properties, and pH-responsive release of tendon stem cell-derived exosomes for infected tendon repair.

The high-efficiency repair of infected bone defects suffers frequently from the insufficient bone differentiation activity and the stubborn biofilm formation resulting from bacterial infections. Herein, we report for the first time the development of Se-doped curcumin-derived carbon dots (Cur/Se-CD) with concurrent antibacterial, anti-inflammatory, and osteogenic activities through the dual regulatory strategy mediated by the traditional Chinese herbal curcumin and immunoregulatory Se ions. The prepared Cur/Se-CD shows outstanding antibacterial, antibiofilm, and anti-inflammatory properties, being able to convert macrophages from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype and realizing the regulation of the bone immune microenvironment. The dual regulatory strategy also endows Cur/Se-CD with excellent osteogenic activity owing to the negatively charged features of Cur/Se-CD. Moreover, doping Se ions can induce the fluorescence emission peak of Cur/Se-CD to shift to 720 nm, providing Cur/Se-CD with NIR imaging capability and allowing for the dynamic monitoring of degradation behaviors of scaffold materials. Finally, the injectable Cur/Se-CD-incorporated GelMA hydrogels achieve almost complete healing of infected bone defects after implanting for two months. Overall, this work presents a novel perspective on the development of a single-component nanomaterial with concurrent NIR imaging, antibacterial, anti-inflammatory, and osteogenic activities for the visualized therapy of infected bone defects.

Heat stroke (HS) is a life-threatening condition exacerbated by rising global temperatures, with children identified as a particularly vulnerable population. Despite this, basic research on age-related differences in thermotolerance remains limited. In this study, we established a high-temperature and high-humidity exposure model with real-time core body temperature (CBT) monitoring to investigate thermotolerance in young versus adult rats. The results showed that young rats exhibited prolonged CBT plateau phases and delayed HS onset, indicating enhanced thermotolerance compared to adult rats. This was accompanied by significantly milder multi-organ injury and reduced intestinal barrier damage. Young rats displayed lower serum levels of D-lactate and intestinal fatty acid-binding protein, better-preserved intestinal epithelial ultrastructure, and higher expression of tight junction proteins such as ZO-1, Occludin, and E-cadherin. Moreover, young rats showed elevated expression of heat shock proteins (HSP40 and HSP70) in intestinal tissues, which likely contributed to improved barrier integrity and cellular protection. These findings suggest that enhanced intestinal barrier stability and robust HSP responses underlie the superior thermotolerance observed in young rats. However, despite their physiological advantages, infants and young children often suffer poor HS outcomes due to behavioral limitations and caregiver negligence, especially in enclosed environments such as parked vehicles. This highlights the critical need for enhanced caregiver awareness, improved pediatric emergency response training, and preventive strategies to mitigate pediatric HS risk.

Objective This study describes a novel localization technique integrating a laser navigation system (LNS) with puncture needles and guidewires, and verifies its efficacy in the removal of soft tissue foreign bodies (FBs). Methods Soft tissue FB retention models were established by inserting marbles into pork. The control group underwent FB removal under ultrasound guidance with puncture needle localization, while the observation group underwent the procedure under LNS guidance with puncture needle localization. The time from the start of observation to detection (T1), puncture localization time (T2), total localization time (T), and the success rate of localization were compared between the two groups. Results Ultrasound successfully detected larger superficial FBs, whereas X-ray identified smaller objects at deeper locations; however, X-ray visualization remained difficult for small, deep-seated plastic FBs. In the LNS-guided group, T1, T2, and total time T were 6.17 ± 1.04 s, 56.77 ± 11.18 s, and 62.94 ± 10.66 s, respectively, all significantly shorter than those in the ultrasound-guided group ( P < 0.001). For larger FBs (Φ = 5 mm), the localization success rate was 90% in LNS group versus 100% in US group, a difference that was not statistically significant ( P > 0.05). Conclusion The localization method combining LNS with puncture needles and guidewires is convenient and effective, significantly reducing localization time and demonstrating high clinical utility.

Chondrosarcoma (CS) is a malignant bone tumor for which treatment efficacy remains clinically challenging owing to chemotherapy resistance. Ferroptosis, an iron-dependent form of regulated cell death initiated by lipid peroxidation, has emerged as a promising strategy for addressing drug resistance. However, the potential of targeting ferroptosis to overcome drug resistance in CS has not been systematically elucidated. Our study identifies REGγ as a critical driver of malignant progression in chondrosarcoma, with its elevated expression correlating with unfavorable patient outcomes. Loss of REGγ potentiates lipid peroxidation and modulates the activation of ferroptosis-associated genes by enhancing WDR6 protein stability. Mechanistically, REGγ degrades WDR6 through a ubiquitin-independent mechanism, inhibiting the ferroptosis pathway governed by the STK11/AMPK axis and consequently promoting tumor drug resistance. Additionally, RLY01, an inhibitor of the REGγ-20S proteasome, effectively suppresses chondrosarcoma growth and sensitizes chondrosarcoma cells to cisplatin. Collectively, REGγ emerges as a highly promising therapeutic target for improving the efficacy of cisplatin and other chemotherapies in CS.

Exertional heat stroke (EHS) is a severe and potentially life-threatening condition that primarily affects healthy individuals engaged in strenuous physical activity under hot and humid environments, representing an escalating public health challenge in the context of global climate change. This study evaluated the preventive potential of a synbiotic formulation containing Lactiplantibacillus plantarum S58 and β-glucan (S58/βG) in a rat model of EHS. Rats received S58/βG pretreatment for 14 or 28 days before EHS induction, and a range of indicators including core temperature, intestinal histopathology, tight junction protein expression, MAPK signaling pathway activation, epithelial apoptosis, and gut microbiota composition were systematically assessed. The results demonstrated that S58/βG effectively enhanced thermotolerance, maintained intestinal integrity, and mitigated systemic organ injury. Mechanistically, it inhibited the phosphorylation of p38 and ERK, attenuated epithelial apoptosis, and maintained the expression of ZO-1, occludin, and E-cadherin. Moreover, S58/βG modulated the gut microbiota by progressively increasing beneficial bacteria and reducing potentially pathogenic bacteria over time. These findings demonstrate, for the first time, that S58/βG confers protection against EHS by concurrently modulating the gut microbiota and MAPK pathway, highlighting its potential as a dietary intervention to prevent EHS in vulnerable populations.

Heat stroke causes life-threatening systemic inflammation and multiorgan injury, but the intracellular mechanisms that sustain inflammatory amplification after heat exposure remain unclear. Here, using heat stroke mouse models, genetic NLRP3 deletion, pharmacological inhibition, myeloid-specific NLRP3 deficiency, macrophage depletion, and heat-stressed macrophage systems, we show that tissue macrophage NLRP3 inflammasome activation is a central driver of interleukin-1β/interleukin-18 release, organ injury, and mortality. Mechanistically, heat stroke enhances phospholipase C delta 4 signaling, promotes diacylglycerol accumulation at trans-Golgi network/Golgi-associated membranes, recruits protein kinase D1, and increases phosphatidylinositol 4-kinase β-dependent phosphatidylinositol 4-phosphate production. This lipid remodeling supports NLRP3 recruitment, ASC speck formation, caspase-1 activation, and inflammatory cytokine release. Phospholipase C delta 4 knockdown preferentially suppresses NLRP3 activation induced by heat stroke, but not by canonical stimuli. These findings link heat stroke to membrane lipid remodeling and spatial inflammasome assembly, identifying a potential organ-protective pathway in heat stroke.

BACKGROUND:The incidence of peripheral nerve injury has increased annually and it has become a common traumatic disease in clinical practice. METHODS:Netrin-1 is a crucial extracellular matrix protein that plays a significant role in nerve development and regeneration, and is involved in the construction of a local neurological injury regional regeneration and repair microenvironment to support axon and myelin repair growth. RESULTS:Recent studies have highlighted its important roles in the repair of peripheral nerve injuries. CONCLUSION:This review clarifies how Netrin-1 in fluences neuronal survival, promotes axonal regeneration, and modulates neuro-inflammation.

Cadmium (Cd) could cause damage on colon promoting inflammatory bowel disease (IBD) through drinking and dietary intake. Cadmium has been proved disturbed the composition and diversity of gut microbiota in mice and enhance the production of bacterial metabolite, oleic acid. However, the modification of oleic acid content in the gut bacterial metabolites when exposed to cadmium needs to be verified, as well as the mechanism of cadmium toxicity on colitis. Thus, we determined the content of oleic acid in gut bacterial metabolites of mice exposed to cadmium and analyzed the core target of Cadmium, oleic acid and IBD to find the mechanism of cadmium toxic effect on promoting DSS-induced intestinal inflammation. In mice exposed to cadmium, oleic acid content in gut microbiota metabolites was significantly increased. Network toxicology analysis found 74 common genes between cadmium and oleic acid, and further identified the core targets of these 74 genes and IBD targets, counting for 53 genes. According to these data, we identified the major genes, including IL1B, BCL2, TNF, IL6 and TP53, and pathways, such as regulation of apoptotic signaling pathway, lipid and atheroscleorsis, involved in cadmium promoted colitis, and the vital receptor, FFAR4, of oleic acid receptor. The blockage of FFAR4 by AH7614 obviously inhibited the DSS-induced colitis exacerbated by cadmium. In conclusion, this study demonstrates cadmium elevates the content of oleic acid in gut microbiota and the mechanism underlying cadmium-aggravated colitis potentially by FFAR4.

Purpose: It is often difficult for surgeons to accurately implant the cannulated screws for fixing femoral neck fractures under C-arm fluoroscopy. Our simulation study attempts to help surgeons identify the optimal positions of screws on anteroposterior and lateral radiographs. Methods: A retrospective study including patients from 2014.01.01 to 2017.12.31 was conducted. Softwares were used for 3-dimensional reconstruction and cross-sections construction of 60 femoral necks. The contours of all cross-sections along the axis of the femoral neck were stacked to identify a safe zone for screws placement. A simulation experiment was carried out with 3 circles of diameter 6.5 mm in the safe zone. The absolute and relative positions of every screw in the anteroposterior radiographs and lateral radiographs were measured Normal distribution, continuous data are presented in mean ± standard deviation, and analyzed by t-test. The category data are presented by n (%) and analyzed by the Chi-square test. Results: The morphologies of the safe zones for screws placement were anteriorly flat ellipses. The best dispersion was obtained with the inverted triangle shape in this zone: the inferior was positioned near the lower 1/10 on the anteroposterior view and near the anterior 3/5 on the lateral view. The anterosuperior and posteriosuperior screws were positioned near the upper 1/5 and 1/4, respectively, on the anteroposterior view, and near the anterior 1/10 and posterior 1/5, respectively, on the lateral view. Conclusion: Simulated screws implantation demonstrates the distribution characteristics of screws in anteroposterior and lateral radiographs. This can help decrease the risk of perforation and iatrogenic injury.

Exertional heat stroke (EHS) is a life-threatening condition characterized by hyperthermia and multi-organ dysfunction, often associated with intestinal barrier disruption. This study evaluated the protective effects of Huoxiang Zhengqi Dropping Pills (HXZQD) against EHS in a rat model. HXZQD was administered via oral gavage at low, medium, and high doses, followed by EHS induction through exercise under high-temperature and high-humidity conditions. The findings revealed that high-dose HXZQD significantly delayed the onset of EHS, reduced core body temperature elevations, and mitigated multi-organ injury, as evidenced by biochemical markers and histopathological examination. This study showed that HXZQD alleviated EHS-induced intestinal damage by preserving barrier proteins (ZO-1, Occludin, and Ecadherin) and maintaining intestinal barrier integrity. Transmission electron microscopy confirmed the preservation of tight junction structures. Further analysis indicated that HXZQD modulated the MAPK/NF-κB signaling pathways, inhibiting heat stress-induced activation and reducing inflammation. Additionally, HXZQD positively regulated gut microbiota, increasing the proportion of beneficial Lactococcus and decreasing harmful Streptococcus. These findings suggest that HXZQD maintains intestinal homeostasis during EHS by preserving barrier function and modulating gut microbiota, offering a promising preventive approach for EHS management.

In image-guided surgery (IGS) practice, combining intraoperative 2D X-ray images with preoperative 3D X-ray images from computed tomography (CT) enables the rapid and accurate localization of lesions, which allows for a more minimally invasive and efficient surgery, and also reduces the risk of secondary injuries to nerves and vessels. Conventional optimization-based methods for 2D X-ray and 3D CT matching are limited in speed and precision due to non-convex optimization spaces and a constrained searching range. Recently, deep learning (DL) approaches have demonstrated remarkable proficiency in solving complex nonlinear 2D–3D registration. In this paper, a fast and robust DL-based registration method is proposed that takes an intraoperative 2D X-ray image as input, compares it with the preoperative 3D CT, and outputs their relative pose in x, y, z and pitch, yaw, roll. The method employs a dual-channel Swin transformer feature extractor equipped with attention mechanisms and feature pyramid to facilitate the correlation between features of the 2D X-ray and anatomical pose of CT. Tests on three different regions of interest acquired from open-source datasets show that our method can achieve high pose estimation accuracy (mean rotation and translation error of 0.142° and 0.362 mm, respectively) in a short time (0.02 s). Robustness tests indicate that our proposed method can maintain zero registration failures across varying levels of noise. This generalizable learning-based 2D (X-ray) and 3D (CT) registration algorithm owns promising applications in surgical navigation, targeted radiotherapy, and other clinical operations, with substantial potential for enhancing the accuracy and efficiency of image-guided surgery.

Heat stroke (HS) is a severe condition associated with prolonged exposure to high temperatures, leading to systemic inflammation and multi-organ damage. Disruption of the intestinal barrier plays a crucial role in HS progression by allowing endotoxins to enter circulation and trigger widespread inflammation. Lactoferrin (LF), known for its immune-modulating and barrier-protective properties, shows promise in mitigating HS-related damage. This study investigated the protective effects of LF on the intestinal barrier under HS conditions using in vitro and in vivo models. In Caco-2 cell monolayers exposed to heat stress, LF improved barrier integrity by increasing transepithelial electrical resistance (TEER) and maintaining tight junctions. In mice, LF supplementation enhanced heat tolerance, delayed HS onset, and reduced multi-organ damage, whereas LF knockout (KO) mice exhibited exacerbated damage. Further analysis revealed that heat stress induced ferroptosis by suppressing GPX4 and SLC7A11, contributing to intestinal injury. LF alleviated ferroptosis by upregulating these proteins and reducing Fe2+ accumulation, reactive oxygen species (ROS) generation, and lipid peroxidation. Additionally, LF inhibited heat stress-induced activation of the MAPK pathway by suppressing the phosphorylation of p38, ERK, and JNK, suggesting that MAPK signaling mediates its protective effects. These findings suggest that LF supplementation may enhance heat tolerance and prevent HS-induced intestinal barrier damage through ferroptosis inhibition and MAPK pathway regulation.

The use of piezoelectric materials to convert micromechanical energy at the fracture site into electrical signals, thereby modulating stress-concentrated inflammation, has emerged as a promising treatment strategy for diabetic fractures. However, traditional bone-guiding membranes often face challenges in diabetic fracture repair due to their passive and imprecise drug release profiles. Herein, a piezoelectric polyvinylidene fluoride (PVDF) fibrous membrane is fabricated through electrospinning and oxidative polymerization to load metformin (Met) into a polypyrrole (PPy) coating (Met-PF@PPy), creating a "mechanical-electrical-pharmaceutical coupling" system. In a micromotion mechanical environment, Met-PF@PPy converts mechanical energy into electrical signals, activating the electrochemical reduction of PPy and triggering stress-responsive Met release. The generated electrical signals suppress inflammation through M1-to-M2 macrophage polarization and simultaneously enhance osteogenesis. Simultaneously, Met inhibits the NF-κB pathway to reduce pro-inflammatory cytokines while activating the AMPK pathway to promote osteogenesis and angiogenesis. In a diabetic mouse femoral fracture model, Met-PF@PPy significantly reduces inflammatory markers, enhances vascularization, and increases bone mineral density and bone volume fraction by over 30%. This "force-electric-drug coupling" strategy provides an innovative approach for active regulation in diabetic fracture repair and offers a versatile platform for advancing piezoelectric materials in regenerative medicine.

Uncontrolled bleeding contributes to 40

BACKGROUND:Exertional heat stroke (EHS) is a life-threatening condition induced by high-temperature environments, which poses significant health risks. The Qingshu Yiqi Decoction (QSYQD) is a traditional Chinese medicine (TCM) formula that is known to clear summer heat, replenish Qi, and protect intestinal function. However, experimental evidence and mechanistic insights into its role in EHS prevention are limited. PURPOSE:The aim of this study is to evaluate the protective effects of QSYQD against EHS-induced hyperthermia and multi-organ injury and investigate the underlying molecular mechanisms. METHODS:An EHS rat model was established using treadmill exercise in a high-temperature environment. The rats were pretreated with low, medium, or high doses of the QSYQD. The intestinal barrier function was assessed using biomarkers, an ultrastructural analysis, and key protein expressions. Network pharmacology was used to identify potential targets, and molecular mechanisms were validated using western blot. The gut microbiota composition was analyzed using 16S rRNA sequencing. RESULTS:The QSYQD significantly alleviated hyperthermia and multi-organ injury in the EHS rats, and the medium dose had the most pronounced effects. It preserved intestinal barrier integrity by maintaining the tight junction protein levels and reducing biomarkers of epithelial damage. Network pharmacology and experimental validation revealed that the QSYQD inhibited the NF-κB and MLC signaling pathways, key regulators of intestinal barrier function. Additionally, the QSYQD altered the gut microbiota composition and notably increased the abundance of Lactobacillus, that has known heat stress protective effects. CONCLUSIONS:QSYQD protects against EHS-induced damage by preserving intestinal barrier integrity, modulating gut microbiota, and inhibiting the NF-κB and MLC signaling pathways. Future studies will focus on identifying active compounds within QSYQD that enhance heat tolerance and provide EHS protection.

With the intensifying trend of global warming, heat stroke (HS) has emerged as a growing public health threat. HS is a life-threatening condition triggered by excessive core body temperature (CBT), often leading to multi-organ failure and high mortality. Sleep deprivation (SD), a common physiological state among individuals frequently exposed to hot environments—such as military personnel and manual laborers—has been clinically associated with increased HS susceptibility. However, its underlying mechanisms remain unclear. In this study, we demonstrate that acute SD significantly reduces thermotolerance and exacerbates HS-induced multi-organ injury in rats. Notably, SD intensifies intestinal barrier disruption by activating the MAPK signaling pathway and promoting epithelial apoptosis. These findings suggest that SD may heighten HS vulnerability through intestinal barrier dysfunction. Our results align with clinical observations and identify intestinal integrity as a potential intervention target. Ensuring sufficient sleep and maintaining intestinal barrier function may represent key strategies to prevent HS, particularly in heat-exposed populations.

Wounds exposed to seawater face life-threatening severe inflammation and infection, driven by the combined effects of the hypertonic, highly alkaline marine environment and invasion by Vibrio vulnificus and other highly pathogenic marine bacteria, which collectively disrupt host repair mechanisms. This often progresses to sepsis, tissue necrosis, or amputation. Conventional dressings lack stable seawater adhesion, effective elimination of V. vulnificus and pathogens, or inflammation regulation. To address this, we developed a smart dual-network hydrogel. Crosslinking hyperbranched polylysine (HBPL) and oxidized dextran (ODEX) via dynamic Schiff base bonds, combined with polyvinyl alcohol (PVA)-borax dynamic borate ester bonds, forms the matrix integrated with Hypo-ADSC-Exos for multifunctionality. The hydrogel exhibits injectable/sprayable fluidity, seawater-resistant adhesion, and optimized exudate management. HBPL eradicates V. vulnificus, P. aeruginosa, and other pathogens, while Hypo-ADSC-Exos modulate inflammation to promote collagen remodeling, neovascularization, and hair follicle regeneration. In V. vulnificus-infected mouse and rabbit ear models, it significantly accelerated healing, reduced scarring, and enhanced regeneration versus conventional dressings. Tackling adhesion instability, persistent infection, and dysregulated inflammation in seawater wounds, this dynamic hydrogel presents a bioactive therapeutic platform for complex infections.

Heatstroke, a global concern exacerbated by climate change, poses significant health risks, potentially leading to multiorgan damage and fatalities. Core body temperature (CBT) is a critical and precise indicator of heatstroke, and its continuous monitoring could serve as a pivotal tool for early detection. Traditional CBT measurements, often invasive (e.g., surgical intubation, rectal or oral placement), and disrupt daily activities, whereas existing wearable devices predominantly measure skin temperatures which is susceptible to ambient environment, thus unreliable for heatstroke alert. To overcome these limitations, this study introduces an innovative in-ear wearable device to measure CBT via the cochlea, which allows for accurate CBT monitoring and timely heatstroke alerts during activities in high-temperature and high-humidity environments. The device comprises a negative temperature coefficient (NTC) thermometer integrated into a flexible precision circuit (FPC), a compact Bluetooth module, an 8 mA h micro battery, and a biocompatible, low-stimulus silica gel casing. With dimensions of 27 mm × 18 mm and a maximum in-ear diameter of 5 mm, weighing just 1.3 g, the device offers high portability and comfort, with a continuous operational lifespan of at least 24 h postcharging. A complementary software system facilitates continuous CBT monitoring, heatstroke alerts, and device management. Preliminary human trials demonstrate the device's accuracy in CBT measurement, rivaling that of rectal thermometry, and superior to the performance of surface body temperature measurement at different body parts. Long-term experiments affirm the device's efficacy in detecting rapid CBT escalations, enabling timely preventive measures against heatstroke.