Bone Homeostasis Modulating Orthopedic Adhesive for the Closed-Loop Management of Osteoporotic Fractures.

Patients with osteoporotic fractures often require effective fixation and subsequent bone repair. However, currently available materials are often limited functionally, failing to improve this cohort's outcomes. Herein, kaempferol-loaded mesoporous bioactive glass nanoparticles (MBGNs)-doped orthopedic adhesives are prepared to assist osteoporotic fracture fixation and restore dysregulated bone homeostasis, including promoting osteoblast formation while inhibiting osteoclastic bone-resorbing activity to synergistically promote osteoporotic fracture healing. The injectability, reversible adhesiveness and malleable properties endowed the orthopedic adhesives with high flexibility and hemostatic performance to adapt to complex clinical scenarios. Moreover, Ca2+ and SiO4 4- ions released from MBGNs can accelerate osteogenesis via the PI3K/AKT pathway, while kaempferol mediated osteoclastogenesis inhibition and can slow down the bone resorption process through NF-κB pathway, which regulated bone regeneration and remodeling. Importantly, implementing the orthopedic adhesive is validated as an effective closed-loop management approach in restoring the dysregulated bone homeostasis of osteoporotic fractures.

Novel Self-Expanding Interwoven Nitinol Stent for Treating Femoropopliteal Artery Disease: 12-Month Results of Single-Center First-in-Man Study.

PURPOSE: To evaluate the safety and efficacy of Innospring® stent, a novel self-expanding interwoven nitinol stent, in treating femoropopliteal atherosclerotic lesions. METHODS: A prospective, single-center, single-arm, first-in-human study enrolled 15 patients (mean age 73.1 years; 13 men) to evaluate the safety and efficacy of the Innospring® stent monitored by core laboratories. The inclusion criteria were claudication or ischemic rest pain, de novo lesions or nonstented restenosis, >70% stenosis, lesion length <20 cm, and a reference vessel diameter of 4-7 mm. The primary safety endpoint was 30-day major adverse events. The primary efficacy end point was stent patency at 12 months. Follow-up evaluations were conducted at 30 days, 6 months, and 12 months. RESULTS: The lesion length was 6.1 ± 3.5 mm. Fourteen (93.3%) patients had lesions of the superficial femoral artery and 3 (20.0%) patients had lesions of the popliteal artery. Nine (60.0%) patients had moderate-to-severe calcified lesion. Technical and procedural success was 100%. No patients experienced major adverse events in the first 30 days. The Rutherford category showed significant and sustained improvement at 6 and 12 months. The 12-month follow-up radiographs obtained in 13 patients confirmed the absence of stent fractures in 100% of examinations. The cumulative primary stent patency rate at 6 and 12 months were 93.3% and 84.6%, respectively. CONCLUSION: Stenting of the superficial femoral and popliteal arteries using the Innospring® stent is safe and effective. This competing interwoven nitinol stent may provide superior stent integrity and fracture-resistance as well as serve areas under extreme mechanical stress. CLINICAL IMPACT: Endovascular recanalization is a widely accepted and recommended treatment for symptomatic peripheral artery diseases. The Innospring® stent is a novel self-expanding interwoven stent containing eight nitinol wires with additional radial force, fracture-resistance, and visibility under fluoroscopy. This first-in-human study using the Innospring® stent in patients with femoropopliteal occlusive disease reported that stenting of the superficial femoral and popliteal arteries using the Innospring® stent is safe and effective. This competing interwoven nitinol stent may provide an impressive stent integrity and fracture-resistance as well as serve areas under extreme mechanical stress.

SOX2-OT induced by PAI-1 promotes triple-negative breast cancer cells metastasis by sponging miR-942-5p and activating PI3K/Akt signaling.

Triple-negative breast cancer (TNBC) has an aggressive biological behavior and poor outcome. Our published study showed that PAI-1 could induce the migration and metastasis of TNBC cells. However, the underlying mechanism by which PAI-1 regulates TNBC metastasis has not been addressed. Here, we demonstrated that PAI-1 is high expressed in TNBC and promotes TNBC cells tumorigenesis. Using microarray analysis of lncRNA expression profiles, we identified a lncRNA SOX2-OT, which is induced by PAI-1 and could function as an oncogenic lncRNA in TNBC. Mechanistic analysis demonstrated that SOX2-OT acts as a molecular sponge for miR-942-5p to regulate the expression of PIK3CA, ultimately leading to activating PI3K/Akt signaling pathway and promoting TNBC metastasis. Taken together, our findings suggest that SOX2-OT regulates PAI-1-induced TNBC cell metastasis through miR-942-5p/PIK3CA signaling and illustrate the great potential of developing new SOX2-OT-targeting therapy for TNBC patients.

One-Year Clinical Outcome and Risk Factor Analysis of Directional Atherectomy Followed With Drug-Coated Balloon for Femoropopliteal Artery Disease.

PURPOSE: This study investigated the 1-year clinical outcomes of directional atherectomy combined with drug-coated balloon (DA + DCB) in femoropopliteal artery disease (FPAD) from real-world experience. MATERIALS AND METHODS: A retrospective study was conducted of patients treated between July 2016 and June 2019 using DA + DCB for FPAD. Patients' demographics, comorbidities, clinical characteristics and outcomes, and angiography and duplex ultrasound findings were analyzed. The 6-month and 1-year primary patency, primary assisted patency, secondary patency, and freedom from clinically-driven target lesion revascularization (CD-TLR) were evaluated. Univariate and multivariate analyses were performed to identify risk factors of primary patency loss or CD-TLR. RESULTS: Seventy-nine consecutive patients (83 lesions, mean age 70.9 years, 52 men) were included. Twenty-seven limbs had lifestyle-limiting claudication and 56 limbs had critical limb ischemia. There were 73 and 10 limbs with de novo lesion and in-stent restenosis, respectively. The mean lesion length of all the patients was 22.1 cm. The mean length of chronic total occlusions (CTOs) was 8.3 cm. Severe calcification was found in 32.5% cases. The 1-year primary patency rate was 80.8% and freedom from CD-TLR was 92.2%. The bailout stenting rate was 2.4%. Patients with CTO >10 cm had significantly lower 1-year primary patency rate and freedom from CD-TLR than did patients with CTO ≤10 cm. Total length of CTO (stratified as ≤5 cm, 5-10 cm, >10 cm) was identified as an independent risk factor of 1-year primary patency loss and CD-TLR. CONCLUSION: DA + DCB appears to be a safe and effective endovascular therapy to treat FPAD in real-world clinical practice, with a promising 1-year patency rate with a low rate of bailout stenting.

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits.

BACKGROUND: Increasing evidence suggests that multiple or long-time exposure to general anaesthesia (GA) could be detrimental to cognitive development in young subjects and might also contribute to accelerated neurodegeneration in the elderly. Iron is essential for normal neuronal function, and excess iron in the brain is implicated in several neurodegenerative diseases. However, the role of iron in GA-induced neurotoxicity and cognitive deficits remains elusive. METHODS: We used the primary hippocampal neurons and rodents including young rats and aged mice to examine whether GA impacted iron metabolism and whether the impact contributed to neuronal outcomes. In addition, a pharmacological suppression of iron metabolism was performed to explore the molecular mechanism underlying GA-mediated iron overload in the brain. RESULTS: Our results demonstrated that GA, induced by intravenous ketamine or inhalational sevoflurane, disturbed iron homeostasis and caused iron overload in both in vitro hippocampal neuron culture and in vivo hippocampus. Interestingly, ketamine- or sevoflurane-induced cognitive deficits, very likely, resulted from a novel iron-dependent regulated cell death, ferroptosis. Notably, iron chelator deferiprone attenuated the GA-induced mitochondrial dysfunction, ferroptosis, and further cognitive deficits. Moreover, we found that GA-induced iron overload was activated by NMDAR-RASD1 signalling via DMT1 action in the brain. CONCLUSION: We conclude that disturbed iron metabolism may be involved in the pathogenesis of GA-induced neurotoxicity and cognitive deficits. Our study provides new vision for consideration in GA-associated neurological disorders.

PIK3CA mutation and clinicopathological features of colorectal cancer: a systematic review and Meta-Analysis.

Background: There is conflicting evidence regarding the association between PIK3CA mutations and clinicopathological features of colorectal cancer (CRC). We performed a comprehensive meta-analysis investigating the association between PIK3CA mutations and clinicopathological features in CRC, including subgroup analysis of mutations in exons 9 and 20, to elucidate the role of PIK3CA mutations in CRC.Materials and Methods: A detailed literature search was performed within the PubMed, Web of Science, and Embase databases, examining the associations between PIK3CA mutations and demographic characteristics, clinicopathologic parameters, and molecular features in patients with CRC. The odds ratios with 95% confidence intervals were used to estimate the effect of PIK3CA mutations on outcome parameters.Results: Forty-four studies enrolling 17621 patients were eligible for inclusion. PIK3CA mutations were associated with proximal tumor location, mucinous differentiation, KRAS mutations, and microsatellite instability (MSI). Subgroup analysis demonstrated that PIK3CA exon 9 mutations were positively associated with proximal tumor location and KRAS mutations, and negatively associated with BRAF mutations and MSI; exon 20 mutations were associated with proximal tumor location, KRAS mutations, BRAF mutations and MSI.Conclusions: Our findings suggest that overall or exon-specific PIK3CA mutations showed null associations with key clinicopathological parameters, including disease stage and tumor differentiation, indicating that PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC. As PIK3CA mutations were found to be closely associated with KRAS mutations, their relationship warrants further investigation. Since PIK3CA exon 9 and 20 mutations showed different tendencies with regard to BRAF mutation and MSI status, they may have distinct molecular impacts on CRC.

Viabahn Stent Graft for the Endovascular Treatment of Occlusive Lesions in the Femoropopliteal Artery: A Retrospective Cohort Study with 4-Year Follow-Up.

BACKGROUND: The polytetrafluoroethylene-covered Viabahn stent may be effective for the endovascular treatment of patients with femoropopliteal artery occlusive lesions. However, the long-term efficacy of Viabahn stent remains unclear. The aim of the study is to evaluate the long-term patency of Viabahn stent grafts in patients with occlusive lesions in the femoropopliteal artery. METHODS: Consecutive patients with occlusive lesions in the femoropopliteal artery who had been treated with Viabahn stent grafts during the period from June 2013 to December 2016 at our center were retrospectively included. Accumulative incidences of primary patency and secondary patency were estimated by Kaplan-Meier survival analysis, and the predictors of primary patency were evaluated by Cox regression analysis. RESULTS: A total of 66 patients underwent successful endovascular treatment and were included in the study. Endovascular treatment with a Viabahn stent was associated with a complication rate of 9.1% and a 30-day mortality rate of 1.5%. Sixty-one patients were followed for a mean duration of 29.5 months. The 1-year, 2-year, 3-year, and 4-year primary patency rates were 81.7%, 74.7%, 67.6%, and 58.9%, respectively. The secondary patency rates were 94.9%, 92.9%, 90.1%, and 90.1%, respectively. The overall major amputation rate was 5.0%. The results of multivariate Cox regression analyses showed that stent location was the only independent predictor of primary patency (P = 0.001). Implantation of a Viabahn stent above the knee, compared with implantation below the knee, was associated with a higher rate of primary patency. CONCLUSIONS: The Viabahn stent graft is associated with a satisfactory rate of long-term patency for the endovascular treatment of occlusive lesions in the femoropopliteal artery, especially for those located above the knee.

Clinical Features and Outcomes of Patients With Acute Mesenteric Ischemia and Concomitant Colon Ischemia: A Retrospective Cohort Study.

BACKGROUND: Early identification of patients with acute mesenteric ischemia (AMI) involving the large bowel may play a decisive role in improving the prognosis of AMI. This study aims to compare the outcomes between patients with isolated AMI and AMI patients with colon involvement (CI) and to identify the predictors of worse outcomes. The different surgical modalities for AMI patients with CI were also evaluated. METHODS: This retrospective cohort study included 199 AMI patients admitted from January 2005 to January 2014. Based on colonoscopy and pathology reports, 39 patients were diagnosed as AMI with CI, and 160 were AMI patients without CI. The clinical outcomes and different surgical modalities were compared. Risk factors of 30-d mortality and short bowel syndrome (SBS) were identified. RESULTS: The 30-d mortality (10% versus 49%, P < 0.01) and SBS incidence (19% versus 49%, P < 0.01) were higher in AMI patients with CI than AMI patients without CI. AMI patients with CI have higher rate of bowel resection (68% versus 95%, P < 0.001) and second-look laparotomy (25% versus 54%, P < 0.001) than patients with AMI alone. For AMI patients with CI, emergent laparotomy was associated with shorter hospital stay (P = 0.04) and less incidence of SBS (74% versus 25%, P < 0.001) than initial endovascular therapy. Patients with ostomy had less repeated bowel resection (11% versus 63%, P = 0.001) and rate of SBS (21% versus 79%, P < 0.001) than patients with primary bowel anastomosis. Serum procalcitonin level and colon ischemia were risk factors of 30-d mortality and SBS for AMI. CONCLUSIONS: AMI patients with CI represent a special cohort of AMI patients with higher risk of poor outcome. Compared to initial endovascular therapy, emergent laparotomy was associated with shorter length of hospital stay and reduced incidence of SBS.

Time course study of intestinal epithelial barrier disruption in acute mesenteric venous thrombosis.

BACKGROUND: Acute superior mesenteric venous thrombosis (ASMVT) is an abdominal vascular condition. Early recanalization is essential to successful treatment. The aim of the study was to establish rabbit models of ASMVT and assess the time course of intestinal epithelial barrier disruption. METHODS: After surgical exposure of superior mesenteric vein (Sham group), large-vessel (L-group) and small-vessel (S-group) models were established by endothelium damage, stenosis creation, and thrombin injection. At baseline, 6, 9, and 12 h, hemodynamic and serum parameters were tested. Serum from ASMVT patients diagnosed at 24, 36, 48, and 60 h from symptom onset was collected. Intestinal barrier disruption was assessed by tight junction (TJ) protein expression, morphology changes, and bacterial translocation. Mesenteric arteriospasm was measured by flow velocity and intestinal wet/dry weight ratio. The serum level of intestinal fatty acid-binding protein and endotoxin in patients was also measured as an indicator for intestinal barrier function. RESULTS: Severe acidosis and lacticemia were observed in both the groups. The L-group experienced greater hemodynamic alteration than the S-group. Intestinal barrier disruption was detected by significantly decreased TJ protein expression, histology and ultrastructure injury of TJ, increased permeability, and bacterial translocation, at 9 h in the S-group and 12 h in the L-group. Secondary mesenteric arteriospasm occurred at the same time of complete intestinal barrier disruption and could be a significant cause of bowel necrosis. Significant increased level of intestinal fatty acid-binding protein and endotoxin was found in patients at 48 h in the S-group type and 60 h in the L-group type. CONCLUSIONS: The ASMVT animal models of both the types were first established. The loss of intestinal barrier function occurred at 6 h in the S-group model and 9 h in the L-group model. For clinical patients, the time window extended to 36 h in the S-group type and 48 h in the L-group type.

Biliary Obstruction following Transjugular Intrahepatic Portosystemic Shunt Creation in Patients with Variceal Bleeding.

This report describes an unusual complication after creation of a transjugular intrahepatic portosystemic shunt (TIPS). Biliary obstruction developed in two patients with portal hypertension accompanied by portal vein thrombosis, one patient with and the other without portal cavernous transformation. The biliary obstruction was thought to be secondary to compression of the bile duct by the stent graft placed in the TIPS. Awareness of this possible complication is important for its early diagnosis.

Postoperative Catheter-Directed Thrombolysis Versus Systemic Anticoagulation for Acute Superior Mesenteric Venous Thrombosis.

BACKGROUND: Little data evaluate catheter-directed thrombolysis (CDT) therapy as a sequential treatment of emergent surgery for patients with acute superior mesenteric venous thrombosis (ASMVT). We compared the outcomes of ASMVT patients receiving CDT via superior mesenteric artery (SMA) with those who had systemic anticoagulation after emergent laparotomy. METHODS: A single-center retrospective study of ASMVT patients receiving emergent laparotomy from May 2012 to April 2014 was performed. Patients in group I had postoperative systemic anticoagulation and patients in group II underwent postoperative CDT. The demography, etiology, imaging features, clinical outcomes, and complications were compared. Moreover, univariate analysis was performed to identify confounding variables of 30-day mortality. RESULTS: Thirty-two patients (20 males, mean age of 44.9 ± 10.6 years) were included, 17 in group I and 15 in group II. No significant differences of demographic data, etiology, baseline value, and perioperative comorbidity were found. The rate of complete thrombus removal was significantly higher in group II than group I (29.4% vs. 80.0%, P = 0.001). The second-look laparotomy and repeat bowel resection (58.8% vs. 13.3%, P = 0.002) were required in fewer patients in group II (20.0% vs. 70.6%, P = 0.001). The incidence of short-bowel syndrome (SBS; 41.2% vs. 6.7%, P = 0.001) and 30-day mortality (41.2% vs. 6.7%, P = 0.001) were lower in group II. The 1-year survival was also better in group II (52.9% vs. 93.3%, P = 0.014). The incidence of massive abdominal hemorrhage requiring blood transfusion and surgical intervention was 11.8% in group I and 20.0% in group II (P = 0.645). The age, serum D-dimer level, SBS, and postoperative CDT were significant risk factors of 30-day mortality in this study. CONCLUSIONS: For ASMVT patients receiving emergent surgery and intraoperative thrombectomy, the algorithm with postoperative CDT via SMA is associated with more favorable clinical outcome compared with systemic anticoagulation.

Early prophylactic anticoagulation via transjugular intrahepatic route for portal vein thrombosis after splenectomy in cirrhotic portal hypertension.

PURPOSE: To evaluate early transcatheter anticoagulation via the transjugular intrahepatic route to prevent portal vein thrombosis (PVT) after splenectomy in cirrhotic patients with portal hypertension. MATERIALS AND METHODS: This retrospective study included 98 cirrhotic patients with portal hypertension who underwent open splenectomy (48 men and 50 women; age, 45.4 y ± 13.6). Systemic anticoagulation was given to 52 patients in group I, and transcatheter anticoagulation was performed in 46 patients in group II. RESULTS: The technical success rate of catheterization by the transjugular intrahepatic route was 93.5% in group II. The 30-day (6.52% vs 23.1%, P < .05) and 6-month (8.70% vs 26.9%, P < .05) incidences of PVT were significantly lower in group II than in group I. The postoperative bleeding rate was 6.52% in group II and 25% in group I (P < .05). There was no significant difference between groups in 30-day (5.77% vs 2.17%) and 6-month (1.92% vs 6.52%) mortality. After splenectomy, the portal trunk vessel diameter was 16.0 mm ± 3.5 in group I and 14.5 mm ± 2.5 in group II (P < .05). The portal flow velocity was 25.9 cm/s ± 7.1 in group I and 28.2 cm/s ± 5.3 in group II (P > .05). During the first week after splenectomy, notable hypercoagulability was detected within the portal vein compared with peripheral blood. Decreased portal flow velocity was considered an independent risk factor for PVT by univariate and multivariate analysis. CONCLUSIONS: Transcatheter anticoagulation via the transjugular intrahepatic route can decrease the incidence of PVT and postoperative bleeding after open splenectomy in cirrhotic patients with portal hypertension.

The effects of amino acid infusions on core body temperature during the perioperative period: a systematic review.

The aim of this systematic review was to determine the effect of amino acid infusions on core body temperature and shivering. We searched the PubMed, EMBASE, CINAHL, and Cochrane Register of Controlled Trials databases to identify randomized controlled trials that met the inclusion criteria. A total of 11 eligible trials involving 506 participants were identified. Amino acid infusions were associated with shorter periods of mechanical ventilation and hospitalization and less perioperative shivering, mechanical intubation, and hospitalization in surgical patients without hepatic, renal, or severe metabolic disorders. It is recommended that infusions are warmed before administration to avoid further decrease in core body temperature.

Mesenchymal stem cell-derived extracellular vesicles accelerate diabetic wound healing by inhibiting NET-induced ferroptosis of endothelial cells.

Impaired angiogenesis is a major factor contributing to delayed wound healing in diabetes. Dysfunctional mitochondria promote the formation of neutrophil extracellular traps (NETs), obstructing angiogenesis during wound healing. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in promoting tissue repair and regeneration in diabetes; however, the precise pathways involved in this process remain unclear. In this study, NET-induced ferroptosis of endothelial cells (ECs) and angiogenesis were assessed in diabetic wound samples from both patients and animal models. In vitro and in vivo experiments were performed to examine the regulatory mechanisms of NETs in ECs using specific inhibitors and gene-knockout mice. MSC-EVs encapsulating dysfunctional mitochondria were used to trigger mitochondrial fusion and restore mitochondrial function in neutrophils to suppress NET formation. Angiogenesis in wound tissue was evaluated using color laser Doppler imaging and vascular density analysis. Wound healing was evaluated via macroscopic analysis and histological evaluation of the epithelial gap. NET-induced ferroptosis of ECs was validated as a crucial factor contributing to the impairment of angiogenesis in diabetic wounds. Mechanistically, NETs regulated ferroptosis by suppressing the PI3K/AKT pathway. Furthermore, MSC-EVs transferred functional mitochondria to neutrophils in wound tissue, triggered mitochondrial fusion, and restored mitochondrial function, thereby reducing NET formation. These results suggest that inhibiting NET formation and EC ferroptosis or activating the PI3K/AKT pathway can remarkably improve wound healing. In conclusion, this study reveals a novel NET-mediated pathway involved in wound healing in diabetes and suggests an effective therapeutic strategy for accelerating wound healing.

Neutrophil extracellular trap-induced ferroptosis promotes abdominal aortic aneurysm formation via SLC25A11-mediated depletion of mitochondrial glutathione.

BACKGROUND: Neutrophil extracellular traps (NETs) induce oxidative stress, which may initiate ferroptosis, an iron-dependent programmed cell death, during abdominal aortic aneurysm (AAA) formation. Mitochondria regulate the progression of ferroptosis, which is characterized by the depletion of mitochondrial glutathione (mitoGSH) levels. However, the mechanisms are poorly understood. This study examined the role of mitoGSH in regulating NET-induced ferroptosis of smooth muscle cells (SMCs) during AAA formation. METHODS: Concentrations of NET markers were tested in plasma samples. Western blotting and immunofluorescent staining were performed to detect the expression and localization of NET and ferroptosis markers in tissue samples. The role of NETs and SMC ferroptosis during AAA formation was investigated using peptidyl arginine deiminase 4 gene (Padi4) knockout or treatment with a PAD4 inhibitor, ferroptosis inhibitor or activator in an angiotensin II-induced AAA mouse model. The regulatory effect of SLC25A11, a mitochondrial glutathione transporter, on mitoGSH and NET-induced ferroptosis of SMCs was investigated using in vitro and in vivo experiments. Transmission electron microscopy was used to detect mitochondrial damage. Blue native polyacrylamide gel electrophoresis was used to analyze the dimeric and monomeric forms of the protein. RESULTS: Significantly elevated levels of NETosis and ferroptosis markers in aortic tissue samples were observed during AAA formation. Specifically, NETs promoted AAA formation by inducing ferroptosis of SMCs. Subsequently, SLC25A11 was identified as a potential biomarker for evaluating the clinical prognosis of patients with AAA. Furthermore, NETs decreased the stability and dimerization of SLC25A11, leading to the depletion of mitoGSH. This depletion induced the ferroptosis of SMCs and promoted AAA formation. CONCLUSION: During AAA formation, NETs regulate the stability of the mitochondrial carrier protein SLC25A11, leading to the depletion of mitoGSH and subsequent activation of NET-induced ferroptosis of SMCs. Preventing mitoGSH depletion and ferroptosis in SMCs is a potential strategy for treating AAA.

PDIA2 has a dual function in promoting androgen deprivation therapy induced venous thrombosis events and castrate resistant prostate cancer progression.

Androgen deprivation therapy (ADT) is the first line of treatment for metastatic prostate cancer (PCa) that effectively delays the tumor progression. However, it also increases the risk of venous thrombosis event (VTE) in patients, a leading cause of mortality. How a pro-thrombotic cascade is induced by ADT remains poorly understood. Here, we report that protein disulfide isomerase A2 (PDIA2) is upregulated in PCa cells to promote VTE formation and enhance PCa cells resistant to ADT. Using various in vitro and in vivo models, we demonstrated a dual function of PDIA2 that enhances tumor-mediated pro-coagulation activity via tumor-derived extracellular vehicles (EVs). It also stimulates PCa cell proliferation, colony formation, and xenograft growth androgen-independently. Mechanistically, PDIA2 activates the tissue factor (TF) on EVs through its isomerase activity, which subsequently triggers a pro-thrombotic cascade in the blood. Additionally, TF-containing EVs can activate the Src kinase inside PCa cells to enhance the AR signaling ligand independently. Androgen deprivation does not alter PDIA2 expression in PCa cells but enhances PDIA2 translocation to the cell membrane and EVs via suppressing the clathrin-dependent endocytic process. Co-recruitment of AR and FOXA1 to the PDIA2 promoter is required for PDIA2 transcription under androgen-deprived conditions. Importantly, blocking PDIA2 isomerase activity suppresses the pro-coagulation activity of patient plasma, PCa cell, and xenograft samples as well as castrate-resistant PCa xenograft growth. These results demonstrate that PDIA2 promotes VTE and tumor progression via activating TF from tumor-derived EVs. They rationalize pharmacological inhibition of PDIA2 to suppress ADT-induced VTE and castrate-resistant tumor progression.

Novel injectable adhesive hydrogel loaded with exosomes for holistic repair of hemophilic articular cartilage defect.

Hemophilic articular cartilage damage presents a significant challenge for surgeons, characterized by recurrent intraarticular bleeding, a severe inflammatory microenvironment, and limited self-repair capability of cartilage tissue. Currently, there is a lack of tissue engineering-based integrated therapies that address both early hemostasis, anti-inflammation, and long-lasting chondrogenesis for hemophilic articular cartilage defects. Herein, we developed an adhesive hydrogel using oxidized chondroitin sulfate and gelatin, loaded with exosomes derived from bone marrow stem cells (BMSCs) (Hydrogel-Exos). This hydrogel demonstrated favorable injectability, self-healing, biocompatibility, biodegradability, swelling, frictional and mechanical properties, providing a comprehensive approach to treating hemophilic articular cartilage defects. The adhesive hydrogel, featuring dynamic Schiff base bonds and hydrogen bonds, exhibited excellent wet tissue adhesiveness and hemostatic properties. In a pig model, the hydrogel could be smoothly injected into the knee joint cartilage defect site and gelled in situ under fluid-irrigated arthroscopic conditions. Our in vitro and in vivo experiments confirmed that the sustained release of exosomes yielded anti-inflammatory effects by modulating macrophage M2 polarization through the NF-κB pathway. This immunoregulatory effect, coupled with the extracellular matrix components provided by the adhesive hydrogel, enhanced chondrogenesis, promoted the cartilage repair and joint function restoration after hemophilic articular cartilage defects. In conclusion, our results highlight the significant application potential of Hydrogel-Exos for early hemostasis, immunoregulation, and long-term chondrogenesis in hemophilic patients with cartilage injuries. This innovative approach is well-suited for application during arthroscopic procedures, offering a promising solution for addressing the complex challenges associated with hemophilic articular cartilage damage.

Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis.

The essence of difference between hemostasis and thrombosis is that the clotting reaction is a highly fine-tuned process. Vascular protein disulfide isomerase (PDI) represents a critical mechanism regulating the functions of hemostatic proteins. Herein we show that histidine-rich glycoprotein (HRG) is a substrate of PDI. Reduction of HRG by PDI enhances the procoagulant and anticoagulant activities of HRG by neutralization of endothelial heparan sulfate (HS) and inhibition of factor XII (FXIIa) activity, respectively. Murine HRG deficiency (Hrg-/-) leads to delayed onset but enhanced formation of thrombus compared to WT. However, in the combined FXII deficiency (F12-/-) and HRG deficiency (by siRNA or Hrg-/-), there is further thrombosis reduction compared to F12-/- alone, confirming HRG's procoagulant activity independent of FXIIa. Mutation of target disulfides of PDI leads to a gain-of-function mutant of HRG that promotes its activities during coagulation. Thus, PDI-HRG pathway fine-tunes thrombosis by promoting its rapid initiation via neutralization of HS and preventing excessive propagation via inhibition of FXIIa.

The role of long non-coding RNA in abdominal aortic aneurysm.

The abdominal aortic aneurysm (AAA) is characterized by segmental expansion of the abdominal aorta and a high mortality rate. The characteristics of AAA suggest that apoptosis of smooth muscle cells, the production of reactive oxygen species, and inflammation are potential pathways for the formation and development of AAA. Long non-coding RNA (lncRNA) is becoming a new and essential regulator of gene expression. Researchers and physicians are focusing on these lncRNAs to use them as clinical biomarkers and new treatment targets for AAAs. LncRNA studies are beginning to emerge, suggesting that they may play a significant but yet unidentified role in vascular physiology and disease. This review examines the role of lncRNA and their target genes in AAA to increase our understanding of the disease's onset and progression, which is crucial for developing potential AAA therapies.