BACKGROUND:During bone tissue healing,promoting the vascularization of new bone is a common strategy to accelerate the repair of bone tissue.However,the rapid fibrosis process during bone defect repair is often ignored.OBJECTIVE:To design and prepare a core-shell structure bionic scaffold to regulate the process of fibrosis and vascularization in new callus,characterize physical characteristics of the scaffold,and verify the anti-fibrosis and osteogenic properties in vitro and in vivo.METHODS:A core-shell structure bionic scaffold to regulate the process of fibrosis and vascularization in new callus was designed and prepared.The outer shell structure of the scaffold was composed of polycaprolactone electrospun nanofibers loaded with fibroblast activating protein inhibitor;and the inner core structure was composed of gelatin methacrylate hydrogel loaded with deferoxamine.The physical characteristics of electrospun and hydrogel were characterized,and the biocompatibility of the material was verified by live-dead staining and CCK-8 assay.The antifibrotic effect of core-shell structure was analyzed by fibroblast in vitro assay.The osteogenic effect of fibroblast activating protein inhibitor in core-shell structure was analyzed by MC3T3-E1 cells in vitro assay.The vasogenic effect of deferoxamine in core-shell structure was analyzed by human umbilical vein endothelial cells.The effect of bionic core-shell scaffold on bone repair was evaluated by critical bone defect test in rats.RESULTS AND CONCLUSION:(1)The core-shell structure bionic scaffold had good biocompatibility.Hydrophobic polycaprolactone electrospun fibers prepared by electrospinning technology could effectively block the ingrowth of exogenous fibrous tissue on the physical level.The electrospun fiber membrane could effectively release the anti-fibrosis drug fibroblast activating protein inhibitor within 2 weeks,and the released anti-fibrosis drug could inhibit the growth and adhesion of fibroblasts around bone defects,effectively reduced the expression of fibroblast-related proteins,promoted the expression of osteoblast protein in MC3T3-E1 cells,and accelerated its mineralization rate.The deferoxamine in the core-shell structure could promote the migration and vascular formation ability of human umbilical vein endothelial cells,and promoted their strong expression of"H"vascular characteristic protein.(2)In critical bone defect model of SD rats established in the femur,compared with polycaprolactone membrane,the core-shell structure bionic scaffold could effectively repair bone defects.(3)These findings indicate that the core-shell structure bionic scaffold can prevent excessive fibrosis of callus and promote the formation of"H"vessels in the new callus,which can effectively avoid the occurrence of nonunion and accelerate the repair process of critical bone defect.

BACKGROUND:Cell senescence is one of the major risk factors for osteoarthritis,but there is no widely accepted anti-osteoarthritis therapy targeting senescent cells.OBJECTIVE:To develop a feasible treatment strategy targeting senescent cells in osteoarthritis.METHODS:The cationic liposome containing rapamycin,RAPA@Lipo,was prepared by thin film dispersion method.Methylallylated hyaluronic acid hydrogel was synthesized,and RAPA@Lipo was added to the methylallylated hyaluronic acid hydrogel aqueous phase solution.The hydrogel microspheres were prepared by microfluidic equipment.Solid hydrogel microspheres(RAPA@Lipo@MS)were crosslinked under violet light.Primary human chondrocytes were co-cultured with RAPA@Lipo and RAPA@Lipo@MS,respectively.The biocompatibility of the materials was evaluated by CCK-8 assay and live/dead staining.Primary rat chondrocytes were cultured in four groups.Normal control group was cultured for 48 hours.The model group was stimulated with H2O2 for 24 hours to establish senescent cell model.RAPA@Lipo group and RAPA@Lipo@MS group were cultured for 24 hours after establishing senescent cell model with RAPA@Lipo and RAPA@Lipo@MS,respectively.After culture,immunofluorescence was used to observe the expression of p62 and type Ⅱ collagen.RT-PCR was used to detect the mRNA expression of interleukin 6,matrix metalloproteinase 13,type Ⅱ collagen,aggrecan,and ADAMTS-5.RESULTS AND CONCLUSION:(1)The results of CCK-8 assay and live/dead staining showed that RAPA@Lipo and RAPA@Lipo@MS had good biocompatibility.(2)Compared with the normal control group,the protein expression of p62 was increased(P<0.05);the expression of type Ⅱ collagen was decreased(P<0.05),and the mRNA expression levels of interleukin 6,matrix metalloproteinase 13,and ADAMTS-5 were increased(P<0.05);mRNA expression levels of type Ⅱ collagen and aggrecan were decreased(P<0.05)in the model group.Compared with the model group,the expression of p62 protein was decreased(P<0.05);the expression of type Ⅱ collagen was increased(P<0.05),and the mRNA expression levels of interleukin 6,matrix metalloproteinase 13,and ADAMTS-5 were decreased(P<0.05);mRNA expression of type Ⅱ collagen and aggrecan increased(P<0.05)in the RAPA@Lipo@MS group.(3)These findings indicate that RAPA@Lipo@MS can control the quality of cells in vivo by enhancing autophagy,reduce senescent cells in vivo,and locally eliminate senescent cells and senescence-associated secretory phenotype factors in osteoarthritis,thereby slowing the progression of osteoarthritis and creating a cartilage microenvironment that promotes regeneration.

BACKGROUND:During bone tissue healing,promoting the vascularization of new bone is a common strategy to accelerate the repair of bone tissue.However,the rapid fibrosis process during bone defect repair is often ignored.OBJECTIVE:To design and prepare a core-shell structure bionic scaffold to regulate the process of fibrosis and vascularization in new callus,characterize physical characteristics of the scaffold,and verify the anti-fibrosis and osteogenic properties in vitro and in vivo.METHODS:A core-shell structure bionic scaffold to regulate the process of fibrosis and vascularization in new callus was designed and prepared.The outer shell structure of the scaffold was composed of polycaprolactone electrospun nanofibers loaded with fibroblast activating protein inhibitor;and the inner core structure was composed of gelatin methacrylate hydrogel loaded with deferoxamine.The physical characteristics of electrospun and hydrogel were characterized,and the biocompatibility of the material was verified by live-dead staining and CCK-8 assay.The antifibrotic effect of core-shell structure was analyzed by fibroblast in vitro assay.The osteogenic effect of fibroblast activating protein inhibitor in core-shell structure was analyzed by MC3T3-E1 cells in vitro assay.The vasogenic effect of deferoxamine in core-shell structure was analyzed by human umbilical vein endothelial cells.The effect of bionic core-shell scaffold on bone repair was evaluated by critical bone defect test in rats.RESULTS AND CONCLUSION:(1)The core-shell structure bionic scaffold had good biocompatibility.Hydrophobic polycaprolactone electrospun fibers prepared by electrospinning technology could effectively block the ingrowth of exogenous fibrous tissue on the physical level.The electrospun fiber membrane could effectively release the anti-fibrosis drug fibroblast activating protein inhibitor within 2 weeks,and the released anti-fibrosis drug could inhibit the growth and adhesion of fibroblasts around bone defects,effectively reduced the expression of fibroblast-related proteins,promoted the expression of osteoblast protein in MC3T3-E1 cells,and accelerated its mineralization rate.The deferoxamine in the core-shell structure could promote the migration and vascular formation ability of human umbilical vein endothelial cells,and promoted their strong expression of"H"vascular characteristic protein.(2)In critical bone defect model of SD rats established in the femur,compared with polycaprolactone membrane,the core-shell structure bionic scaffold could effectively repair bone defects.(3)These findings indicate that the core-shell structure bionic scaffold can prevent excessive fibrosis of callus and promote the formation of"H"vessels in the new callus,which can effectively avoid the occurrence of nonunion and accelerate the repair process of critical bone defect.

BACKGROUND:Cell senescence is one of the major risk factors for osteoarthritis,but there is no widely accepted anti-osteoarthritis therapy targeting senescent cells.OBJECTIVE:To develop a feasible treatment strategy targeting senescent cells in osteoarthritis.METHODS:The cationic liposome containing rapamycin,RAPA@Lipo,was prepared by thin film dispersion method.Methylallylated hyaluronic acid hydrogel was synthesized,and RAPA@Lipo was added to the methylallylated hyaluronic acid hydrogel aqueous phase solution.The hydrogel microspheres were prepared by microfluidic equipment.Solid hydrogel microspheres(RAPA@Lipo@MS)were crosslinked under violet light.Primary human chondrocytes were co-cultured with RAPA@Lipo and RAPA@Lipo@MS,respectively.The biocompatibility of the materials was evaluated by CCK-8 assay and live/dead staining.Primary rat chondrocytes were cultured in four groups.Normal control group was cultured for 48 hours.The model group was stimulated with H2O2 for 24 hours to establish senescent cell model.RAPA@Lipo group and RAPA@Lipo@MS group were cultured for 24 hours after establishing senescent cell model with RAPA@Lipo and RAPA@Lipo@MS,respectively.After culture,immunofluorescence was used to observe the expression of p62 and type Ⅱ collagen.RT-PCR was used to detect the mRNA expression of interleukin 6,matrix metalloproteinase 13,type Ⅱ collagen,aggrecan,and ADAMTS-5.RESULTS AND CONCLUSION:(1)The results of CCK-8 assay and live/dead staining showed that RAPA@Lipo and RAPA@Lipo@MS had good biocompatibility.(2)Compared with the normal control group,the protein expression of p62 was increased(P<0.05);the expression of type Ⅱ collagen was decreased(P<0.05),and the mRNA expression levels of interleukin 6,matrix metalloproteinase 13,and ADAMTS-5 were increased(P<0.05);mRNA expression levels of type Ⅱ collagen and aggrecan were decreased(P<0.05)in the model group.Compared with the model group,the expression of p62 protein was decreased(P<0.05);the expression of type Ⅱ collagen was increased(P<0.05),and the mRNA expression levels of interleukin 6,matrix metalloproteinase 13,and ADAMTS-5 were decreased(P<0.05);mRNA expression of type Ⅱ collagen and aggrecan increased(P<0.05)in the RAPA@Lipo@MS group.(3)These findings indicate that RAPA@Lipo@MS can control the quality of cells in vivo by enhancing autophagy,reduce senescent cells in vivo,and locally eliminate senescent cells and senescence-associated secretory phenotype factors in osteoarthritis,thereby slowing the progression of osteoarthritis and creating a cartilage microenvironment that promotes regeneration.

With the establishment of bio-psycho-social medical model,both social and psychological factors play an important role in the occurrence,development and treatment of diseases.Hypertension is a common chronic multiple disease in China,and patients are often complicated with depression and other e-motional disorders.The interaction between hypertension and depression significantly increases the risk of poor prognosis.Current studies have shown a bidirectional promoting relationship between hypertension and depression,and they have some com-mon pathogenesis.However,the specific mechanism of their co-morbidity has not been fully elucidated.Renin-angiotensin sys-tem(RAS)plays an important role in the regulation of hyperten-sion and depression and other emotions.It is composed of two antagonistic pathways.The balance is maintained by angioten-sin-converting enzyme 2(ACE2).Therefore,this article reviews the relationship and mechanism of RAS in hypertension,depres-sion and comorbid states,in order to provide new treatment ide-as for hypertension and depression.

With the establishment of bio-psycho-social medical model,both social and psychological factors play an important role in the occurrence,development and treatment of diseases.Hypertension is a common chronic multiple disease in China,and patients are often complicated with depression and other e-motional disorders.The interaction between hypertension and depression significantly increases the risk of poor prognosis.Current studies have shown a bidirectional promoting relationship between hypertension and depression,and they have some com-mon pathogenesis.However,the specific mechanism of their co-morbidity has not been fully elucidated.Renin-angiotensin sys-tem(RAS)plays an important role in the regulation of hyperten-sion and depression and other emotions.It is composed of two antagonistic pathways.The balance is maintained by angioten-sin-converting enzyme 2(ACE2).Therefore,this article reviews the relationship and mechanism of RAS in hypertension,depres-sion and comorbid states,in order to provide new treatment ide-as for hypertension and depression.

Objective:To investigate the impact of plasmapheresis therapy on the clinical efficacy in predicted severe hypertriglyceridemia-associated acute pancreatitis (HTG-AP) patients.Methods:The clinical data of 500 HTG-AP patients admitted to 36 medical centers across China in the Chinese Acute Pancreatitis Clinical Trials Group-PERFORM database from November 2020 to June 2023 were retrospectively analyzed. Besides the inclusion and exclusion criteria from PERFORM study, patients who had acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score ≥8 or CRP>150 mg/L on admission were included in the final analyses ( n=189). Patients were categorized into the plasmapheresis group ( n=51) and the routine treatment group ( n=138) according to the triglyceride-lowering therapies they received. General data, laboratory findings, AP severity, and clinical outcomes were recorded. Results:Patients undergoing plasmapheresis had higher initial triglyceride levels, APACHEⅡ score, SOFA score, and more organ failure than those receiving routine medical treatment. Results of multivariable logistic regression models showed that the plasmapheresis group, as compared to the routine treatment group, was neither associated with decreased risk of persistent organ failure within 14 days [54.9% (28/51) vs 37.7% (52/138), OR=0.89, 95% CI 0.36-2.21, P=0.810], nor with reduced incidence of organ failure on day 7 [17.7% (9/51) vs 15.9% (22/138), OR=0.60, 95% CI 0.19-1.88, P=0.378]. There was no significant difference on the dynamic changes of serum triglyceride within the first three days of admission ( P=0.108). Conclusions:Early plasmapheresis is not associated with reduced incidence of persistent organ failure in predicted severe HTG-AP patients.

Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to pyruvate kinase M2 (PKM2)-dependent conventional caspase-3/gasdermin E (GSDME) cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-programmed death-1 (anti-PD-1). In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.
Pyroptosis/immunology* ; Humans ; Endoplasmic Reticulum/immunology* ; Animals ; Nogo Proteins/antagonists & inhibitors* ; Mice ; Cell Line, Tumor ; Xanthones/pharmacology* ; Neoplasms/pathology* ; Mice, Nude

Objective:To explore the short-term clinical effects of deep cervical lymph node-venous anastomosis in the treatment of Alzheimer’s disease (AD).Methods:A prospective exploratory study was conducted on the treatment of AD patients using the cervical deep lymph node-venous anastomosis technique in Scar and Wound Treatment Department, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, from September to October 2024. The patients underwent high-frequency ultrasound to locate deep cervical lymph nodes and the external jugular vein. Under general anesthesia, bilateral deep cervical lymph node-venous anastomoses were performed. Indocyanine green (ICG) lymphography was conducted via subcutaneous injection behind the ear to visualize lymph nodes in levels Ⅱ and Ⅲ. After making a skin incision along the posterior margin of the sternocleidomastoid muscle, the external jugular vein, internal jugular veins, and associated lymph nodes were exposed. Adjacent veins were selected for anastomosis of lymph node. Using microsurgical techniques, end-to-side or end-to-end anastomosis was completed for lymph nodes in levels Ⅱ and Ⅲ. Preoperative assessments included the mini-mental state examination (MMSE, a higher score indicates better cognitive function), Alzheimer’s disease assessment scale-cognitive subscale (ADAS-Cog, a higher score indicates greater impairment of cognitive function), Alzheimer’s disease cooperative study scale for activities of daily living (ADCS-ADL, a higher score indicates better ability to perform daily activity), and neuropsychiatric inventory (NPI, a higher score indicates more severe behavioral and emotional symptom). Postoperative follow-up included the same scales to observe changes in cognitive function, activities of daily living, and emotional communication.Results:Four patients (1 male, 3 females, aged 58-79 years) with AD were included. All were diagnosed based on cerebrospinal fluid biomarkers. All patients successfully underwent bilateral deep cervical lymph node-venous anastomoses. On average, 4.3 (2-7 per person) anastomoses were performed per patient. Surgical procedures lasted an average of 6.5 h (5.5-8.5 h) with minimal blood loss (less than 50 ml). Patients resumed normal activity within 6 hours postoperatively and were discharged after an average of 4.1 d (3.5-5.0 d). Postoperative complications included one case each of aspiration pneumonia, lower limb venous thrombosis, and transient delirium, all of whom resolved without long-term effects. Clinical symptoms, including memory decline, mood swings, and anxiety, showed varying degrees of improvement. Patients reported enhanced quality of life, emotional stability, and social engagement, confirming the procedure’s safety and potential cognitive benefits. At one month postoperatively, the MMSE scores of the four patients increased by an average of 0.8 points compared to preoperative levels. Additionally, the two patients who completed the ADAS-Cog assessments showed a decrease in their scores (reduced by 1.0 points and 11.3 points, respectively, compared to preoperative scores), indicating a certain degree of improvement in cognitive function during this period. The ADCS-ADL and NPI scores of four patients varied significantly, without showing any clear pattern.Conclusion:Lymphovenous anastomosis of the deep cervical lymph node-venous anastomosis may provide a new surgical intervention approach for AD, but further large-scale studies and long-term follow-up are needed to validate its safety and effectiveness.

OBJECTIVE: The relationship between fish consumption and stroke is inconsistent, and it is uncertain whether this association varies across predicted stroke risks. METHODS: A cohort study comprising 95,800 participants from the Prediction for Atherosclerotic Cardiovascular Disease Risk in China project was conducted. A standardized questionnaire was used to collect data on fish consumption. Participants were stratified into low- and moderate-to-high-risk categories based on their 10-year stroke risk prediction scores. Hazard ratios ( HRs) and 95% confidence intervals ( CIs) were estimated using Cox proportional hazard models and additive interaction by relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). RESULTS: During 703,869 person-years of follow-up, 2,773 incident stroke events were identified. Higher fish consumption was associated with a lower risk of stroke, particularly among moderate-to-high-risk individuals ( HR = 0.53, 95% CI: 0.47-0.60) than among low-risk individuals ( HR = 0.64, 95% CI: 0.49-0.85). A significant additive interaction between fish consumption and predicted stroke risk was observed (RERI = 4.08, 95% CI: 2.80-5.36; SI = 1.64, 95% CI: 1.42-1.89; AP = 0.36, 95% CI: 0.28-0.43). CONCLUSION Higher fish consumption was associated with a lower risk of stroke, and this beneficial association was more pronounced in individuals with moderate-to-high stroke risk.
Humans ; China/epidemiology* ; Male ; Female ; Stroke/etiology* ; Middle Aged ; Prospective Studies ; Incidence ; Aged ; Animals ; Fishes ; Risk Factors ; Diet ; Seafood ; Adult ; Cohort Studies