Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.

Objective:To evaluate the clinical efficacy of a novel surgical approach of debridement, antibiotics, and implant retention (DAIR) with flap transfer, for treating chronic implant infections in bone tumor patients.Methods:A retrospective review was conducted on nine consecutive patients [6 males, 3 females; median age 35(27, 51) years, range 9-71] who underwent a modified procedure of DAIR plus flap transfer between November 2022 and January 2024. The cohort included six cases of chronic periprosthetic joint infection and three cases of chronic plate and screw infection. Tumor diagnoses included seven primary malignant tumors (osteosarcoma=5, undifferentiated pleomorphic sarcoma of bone=1, synovial sarcoma=1) and two bone metastasis of renal cell carcinoma. The procedure involved wide, radical debridement, meticulous removal of biofilm from implants and surrounding soft tissue, followed by the transfer of a well vascularized musculocutaneous flap to fully envelope the contaminated interface. Pre-operative clinicopathological data, surgical details, postoperative complications and infection recurrence were analyzed.Results:The median interval between initial implantation and debridement was 10.0(3.3, 14.8) months. Median follow-up after debridement was 15.9(15.4, 18.2) months. All nine surgeries were completed as planned: six musculocutaneous flaps, two fasciocutaneous flaps and one muscle-only flap. Implants were preserved in six patients; two required subsequent removal for recurrent infection, and one patient later underwent amputation for tumor recurrence. Infection-free implant survival at 3, 6 and 12 months was 88.9%, 87.5% and 87.5%, respectively. Major complications included one donor-site hematoma, one donor-site sensory deficit and one wound healing delay. All the complications were well management. Both reinfections occurred in proximal tibial prostheses, likely due to limited flap coverage options and local anatomical constraints.Conclusion:Although reinfections happened in two cases DAIR with flap transfer provides promising short-term infection control in patients with chronic implant-associated infections following bone tumor surgery.

Objective:To evaluate the clinical efficacy of a novel surgical approach of debridement, antibiotics, and implant retention (DAIR) with flap transfer, for treating chronic implant infections in bone tumor patients.Methods:A retrospective review was conducted on nine consecutive patients [6 males, 3 females; median age 35(27, 51) years, range 9-71] who underwent a modified procedure of DAIR plus flap transfer between November 2022 and January 2024. The cohort included six cases of chronic periprosthetic joint infection and three cases of chronic plate and screw infection. Tumor diagnoses included seven primary malignant tumors (osteosarcoma=5, undifferentiated pleomorphic sarcoma of bone=1, synovial sarcoma=1) and two bone metastasis of renal cell carcinoma. The procedure involved wide, radical debridement, meticulous removal of biofilm from implants and surrounding soft tissue, followed by the transfer of a well vascularized musculocutaneous flap to fully envelope the contaminated interface. Pre-operative clinicopathological data, surgical details, postoperative complications and infection recurrence were analyzed.Results:The median interval between initial implantation and debridement was 10.0(3.3, 14.8) months. Median follow-up after debridement was 15.9(15.4, 18.2) months. All nine surgeries were completed as planned: six musculocutaneous flaps, two fasciocutaneous flaps and one muscle-only flap. Implants were preserved in six patients; two required subsequent removal for recurrent infection, and one patient later underwent amputation for tumor recurrence. Infection-free implant survival at 3, 6 and 12 months was 88.9%, 87.5% and 87.5%, respectively. Major complications included one donor-site hematoma, one donor-site sensory deficit and one wound healing delay. All the complications were well management. Both reinfections occurred in proximal tibial prostheses, likely due to limited flap coverage options and local anatomical constraints.Conclusion:Although reinfections happened in two cases DAIR with flap transfer provides promising short-term infection control in patients with chronic implant-associated infections following bone tumor surgery.

Objective·To investigate the effect of early postoperative administration of zoledronic acid on fracture healing and functional recovery in elderly patients with osteoporotic femoral intertrochanteric fracture treated with proximal femoral nail antirotation(PFNA)surgery,and explore other potential prognostic factors.Methods·A total of 174 patients with femoral intertrochanteric fractures of 80 years old or above who underwent PFNA treatment in Ruijin Hospital,Shanghai Jiao Tong University School of Medicine from January,2016 to February,2022,were divided into experimental group(n=26)and control group(n=148)according to whether they received zoledronic acid early after surgery.All patients were followed up twice at 6 weeks and 12 weeks after surgery.The patients in the experimental group were matched with the control group by propensity score matching(PSM)at a ratio of 1:3(the matching factors included age,gender,fracture type,and body mass index).General characteristics,as well as fracture healing and functional recovery at the two follow-up visits were compared between the two groups after matching.Subsequently,Logistic regression was used to explore the potential prognostic factors on fracture healing at 12 weeks after surgery.Results·PSM resulted in 25 patients in the experimental group and 65 patients in the control group,and there were no statistically significant differences in baseline characteristics between the two groups.The fracture healing rates at 6 weeks and 12 weeks after surgery in the experimental group(16.0%and 96.0%,respectively)were higher than those in the control group(1.5%and 73.8%),and the differences were statistically significant(P<0.05).Harris hip function score in the experimental group at 12 weeks was significantly higher than that of the control group(P=0.019).The results of Logistic regression analysis showed that good surgical reduction(OR=12.52,95%CI 2.67?58.74,P=0.001),early postoperative administration of zoledronic acid(OR=10.14,95%CI 1.01?102.09,P=0.049),and higher serum albumin level(OR=1.15,95%CI 1.02?1.29,P=0.025)were the favorable factors of early fracture healing,while unstable fracture(OR=0.10,95%CI 0.03?0.31,P=0.000)was the unfavorable factor.Conclusion·For elderly patients with osteoporotic intertrochanteric femoral fractures treated with PFNA surgery,early postoperative administration of zoledronic acid can promote fracture healing and lead to better functional recovery;in addition,good surgical reduction and higher serum albumin levels are favorable factors for fracture healing,whereas unstable fracture presents as a hindrance to the healing process.

Metabolic disorders are observed in women after menopause, and the postmenopausal women suffering from chronic liver diseases have an increased risk of progression to liver fibrosis, with a higher risk than male patients of the same age, which may be associated with the decline of ovarian function and the reduction of estrogen level after menopause. This article summarizes the research advances in the molecular mechanism of progression to liver fibrosis from the aspects of estrogen and oxidative stress, activation of hepatic stellate cells, accumulation of extracellular matrix, and immune regulation. It is pointed out supplementation with an appropriate amount of estrogen in the perimenopausal period and the early menopausal period can reduce the risk of liver fibrosis and delay or even reverse the process of liver fibrosis, thereby improving quality of life and prolonging survival time in elderly female patients.

Objective:To evaluate the relationship between phosphorylation of Tau protein and apolipoprotein E (ApoE) containing 18 kDa fragments and investigate the mechanism of neuronal damage induced by sevoflurane.Methods:Primary neurons (ApoE3 and ApoE2 genotypes, 24 dishes for each genotype) of fetal mice cultured until the 5th day were divided into 4 groups ( n=12 each) using a random number table method: ApoE3 control group (A3C group), ApoE3 sevoflurane group (A3S group), ApoE2 control group (A2C group) and ApoE2 sevoflurane group (A2S group). Neurons were treated with 21% oxygen + 5% carbon dioxide + 4.1% sevoflurane for 4 h in A3S and A2S groups, while the neurons were only treated with 21% oxygen + 5% carbon dioxide in A3C and A2C groups.The cell proteins were then extracted to detect the expression of full-length ApoE and ApoE, AT8 and PHF1 containing 18 kDa fragments (by Western blot), expression of ApoE mRNA (by real-time polymerase chain reaction), and concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in the supernatant (by enzyme-linked immunosorbent assay). Results:Compared with A2C group, the expression of ApoE mRNA and full-length ApoE in neurons was up-regulated ( P<0.05), and no significant change was found in the expression of AT8 and PHF1 and concentrations of TNF-α and IL-6 in the supernatant in A2S group ( P>0.05). Compared with A3C group, the expression of ApoE mRNA, full-length ApoE, and ApoE, AT8 and PHF1 containing 18 kDa fragments was up-regulated, and the concentrations of TNF-α and IL-6 in the supernatant were increased in A3S group ( P<0.05). Conclusion:Sevoflurane may promote phosphorylation of Tau proteins and increase inflammatory responses through up-regulating the expression of ApoE containing 18 kDa fragments, thus leading to neuronal damage.

Objective: To evaluate the effect of hydrogen on the mitochondrial function in brain tissues of mice with sepsis-associated encephalopathy (SAE). Methods: Two hundred and sixty-eight healthy male C57 mice, aged 6 weeks, weighing 20-25 g, were divided into 4 groups (n=67 each) using a random number table method: sham operation group (group SH), sham operation plus hydrogen gas group (group SH+ H₂), group SAE, and SAE plus hydrogen gas group (group SAE+ H₂). Sepsis was produced by cecal ligation and puncture in anesthetized mice.The mice in group SH+ H₂ and group SAE+ H₂ inhaled 2% hydrogen gas for 1 h starting from 1 and 6 h after operation, respectively.The postoperative 7-day survival rate was recorded.Brain tissues were obtained at 24 h after operation to count the normal neurons in hippocampal CA1 region.At 6, 12 and 24 h after operation, hippocampal mitochondria were isolated for determination of mitochondrial membrane potential (MMP) by fluorescence spectrophotometry and ATP content by a bioluminescence assay.Y-maze (spontaneous alternation) test was performed at days 3, 5 and 7 after operation. Results: Compared with group SH, the 7-day survival rate was significantly decreased, the number of normal neurons in hippocampal CA1 region, MMP, mitochondrial ATP content and spontaneous alternation percentage in Y-maze test were significantly decreased in group SAE and group SAE+ H₂ (P<0.05). Compared with group SAE, the 7-day survival rate, the number of normal neurons in hippocampal CA1 region, MMP, mitochondrial ATP content and spontaneous alternation percentage in Y-maze test were significantly increased in group SAE+ H₂ (P<0.05). Conclusion The mechanism by which hydrogen reduces SAE is probably associated with improving mitochondrial function in brain tissues of mice.

Objective: To evaluate the effect of hydrogen on mitochondrial biosynthesis in the hippocampus of mice with sepsis-associated encephalopathy (SAE). Method: Two hundred and twenty-four healthy clean-grade male C57BL/6J mice, aged 6-8 weeks, weighing 20-25 g, were divided into 4 groups (n=56 each) using a random number table method: sham operation group (group SH), sham operation plus hydrogen group (group SH+ H₂), group SAE, and SAE plus hydrogen group (group SAE+ H₂). The model of SAE was established by cecal ligation and puncture in anesthetized mice.Group SH+ H₂ and group SAE+ H₂ inhaled 2% hydrogen for 1 h starting from 1 and 6 h after operation, respectively.Twenty mice were selectde to record the postoperative 7-day survival rate.The remaining animals were sacrificed at 24 h after operation, and brain tissues were taken for examination of the pathological changes in hippocampal CA1 region (with a light microscope) and for determination of neuronal apoptosis (by TUNEL), mitochondrial membrane potential (MMP) (by fluorescence spectrophotometry) and ATP content (by a bioluminescence assay). The apoptosis rate was calculated.The expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) in hippocampus was determined by Western blot at 6, 12 and 24 h after operation. Results: Compared with group SH, the postoperative 7-day survival rate was significantly decreased, the apoptosis rate of hippocampal neurons was increased, the contents of MMP and ATP were decreased, and the expression of PGC-1α was up-regulated in SAE and SAE+ H₂groups (P<0.05), and no significant change was found in the parameters mentioned above in group SH+ H₂(P>0.05). Compared with group SAE, the postoperative 7-day survival rate was significantly increased, and the apoptosis rate of hippocampal neurons was decreased, the contents of MMP and ATP were increased, and the expression of PGC-1α was up-regulated (P<0.05), and the pathological changes of hippocampal tissues were significantly attenuated in group SAE+ H₂. Conclusion The mechanism by which hydrogen mitigates SAE may be related to promoting mitochondrial biosynthesis in mice.

Objective To evaluate the effect of hydrogen on the mitochondrial function in brain tis-sues of mice with sepsis-associated encephalopathy(SAE).Methods Two hundred and sixty-eight healthy male C57 mice,aged 6 weeks,weighing 20-25 g,were divided into 4 groups(n＝67 each)using a ran-dom number table method: sham operation group(group SH),sham operation plus hydrogen gas group(group SH+H2),group SAE,and SAE plus hydrogen gas group(group SAE+H2).Sepsis was produced by cecal ligation and puncture in anesthetized mice.The mice in group SH+H2 and group SAE+H2 inhaled 2％hydrogen gas for 1 h starting from 1 and 6 h after operation,respectively.The postoperative 7-day sur-vival rate was recorded.Brain tissues were obtained at 24 h after operation to count the normal neurons in hippocampal CA1 region.At 6,12 and 24 h after operation,hippocampal mitochondria were isolated for determination of mitochondrial membrane potential(MMP)by fluorescence spectrophotometry and ATP con-tent by a bioluminescence assay.Y-maze(spontaneous alternation)test was performed at days 3,5 and 7 after operation.Results Compared with group SH,the 7-day survival rate was significantly decreased,the number of normal neurons in hippocampal CA1 region,MMP,mitochondrial ATP content and sponta-neous alternation percentage in Y-maze test were significantly decreased in group SAE and group SAE+H2(P＜0.05).Compared with group SAE,the 7-day survival rate,the number of normal neurons in hipp-ocampal CA1 region,MMP,mitochondrial ATP content and spontaneous alternation percentage in Y-maze test were significantly increased in group SAE+H2(P＜0.05).Conclusion The mechanism by which hy-drogen reduces SAE is probably associated with improving mitochondrial function in brain tissues of mice.

Objective To evaluate the effect of hydrogen on the expression of matrix metalloproteinase-9 (MMP-9) in brain tissues of mice with sepsis-associated encephalopathy (SAE).Methods A total of 212 clean-grade healthy male C57BL/6J mice,aged 6-8 weeks,weighing 20-25 g,were divided into 4 groups (n =53 each) using a random number table method:sham operation group (group Sham),sham operation plus hydrogen group (group Sham+H2),group SAE and SAE plus hydrogen group (group SAE+ H2).The sepsis model was established by intraperitoneally injecting human fecal suspension.Sham+H2 and SAE+H2 groups inhaled 2％ hydrogen for 1 h at 1 and 6 h after establishing the model,respectively.Postoperative 14-day survival rate was recorded.Evans blue (EB) was injected into the tail vein at 24 h after establishing the model,and the content of EB in brain tissues was calculated.Brain tissues were taken for determination of brain water content.The expression of tumor necrosis factor-alpha (TNF-α),interleukin-6 (IL-6) and high-mobility group box 1 protein (HMGB1) in hippocampal tissues was detected by enzymelinked immunosorbent assay.The expression of MMP-9 and ZO-1 protein and mRNA in hippocampal tissues was determined by Western blot and real-time polymerase chain reaction,respectively,at 6,12 and 24 h after establishing the model.Results Compared with Sham group,the 14-day survival rate was significantly decreased,the EB content in brain tissues,brain water content,and contents of TNF-α,IL-6 and HMGB1 were significantly increased,the expression of MMP-9 protein and mRNA was up-regulated,and the expression of ZO-1 protein and mRNA was down-regulated in SAE and SAE+H2 groups (P＜0.05),and no significant change was found in the parameters mentioned above in group Sham+H2 (P＞0.05).Compared with group SAE,the 14-day survival rate was significantly increased,the EB content in brain tissues,brain water content,and contents of TNF-α,IL-6 and HMGB1 were significantly decreased,the expression of MMP-9 protein and mRNA was down-regulated,and the expression of ZO-1 protein and mRNA was up-regulated in group SAE+H2 (P＜0.05).Conclusion The mechanism by which hydrogen attenuates the blood-brain barrier damage may be related to inhibiting MMP-9 expression and to reducing inflammatory responses in brain tissues of SAE mice.