Ferrostatin-1 inhibits ferroptosis of vascular smooth muscle cells and alleviates abdominal aortic aneurysm formation through activating the SLC7A11/GPX4 axis.

Ferroptosis, a type of iron-catalyzed necrosis, is responsible for vascular smooth muscle cell (VSMC) death and serves as a potential therapeutic target for alleviating aortic aneurysm. Here, our study explored the underlying mechanism of ferroptosis affecting VSMC functions and the resultant formation of AAA using its inhibitor Ferrostatin-1 (Fer-1). Microarray-based gene expression profiling was employed to identify differentially expressed genes related to AAA and ferroptosis. An AAA model was established by angiotensin II (Ang II) induction in apolipoprotein E-knockout (ApoE-/- ) mice, followed by injection of Fer-1 and RSL-3 (ferroptosis inducer). Then, the role of Fer-1 and RSL-3 in the ferroptosis of VSMCs and AAA formation was analyzed in Ang II-induced mice. Primary mouse VSMCs were cultured in vitro and treated with Ang II, Fer-1, sh-SLC7A11, or sh-GPX4 to assess the effect of Fer-1 via the SLC7A11/GPX axis. Bioinformatics analysis revealed that GPX4 was involved in the fibrosis formation of AAA, and there was an interaction between SLC7A11 and GPX4. In vitro assays showed that Fer-1 alleviated Ang II-induced ferroptosis of VSMCs and retard the consequent AAA formation. The mechanism was associated with activation of the SLC7A11/GPX4 pathway. Silencing of SLC7A11 or GPX4 could inhibit the ameliorating effect of Fer-1 on the ferroptosis of VSMCs. In vivo animal studies further demonstrated that Fer-1 inhibited Ang II-induced ferroptosis and vessel wall structural abnormalities in AAA mouse through activation of the SLC7A11/GPX4 pathway. Fer-1 may prevent AAA formation through activation of the SLC7A11/GPX4 pathway.

Neuraxial versus general anesthesia for perioperative outcomes and resource utilization following knee arthroplasty: experience from a large national database.

INTRODUCTION: Attentions have been paid to the optimal anesthesia for knee arthroplasty (KA). We sought to investigate whether neuraxial anesthesia (NA) is superior to general anesthesia (GA) in terms of perioperative outcomes and resource utilization following KA. METHODS: Patients undergoing primary KA registered in the Hospital Quality Monitoring System (HQMS) in China during 2013-2019 were identified. By utilizing a time-stratified propensity score matching, every patient receiving NA was matched by propensity score to a patient receiving GA. Then, we conducted Poisson, logistic, and linear regression to compare NA with GA in terms of perioperative outcomes and resource utilization. RESULTS: Of 109,132 included participants, 75,945 (69.59%) underwent KA with GA and 33,187 (30.41%) with NA. After propensity score matching (26,425 participants per group), NA was associated with lower incidence of blood transfusion (OR: 0.82, 95% CI 0.77-0.87; p < 0.0001), 30-day readmission (OR: 0.76, 95% CI 0.68-0.84; p < 0.0001), and 90-day readmission (OR: 0.83, 95% CI 0.77-0.90; p < 0.0001). No statistically significant difference in in-hospital mortality, incidence of pulmonary embolism, deep vein thrombosis, and surgical site infection was found. In addition, NA was associated with a 1% decrease in length of stay (95% CI 0-2%; p = 0.0070) and a 3% lower total hospital charge (95% CI 2-4%; p < 0.0001) when compared with GA. CONCLUSION: Compared with GA, NA was associated with decreased incidence of blood transfusion, readmission, reduced length of stay, and total hospital charge following KA, suggesting the favorable role of NA for perioperative outcomes and resource utilization in KA.

Minocycline Relieves Depressive-Like Behaviors in Rats With Bone Cancer Pain by Inhibiting Microglia Activation in Hippocampus.

BACKGROUND: Pain and depression are highly prevalent symptoms in cancer patients. They tend to occur simultaneously and affect each other and share biological pathways and neurotransmitters. In this study, we investigated the roles of microglia in the hippocampus in the comorbidity of bone cancer pain and depressive-like behaviors in an animal model of bone cancer pain. METHODS: Bone cancer pain was induced by injection of Walker 256 mammary gland carcinoma cells into the tibia of rats. The effects of intracerebroventricular administration of microglia inhibitor minocycline were examined. RESULTS: Carcinoma intratibia injection caused comorbidity of mechanical allodynia and depressive-like behaviors in rats and activation of microglia in the hippocampus. Both mechanical allodynia and depressive-like behaviors were attenuated by minocycline. Enzyme-linked immunosorbent assay analysis showed that the enhanced expressions of M1 microglia marker (CD 86) and the proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß in the hippocampus of cancer-bearing rats were decreased by minocycline. On the other hand, minocycline also increased the expressions of M2 microglia marker (MRC1) and anti-inflammatory cytokine interleukin-10. CONCLUSIONS: The results suggest that the activation of microglia in the hippocampus plays an important role in the development of pain and depressive-like behaviors in bone cancer condition.

[Cross-sectional association between dietary zinc intake and phalangeal osteoporosis].

OBJECTIVE: To examine the association between dietary zinc intake and phalangeal osteoporosis.
 Methods: The subjects of this study were members aged over 40 years or above of the general population who had undergone routine health examinations at Xiangya Hospital, Central South University in Changsha, Hunan, China, between October 2013 and December 2015. Dietary zinc intake was measured using the semi-quantitative food frequency questionnaire. Phalangeal osteoporosis was diagnosed according to the WHO criteria based on the assessment of bone mineral density. According to the quartile distribution, serum zinc concentrations were classified into categories: Q1≤15.40 mg/d, Q2 15.41-18.67 mg/d, Q3 18.68-22.76 mg/d, and Q4≥22.77 mg/d. The association between dietary zinc intake with phalangeal osteoporosis was evaluated by conducting multivariable adjusted logistic regression. The dose-response relationship between them was assessed by restricted cubic spline regression.
 Results: A total of 6 267 subjects were included, 602 (9.6%) among them were suffered from phalangeal osteoporosis. The multivariable-adjusted models (i.e. Model 2 and 3) showed that, compared with the lowest quartile, the odds ratios (ORs) for phalangeal osteoporosis were lower in the second, third and fourth quartiles of dietary zinc intake (Model 2: P for trend = 0.045; Model 3: P for trend = 0.031) in the total population; the ORs for phalangeal osteoporosis were lower in the third and fourth quartiles of dietary zinc intake (Model 2 and 3: P for trend = 0.018) in the male population; and the ORs for phalangeal osteoporosis were lower in the second, third and fourth dietary zinc intake quartiles (Model 2: P for trend = 0.227; Model 3: P for trend = 0.217) in the female population. There also existed dose-response relationship between dietary zinc intake and the prevalence of phalangeal osteoporosis (P<0.001).
 Conclusion: Dietary zinc intake is negatively associated with phalangeal osteoporosis in the total population and male subgroup, but not female subgroup.

[Association between serum copper concentration and hypertension in knee osteoarthritis patients].

OBJECTIVE: To examine the association between serum copper concentration and the prevalence of hypertension in patients with knee osteoarthritis (OA).
 Methods: A total of 935 patients who were aged ≥40 years and underwent routine checkups from October 2013 to November 2014 at the Health Management Center of Xiangya Hospital, Central South University were included. They were diagnosed as knee OA by weight-bearing bilateral anteroposterior radiography. Serum copper concentration was measured using the chemiluminescence method. Blood pressure was measured by an electronic sphygmomanometer. The association between serum copper concentration and hypertension was evaluated by conducting multivariable adjusted logistic regression.
 Results: Compared with the lowest quintile, the multivariable-adjusted odds ratio (OR) and related 95% confidence interval (95% CI) of hypertension were 1.46 (95% CI 1.02 to 2.09, P for trend=0.035) and 1.47 (95% CI 0.77 to 2.78, P for trend=0.032) in the total population and female subgroup of the highestest quintile, respectively. There was no significant association between serum copper and hypertension in male subgroup among OA patients (OR=1.21, 95% CI 0.76 to 1.93, P for trend=0.354).
 Conclusion: The serum copper concentration was significantly associated with the prevalence of hypertension in total population and female subgroup, but may not in male subgroup among patients with knee OA.

Ketamine induces hippocampal apoptosis through a mechanism associated with the caspase-1 dependent pyroptosis.

Ketamine, a pediatric anesthetic, is widely used in clinical practice. There was growing evidence showing that ketamine can promote neuronal death in developing brains of both humans and animals. In this study, we used in vivo neonatal and juvenile mouse models to induce ketamine-related neurotoxicity in the hippocampus. Active caspase-3 and -9 proteins, which are responsible for the release of cytochrome C, and the mitochondrial translocation of p53, which is associated with mitochondrial apoptosis, were found to be significantly up-regulated in the ketamine-induced hippocampal neurotoxicity. Furthermore, we demonstrated that the levels of pyroptosis-related proteins, including caspase-1 and -11, NOD-like receptor family, pyrin domain containing 3 (NLRP3), and IL-1ß and IL-18, significantly increased after multiple doses of ketamine administration. We speculated that ketamine triggered the formation of NLRP3 and caspase-1 complex and its translocation to the mitochondria. In consistent with this, ketamine treatment was found to induce pyroptosis in mouse primary hippocampal neurons, which was characterized by increased pore formation and elevated lactate dehydrogenase release in mitochondria. Silencing caspase-1 with lentivirus-mediated short hairpin RNA (shRNA) significantly decreased the levels of not only pyroptosis-related proteins but also mitochondrial apoptosis-associated proteins in mouse primary hippocampal neurons. We conclude that caspase-1-dependent pyroptosis is an important event which may be an essential pathway involved in the mitochondria-associated apoptosis in ketamine-induced hippocampal neurotoxicity.

[Effect of cerebral state index as a measure of depth of sedation during target controlled infusion of propofol in patients of different ages].

OBJECTIVE: To investigate the effect of cerebral state index (CSI) in measuring the level of sedation during target controlled infusion (TCI) of propofol in patients of different ages. METHODS: Forty ASA class I-II patients undergoing general anesthesia were divided into group A (65 to 79 years old, n=20) and group B (20 to 55 years, n=20). The sedation level was assessed using OAA/S scale. Anesthesia was induced with TCI of propofol. The target effect-site concentration (CE) was set initially at 0.5 µg/ml followed by increments of 0.5 µg/ml every 5 min until 5 min after the patients lost consciousness and did not respond to pain stimulation (OAA/S=0). OAA/S score was recorded every 20 s, and MAP, HR, SPO(2) and CSI were recorded. Spearman correlation coefficient between OAA/S score and CSI and their prediction probabilities (Pk) were calculated. The values of CE(05), CE(50), CE(95) and CSI(05), CSI(50), CSI(95) at loss of verbal contact (LVC) (OAA/S=2) and loss of consciousness (LOC) (OAA/s≤1) were also calculated. RESULTS: CSI was well correlated to the sedation depth. The values of CE(50) and CSI50 were 1.3 µg/ml and 69.7 at LVC in group A, and were 1.8 µg/ml and 65.9 at LVC in group B, respectively. The values of CE(50) and CSI(50) were 1.5 µg/ml and 64.3 at LOC in group A, as compared to 2.5 µg/ml and 54.8 at LOC in group B, respectively. When the OAA/S scale was lower than 3, the CSI values in group A were significantly higher than those in group B (P<0.05). CONCLUSION: CSI can effectively and rapidly distinguish the level of sedation in different age groups. At the same OAA/S scale, the target effect-site concentration in the elderly is obviously lower than that in the young patients, but CSI values were significantly higher in the elderly than in the young patients during TCI of propofol.

[Three subanaesthetic dose ketamines mixed with butorphanol in the postoperative continuous intravenous analgesia].

OBJECTIVE: To determine an optimal clinical dose of ketamine after comparing the efficacy and security of 3 low dose ketamines mixed with butorphanol in the postoperative continuous intravenous analgesia. METHODS: Eighty ASA (American Society of Anesthesiologists) I-II patients scheduled for elective gynecological surgery under general anesthesia were divided randomly into 4 groups (n=20): Group B received butorphanol 3 microg/(kg x h);Group BK1 received butorphanol 2 microg/(kg x h) mixed with ketamine 60 microg/(kg x h); Group BK2 received butorphanol 2 microg/(kg x h) mixed with ketamine 90 microg/(kg.h); and Group BK3 received butorphanol 2 microg/(kg x h) mixed with ketamine 120 microg/(kg x h). Continuous intravenous infusion pump was used when the patients had obvious pain (visual analgesia scale of five), and the bolus infusion (4 mL) was given before the operation, and continuous infusion at 2 mL/h. In the postoperative period, pain was assessed using visual analogue scale (VAS) at 2,6,12,24, and 48 h.At the same time, Ramsay scores and adverse effects were recorded. RESULTS: There was no significant difference in the adverse effects and the postoperative mean arterial pressure, heart rate, respiratory rate values, and pulse oxygen among the 4 groups. Postoperative VAS values in Group BK3 was the lowest, followed by Group BK2. There was no significant difference between Group BK1 and Group B. The incidence of somnolence in Group B was higher than that in Group BK1, BK2 and BK3(P<0.05). CONCLUSION: Ketamine in subanaesthetic dose added to butorphanol for postoperative continuous intravenous infusion has a better postoperative analgesic effect and sedation. It can effectively spare butorphanol consumption without increasing adverse effects. The optimal combined dose is 90-120 microg/(kg x h).