Recent progress in neonatal hyperoxic lung injury.

With the progress in neonatal intensive care, there has been an increase in the survival rates of premature infants. However, this has also led to an increased incidence of neonatal hyperoxia lung injury and bronchopulmonary dysplasia (BPD), whose pathogenesis is believed to be influenced by various prenatal and postnatal factors, although the exact mechanisms remain unclear. Recent studies suggest that multiple mechanisms might be involved in neonatal hyperoxic lung injury and BPD, with sex also possibly playing an important role, and numerous drugs have been proposed and shown promise for improving the treatment outcomes of hyperoxic lung injury. Therefore, this paper aims to analyze and summarize sex differences in neonatal hyperoxic lung injury, potential pathogenesis and treatment progress to provide new ideas for basic and clinical research in this field.

Transcutaneous electrical acupoint stimulation in adult patients receiving gastrectomy/colorectal resection: A randomized controlled trial.

BACKGROUND: Acupuncture promotes the recovery of gastrointestinal function and provides analgesia after major abdominal surgery. The effects of transcutaneous electrical acupoint stimulation (TEAS) remain unclear. AIM: To explore the potential effects of TEAS on the recovery of gastrointestinal function after gastrectomy and colorectal resection. METHODS: Patients scheduled for gastrectomy or colorectal resection were randomized at a 2:3:3:2 ratio to receive: (1) TEAS at maximum tolerable current for 30 min immediately prior to anesthesia induction and for the entire duration of surgery, plus two 30-min daily sessions for 3 consecutive days after surgery (perioperative TEAS group); (2) Preoperative and intraoperative TEAS only; (3) Preoperative and postoperative TEAS only; or (4) Sham stimulation. The primary outcome was the time from the end of surgery to the first bowel sound. RESULTS: In total, 441 patients were randomized; 405 patients (58.4 ± 10.2 years of age; 247 males) received the planned surgery. The time to the first bowel sounds did not differ among the four groups (P = 0.90; log-rank test). On postoperative day 1, the rest pain scores differed significantly among the four groups (P = 0.04; Kruskal-Wallis test). Post hoc comparison using the Bonferroni test showed lower pain scores in the perioperative TEAS group (1.4 ± 1.2) than in the sham stimulation group (1.7 ± 1.1; P = 0.04). Surgical complications did not differ among the four groups. CONCLUSION: TEAS provided analgesic effects in adult patients undergoing major abdominal surgery, and it can be added to clinical practice as a means of accelerating postoperative rehabilitation of these patients.

Recent Progress of Ferroptosis in Lung Diseases.

Ferroptosis is a new form of programmed cell death due to iron-dependent excess accumulation of lipid peroxides and differs from other programmed cell deaths in morphological and biochemical characteristics. The process of ferroptosis is precisely regulated by iron metabolism, lipid metabolism, amino acid metabolism, and numerous signaling pathways, and plays a complex role in many pathophysiological processes. Recent studies have found that ferroptosis is closely associated with the development and progression of many lung diseases, including acute lung injury, pulmonary ischemia-reperfusion injury, lung cancer, chronic obstructive pulmonary disease, and pulmonary fibrosis. Here, we present a review of the main regulatory mechanisms of ferroptosis and its research progress in the pathogenesis and treatment of lung diseases, with the aim of providing new ideas for basic and clinical research of lung-related diseases.

Ferroptosis is Involved in Hyperoxic Lung Injury in Neonatal Rats.

PURPOSE: To evaluate whether ferroptosis is involved in hyperoxic acute lung injury (HALI) and its mechanisms through the HALI model. METHODS: HE staining was used to assess lung injury pathology after the establishment of neonatal rat HALI model. ELISA was used to detect ROS, GPX4, and GSH expression. Prussian blue staining and Western Blot were used to detect iron deposition and the expression of ferroptosis-related proteins, respectively. RESULTS: The HALI group showed pathological changes with larger and fewer alveoli and thicker alveolar septa after HE staining. Prussian blue staining detected significant iron deposition in the lung tissue of the HALI group. GPX4, GSH, GSS, and SLC7A11 expressions were significantly decreased in the HALI group than in the normal control group. In contrast, ROS, TFRC, FHC, and FLC expressions showed opposite results (p<0.05). CONCLUSION: Ferroptosis may be involved in the pathological process of hyperoxic lung injury in neonatal rats.

Association of Different Lactate Indices with 30-Day and 180-Day Mortality in Patients with ST-Segment Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention: A Retrospective Cohort Study.

BACKGROUND: Admission lactate level has been reported as a useful marker of mortality. In this study, we compared the relative value of different lactate indices to predict survival in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: This was a retrospective observational study including consecutive patients with STEMI undergoing primary PCI who admitted to the Coronary Care Unit of the First Affiliated Hospital of Wenzhou Medical University between 2014 and 2017. The predictive value of lactate indices for mortality was compared using receiver operator characteristic (ROC) analysis, and DeLong's test was used to compare the AUC. We compared the AUC between GRACE score and GRACE score + lactate index. RESULTS: A total of 1080 patients were included. Fifty-nine died in 30 days and 68 died in 180 days. Most lactate indices (Lacadm, Lac24max, Lac24min and Lac24tw) were significantly lower in survivors (all P<0.001). In Cox proportional hazards model, each lactate index showed as an independent factor of 30-day and 180-day mortality except LacΔ. Kaplan-Meier curves demonstrated that the patients of higher lactate indices group had higher rates of mortality (all P<0.0001, except LacΔ P=0.0485). In receiver operator characteristic analysis, Lac24max was significantly larger than Lacadm(P<0.001) while the AUC value for Lacadm was similar to Lac24min and Lac24tw. Lac24tw improved the predictive probability of 30-day mortality (P=0.0415). Lac24max improved the predictive probability of GRACE score for both 30-day and 180-day mortality (P<0.05). CONCLUSION: In patients with STEMI undergoing primary PCI, most lactate indices are all associated with 30-day and 180-day mortality except LacΔ. In prediction of both 30-day and 180-day mortality, Lac24max is superior to Lacadm and significantly enhances the ability of risk stratification and prognostic evaluation when adding Lac24max to the GRACE score.

Electro-Acupuncture on ST36 and SP6 Acupoints Ameliorates Lung Injury via Sciatic Nerve in a Rat Model of Limb Ischemia-Reperfusion.

INTRODUCTION: Electro-acupuncture (EA) can significantly improve inflammatory response, but the specific mechanism is not clear. Limb ischemia-reperfusion (I/R) first produces inflammatory reactions in the lungs. In this study, EA on Zusanli (ST36) and Sanyinjiao (SP6) were used to explore the mechanism of improving tissue inflammation by sciatic nerve disconnection. MATERIAL AND METHODS: A total of 56 male Sprague-Dawley rats were randomly divided into sham group, model group, EA group, SEA group, SNC+EA group, TNC+EA group and PNC+EA group. The sham groups were not given any treatment. Rats in the model group were treated with limb I/R without acupuncture intervention. In the EA group, ST36 and SP6 were given EA treatment for 30min before modeling. No electric current was given in the SEA group, and other operations were the same as those in the EA group. The SNC+EA group, TNC+EA group and PNC+EA group were respectively given sciatic nerve, tibial nerve or peroneal nerve amputation 72h before modeling, and the others were the same as the model group. RESULTS: Compared with the sham group, PaO2 and a/A ratios decreased significantly in the model group (P <0.05), while PA-aO2, RI, the ratio of wet to dry, lung injury value and inflammatory factor TNF-α, IL-1, IL-6, and MPO increased significantly (P <0.05). Compared with the model group, PaO2, a/A ratios increased significantly in the EA group (P <0.05), while PA-aO2, RI, the ratio of wet to dry lung, lung injury value, and TNF-α, IL-1, IL-6, and MPO decreased significantly (P <0.05). After transection of the sciatic nerve, the protective effect of EA disappeared. However, when the peroneal or tibial nerve was severed, EA continued to maintain the protective effect. CONCLUSION: EA on ST36 and SP6 can alleviate lung injury caused by limb I/R through the sciatic nerve.

JNK-IN-8, a c-Jun N-terminal kinase inhibitor, improves functional recovery through suppressing neuroinflammation in ischemic stroke.

C-Jun N-terminal kinase (JNK) is a pivotal MAPK (mitogen-activated protein kinase), which activated by ischemia brain injury and plays a fairly crucial function in cerebral ischemic injury. Emerging studies demonstrated that JNK-IN-8 (a JNK inhibitor with high specificity) regulates traumatic brain injury through controlling neuronal apoptosis and inflammation. However, the function of JNK-IN-8 in ischemic stroke and the mechanisms underlying of JNK-IN-8 about neuroprotection are not well understood. In this work, male rats were treated with JNK-IN-8 after transient middle cerebral artery occlusion, and then the modified improved neurological function score (mNSS), the foot-fault test (FFT), interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) levels were assessed. We found that JNK-IN-8-treated rats with MCAO exerted an observable melioration in space learning as tested by the improved mNSS, and showed sensorimotor functional recovery as measured by the FFT. JNK-IN-8 also played anti-inflammatory roles as indicated through decreased activation of microglia and decreased IL-6, IL-1ß, and TNF-α expression. Furthermore, JNK-IN-8 suppressed the activation of JNK and nuclear factor-κB (NF-κB) signaling as indicated by the decreased level of phosphorylated-JNK and p65. All data demonstrate that JNK-IN-8 inhibits neuroinflammation and improved neurological function by inhibiting JNK/NF-κB and is a promising agent for the prevention of ischemic brain injury.

Integrative analysis of DNA methylation and gene expression to identify key epigenetic genes in glioblastoma.

Glioblastoma (GBM) ranks the most common and aggressive primary brain malignant tumor worldwide. However, the survival rates of patients remain very poor. Therefore, molecular oncology of GBM are urgently needed. In this study, we performed an integrative analysis of DNA methylation and gene expression to identify key epigenetic genes in GBM. The methylation and gene expression of GBM patients in The Cancer Genome Atlas (TCGA) database were downloaded. After data preprocessing, we identified 4,881 differentially expressed genes (DEGs) between tumor and normal samples, including 1,111 upregulated and 3,770 downregulated genes. Then, we randomly separated all samples into training set (n = 69) and testing set (n = 69). We next obtained 11,269 survival-methylation sites by univariate and multivariate Cox regression analyses. In the correlation analysis, we defined 198 low promoter methylation with high gene expression as epigenetically induced (EI) genes and 111 high promoter methylation with low gene expression as epigenetically suppressed (ES) genes. Key markers including C1orf61 and FAM50B were selected with a Pearson correlation coefficient greater than 0.75. Further, we chose the 20 CpG methylation sites of above two genes in unsupervised clustering analysis using the Euclidean distance. We found that the prognosis of the hypomethylated group was significantly better than that in the hypermethylated group (log-rank test p-value = 0.011). Based on the validation in the TCGA testing set and GEO dataset, we validated the prognostic value of our signature (p-value = 0.02 in TCGA and 0.012 in GEO). In conclusion, our findings provided predictive and prognostic value as methylation-based biomarkers for the diagnosis and treatment of GBM.

Ginsenoside Rb1 pretreatment reverses hippocampal changes in BDNF/TrkB mRNA and protein in rats subjected to acute immobilization stress.

PURPOSE: Episodes of acute emotional or physical stress can have significant adverse effects on the hippocampus. Ginsenoside Rb1, the most predominant ginsenoside present in Panax species, has been reported to show a neuroprotective effect. The purpose of this study was to investigate the influence of ginsenoside Rb1 on plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels and hippocampal brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) levels in rats subjected to acute immobilization stress. METHODS: Wistar rats were divided into controls treated with saline only (N), rats exposed to stress only (M), and rats pretreated with Rb1 (40 mg.kg (-1)) thirty minutes prior to stress exposure (R). In the model, animals were restrained in a plastic immobilizer for 2 h of acute immobilization stress at room temperature. ELISA was used to determine plasma levels of CORT and ACTH. The effect of Rb1 pretreatment on the expression of BDNF and TrkB was determined by immunofluorescence, real-time PCR, and Western blotting analysis. RESULTS: The R group showed significantly increased plasma CORT and ACTH levels compared to the N and M groups. Acute stress stimulation suppressed BDNF and TrkB protein and mRNA expression in the hippocampus; otherwise, Rb1 pretreatment reversed the decreases. CONCLUSION: The results from this study demonstrate that Rb1 pretreatment reverses the decreases in hippocampal BDNF/TrkB and increases the plasma levels of CORT and ACTH, indicating a potential neuroprotective effect of Rb1 against acute stress.

Loss of ICA69 potentiates long-lasting hyperalgesia after subcutaneous formalin injection into the mouse hindpaw.

Islet-cell autoantigen 69 kDa (ICA69) plays an important role in many diseases and physiological activities by forming heteromeric complexes with protein interacts with C-kinase 1 (PICK1). PICK1 is critical for inflammatory pain hypersensitivity by regulating trafficking of AMPA receptor subunit GluA2 in spinal neurons. However, the role of ICA69 in inflammatory pain has not yet been investigated. Here we reported that expression of PICK1 in spinal cord was reduced largely in ICA69 knockout mice. The pain hypersensitivity was enhanced in the second phase 7 days after formalin administration. Meanwhile, increased Ser880 phosphorylation in GluA2 and decreased surface GluA2 were concordant with the pain. Furthermore, the number of activated microglia in spinal dorsal horn increased in line with pain hypersensitivity. Together, ICA69 deficiency promoted the internalization of GluA2 and FML-induced long-lasting pain hypersensitivity. In addition, microglia activation might be an important factor in the development of the pain hypersensitivity.

[The role of adenosine deaminase in the electroacupuncture preconditioning induced rapid tolerance to focal cerebral ischemia].

OBJECTIVE: To observe the electroacupuncture (EA) pretreatment at Baihui (GV20) on the concentration of adenosine deaminase (ADA) and adenosine, and to evaluate its effects on the neurologic function score and the infarction volume after middle cerebral artery occlusion (MCAO) ischemia/reperfusion (I/R), thus exploring its mechanisms for relieving the ischemia/reperfusion injury. METHODS: Totally 54 male SD rats were randomly divided into 3 groups, the sham-EA group, the EA group, and the control group, 18 in each group. Rats in the control group were not intervened after anesthesia. Rats in the EA group were needled at Baihui (GV20) for 30 min. Rats in the sham-EA group received the same procedure as those performed in the EA group without electricity connected. The changes of adenosine and ADA contents were detected at 30, 60, and 120 min after EA respectively. The I/R model was established. Totally 48 male SD rats were randomly divided into 6 groups, i.e., the model group (Group A), the EA group (Group B), the EA +8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) group (Group C), the EA + DMSO group (Group D), the Deoxycoformycin (Deo) group (Group E), and the normal saline group (Group F). Rats in Group B, C, and D received EA for 30 min before modeling. Rats in Group C and D were peritoneally injected with DPCPX (1 mg/kg) and DMSO (1 mL/kg) at 30 min before EA. The neurologic function score was evaluated and the infarct volumes were detected after 24-h reperfusion. RESULTS: Compared with the sham-EA group, there was no statistical difference in the contents of the adenosine or ADA in the control group at each time point (P > 0.05). Compared with the control group at the same time point, the content of ADA significantly decreased at 60 min in the EA group [(315.0 +/- 22.9 U/L), P < 0.05], and restored to the normal level at 120 min after EA. The content of adenosine increased in the EA group at 120 min [(20.4 +/- 2.2) ng/microL, P < 0.05]. Compared with the model group, the neurologic function score decreased (P < 0.05) and the infarct volumes were obviously reduced (P < 0.01) in Group B, D and E. There was no statistical difference in the neurologic function score or the infarct volumes in other groups, when compared with the model group (P > 0.05) CONCLUSION: EA at Baihui (GV20) showed protective effects on the cerebral I/R rats, which might be achieved through lowering the ADA concentration and elevating the adenosine content, and further activating adenosine A1 receptor.

[Effects of ginsenoside Rb1 on the mRNA expression of tyrosine kinase B in the hippocampus of acute immobilization stress rats].

OBJECTIVE: To observe the effects of acute immobilization stress on the mRNA expression of tyrosine kinase B (TrkB) in rats' hippocampus. METHODS: Eighteen SD rats were randomly divided into three groups, i.e., the normal control group, the model group, and the medication group, 6 in each group. The acute immobilization stress model was prepared in the model group using acute immobilization for 2 h. Ginsenoside Rb1 (40 mg/kg) was peritoneally injected to rats in the medication group 30 min before modeling, with the same procedure as those for rats in the model group. No treatment was performed to rats in the normal control group. The plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) contents were detected using ELISA. The mRNA expression of TrkB in the rats' hippocampus was detected using real-time fluorescence quantitative RT-PCR. RESULTS: Before modeling there was no statistical difference of plasma CORT or ACTH concentrations among three groups (P >0.05). The plasma CORT and ACTH concentrations increased in the model group and the medication group more significantly after modeling than before modeling, showing statistical difference (P <0.05). Besides, they were obviously higher in the model group than in the normal control group (P <0.05). They were obviously higher in the medication group than in the model control group (P <0.05). Compared with the normal control group, the mRNA expression of TrkB significantly decreased in the model group (87.73 +/- 7.62 vs 50.65 +/- 5.19, P < 0.05), showing statistical difference. The mRNA expression of TrkB was significantly higher in the medication group (78.91 +/- 18.07) than in the model group, showing statistical difference (P <0.05). CONCLUSION: Pretreatment by ginsenoside Rb1 could increase the plasma CORT and ACTH concentrations, maintain the mRNA expression of TrkB, thus relieving injury induced by acute immobilization stress.