Value of serum iron and urine neutrophil gelatinase-associated lipocalin in predicting the mortality of critically ill patients with sepsis.

INTRODUCTION: We aimed to investigate the association of iron metabolism-related parameters with 60-day mortality in critically ill patients with sepsis. METHODS: Serum or urine concentrations of iron metabolism-related parameters on intensive care unit admission were measured in a prospective cohort of 133 eligible patients with sepsis according to the Sepsis-3 criteria, and these values were compared between survivors and nonsurvivors, categorized according to their 60-day survival status. Cox regression analyses were performed to examine the association between iron parameters and 60-day mortality. Kaplan-Meier methods were used to illustrate the differences in survival between different iron parameters. RESULTS: Of the 133 patients included in the study, 61 (45.8%) had died by day 60. After adjusting for confounding variables, higher concentrations of serum iron (cut-off 9.5 µmol/mL) and higher concentrations of urine neutrophil gelatinase-associated lipocalin (uNGAL; cut-off 169.3 ng/mL) were associated with a significantly greater risk of death in the Cox regression analysis. These two biomarkers combined with Sequential Organ Failure Assessment (SOFA) scores increased the area under the receiver operating characteristic (AUROC) curve to 0.85. DISCUSSION: These findings suggest that higher concentrations of serum iron and uNGAL are each associated with higher 60-day mortality, and they add significant accuracy to this prediction in combination with SOFA. Abbreviations: uNGAL: urine neutrophil gelatinase-associated lipocalin; ICU: intensive care unit; SOFA: Sequential Organ Failure Assessment; APACHE II: the Acute Physiology and Chronic Health Evaluation II; ELISA: enzyme-linked immunosorbent assay; HR: hazard ratio; CIs: confidence intervals; WBC: white blood cell; TBIL: total bilirubin.

Serum zinc-α2-glycoprotein levels are elevated and correlated with thyroid hormone in newly diagnosed hyperthyroidism.

BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a recently novel lipolytic adipokine implicated in regulation of glucose and lipid metabolism in many metabolic disorders. In vitro and animal studies suggest that thyroid hormones (TH) up-regulates ZAG production in hepatocytes. However, there is no data evaluating the possible relationship between ZAG and TH in a human model of hyperthyroidism. The objective of the present study is to assess the association of serum ZAG levels with TH and lipid profile in patients with hyperthyroidism before and after methimazole treatment. METHODS: A total of 120 newly diagnosed overt hyperthyroidism and 122 healthy control subjects were recruited. Of them, 39 hyperthyroidism patients were assigned to receive methimazole treatment as follow-up study for 2 months. RESULTS: The clinical consequence showed that serum ZAG levels were elevated in patients with hyperthyroidism (P < 0.01). Adjust for age, gender and BMI, serum ZAG levels were positively related with serum free T3 (FT3), free T4 (FT4) levels and negatively correlated with serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) levels in hyperthyroidism subjects (all P < 0.01). After methimazole treatment, serum ZAG levels were decreased and the decline was associated with decreased FT3, FT4 and increased TC levels (all P < 0.001). CONCLUSION: We conclude that ZAG may be involved in the pathogenesis of lipid metabolism disorder in patients with hyperthyroidism. TRIAL REGISTRATION: ChiCTR-ROC-17012943 . Registered 11 October 2017, retrospectively registered.

Targeted Polypeptide-Microtubule Aggregation with Cucurbit[8]uril for Enhanced Cell Apoptosis.

Tunable protein assemblies not only hold a dominant position in vital biological events but are also a significant theme in supramolecular chemistry. Herein, we demonstrated that the intertubular aggregation of microtubules (MTs) could be efficiently regulated by a synergistic polypeptide-tubulin interaction and host-guest complexation. The benzylimidazolium-modified antimitotic peptide (BP) could recognize the MTs and concurrently form stable inclusion complexes with avirulent cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) in different binding stoichiometries. The self-assembling morphology of MTs was converted from fibrous to nanoparticulate aggregates via extensive BP⊂CB[8] cross-linkage, leading to significant cell apoptosis and tumor ablation in vivo. The targeted (BP⊂CB[8])@MT ternary assembly provides a facile supramolecular method to enhance the protein-protein interactions, which may be developed as a therapy for degenerative diseases, such as cancer.

Zinc alpha2 glycoprotein promotes browning in adipocytes.

Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called "browning") would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.

Zinc alpha2 glycoprotein protects against obesity-induced hepatic steatosis.

BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. Our previous studies indicated that zinc alpha2 glycoprotein (ZAG) alleviates palmitate (PA)-induced intracellular lipid accumulation in hepatocytes. This study is to further characterize the roles of ZAG on the development of hepatic steatosis, insulin resistance (IR), and inflammation. METHODS: ZAG protein levels in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in PA-treated hepatocytes were determined by western blotting. C57BL/6J mice injected with an adenovirus expressing ZAG were fed HFD for indicated time to induce hepatic steatosis, IR, and inflammation, and then biomedical, histological, and metabolic analyses were conducted to identify pathologic alterations in these mice. The molecular mechanisms underlying ZAG-regulated hepatic steatosis were further explored and verified in mice and hepatocytes. RESULTS: ZAG expression was decreased in NAFLD patient liver biopsy samples, obese mice livers, and PA-treated hepatocytes. Simultaneously, ZAG overexpression alleviated intracellular lipid accumulation via upregulating adiponectin and lipolytic genes (FXR, PPARα, etc.) while downregulating lipogenic genes (SREBP-1c, LXR, etc.) in obese mice as well as in cultured hepatocytes. ZAG improved insulin sensitivity and glucose tolerance via activation of IRS/AKT signaling. Moreover, ZAG significantly inhibited NF-ĸB/JNK signaling and thus resulting in suppression of obesity-associated inflammatory response in hepatocytes. CONCLUSIONS: Our results revealed that ZAG could protect against NAFLD by ameliorating hepatic steatosis, IR, and inflammation.

Meta-analysis of transforming growth factor ß receptor I 6A/9A gene polymorphism and breast cancer risk: the picture remains murky.

Breast cancer is currently the second most common cancer worldwide and the most frequent malignant tumor among women. However, the exact contribution of various allelic alterations remains unclear. This meta-analysis was conducted to evaluate the association of the transforming growth factor ß receptor I 6A/9A (TßR-I 6A/9A) gene polymorphism with breast cancer risk. Relevant studies were identified from PubMed and Cochrane Library on 1 October 2013, and eligible reports were recruited and synthesized. Eleven reports that included a total of 12 studies were recruited into this meta-analysis for the association of the TßR-I 6A/9A gene polymorphism and breast cancer risk. The results indicated that overall the TßR-I 6A allele was associated with breast cancer risk (OR = 1.33, 95% CI: 1.02-1.73, p = 0.04). However, the TßR-I 6A/6A and 9A/9A genotypes were not associated with an increased risk of developing breast cancer (6A/6A: OR = 1.71, 95% CI: 0.95-3.08, p = 0.07; 9A/9A: OR = 0.82, 95% CI: 0.66-1.02, p = 0.08). In the Caucasian population, no such association could be established. In conclusion, the TßR-I 6A allele might represent a risk factor for breast cancer risk, but significantly larger data sets from a larger number of studies, including studies that allow ethnicity, subgroup analysis and environmental impact evaluation, are required to maximize statistical significance and meta-analysis robustness.

[Effect of Herba Lycopodii Alcohol Extracted Granule Combined Methylprednisolone on Expression Levels of BDNF and NMDA and Behavior of Traumatic Spinal Cord Injury Rats].

OBJECTIVE: To study different effects of Herba Lycopodii (HL) Alcohol Extracted Granule combined methylprednisolone on behavioral changes, brain derived neurotrophic factor (BDNF) expression levels, and N-methyl-D-aspartate (NMDA) receptor levels in rats with spinal cord injury (SCI). METHODS: Male adult SD rats were randomly divided into five groups, i.e., the sham-operation group, the model group, the HL treatment group, the methylprednisolone treatment group, the HL + methylprednisolone treatment group. Rats in the HL treatment group were intragastrically administered with HL at the daily dose of 50 mg/kg for 5 successive days. Rats in the methylprednisolone treatment group were intramuscularly injected with 50 mg/kg methylprednisolone within 8 h after spinal cord contusion, and then the dose of methylprednisolone was reduced for 10 mg/kg for 5 successive days. Rats in the HL + methylprednisolone treatment group received the two methods used for the aforesaid two groups. Basso Beattie and Bresnahan (BBB) score (for hindlimb motor functions) were assessed at day 0, 3, 7, and 28 after operation. At day 13 after SCI, injured spinal T8-10 was taken from 8 rats of each group and stored in liquid nitrogen. The N-methyl-D-aspartate (NMDA) receptor affinity (Kd) and the maximal binding capacity (Bmax) were determined using [3H]MK-801 radioactive ligand assay. Rats' injured spinal cords were taken for immunohistochemical assay at day 28 after SCI. Expression levels of BDNF in the ventral and dorsal horn of the spinal cord were observed. RESULTS: Compared with the sham-operation group, the number of BDNF positive neurons in the ventral and dorsal horn of the spinal cord increased in the model group, Bmax increased (470 ± 34), Kd decreased, and BBB scores decreased at day 3 -28 (all P <0. 05). Compared with the SCI model group, the number of BDNF positive neurons and Kd increased, BBB scores at day 3 -28 increased (P <0. 05) in each medicated group. Bmax was (660 ± 15) in the methylprednisolone treatment group, (646 ± 25) in the HL treatment group, and (510 ± 21) in the HL +methylprednisolone treatment group (P <0. 05). Compared with the methylprednisolone treatment group, the number of BDNF positive neurons and Kd increased, BBB scores at day 7 -28 increased, and Bmax decreased in the HL treatment group and the HL + methylprednisolone treatment group (all P <0. 05). Compard with the HL treatment group, the number of BDNF positive neurons and Kd increased, and Bmax decreased (all P < 0.05). CONCLUSIONS: HL could effectively improve motor functions of handlimbs, increase expression levels of BDNF in the spinal cord, and lessen secondary injury by affecting spinal levels of NMDA receptors. It showed certain therapeutic and protective roles in treating SCI. Its effect was better than that of methylprednisolone with synergism.

A New Strategy for Obesity Treatment: Revealing the Frontiers of Anti-obesity Medications.

Obesity dramatically increases the risk of type 2 diabetes, fatty liver, hypertension, cardiovascular disease, and cancer, causing both declines in quality of life and life expectancy, which is a serious worldwide epidemic. At present, more and more patients with obesity are choosing drug therapy. However, given the high failure rate, high cost, and long design and testing process for discovering and developing new anti-obesity drugs, drug repurposing could be an innovative method and opportunity to broaden and improve pharmacological tools in this context. Because different diseases share molecular pathways and targets in the cells, anti-obesity drugs discovered in other fields are a viable option for treating obesity. Recently, some drugs initially developed for other diseases, such as treating diabetes, tumors, depression, alcoholism, erectile dysfunction, and Parkinson's disease, have been found to exert potential anti-obesity effects, which provides another treatment prospect. In this review, we will discuss the potential benefits and barriers associated with these drugs being used as obesity medications by focusing on their mechanisms of action when treating obesity. This could be a viable strategy for treating obesity as a significant advance in human health.

Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders?: Evidence from Observational and 2-Sample Mendelian Randomization Analyses.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and spinal degenerative disorders (SDD) are common diseases that frequently coexist. However, both traditional observational studies and recent Mendelian randomization (MR) studies have demonstrated conflicting evidence on the association between T2DM and SDD. This comparative study explored and compared the association between T2DM and SDD using observational and MR analyses. METHODS: For observational analyses, cross-sectional studies (44,972 participants with T2DM and 403,095 participants without T2DM), case-control studies (38,234 participants with SDD and 409,833 participants without SDD), and prospective studies (35,550 participants with T2DM and 392,046 participants without T2DM with follow-up information until 2022) were performed to test the relationship between T2DM and SDD using individual-level data from the U.K. Biobank from 2006 to 2022. For MR analyses, the associations between single-nucleotide polymorphisms with SDD susceptibility obtained using participant data from the U.K. Biobank, which had 407,938 participants from 2006 to 2022, and the FinnGen Consortium, which had 227,388 participants from 2017 to 2022, and genetic predisposition to T2DM obtained using summary statistics from a pooled genome-wide association study involving 1,407,282 individuals were examined. The onset and severity of T2DM are not available in the databases being used. RESULTS: Participants with T2DM were more likely to have SDD than their counterparts. Logistic regression analysis identified T2DM as an independent risk factor for SDD, which was confirmed by the Cox proportional hazard model results. However, using single-nucleotide polymorphisms as instruments, the MR analyses demonstrated no causal relationship between T2DM and SDD. The lack of such an association was robust in the sensitivity analysis, and no pleiotropy was seen. CONCLUSIONS: Our results suggest that the association between T2DM and SDD may be method-dependent. Researchers and clinicians should be cautious in interpreting the association, especially the causal association, between T2DM and SDD. Our findings provide fresh insights into the association between T2DM and SDD by various analysis methods and guide future research and clinical efforts in the effective prevention and management of T2DM and SDD. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The relationship between bone marrow characteristics and the clinical prognosis of antithyroid drug-induced agranulocytosis.

This study is aimed to explore the relationship between bone marrow characteristics and clinical prognosis of antithyroid drug (ATD) induced agranulocytosis. A retrospective study was conducted in the first affiliated hospital of the University of South China. A total of 33 hospitalized patients diagnosed with ATD-induced agranulocytosis were analyzed. The bone marrow characteristics were classified into two types. Type I was characterized by reduction or absence of granulocytic precursors and type II was recognized as hypercellular bone marrow with dysmaturity of granulocytic cells. Bone marrow of 20 cases (61%) were characterized with type I whereas 13 cases (39%) with type II. The median duration of neutrophil recovery and high-grade fever were 4.7 ± 1.0 days and 3.6 ± 2.5 days respectively for type II, compared to 8.0 ± 2.8 days and 8.6 ± 3.1 days for type I (p < 0.01 in both compared groups). However, there was no significant difference between the two types in terms of age, median duration of drug administration before the diagnosis of agranulocytosis, the amount of neutrophil count on admission and the total administration dose of granulocyte-colony stimulating factor (G-CSF) before bone marrow examination. Two cases of type I died of complications from infection. This study showed that the bone marrow characteristics of ATD-induced agranulocytosis could be classifed into two types. Also, the clinical prognosis was closely related to the bone marrow features. Type I is the dominant type which is usually associated with worse clinical prognosis compared to type II.

[Comparative Analysis of Primary and Reactivated EB Virus Infection Associated Hemophagocytic Lymphohistiocytosis].

OBJECTIVE: To compare the clinical characteristics of children with hemophagocytic lymphocytosis (HLH) associated with primary Epstein-Barr virus (EBV) infection and EBV reactivation, and explore the effects of different EBV infection status on the clinical indexes and prognosis of HLH. METHODS: The clinical data of 51 children with EBV associated HLH treated in Henan Children's Hospital from June 2016 to June 2021 were collected. According to the detection results of plasma EBV antibody spectrum, they were divided into EBV primary infection-associated HLH group (18 cases) and EBV reactivation-associated HLH group (33 cases). The clinical features, laboratory indexes and prognosis of the two groups were analyzed and compared. RESULTS: There were no significant differences in age, gender, hepatomegaly, splenomegaly, lymphadenopathy, neutrophil count in peripheral blood, hemoglobin content, platelet count, plasma EBV-DNA load, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, albumin, fibrinogen, triglyceride, ferritin, hemophagocytosis in bone marrow, NK cell activity and sCD25 between the two groups(P>0.05). The central nervous system involvement and CD4/CD8 in EBV reactivation-associated HLH group were significantly higher than those in primary infection-associated HLH group, but the total bilirubin was significantly lower than that in primary infection-associated HLH group (P<0.05). After treatment according to HLH-2004 protocol, the remission rate, 5-year OS rate and 5-year EFS rate of patients in EBV reactivation-associated HLH group were significantly lower than those in EBV primary infection-associated HLH group (P<0.05). CONCLUSION: EBV reactivation-associated HLH is more likely to cause central nervous system involvement and the prognosis is worser than EBV primary infection-associated HLH, which requires intensive treatment.

Potential Effects of Akkermansia Muciniphila in Aging and Aging-Related Diseases: Current Evidence and Perspectives.

Akkermansia muciniphila (A. muciniphila) is an anaerobic bacterium that widely colonizes the mucus layer of the human and animal gut. The role of this symbiotic bacterium in host metabolism, inflammation, and cancer immunotherapy has been extensively investigated over the past 20 years. Recently, a growing number of studies have revealed a link between A. muciniphila, and aging and aging-related diseases (ARDs). Research in this area is gradually shifting from correlation analysis to exploration of causal relationships. Here, we systematically reviewed the association of A. muciniphila with aging and ARDs (including vascular degeneration, neurodegenerative diseases, osteoporosis, chronic kidney disease, and type 2 diabetes). Furthermore, we summarize the potential mechanisms of action of A. muciniphila and offer perspectives for future studies.

New insight of obesity-associated NAFLD: Dysregulated "crosstalk" between multi-organ and the liver?

Obesity plays a crucial role in the development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism for the pathogenesis of obesity-associated NAFLD remains largely obscure. Although the "multiple hit" theory provides a more accurate explanation of NAFLD pathogenesis, it still cannot fully explain precisely how obesity causes NAFLD. The liver is the key integrator of the body's energy needs, receiving input from multiple metabolically active organs. Thus, recent studies have advocated the "multiple crosstalk" hypothesis, highlighting that obesity-related hepatic steatosis may be the result of dysregulated "crosstalk" among multiple extra-hepatic organs and the liver in obesity. A wide variety of circulating endocrine hormones work together to orchestrate this "crosstalk". Of note, with deepening understanding of the endocrine system, the perception of hormones has gradually risen from the narrow sense (i.e. traditional hormones) to the broad sense of hormones as organokines and exosomes. In this review, we focus on the perspective of organic endocrine hormones (organokines) and molecular endocrine hormones (exosomes), summarizing systematically how the two types of new hormones mediate the dialogue between extra-hepatic organs and liver in the pathogenesis of obesity-related NAFLD.

IGF2/IGF2R/Sting signaling as a therapeutic target in DSS-induced ulcerative colitis.

Ulcerative colitis is an inflammatory bowel disease with increasing prevalence and incidence. Current treatments for ulcerative colitis are not generally applicative and are often accompanied by side effects. IGF2 is an endogenous protein that plays roles in anti-inflammation and stemness maintenance, but little is known about its mechanism and function in the progression of ulcerative colitis. In this study, mouse recombinant IGF2 was used in a mouse model of ulcerative colitis established by DSS. IGF2 expression was reduced in colon tissues but not plasma of DSS-induced colitis mice. IGF2R expression was also decreased in colitis colons, which was then elevated by recombinant IGF2. Recombinant IGF2 alleviated colon injury in colitis, which was evaluated by colon shortening, body weight loss and DAI score. IGF2 treatment also relieved the inflammatory response in colitis, which was assessed by the spleen weight index, MPO activity and proinflammatory cytokine expression and was also detected in LPS-stimulated RAW264.7 cells in vitro. Moreover, IGF2R was predicted and further verified to interact with the Sting protein, and the cGAS-Sting pathway as a key pathway for stemness regulation, was upregulated in colonic colons, which was blocked by IGF2 treatment. Additionally, IGF2 treatment can maintain colonic stemness and further repair colonic tight junction function in DSS-induced colitis. In conclusion, IGF2/IGF2R downregulated the cGAS-Sting pathway to sustain colonic stemness and barrier integrity to protect against ulcerative colitis induced by DSS.

Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes.

Hyperglycemia, which can be caused by either an insulin deficit and/or insulin resistance, is the main symptom of Type 2 diabetes, a significant endocrine metabolic illness. Conventional medications, including insulin and oral antidiabetic medicines, can alleviate the signs of diabetes but cannot restore insulin release in a physiologically normal amount. The liver detects and reacts to shifts in the nutritional condition that occur under a wide variety of metabolic situations, making it an essential organ for maintaining energy homeostasis. It also performs a crucial function in glucolipid metabolism through the secretion of hepatokines. Emerging research shows that feeding induces hepatokines release, which regulates glucose and lipid metabolism. Notably, these feeding-induced hepatokines act on multiple organs to regulate glucolipotoxicity and thus influence the development of T2DM. In this review, we focus on describing how feeding-induced cross-talk between hepatokines, including Adropin, Manf, Leap2 and Pcsk9, and metabolic organs (e.g.brain, heart, pancreas, and adipose tissue) affects metabolic disorders, thus revealing a novel approach for both controlling and managing of Type 2 diabetes as a promising medication.

miR-32-5p induces hepatic steatosis and hyperlipidemia by triggering de novo lipogenesis.

BACKGROUND AND OBJECTIVES: MicroRNA-dependent regulation of hepatic lipid metabolism has been recognized recently as a key pathological mechanism contributing to the development of NAFLD. However, whether miR-32-5p (miR-32) plays a role in lipid metabolism or contributes to NAFLD remains unclear. METHODS AND RESULTS: A marked increase in miR-32 expression was observed in liver samples from patients and mice with NAFLD, as well as in palmitate-induced hepatocytes. Hepatocyte-specific miR-32 knockout (miR-32-HKO) dramatically ameliorated hepatic steatosis and metabolic disorders in high-fat diet-fed mice. Conversely, hepatic miR-32 overexpression markedly exacerbated the progression of these abnormalities. Further, combinational analysis of transcriptomics and lipidomics suggested that miR-32 was a key trigger for de novo lipogenesis in the liver. Mechanistically, RNA sequencing, luciferase assay and adenovirus-mediated downstream gene rescue assay demonstrated that miR-32 directly bound to insulin-induced gene 1 (INSIG1) and subsequently activated sterol regulatory element binding protein-mediated lipogenic gene programs, thereby promoting hepatic lipid accumulation and metabolic disorders. Notably, pharmacological administration of miR-32 antagonist significantly inhibited palmitate-induced triglyceride deposition in hepatocytes and markedly mitigated hepatic steatosis and metabolic abnormalities in obesity-associated NAFLD mice. CONCLUSION: miR-32 is an important checkpoint for lipogenesis in the liver, and targeting miR-32 could be a promising therapeutic approach for NAFLD treatment.

Reassessing endothelial-to-mesenchymal transition in mouse bone marrow: insights from lineage tracing models.

Endothelial cells (ECs) and bone marrow stromal cells (BMSCs) play crucial roles in supporting hematopoiesis and hematopoietic regeneration. However, whether ECs are a source of BMSCs remains unclear. Here, we evaluate the contribution of endothelial-to-mesenchymal transition to BMSC generation in postnatal mice. Single-cell RNA sequencing identifies ECs expressing BMSC markers Prrx1 and Lepr; however, this could not be validated using Prrx1-Cre and Lepr-Cre transgenic mice. Additionally, only a minority of BMSCs are marked by EC lineage tracing models using Cdh5-rtTA-tetO-Cre or Tek-CreERT2. Moreover, Cdh5+ BMSCs and Tek+ BMSCs show distinct spatial distributions and characteristic mesenchymal markers, suggestive of their origination from different progenitors rather than CDH5+ TEK+ ECs. Furthermore, myeloablation induced by 5-fluorouracil treatment does not increase Cdh5+ BMSCs. Our findings indicate that ECs hardly convert to BMSCs during homeostasis and myeloablation-induced hematopoietic regeneration, highlighting the importance of using appropriate genetic models and conducting careful data interpretation in studies concerning endothelial-to-mesenchymal transition.

An involvement of SR-B1 mediated PI3K-Akt-eNOS signaling in HDL-induced cyclooxygenase 2 expression and prostacyclin production in endothelial cells.

It is well-known that sphingosine-1-phosphate (S1P), the phospholipid content of HDL, binding to S1P receptors can raise COX-2 expression and PGI(2) release through p38MAPK/CREB pathway. In the present study we assess the action of SR-B1 initiated PI3K-Akt-eNOS signaling in the regulation of COX-2 expression and PGI(2) production in response to HDL. We found that apoA1 could increase PGI(2) release and COX-2 expression in ECV 304 endothelial cells. Furthermore, SR-B1 was found to be involved in HDL induced up-regulation of COX-2 and PGI(2). Over-expressed SR-B1 did not significantly increase the expression of COX-2 and the PGI(2) levels, but knock-down of SR-B1 by siRNA could significantly attenuate COX-2 expression and PGI(2) release together with p38MAPK and CREB phosphorylation. Consistently, the declines of p-p38MAPK, p-CREB, COX-2 and PGI(2) were also observed after incubation with LY294002 (25µmol/L; PI3K special inhibitor) or L-NAME (50µmol/L; eNOS special inhibitor). In addition, we demonstrated the increases of PGI(2) release, COX-2 expression and p38MAPK phosphorylation, when nitric oxide level was raised through the incubation of L-arginine (10 or 20nmol/L) in endothelial cells. Taking together, our data support that SR-B1 mediated PI3K-Akt-eNOS signaling was involved in HDL-induced COX-2 expression and PGI(2) release in endothelial cells.

[Effect of methylprednisolone on neurological behavior and the BDNF and NMDA receptor expression after traumatic spinal cord injury in rats].

OBJECTIVE: To study the effect of methylprednisolone on spinal cord injury rats' neural behavior and the expression of brain derived neurotrophic factor (BDNF) and N-methyl-D-aspartic acid (NMDA). METHODS: To establish rat model of spinal cord injury (SCI), the rats were randomly divided into sham operation group, SCI group and methylprednisolone group (n = 16 in each group). Eight rats were used for the behavioral assessment and BDNF measurement,the other eight animals was for the NMDA receptor test in each group. Within 8 h spinal cord contusion, methylprednisolone (50 mg/kg) was injected for methylprednisolone group, then after that the intramuscular injection of methylprednisolone was per day reduction in 10 mg/kg, till 5 days. By using immunohistochemical staining, the distribution of BDNF in the spinal cord and positive cell localization was observed and the number of positive cells were counted. The NMDA receptor affinity (Kd) and maximum binding amount (Bmax) were measured with [3H] MK-801 radioligand method, and the rat hind limb functional was also evaluated with BBB score analysis. RESULTS: Both the number of BDNF positive cells and the BBB score in methylprednisolone group was significant higher than that of SCI group; While increased receptor affinity (Kd) and decreased Bmax for NMDA receptor in methylprednisolone group was seen less than in SCI group (P < 0.05). CONCLUSION: Methylprednisolone can improve the function of rat hind limb, increase BDNF level and decreased NMDA receptor expression after spinal cord injury.

[Effect of gold belt on the BDNF and NMDA receptor expression and behaviour changes in rats following traumatic spinal cord injury].

OBJECTIVE: To study the effects of gold belt (GB), a Chinese Herbal, on behavioral changes and brain derived neutrophic factor (BDNF) expression and N-methyl-D-aspartic acid (NMDA) receptor level in rats subjected to spinal cord injury (SCI). METHODS: Adult male SD rats were randomly divided into three groups: (1) Sham group; (2) Spinal cord injury group (SCI group); (3) Spinal cord injury followed with gold belt treatment (gold belt 50 mg/(kg x d), intragastric gavage once daily for 7 days) group (GB group). The Basso, Beattie and Bresnahan (BBB) locomotor scale method was performed to evaluate the hindlimb motor function in the days 0, 3, 10 and 28. After 13 days, 8 rats in each group were treated with 1% sodium pentobarbital (30 mg/kg), myoloid tissue in T10 position was taken and stored in liquid nitrogen to detect NMDA receptor affinity and maximum binding amount (Bmax) with radioligand binding assay. After 28 days, rats were sacrificed and the spinal cords were harvested for immunohistochemistry to observe the localization of BDNF in the ventral and dorsal horn of the spinal cord. RESULTS: After spinal cord contusion, GB resulted in a significant increase on the number of BDNF positive neurons compared with traumatic group, and increased BBB score and decreased NMDA receptor were also found in GB group. Whereas decreased BDNF expression, NMDA receptor affininty (Kd) were observed in traumatic injury group. CONCLUSION: The gold belt treatment could effectively improve motor function, increase expression of BDNF, reduce the level of NMDA receptors in SCI rats. These data suggested that the gold belt played a role in the neuroplasticity after spinal cord injury.