Management of ROS and Regulatory Cell Death in Myocardial Ischemia-Reperfusion Injury.

Myocardial ischemia-reperfusion injury (MIRI) is fatal to patients, leading to cardiomyocyte death and myocardial remodeling. Reactive oxygen species (ROS) and oxidative stress play important roles in MIRI. There is a complex crosstalk between ROS and regulatory cell deaths (RCD) in cardiomyocytes, such as apoptosis, pyroptosis, autophagy, and ferroptosis. ROS is a double-edged sword. A reasonable level of ROS maintains the normal physiological activity of myocardial cells. However, during myocardial ischemia-reperfusion, excessive ROS generation accelerates myocardial damage through a variety of biological pathways. ROS regulates cardiomyocyte RCD through various molecular mechanisms. Targeting the removal of excess ROS has been considered an effective way to reverse myocardial damage. Many studies have applied antioxidant drugs or new advanced materials to reduce ROS levels to alleviate MIRI. Although the road from laboratory to clinic has been difficult, many scholars still persevere. This article reviews the molecular mechanisms of ROS inhibition to regulate cardiomyocyte RCD, with a view to providing new insights into prevention and treatment strategies for MIRI.

ROS: Executioner of regulating cell death in spinal cord injury.

The damage to the central nervous system and dysfunction of the body caused by spinal cord injury (SCI) are extremely severe. The pathological process of SCI is accompanied by inflammation and injury to nerve cells. Current evidence suggests that oxidative stress, resulting from an increase in the production of reactive oxygen species (ROS) and an imbalance in its clearance, plays a significant role in the secondary damage during SCI. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulatory molecule for cellular redox. This review summarizes recent advancements in the regulation of ROS-Nrf2 signaling and focuses on the interaction between ROS and the regulation of different modes of neuronal cell death after SCI, such as apoptosis, autophagy, pyroptosis, and ferroptosis. Furthermore, we highlight the pathways through which materials science, including exosomes, hydrogels, and nanomaterials, can alleviate SCI by modulating ROS production and clearance. This review provides valuable insights and directions for reducing neuronal cell death and alleviating SCI through the regulation of ROS and oxidative stress.

Mechanism of regulating macrophages/osteoclasts in attenuating wear particle-induced aseptic osteolysis.

Joint replacement surgery is the most effective treatment for end-stage arthritis. Aseptic loosening caused by periprosthetic osteolysis is a common complication after joint replacement. Inflammation induced by wear particles derived from prosthetic biomaterials is a major cause of osteolysis. We emphasize that bone marrow-derived macrophages and their fusion-derived osteoclasts play a key role in this pathological process. Researchers have developed multiple intervention approaches to regulate macrophage/osteoclast activation. Aiming at wear particle-induced periprosthetic aseptic osteolysis, this review separately discusses the molecular mechanism of regulation of ROS formation and inflammatory response through intervention of macrophage/osteoclast RANKL-MAPKs-NF-κB pathway. These molecular mechanisms regulate osteoclast activation in different ways, but they are not isolated from each other. There is also a lot of crosstalk among the different mechanisms. In addition, other bone and joint diseases related to osteoclast activation are also briefly introduced. Therefore, we discuss these new findings in the context of existing work with a view to developing new strategies for wear particle-associated osteolysis based on the regulation of macrophages/osteoclasts.

The dual role of autophagy in periprosthetic osteolysis.

Periprosthetic osteolysis (PPO) induced by wear particles is an important cause of aseptic loosening after artificial joint replacement, among which the imbalance of osteogenesis and osteoclastic processes occupies a central position. The cells involved in PPO mainly include osteoclasts (macrophages), osteoblasts, osteocytes, and fibroblasts. RANKL/RANK/OGP axis is a typical way for osteolysis. Autophagy, a mode of regulatory cell death and maintenance of cellular homeostasis, has a dual role in PPO. Although autophagy is activated in various periprosthetic cells and regulates the release of inflammatory cytokines, osteoclast activation, and osteoblast differentiation, its beneficial or detrimental role remains controversy. In particular, differences in the temporal control and intensity of autophagy may have different effects. This article focuses on the role of autophagy in PPO, and expects the regulation of autophagy to become a powerful target for clinical treatment of PPO.

Apelin-13, a regulator of autophagy, apoptosis and inflammation in multifaceted bone protection.

Apelin/APJ is widely distributed in various tissues in the body and participates in the regulation of physiological and pathological mechanisms such as autophagy, apoptosis, inflammation, and oxidative stress. Apelin-13 is an adipokine family member with multiple biological roles and has been shown to be involved in the development and progression of bone diseases. In the process of osteoporosis and fracture healing, Apelin-13 plays an osteoprotective role by regulating the autophagy and apoptosis of BMSCs, and promotes the osteogenic differentiation of BMSCs. In addition, Apelin-13 also attenuates the progression of arthritis by regulating the inflammatory response of macrophages. In conclusion, Apelin-13 has an important connection with bone protection, which provides a new strategy for the clinical treatment of bone-related diseases.

Pyroptosis in spinal cord injury.

Spinal cord injury (SCI) often brings devastating consequences to patients and their families. Pathophysiologically, the primary insult causes irreversible damage to neurons and glial cells and initiates the secondary damage cascade, further leading to inflammation, ischemia, and cells death. In SCI, the release of various inflammatory mediators aggravates nerve injury. Pyroptosis is a new pro-inflammatory pattern of regulated cell death (RCD), mainly mediated by caspase-1 or caspase-11/4/5. Gasdermins family are pore-forming proteins known as the executor of pyroptosis and the gasdermin D (GSDMD) is best characterized. Pyroptosis occurs in multiple central nervous system (CNS) cell types, especially plays a vital role in the development of SCI. We review here the evidence for pyroptosis in SCI, and focus on the pyroptosis of different cells and the crosstalk between them. In addition, we discuss the interaction between pyroptosis and other forms of RCD in SCI. We also summarize the therapeutic strategies for pyroptosis inhibition, so as to provide novel ideas for improving outcomes following SCI.

lncRNA260 siRNA Accelerates M2 Macrophage Polarization and Alleviates Oxidative Stress via Inhibiting IL28RA Gene Alternative Splicing.

The macrophage transformation of inflammatory M1 to anti-inflammatory M2 could be promoted by activating PI3K/AKT signaling pathway. In our previous study, it was found that downregulation of lncRNA260 could ameliorate hypoxic cardiomyocyte injury by regulating IL28RA through the activation of PI3K/AKT signaling pathways. It was suggested that lncRNA260 siRNA could promote the macrophages toward M2 polarization by regulating IL28RA. In this study, lncRNA260 siRNA was used to observe its effect on the polarization of murine bone marrow-derived macrophages (BMDM) and investigate its related mechanisms. lncRNA 260 specific siRNA were designed and synthesized which were transfected into murine BMDM with liposomes. The experiment was divided into three groups: Hypoxia group, Hypoxia+lncRNA 260-specific siRNA transfection group, and Normoxia group. The CD206-APC/CD11b-FITC or CD206-FITC/CD107b (Mac-3) double positive proportions were used to compare the M2 polarization proportions in the hypoxia process by using the immunofluorescence staining method. The p-AKT, Arg 1, PI3KCG, IL28RAV1, and IL28RAV2 protein expression changes were observed by using the western blot method. Compared with the Normoxia group, the M2 proportions were significantly decreased in the Hypoxia group (P < 0.05). Compared with the hypoxia group, the M2 proportions were significantly increased in the Hypoxia+lncRNA260 siRNA transfection group (P < 0.05). In the Hypoxia group, the ratios of Arg 1/ß-Actin, p-AKT/ß-Actin, PI3KCG/ß-Actin, and IL28RAV1/ß-Actin were significantly lower than those in the Normoxia group (P < 0.05). After transfection with lncRNA260 siRNA, the ratios of Arg1/ß-Actin, p-AKT/ß-Actin, PI3KCG/ß-Actin, and IL28RAV1/ß-Actin were significantly higher than those in the Hypoxia group (P < 0.05). Compared with the Normoxia group, the IL28RAV2/ß-Actin in the Hypoxia group was significantly increased (P < 0.05). After transfection with lncRNA260 siRNA, the ratio of IL28RAV2/ß-Actin was significantly decreased than that in the Hypoxia group (P < 0.05). lncRNA260 siRNA could promote the M2 polarization of the hypoxia macrophages by reducing the IL28RAV2 alternative splicing variant, which might be related to the activation of the JAK-STAT and PI3K/AKT signaling pathways. It will provide a new strategy for the anti-inflammation, antioxidative stress therapy, and cardiac remodeling after AMI.

The Age-Adjusted Charlson Comorbidity Index Predicts Prognosis in Elderly Cancer Patients.

Purpose: The age-adjusted Charlson comorbidity index (ACCI) is a useful measure of comorbidity to standardize the evaluation of elderly patients and has been reported to predict mortality in various cancers. To our best knowledge, no studies have examined the relationship between the ACCI and survival of elderly patients with cancer. Therefore, the primary objective of this study was to investigate the relationship between the ACCI and survival of elderly patients with cancer. Patients and Methods: A total of 64 elderly patients (>80 years) with cancer between 2011 and 2021 were enrolled in this study. According to the ACCI, the age-adjusted comorbidity index was calculated by weighting individual comorbidities; patients with ACCI<11 were considered the low-ACCI group, whereas those with ACCI≥11 were considered the high-ACCI group. The correlations between the ACCI score and survival outcomes were statistically analyzed. Results: There was a significant difference in overall survival (OS) and progression-free survival (PFS) between the high-ACCI group and the low-ACCI group (P<0.001). The median OS time of the high-ACCI group and the low-ACCI group were 13.9 (10.5-22.0) months and 51.9 (34.1-84.0) months, respectively. The 2-, 3-, and 5-year survival rates of the high-ACCI group were 28.1%, 18.8%, and 4.2%, respectively, whereas the 2-, 3-, and 5-year survival rates of the low-ACCI group were 77.3%, 66.4%, and 39.1%, respectively. Multivariate analysis showed that ACCI was independently associated with OS (HR=1.402, 95% CI: 1.226-1.604, P < 0.05) and PFS (HR=1.353, 95% CI: 1.085-1.688, P = 0.0073). Conclusion: The ACCI score is a significant independent predictor of prognosis in elderly patients with cancer.

Triple chemical derivatization strategy assisted liquid chromatography-mass spectrometry for determination of retinoic acids in human serum.

Retinoic acids (RAs), an important class of fatty acid derived from vitamin A, are closely associated with various human diseases including cancer. Hence, determination of endogenous RAs would help to uncover the mechanisms underlying RAs-related diseases. However, accurate quantification of RAs is still a challenge due to their high structure similarity, low abundance in biological samples and the lack of isotope internal standards (ISs). In this study, a liquid chromatography-mass spectrometry (LC-MS) method with high-sensitivity and high-throughput was developed to simultaneously determine 5 RAs (all-trans-retinoic acid, 13-cis-retinoic acid, 9,13-cis-retinoic acid, all-trans-4-oxoretinoic acid and 4-hydroxy-retinoic acid) in human serum. In the method, three derivatization reagents, N, N-dimethylethylenediamine (DMED), d4-N,N-dimethylethylenediamine (d4-DMED) and 13C2-N,N-dimethylethylenediamine (13C2-DMED), were used for triple chemical derivatization of RAs, thus the detection sensitivity and analysis throughput of endogenous RAs could be achieved. Benefiting from the developed strategy, the analysis throughput was enhanced and the detection sensitivity of RAs was increased by 14-398 folds. The limits of quantification (LOQs) of RAs were found to be between 8.4 and 130 pg/mL, which were better than previously reported methods. Good linearities of RAs were obtained with determination coefficient (R2) ranging from 0.9774 to 0.9999. The intra- and inter-day relative standard deviations (RSDs) were below 11.7% and 12.7%, respectively, indicating the acceptable reproducibility of the method. Using the developed method, we successfully quantified 4 RAs (all-trans-retinoic acid, 13-cis-retinoic acid, 9,13-cis-retinoic acid and all-trans-4-oxoretinoic acid) in health controls and cancer patient serum samples. Furthermore, t-test analysis showed that the concentration of three RAs (all-trans-retinoic acid, 13-cis-retinoic acid and all-trans-4-oxoretinoic acid) in cancer patient serum samples were significantly decreased compared with health controls, which indicated that RAs might play an important role in the formation and development of cancer.

Angucycline and angucyclinone derivatives from the marine-derived Streptomyces sp.

Atramycin C (1), one new angucycline bearing an O-6 rhamnose side chain, along with one new highly hydroxylated angucyclinone emycin G (2), and ten known analogs (3-12) were isolated from the marine-derived Streptomyces sp. strain BHB-032. Their structures were assigned by spectroscopic analysis and comparison with literature data. The absolute configuration of the sugar unit of 1 was assigned as 6-O-α-l-rhamnoside, based on the analysis of the coupling constants and chemical derivatization, whereas the absolute configuration of 2 was determined by X-ray diffraction. Furthermore, the stereochemistry of saccharothrixin A (3) and SNA-8073-A (4) was established unequivocally by X-ray crystallography for the first time. Compounds 1 and 2 exhibited moderate antimicrobial activities with minimum inhibitory concentration (MIC) values ranging from 16 to 64 µg/ml.

[Effect of Sarcopenia on the Efficacy of Percutaneous Kyphoplasty in the Treatment of Osteoporotic Spinal Compression Fractures in Elderly Patients].

Objective To investigate the effect of sarcopenia on the efficacy of percutaneous kyphoplasty(PKP)in the treatment of osteoporotic spinal compression fracture(OSCF)in elderly patients. Methods From February 2017 to June 2018,a total of 77 elderly patients who met the inclusion and exclusion criteria were included in this study.Grip strength of dominant hand was measured by an electronic grip dynamometer with cut-off values of 27 kg for males and 16 kg for females.The cross-sectional area of the pedicle level muscle of the 12th thoracic vertebra(T12)was measured by chest CT.The skeletal muscle index(SMI)was calculated by dividing the T12 pedicle level muscle cross-sectional area by the square of body height.The SMI cut-off value used to diagnose sarcopenia was 42.6 cm2/m2for males and 30.6 cm2/m2 for females.Sarcopenia is confirmed when both grip strength and SMI are below the cut-off values.The patients with OSCF all received PKP.The patients in the sarcopenia and non-sarcopenia groups were compared in terms of age,gender,body weight,operation duration,the amount of bleeding,time to ambulation,hospital stay,visual analogue scale(VAS)before and 1 month after operation,Oswestry disability index(ODI)1 month after operation as well as the incidence of refracture within 1 year after operation. Results Gender,body weight,operation duration,the amount of bleeding and the preoperative VAS score showed no significant difference between the two groups(χ2=3.563,P=0.059;t=0.406,P=0.686;t=1.119,P=0.267;t=-0.166,P=0.868;z=-1.076,P=0.282).The patients in the sarcopenia group showed longer time to ambulation,longer hospital stay,higher VAS score and ODI 1 month after operation than those in the non-sarcopenia group(t=3.938,P<0.001;t=5.655,P<0.001;z=-4.562,P<0.001;z=-5.222,P<0.001).There was no significant difference in the incidence of refracture within 1 year after operation between the two groups(χ2=0.596,P=0.440).Linear regression results showed that age did not affect the hospital stay,rehabilitation duration,VAS score or ODI(P=0.519,P=0.870,P=0.332,P=0.126),whereas sarcopenia had significant effects(P<0.001,P=0.001,P<0.001,P<0.001). Conclusions Sarcopenia with OSCF has poorer limb function recovery.Reasonable rehabilitation exercise and dietary therapy are necessary for patients with sarcopenia.

High Coverage Profiling of Carboxylated Metabolites in HepG2 Cells Using Secondary Amine-Assisted Ultrahigh-Performance Liquid Chromatography Coupled to High-Resolution Mass Spectrometry.

Carboxylic metabolites are an important class of metabolites, which widely exist in mammals with various types. Chemical isotope labeling liquid chromatography-mass spectrometry (CIL-LC-MS) has been widely used for the detection of carboxylated metabolites. However, high coverage analysis of carboxylated metabolites in biological samples is still challenging due to improper reactivity and selectivity of labeling reagents to carboxylated metabolites. In this study, we used N-methylphenylethylamine (MPEA) to label various types of carboxylated metabolites including short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), long-chain fatty acids (LCFAs), polycarboxylic acids (polyCAs), amino acids (AAs), and aromatic acids. Additionally, metabolites containing other functional groups, such as phenol, sulfhydryl, and phosphate groups, could not be labeled under the conditions of MPEA labeling. After MPEA labeling, the detection sensitivity of carboxylic acids was increased by 1-2 orders of magnitude, and their chromatographic retention on a reversed-phase (RP) column was enhanced (RT > 3 min). Under optimized labeling conditions, we used MPEA and d3-N-methylphenylethylamine (d3-MPEA) for high coverage screening of carboxylated metabolites in HepG2 cells by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). As a result, a total of 403 potential carboxylated metabolites were obtained of which 68 were confirmed based on our established in-house chemically labeled metabolite database (CLMD). SCFAs, MCFAs, LCFAs, polyCAs, AAs, and aromatic acids were all detected in HepG2 cell extracts. Due to the successful identification of AAs, the current method increased the coverage of carboxylated metabolites compared with our previous work. Moreover, 133 and 109 carboxylated metabolites with changed contents were obtained in HepG2 cells incubated with curcumin and R-3-hydroxybutyric acid, respectively. In general, our established method realized high coverage analysis of carboxylated metabolites in HepG2 cells.

PCSK9 Gene E670G Polymorphism and Coronary Artery Disease: An Updated Meta-Analysis of 5,484 Subjects.

Objective: Research has shown a possible relationship between the E670G polymorphism of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and an increased risk of coronary artery disease (CAD). However, there is no clear consensus on the subject because of conflicting results in the literature. The current meta-analysis was performed to better elucidate the potential relationship between the PCSK9 gene E670G polymorphism and CAD. Methods: There were 5,484 subjects from 13 individual studies who were included in the current meta-analysis. The fixed- or random-effects models were used to evaluate the pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Results: The current meta-analysis found a significant association between PCSK9 gene E670G polymorphism and CAD under allelic (OR = 1.79, 95% CI = 1.42-2.27, P = 1.00 × 10-6), dominant (OR = 2.16, 95% CI = 1.61-2.89, P = 2.22 × 10-7), heterozygous (OR = 2.02, 95% CI = 1.55-2.64, P = 2.47 × 10-7), and additive genetic models (OR = 1.92, 95% CI = 1.49-2.49, P = 6.70 × 10-7). Conclusions: PCSK9 gene E670G polymorphism was associated with an elevated risk of CAD, especially in the Chinese population. More specifically, carriers of the G allele carriers of the PCSK9 gene may be predisposed to developing CAD.

Angiopoietin-1 protects neurons by inhibiting autophagy after neuronal oxygen-glucose deprivation/recovery injury.

Angiopoietin-1 (Ang-1) is a new neuroprotective agent, which can protect neurons from apoptosis. Increased autophagy in neurons subjected to oxygen-glucose deprivation/recovery (OGD/R) injury may lead to autophagic cell death; therefore, the present study investigated the effect of Ang-1 on neurons subjected to OGD/R injury. Neuronal viability was detected by using the Cell Counting Kit-8, which was then used to select the appropriate concentration of Ang-1 and rapamycin used in the OGD/R injury model. The mechanistic role of Ang-1 was observed by detecting the survival rate of neurons and the level of autophagy. Results showed that Ang-1 significantly reduced neuronal cell injury induced by OGD/R and the expression of the autophagy-related proteins LC3 II/I and Beclin-1, and increased the expression of P62/SQSTM1. However, the neuroprotective effects of Ang-1 were counteracted by rapamycin, an autophagy activating agent. The changes of autophagy intensity were further confirmed by transmission electron microscopy observation of autophagosomes. Ang-1 appears to have a neuroprotective role by inhibiting autophagy expression in OGD/R. Thus, these findings could be useful for the treatment of OGD/R injury.

Correlation between the Charlson comorbidity index and skeletal muscle mass/physical performance in hospitalized older people potentially suffering from sarcopenia.

BACKGROUND: Sarcopenia is a decrease in skeletal muscle mass, physical performance, and muscle strength in older people. In this study, we aimed to explore the correlation between comorbidity and skeletal muscle mass and physical performance in older people. METHODS: This retrospective study included 168 subjects. Their medical history, physical function, computed tomography (CT) chest scans, and blood tests for nutrition were evaluated. The patients were divided into two groups: (1) a low muscle mass group and (2) a normal muscle mass group. Multivariate analysis of variance was used to compare multiple sets of mean vectors. RESULTS: Overall, 72.02% of the subjects had a low skeletal muscle index (SMI) and low gait speed. The patients with low skeletal muscle mass and physical performance were older, had more serious comorbidities, and had longer average hospitalization periods and lower albumin and hemoglobin levels. Subjects with a high Charlson comorbidity index (CCI) were more likely to be in the sarcopenic group than in the non-sarcopenic group. In addition, there was a linear correlation between the CCI and SMI (r = - 0.549, P < 0.05), and between the CCI and gait speed (r = - 0.614, P < 0.05). The area under the curve (AUC) value for low skeletal muscle mass with the CCI was 0.879. CONCLUSIONS: We identified an independent association between comorbidity and skeletal muscle mass/physical performance by researching the correlation between the CCI and SMI/gait speed. Our results suggested that the CCI score may have important clinical diagnostic value for sarcopenia.

Angiopoietin-1 Protects Spinal Cord Ischemia and Reperfusion Injury by Inhibiting Autophagy in Rats.

Spinal cord ischemia and reperfusion (SCIR) injury can induce autophagy, which is involved in the survival of neurons. However, whether autophagy plays a neuroprotective or a detrimental role in SCIR injury remains controversial. Angiopoietin-1 (Ang-1), an endothelial growth factor, has been shown to have neuroprotective effects. The present study aimed to explore the neuroprotective mechanisms of Ang-1 in neuronal cells in a rat model of SCIR injury in vivo. Ang-1 protein and rapamycin were injected intrathecally. Basso Beattie Bresnahan (BBB) scoring and hematoxylin and eosin staining were used to assess the degree of SCIR injury. Proteins that reflected the level of autophagy expression, such as Beclin-1 and LC3, were evaluated by western blotting. The results indicated that SCIR injury resulted in loss in lower limb motor function. Ang-1 protein inhibited the expression of Beclin-1 and LC3, which improved the BBB score and alleviated spinal cord injury. In contrast, rapamycin, an autophagy activator, caused the opposite effect. This study provides evidence that Ang-1 plays a neuroprotective role by inhibiting of autophagy expression in SCIR injury. Overall, findings could be useful for the treatment of SCIR injury.

GHRL Gene Leu72Met Polymorphism and Type 2 Diabetes Mellitus: A Meta-Analysis Involving 8,194 Participants.

Background: Although many studies indicate a positive correlation between GHRL gene Leu72Met polymorphism and an increased susceptibility to type 2 diabetes mellitus (T2DM), inconsistencies between independent studies still remain. Objective: Considering the inconsistencies between them, we have performed the current meta-analysis study. The objective of this study is to better examine the correlation of the GHRL gene Leu72Met polymorphism and T2DM. Methods: The current meta-analysis, involving 8,194 participants from 11 independent studies, was performed. A fixed effect model was used to evaluate the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs). Results: A significant association was found between T2DM and GHRL gene Leu72Met polymorphism under recessive (OR: 1.33, 95% CI: 1.01-1.76, P = 0.04), and homozygous genetic models (OR: 1.34, 95% CI: 1.01-1.78, P = 0.04) in the whole population. The correlation was more distinct in our subgroup analysis of the Chinese population under recessive (OR: 1.52, 95% CI: 1.07-2.15, P = 0.02), dominant (OR: 1.70, 95% CI: 1.38-2.10, P < 0.00001), additive (OR: 1.16, 95% CI: 1.02-1.33, P = 0.02), and homozygous genetic models (OR: 1.54, 95% CI: 1.07-2.20, P = 0.02). Conclusions: In short, GHRL gene Leu72Met polymorphism was significantly correlated with increased T2DM risk, particularly in the Chinese population. Individuals carrying the Met72 allele of GHRL Leu72Met gene polymorphism, particularly those of Chinese ancestry, may be more susceptible to developing T2DM disease.

Angiopoietin: A Novel Neuroprotective/Neurotrophic Agent.

Angiopoietin (Ang) is an angiogenic factor, but its neuroprotective and neurotrophic effects have recently come to light. Ang exerts neuroprotective effects by inhibiting neuronal apoptosis, protecting the blood-brain/blood-spinal cord barrier, reducing inflammation and promoting neovascularization. In addition, Ang can also promote neural development and neurite outgrowth via activation of the PI3K/Akt signaling pathway and binding to the Tie2 receptor and/or integrin receptor. In addition, Ang and vascular endothelial growth factor (VEGF) are known to interact in blood vessels in the nervous system and the combination of Ang and VEGF can mitigate the negative effects of VEGF, such as inflammation and local edema. These data indicated that Ang is a novel neuroprotective/neurotrophic factor, which may become a new tool for the treatment of nerve injury.

Angiopoietin 2 promotes angiogenesis in tissue-engineered bone and improves repair of bone defects by inducing autophagy.

Angiogenesis plays a key role in the repair of large segmental bone defects with tissue-engineered bones. However, there is no effective method of promoting angiogenesis in tissue-engineered bone. Both angiopoietin 2 (Ang2) and autophagy have been shown to be involved in angiogenesis, but their roles in angiogenesis of tissue-engineered bone remains unknown. In this in vivo study, a radius bone defect was created in New Zealand white rabbits, which were then treated by implantation of a hydroxyapatite/collagen scaffold followed by injection of different concentrations of Ang2. Expression of the autophagic modulators microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and SQSTM1/P62 were measured via western blotting, while the angiogenic modulators VEGF and CD31 were detected by western blotting and immunohistochemistry, respectively. X-ray imaging combined with general observation was used to evaluate bone defect healing. Expression of LC3 -I/LC3-II, Beclin-1, VEGF, and CD31 in the callus area increased and SQSTM1/p62 decreased in a dose-dependent manner with increasing Ang2 concentration. In the group treated with a high concentration of Ang2, the new callus grew well, accompanied by remarkable angiogenesis, leading to good repair of the bone defects. However, in the low concentration of Ang2 group, in spite of the existence of angiogenesis and new bone formation, the bone defects were not repaired. Furthermore, angiogenesis and osteogenesis were both obstructed in the control group. In conclusion, our study demonstrated that a high concentration of Ang2 promoted angiogenesis in tissue-engineered bone and improved repair of bone defects by inducing autophagy.

Solute Carrier Family 30 Member 8 Gene 807C/T Polymorphism and Type 2 Diabetes Mellitus in the Chinese Population: A Meta-Analysis Including 6,942 Subjects.

BACKGROUND: Although solute carrier family 30 (zinc transporter) member 8 (SLC30A8) gene 807C/T polymorphism is associated with an increased risk of type 2 diabetes mellitus (T2DM) risk, there remains some inconsistency between individual studies. OBJECTIVE: The aim of the study is to explore the relationship between SLC30A8 gene 807C/T polymorphism and T2DM in the Chinese population. METHODS: The current meta-analysis compiles and analyzes the data of 6,942 participants from 10 independent studies. Either a fixed or random-effects model was adopted to evaluate the pooled odds ratio (ORs) and the corresponding 95% confidence interval (95% CI). RESULTS: A significant association between SLC30A8 gene 807C/T polymorphism and T2DM was found in the Chinese population under allelic (OR: 0.85, 95% CI: 0.80-0.91, P = 7.42 × 10-7), recessive (OR: 0.52, 95% CI: 0.38-0.72, P = 8.49 × 10-5), dominant (OR: 2.40, 95% CI: 1.68-3.41, P = 1.30 × 10-6), homozygous (OR: 0.52, 95% CI: 0.40-0.67, P = 2.90 × 10-7), heterozygous (OR: 0.79, 95% CI: 0.71-0.88, P = 1.63 × 10-5), and additive genetic models (OR: 0.73, 95% CI: 0.64-0.83, P = 7.05 × 10-7). CONCLUSION: SLC30A8 gene 807C/T polymorphism was significantly associated with an increased T2DM risk in the Chinese population. Therefore, individuals of Chinese descent with the C allele of SLC30A8 gene 807C/T polymorphism may be more susceptible to developing T2DM, while individuals with the T allele may be protected against T2DM.